biomarkers

Abstract

The invention provides biomarkers to predict effective treatment of cancer using an IAP antagonist. Identifying one or more of the identified biomarkers in a cancer patient allows a determination to be made whether the patient's cancer is likely to be successfully treated using an IAP antagonist. Accordingly, the invention relates generally to a companion diagnostic for IAP antagonist therapy. In particular, the biomarkers include IL-2Rα, IL-6r, CRP, EPO, CD27, CD40, TN-C, IL-18, PLGF, TNFrl and MCP-4.

Description

[0001] DESCRIPTION

[0002] TITLE OF INVENTION

[0003] BIOMARKERS

[0004] FIELD OF THE INVENTION

[0005] This invention relates to biomarkers for cancer therapy. In particular, the invention provides biological markers that identify a patient with cancer as likely to be sensitive to an IAP antagonist. These biomarkers can be incorporated into methods, systems and kits for predicting response to treatment, and into personalised treatments for cancer.

[0006] BACKGROUND TO THE INVENTION

[0007] Precision medicine, or personalised medicine, is an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment and lifestyle for each patient. It is often said to be the practice of administering the right dosage of the right drug at the right time.

[0008] A particular focus of precision medicine is the need to predict whether a given patient will respond to a specific drug. A test that is able to predict whether a particular drug will effectively treat an individual patient is often referred to as a companion diagnostic. Effective companion diagnostics are very desirable because of their ability to improve treatment outcomes for patients while also saving the significant economic cost of providing ineffective treatments. An effective companion diagnostic for a new therapeutic agent can also increase the chances of that therapy being trialled in the correct population and ultimately being approved.

[0009] Precision medicines and companion diagnostics often rely on biomarkers that are able to predict reliably whether a patient is likely to respond to a specific treatment. Identifying reliable biomarkers for every therapy and disease is a very significant challenge.

[0010] There remains a need to identify reliable biomarkers for use in precision medicine.

[0011] SUMMARY OF THE INVENTION

[0012] The invention is based on the identification of biomarkers that can be used to predict effective treatment of cancer using an IAP (Inhibitor of Apoptosis Protein) antagonist. Identifying one or more of these biomarkers in a cancer patient allows a determination to be made whether the patient’s cancer is likely to be treated or likely to be successfully treated using an IAP antagonist. Accordingly, in certain aspects the invention relates generally to a companion diagnostic for IAP antagonist therapy.

[0013] In particular, the invention relates to plasma protein markers of response to IAP antagonist therapy. The therapy is typically of a cancer, more typically a blood cancer. The cancer is typically a T-Cell Lymphoma, for example Peripheral T-Cell Lymphoma (PTCL) or Cutaneous T-cell lymphoma (CTCL). In certain embodiments, the invention relates to plasma protein markers of response to IAP antagonist therapy of PTCL. In some embodiments the IAP antagonist is a compound of formula (I). In some embodiments the IAP antagonist is tolinapant. The biomarkers can also be used with other IAP antagonists, for example those known in the art including those described below such as Debio 1143, LCL161 or Birinapant. The markers described herein are each individual markers of response. Each marker is an effective biomarker on its own. While combinations of two or more of the identified markers are provided, and while the markers can be combined with other markers, this is not required. The provision of simple, individual biomarkers is therefore highly advantageous and can simplify and streamline the analysis of patients. These advantages are heightened further because the markers are simple protein markers that can be assessed in the plasma, which is a straightforward fluid to obtain from a patient and assess.

[0014] The markers of the invention are provided in the examples, and include:

[0015] IL-2 receptor alpha (lnterleukin-2 receptor alpha): Swiss-Prot accession number: P01589

[0016] I L-6r (lnterleukin-6 receptor): Swiss-Prot accession number: P08887

[0017] CRP (C-Reactive Protein): Swiss-Prot accession number: P02741

[0018] EPO (Erythropoietin): Swiss-Prot accession number: P01588

[0019] CD27 (CD27 antigen): Swiss-Prot accession number: P26842

[0020] CD40 (CD40 antigen): Swiss-Prot accession number: Q6P2H9

[0021] TN-C (Tenascin-C): Swiss-Prot accession number: P24821

[0022] IL-18 (Interleukin-18): Swiss-Prot accession number: Q14116

[0023] PLGF (Placenta Growth Factor): Swiss-Prot accession number: P49763

[0024] TNF Rl (Tumor Necrosis Factor Receptor I): Swiss-Prot accession number: P19438

[0025] MCP-4 (Monocyte Chemotactic Protein 4): Swiss-Prot accession number: Q99616

[0026] VCAM-1 (Vascular cell adhesion protein 1 : Swiss-Prot accession number: P19320

[0027] PAI-1 (Plasminogen activator inhibitor-1 ): Swiss-Prot accession number, P05121

[0028] TIMP-1 (TIMP metallopeptidase inhibitor 1): Swiss-Prot accession number, P01033

[0029] IgA (Immunoglobulin A): Swiss-Prot accession number, P01876, P01877

[0030] RANTES (regulated on activation, normal T-cell expressed and secreted): Swiss-Prot accession number, P13501

[0031] IL-1 p (lnterleukin-1 beta): Swiss-Prot accession number, P01584 MIP-3P (Macrophage Inflammatory Protein 3 beta): Swiss-Prot accession number: Q99731

[0032] MIP-3a (Macrophage Inflammatory Protein 3 alpha): Swiss-Prot accession number: P78556

[0033] TNFR2 (Tumor necrosis factor receptor type 2): Swiss-Prot accession number: P20333

[0034] VEGF (Vascular endothelial growth factor): Swiss-Prot accession number: P15692

[0035] Cathepsin D: Swiss-Prot accession number: P07339

[0036] BDNF (Brain-derived neurotrophic factor): Swiss-Prot accession number: P23560

[0037] MPO (Myeloperoxidase): Swiss-Prot accession number: P05164

[0038] HB-EGF (Heparin-binding EGF-like growth factor): Swiss-Prot accession number: Q99075

[0039] OPG (Osteoprotegerin) Swiss-Prot accession number: 000300

[0040] MMP-2 (matrix metalloproteinase-2): Swiss-Prot accession number: P08253

[0041] ANG-2 (Angiopoietin-2)” Swiss-Prot accession number: 015123

[0042] Myoglobin: Swiss-Prot accession number: P02144

[0043] IL-16 (Interleukin-16): Swiss-Prot accession number: Q14005

[0044] ICAM-1 (Intercellular Adhesion Molecule 1 ): Swiss-Prot accession number: P05362

[0045] IL-12p40 (Interleukin-12 subunit beta): Swiss-Prot accession number: P29460

[0046] MMP-1 (matrix metalloproteinase-1 ): Swiss-Prot accession number: P03956

[0047] B2M (|32 microglobulin): Swiss-Prot accession number: P61769

[0048] Tweak (Tumor necrosis factor ligand superfamily member 12): Swiss-Prot accession number: 043508

[0049] FAS (apoptosis antigen 1 ): Swiss-Prot accession number: P25445

[0050] E-Selectin: Swiss-Prot accession number: P16581 FRTN (Ferritin): Swiss-Prot accession number: P02794, P02792

[0051] C3 (Complement component 3): Swiss-Prot accession number: P01024

[0052] PSA-f (Prostate-Specific Antigen, Free): Swiss-Prot accession number: P07288

[0053] EGFR (epidermal growth factor receptor): Swiss-Prot accession number: P00533

[0054] IL-1 RI (Interleukin 1 receptor, type I): Swiss-Prot accession number: P14778

[0055] YKL-40 (Chitinase-3-like protein 1): Swiss-Prot accession number: P36222

[0056] IL-17 (Interleukin 17): Swiss-Prot accession number: Q16552

[0057] Eotaxin-2 (eosinophil chemotactic protein 2): Swiss-Prot accession number: 000175

[0058] IL-1 Ra (interleukin-1 receptor antagonist): Swiss-Prot accession number: P18510

[0059] ENA-78 (C-X-C motif chemokine 5): Swiss-Prot accession number: P42830

[0060] AXL (Tyrosine-protein kinase receptor UFO): Swiss-Prot accession number: P30530

[0061] MMP-3 (matrix metalloproteinase-3): Swiss-Prot accession number: P08254

[0062] IL-8 (Interleukin 8): Swiss-Prot accession number: P10145

[0063] HGF, (Hepatocyte growth factor): Swiss-Prot accession number: P14210

[0064] TECK, (thymus-expressed chemokine): Swiss-Prot accession number: 015444

[0065] Alpha-1 -Antitrypsin: Swiss-Prot accession number: P01009

[0066] IL-6R p, (lnterleukin-6 receptor subunit beta): Swiss-Prot accession number: P40189

[0067] FasL (Fas Ligand): Swiss-Prot accession number: P48023

[0068] 6Ckine: Swiss-Prot accession number: 000585

[0069] Haptoglobin: Swiss-Prot accession number: P00738

[0070] MCP-1 (Monocyte Chemotactic Protein 1 ): Swiss-Prot accession number: P13500

[0071] TRAIL-R3 (TNF-Related Apoptosis-Inducing Ligand Receptor3): Swiss-Prot accession number: 014798 MMP-7 (Matrix Metalloproteinase-7): Swiss-Prot accession number: P09237

[0072] G-CSF (Granulocyte Colony-Stimulating Factor): Swiss-Prot accession number: P09919

[0073] IL-1 RII (lnterleukin-1 receptor type 2): Swiss-Prot accession number: P27930

[0074] FGF-21 (Fibroblast Growth Factor 21): Swiss-Prot accession number: Q9NSA1

[0075] IL-10 (Interleukin-10): Swiss-Prot accession number: P22301

[0076] SCF (Stem Cell Factor): Swiss-Prot accession number: P21583 vWF (von Willebrand Factor): Swiss-Prot accession number: P04275

[0077] PARC (Pulmonary and Activation-Regulated Chemokine): Swiss-Prot accession number: P55774

[0078] IL-6 (lnterleukin-6): Swiss-Prot accession number: P05231

[0079] In some embodiments, the biomarkers are selected from:

[0080] IL-2 receptor alpha (lnterleukin-2 receptor alpha), soluble

[0081] I L-6r (lnterleukin-6 receptor), soluble

[0082] CRP (C-Reactive Protein)

[0083] CD27 (CD27 antigen), soluble

[0084] CD40 (CD40 antigen), soluble

[0085] TN-C (Tenascin-C)

[0086] IL-18 (Interleukin-18)

[0087] Erythropoietin (EPO)

[0088] VCAM-1 (Vascular cell adhesion protein 1)

[0089] PAI-1 (Plasminogen activator inhibitor-1 )

[0090] TIMP-1 (TIMP metallopeptidase inhibitor 1)

[0091] IgA (Immunoglobulin A)

[0092] RANTES (regulated on activation, normal T-cell expressed and secreted)

[0093] IL-1 p (lnterleukin-1 beta)

[0094] MIP-30 (Macrophage Inflammatory Protein 3 beta)

[0095] MIP-3a (Macrophage Inflammatory Protein 3 alpha) TNFR2 (Tumor necrosis factor receptor type 2)

[0096] VEGF (Vascular endothelial growth factor)

[0097] Cathepsin D

[0098] BDNF (Brain-derived neurotrophic factor)

[0099] MPO (Myeloperoxidase)

[0100] HB-EGF (Heparin-binding EGF-like growth factor)

[0101] OPG (Osteoprotegerin)

[0102] MMP-2 (matrix metalloproteinase-2)

[0103] ANG-2 (Angiopoietin-2)

[0104] Myoglobin

[0105] IL-16 (Interleukin-16)

[0106] ICAM-1 (Intercellular Adhesion Molecule 1)

[0107] TNF Rl (Tumor necrosis factor receptor 1)

[0108] IL-12p40 (Interleukin-12 subunit beta)

[0109] MMP-1 (matrix metalloproteinase-1)

[0110] B2M ((32 microglobulin)

[0111] Tweak (Tumor necrosis factor ligand superfamily member 12)

[0112] FAS (apoptosis antigen 1 )

[0113] E-Selectin

[0114] FRTN (Ferritin)

[0115] C3 (Complement component 3)

[0116] PSA-f (Prostate Specific Antigen Free)

[0117] EGFR (epidermal growth factor receptor)

[0118] IL-1 Rl (Interleukin 1 receptor, type I)

[0119] YKL-40 (Chitinase-3-like protein 1)

[0120] IL-17 (Interleukin 17)

[0121] Eotaxin-2 (eosinophil chemotactic protein 2)

[0122] IL-1 Ra (interleukin-1 receptor antagonist)

[0123] ENA-78 (C-X-C motif chemokine 5)

[0124] AXL (Tyrosine-protein kinase receptor UFO) MCP-4 (Monocyte chemotactic protein 4)

[0125] MMP-3 (matrix metalloproteinase-3)

[0126] IL-8 (Interleukin 8

[0127] HGF (Hepatocyte growth factor)

[0128] TECK (thymus-expressed chemokine)

[0129] Alpha-1 -Antitrypsin

[0130] IL-6R p (lnterleukin-6 receptor subunit beta)

[0131] PLGF (Placenta Growth Factor)

[0132] FasL (Fas Ligand)

[0133] 6Ckine

[0134] Haptoglobin

[0135] MCP-1 (Monocyte Chemotactic Protein 1)

[0136] TRAIL-R3 (TNF-Related Apoptosis-Inducing Ligand Receptor3)

[0137] MMP-7 (Matrix Metalloproteinase-7)

[0138] G-CSF (Granulocyte Colony-Stimulating Factor)

[0139] IL-1 RII (lnterleukin-1 receptor type 2)

[0140] FGF-21 (Fibroblast Growth Factor 21)

[0141] IL-10 (Interleukin-10)

[0142] SCF (Stem Cell Factor) vWF (von Willebrand Factor)

[0143] PARC (Pulmonary and Activation-Regulated Chemokine)

[0144] IL-6 (Interleukin 6)

[0145] IL-2Ra, IL-6r and CRP are each typically assessed in the patient’s plasma several weeks after the patient has been administered a first dose of the IAP antagonist, typically approximately 4 weeks (e.g. 26 days, 27 days, 28 days, 29 days or 30 days) after the first dose of IAP antagonist. These markers are typically present in the patient’s plasma at a lower level in responders than in non-responders.

[0146] TECK, PLGF, FAS, C3 and MMP-2 are each typically assessed in the patient’s plasma several weeks after the patient has been administered a first dose of the IAP antagonist, typically approximately 4 weeks (e.g. 26 days, 27 days, 28 days, 29 days or 30 days) after the first dose of IAP antagonist. These markers are typically present in the patient’s plasma at a lower level in responders than in non- responders. TN-C, IL-2Rct, Cathepsin D, and CD27 are each typically assessed in the patient’s plasma several weeks after the patient has been administered a first dose of the IAP antagonist, typically approximately 4 weeks (e.g. 26 days, 27 days, 28 days, 29 days or 30 days) after the first dose of IAP antagonist. These markers are typically present in the patient’s plasma at a lower level in responders than in non-responders.

[0147] TN-C, IL-2Ra, Cathepsin D, CD27, IL-6r, MMP-7, CRP, HGF, C3, G-CSF, VCAM-1 , ICAM-1, haptoglobin, TNFR2, HB-EGF, IL-6, IL-1 RII, IL-1 Ra, MIP-3 alpha, FGF-21 , PLGF, IL-10, CD40, SCF, TIMP-1 , B2M, IL-1 R1 , IL-1 beta, YKL-40, vWF, VEGF, and PARC are also each typically assessed in the patient’s plasma several weeks after the patient has been administered a first dose of the IAP antagonist, typically approximately 4 weeks (e.g. 26 days, 27 days, 28 days, 29 days or 30 days) after the first dose of IAP antagonist. These markers are typically present in the patient’s plasma at a different level in responders than in non-responders as shown in the Examples herein.

[0148] TECK, PLGF, FAS, C3, MMP-2, HGF, FasL, VCAM-1 , Tweak, IL-1ra, IL-6R beta, VEGF, 6Ckine, Haptoglobin, Eotaxin-2, MCP-1 , TRAIL-R3, PAS-f, IL-1 beta and IL-2Ra are also each typically assessed in the patient’s plasma several weeks after the patient has been administered a first dose of the IAP antagonist, typically approximately 4 weeks (e.g. 26 days, 27 days, 28 days, 29 days or 30 days) after the first dose of IAP antagonist. These markers are typically present in the patient’s plasma at a different level in responders than in non-responders, as shown in the examples herein.

[0149] TN-C, IL-2Ra, Cathepsin D, CD27, IL-6r, MMP-7, CRP, HGF, C3, G-CSF, VCAM-1 , ICAM-1 , haptoglobin, TNFR2, HB-EGF, IL-6, IL-1 RII, IL-1 Ra, MIP-3 alpha, FGF-21 , PLGF, IL-10, CD40, SCF, TIMP-1 , B2M, IL-1 R1 , IL-1 beta, YKL-40, vWF, VEGF, and PARC are typically present in the patient’s plasma at a lower level in responders than in non-responders when the patient has PTCL.

[0150] TECK, PLGF, FAS, C3, MMP-2, HGF, FasL, VCAM-1 , Tweak, IL-1 ra, IL-6R beta, VEGF, 6Ckine, Haptoglobin, Eotaxin-2, MCP-1 , TRAIL-R3, PAS-f, IL-1 beta, and IL-2Ra are typically present in the patient’s plasma at a lower level in responders than in non-responders when the patient has CTCL.

[0151] Biomarkers that are typically present in the patient’s plasma at a lower level in responders than in non- responders may be referred to as downregulated biomarkers.

[0152] SCF and IL-1 beta are typically present in the patient’s plasma at a higher level in responders than in non-responders when the patient has PTCL.

[0153] FASL, Tweak, 6Ckine, PSA-f, IL-1 beta are typically present in the patient’s plasma at a higher level in responders than in non-responders when the patient has CTCL.

[0154] Biomarkers that are typically present in the patient’s plasma at a higher level in responders than in non- responders may be referred to as upregulated biomarkers. In some embodiments, IL-2Ra, IL-6r or CRP; or TN-C, Cathepsin D, CD27, MMP-7, HGF, C3, G-CSF, VCAM-1 , ICAM-1 , haptoglobin, TNFR2, HB- EGF, IL-6, IL-1 RII, IL-1 Ra, MIP-3 alpha, FGF-21 , PLGF, IL-10, CD40, SCF, TIMP-1 , B2M, IL-1 R1 , IL-1 beta, YKL-40, vWF, VEGF, or PARC; or TECK, PLGF, FAS, C3, MMP-2, HGF, FasL, VCAM-1 , Tweak, IL-1 ra, IL-6R beta, VEGF, 6Ckine, Haptoglobin, Eotaxin-2, MCP-1 , TRAIL-R3, PAS-f, IL-1 beta, or IL- 2Ra are assessed in the patient’s plasma after an off-treatment period. In certain embodiments, the biomarker assessment is carried out several weeks after the first dose (which may or may not be the only dose before the biomarker testing) of the IAP antagonist, for example around 2 weeks, 3, weeks, 4 weeks, 5 weeks or 6 weeks after, and typically approximately 4 weeks after, the first dose of IAP antagonist. In certain embodiments, the biomarker assessment is carried out several weeks after the first and only dose before the biomarker assessment, for example around 2 weeks, 3, weeks, 4 weeks, 5 weeks or 6 weeks after, and typically approximately 4 weeks after, the first dose of IAP antagonist. These markers are typically present in the patient’s plasma at a lower level in responders than in nonresponders.

[0155] In some embodiments, IL-2Ra, IL-6r or CRP; or TN-C, Cathepsin D, CD27, MMP-7, HGF, C3, G-CSF, VCAM-1 , ICAM-1 , haptoglobin, TNFR2, HB-EGF, IL-6, IL-1 RII, IL-1 Ra, MIP-3 alpha, FGF-21 , PLGF, IL- 10, CD40, SCF, TIMP-1 , B2M, IL-1 R1 , IL-1 beta, YKL-40, vWF, VEGF, or PARC; or TECK, PLGF, FAS, C3, MMP-2, HGF, FasL, VCAM-1 , Tweak, IL-1 ra, IL-6R beta, VEGF, 6Ckine, Haptoglobin, Eotaxin-2, MCP-1 , TRAIL-R3, PAS-f, IL-1 beta, or IL-2Ra are assessed in the patient’s plasma several weeks after the first dose of the IAP antagonist, typically approximately 4 weeks after the first dose of IAP antagonist. In some embodiments, the patient may continue to be treated with one or more further doses of IAP antagonist after the first dose of IAP antagonist, such that there is no off-treatment period or the off- treatment period is shorter than the period between the first dose and the biomarker assay. The off- treatment period (i.e. the period since the last dose of IAP inhibitor), when present, may, in some embodiments, be approximately 1 week, approximately 2 weeks, approximately 3 weeks or approximately 4 weeks. Again, these markers are typically present in the patient’s plasma at a lower level in responders than in non-responders.

[0156] Some of the other biomarkers of the invention (e.g. EPO, CD27, CD40, TN-C, IL-18, PLGF, TNFrl, IL- 6r and MCP-4; or TECK, IL-8, Alpha-1 -Antitrypsin, IL-6R p, FRTN, and Cathepsin D) are each typically assessed at baseline, e.g. before dosing the patient, or up to 24 hours after the patient has been administered a first dose of the IAP antagonist. These markers are typically present in the patient’s plasma at a lower level in responders than in non-responders. EPO, CD27, CD40, TN-C, IL-18, PLGF, TNFrl, IL-6r and MCP-4 may be present at a lower level in responders with PTCL. TECK, IL-8, Alpha- 1 -Antitrypsin, IL-6R p, FRTN, and Cathepsin D may be present at a lower level in responders with CTCL.

[0157] Some of the other biomarkers of the invention are assessed in the patient’s plasma at baseline, e.g. before dosing the patient, or up to 24 hours after the patient has been administered a first dose of the IAP antagonist, and several weeks after the patient has been administered a first dose of the IAP antagonist, typically approximately 4 weeks (e.g. 26 days, 27 days, 28 days, 29 days or 30 days) after the first dose of IAP antagonist. A difference in the change in level of these markers in the patient’s plasma between two time points is indicative of responders or non-responders. Preferably, the difference is a change in level as compared to the baseline level of the same biomarker. The level of the biomarker may increase or decrease at the second time point as compared to the baseline level. Biomarkers of the invention that are assessed in the patient's plasma at baseline and at a subsequent timepoint are called Delta biomarkers. As indicated in the Examples below, the Delta value is calculated by determining the change in the level of the biomarker from the baseline level as compared to the level of the same biomarker at the second time point. Delta values may be positive, indicating a relative increase in level as compared to baseline, or negative, indicating a relative decrease in level as compared to baseline. Delta biomarkers may be indicative of responders or non-responders. A Delta biomarker is said to be upregulated if the Delta value is higher in the responder group than the non-responder group. A Delta biomarker is said to be downregulated if the Delta value is lower in the responder group as compared to the non-responder group.

[0158] A Delta biomarker may be regarded as “Delta-upregulated” in responders even if it has a negative Delta value indicating a relative decrease in the level of the biomarker from baseline, provided that the relative decrease in the level of the same biomarker is greater in non-responders than in responders - i.e. the Delta value is higher in responders.

[0159] A Delta biomarker may be regarded as "Delta-downregulated” in responders even if it has a positive Delta value indicating a relative increase in the level of the biomarker from baseline, provided that the relative increase in the level of the same biomarker is greater in responders than in non-responders - i.e. the Delta value is lower in responders.

[0160] In one embodiment, Delta up-regulation of one or more of the biomarkers selected from the group consisting of IgA, MPO and MMP-2; or the group consisting of Tweak, I L-6r, MPO, FRTN, PSA-f, EGFR, IL-17, Eotaxin-2, ENA-78, Myoglobin, IL-8, and BDNF between two time points is indicative of responders. In one embodiment the time points are before (or up to 24 hours after the patient has been administered a first dose of the IAP antagonist) and after treatment with and IAP antagonist.

[0161] In another aspect, Delta down-regulation of one or more of the biomarkers selected from the group consisting of IL-2Ra, VCAM-1 , PAI-1 , TIMP-1 , RANTES, IL-1 [3, CD27, MIP-3 p, MIP-3 a, TNFR2, TN- C, VEGF, Cathepsin D, BDNF, HB-EGF, OPG, ANG-2, Myoglobin, IL-16, ICAM-1 , TNF Rl, IL-12p40, MMP-1 , and B2M; or the group consisting of FAS, TNFR2, VCAM-1 , E-Selectin, CD40, C3, CD27, IL- 1 Rl, YKL-40, IL-1 ra, AXL, MCP-4, TIMP-1 , MMP-3, MIP-3 p, IL-16, HGF, and IL-2Ra between two time points is indicative of responders. In one embodiment the time points are before (or up to 24 hours after the patient has been administered a first dose of the IAP antagonist) and after treatment with and IAP antagonist.

[0162] Certain biomarkers of the invention (e.g. IL-2Ra, VCAM-1 , PAI-1 , TIMP-1 , IgA, RANTES, IL-1 p, CD27, MIP-3 p, MIP-3 a, TNFR2, TN-C, VEGF, Cathepsin D, BDNF, MPO, HB-EGF, OPG, MMP-2, ANG-2, Myoglobin, IL-16, ICAM-1 , TNF Rl, IL-12p40, MMP-1 , B2M) may be particularly associated with certain cancers such as PTCL.

[0163] Certain biomarkers of the invention (e.g. Tweak, FAS, TNFR2, VCAM-1 , E-Selectin, CD40, IL-6r, MPO, FRTN, C3, CD27, PSA f, EGFR, IL-1 Rl, YKL-40, IL-17, Eotaxin-2, IL-1 ra, ENA-78, AXL, MCP-4, TIMP- 1 , Myoglobin, MMP-3, IL-8, MIP-3 p, IL-16, HGF, BDNF, and IL-2Ra) may be particularly associated with certain cancers such as CTCL. It can be seen from the disclosure above, and the experimental data reported below, that IL-6r can be assessed at baseline (e.g. before dosing or up to 24 hours after the patient has been administered a first dose of the IAP antagonist) or after dosing (e.g. around 4 weeks after first dose). IL-6r may also be assessed at baseline (e.g. before dosing or up to 24 hours after the patient has been administered a first dose of the IAP antagonist) and after dosing (e.g. around 4 weeks after first dose) and the levels at both timepoints may be compared.

[0164] It can be seen from the disclosure above, and the experimental data reported below, that IL-2Ra, CD27, CD40, TN-C, IL-18 and TNF Rl can be assessed at baseline (e.g. before dosing or up to 24 hours after the patient has been administered a first dose of the IAP antagonist). IL-2Ra, CD27, CD40, TN-C, IL- 18 and TNF Rl may also be assessed at baseline (e.g. before dosing or up to 24 hours after the patient has been administered a first dose of the IAP antagonist) or after dosing (e.g. around 4 weeks after first dose) and the levels at both timepoints may be compared.

[0165] It can be seen from the disclosure above, and the experimental data reported below, that several biomarkers show a difference in biomarker level at baseline (e.g. before dosing or up to 24 hours after the patient has been administered a first dose of the IAP antagonist) and several weeks after the patient has been administered a first dose of the IAP antagonist in both the PTCL and CTCL cohorts, e.g. VCAM-1 , CD27, TIMP-1 , TNFR2, MIP-3 0, MPO, Myoglobin, IL-16, BDNF, IL-2Ra. As seen in the data presented herein, myoglobin and BDNF are upregulated in CTCL but downregulated in PTCL.

[0166] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, or two or more protein biomarkers, selected from: a. IL-2Ra, IL-6r, CRP, EPO, CD27, CD40, TN-C, IL-18, PLGF, TNFrl, and MCP-4; b. TECK, IL-8, Alpha-1 -Antitrypsin, IL-6R0, FRTN, and Cathepsin D; or c. TN-C, IL-2Ra, Cathepsin D, CD27, IL-6r, MMP-7, CRP, HGF, C3, G-CSF, VCAM-1 , ICAM-1 , haptoglobin, TNFR2, HB-EGF, IL-6, IL-1 RII, IL-1 Ra, MIP-3 alpha, FGF-21 , PLGF, IL-10, CD40, SCF, TIMP-1 , B2M, IL-1 R1 , IL-1 beta, YKL-40, vWF, VEGF or PARC; d. TECK, PLGF, FAS, C3, MMP-2, HGF, FasL, VCAM-1 , Tweak, IL-1ra, IL-6R beta, VEGF, 6Ckine, Haptoglobin, Eotaxin-2, MCP-1 , TRAIL-R3, PAS-f, IL-1 beta, or IL-2Ra e. IL-2Ra, VCAM-1 , PAI-1 , TIMP-1 , IgA, RANTES, IL-1 0, CD27, MIP-30, MIP-3a, TNFR2, TN-C, VEGF, Cathepsin D, BDNF, MPO, HB-EGF, OPG, MMP-2, ANG-2, Myoglobin, IL-16, ICAM-1 , TNF Rl, IL-12p40, MMP-1 , and B2M; or f. Tweak, FAS, TNFR2, VCAM-1 , E-Selectin, CD40, IL-6r, MPO, FRTN, C3, CD27, PSA-f, EGFR, IL-1 RI, YKL-40, IL-17, Eotaxin-2, IL-1 ra, ENA-78, AXL, MCP-4, TIMP-1 , Myoglobin, MMP-3, IL-8, MIP-3 0, IL-16, HGF, BDNF, and IL-2Ra.

[0167] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is IL-2Ra. In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is IL-6r.

[0168] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is GRP.

[0169] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is EPO.

[0170] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is CD27.

[0171] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is CD40.

[0172] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is TN-C.

[0173] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is IL-18.

[0174] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is PLGF.

[0175] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is TNFrl.

[0176] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is MCP-4.

[0177] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is VCAM-1 .

[0178] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is PAI-1 . In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is TIMP-1.

[0179] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is IgA.

[0180] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is RANTES.

[0181] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is IL-1 |3.

[0182] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is MIP-3 p.

[0183] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is MIP-3 a.

[0184] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is TNFR2.

[0185] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is VEGF.

[0186] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is Cathepsin D.

[0187] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is BDNF.

[0188] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is MPO.

[0189] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is HB-EGF. In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is OPG.

[0190] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is MMP-2.

[0191] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is ANG-2.

[0192] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is Myoglobin.

[0193] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is IL-16.

[0194] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is ICAM-1.

[0195] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is IL-12p40.

[0196] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is MMP-1.

[0197] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is B2M.

[0198] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is Tweak.

[0199] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is FAS.

[0200] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is E-Selectin. In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is FRTN.

[0201] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is C3.

[0202] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is PSA-f.

[0203] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is EGFR.

[0204] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is YKL-40.

[0205] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is IL-17.

[0206] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is Eotaxin-2.

[0207] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is IL-1 ra.

[0208] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is ENA-78.

[0209] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is AXL.

[0210] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is MMP-3.

[0211] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is IL-8. In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is HGF.

[0212] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is TECK.

[0213] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is Alpha-1 -Antitrypsin.

[0214] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is IL-6R 0.

[0215] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is PLGF.

[0216] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is FasL.

[0217] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is 6Ckine.

[0218] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is Haptoglobin.

[0219] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is MCP-1.

[0220] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is TRAIL-R3.

[0221] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is MMP-7. In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is G-CSF.

[0222] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is IL-1 RII.

[0223] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is FGF-21 .

[0224] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is IL-10.

[0225] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is SCF.

[0226] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is B2M.

[0227] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is IL-1 Rl.

[0228] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is vWF.

[0229] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is PARC.

[0230] In particular, in one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one protein biomarker, wherein the one protein biomarker is IL-6.

[0231] In one embodiment, the plasma level of the marker protein is assessed before dosing the patient with the IAP antagonist, or within one day of dosing the patient, typically up to two hours after the first dose. Typically, the biomarker assessed at this so-called “baseline” time is one (or more) of: EPO, CD27, CD40, TN-C, IL-18, PLGF, TNFrl, IL-6r and MCP-4; or one or more of TECK, IL-8, Alpha-1 -Antitrypsin, IL-6R (3, FRTN, Cathepsin D.

[0232] In one embodiment, the plasma level of the marker protein is assessed after three to five weeks after dosing the patient with the IAP antagonist, typically approximately four weeks after dosing the patient, for example 26, 27, 28 or 29 or 30 days after the initial dose, typically four weeks after the first dose. This may be following an off-treatment period. Typically, the biomarker assessed at this time is one (or more) of IL-2Ra, IL-6r and CRP; or TN-C, Cathepsin D, CD27, MMP-7, HGF, 03, G-CSF, VCAM-1 , ICAM-1 , haptoglobin, TNFR2, HB-EGF, IL-6, IL-1 RII, IL-1 Ra, MIP-3 alpha, FGF-21 , PLGF, IL-10, CD40, SCF, TIMP-1 , B2M, IL-1 R1 , IL-1 beta, YKL-40, vWF, VEGF, or PARC; or TECK, PLGF, FAS, C3, MMP- 2, HGF, FasL, VCAM-1 , Tweak, IL-1 ra, IL-6R beta, VEGF, 6Ckine, Haptoglobin, Eotaxin-2, MCP-1 , TRAIL-R3, PAS-f, IL-1 beta, or IL-2Ra. In patients already receiving treatment (i.e. having received one or more doses of an IAP antagonist), the biomarker determines the likelihood of successful treatment mid-treatment (as an intermediate marker of response). If the treatment is not likely to be successful then it can be discontinued. Typically, an alternative treatment would then be provided for the patient. The patient is selected for treatment, based on the biomarker profile, with regard to the next potential dose of the IAP antagonist. When the patient has not yet received a dose, i.e. when the biomarker is assessed at baseline before IAP antagonist treatment, then the next dose is the first dose. When the biomarker is assessed after one or more doses, for example after an off-treatment period (typically e.g. 4 weeks after the first dose) then the biomarker assessment determines whether the patient should receive a second or further dose. Accordingly, the biomarkers provide for assessing the likelihood of success for initiation of treatment or continuation of treatment.

[0233] As shown in the Examples, the marker protein is typically present at a lower level in patients that are expected to respond to IAP antagonist treatment, than in patients that are not expected to respond. As shown in the Examples, certain marker proteins may be present at a higher level in patients that are expected to respond to IAP antagonist treatment. Therefore, the patient’s plasma level of the marker protein (or proteins) can be compared to the level in a control sample from a patient or population of patients that are known to be responders or are known to be non-responders.

[0234] In some embodiments, the patient’s plasma level of the marker protein (or proteins) can be compared to a control sample from a patient or population of patients that are known to be responders. In some embodiments, the patient’s plasma level of the marker protein (or proteins) can be compared to a control sample from a patient or population of patients that are known to be non-responders. In some embodiments, the patient’s plasma level of the marker protein (or proteins) can be compared to a control sample from a patient or population of patients that are known to be responders and also to a control sample from a patient or population of patients that are known to be non-responders, Based on the comparison to control or controls, an assessment can be made as to whether the test sample is likely to represent a responder or a non-responder.

[0235] In some embodiments, a threshold level can be established for responders and / or non-responders, and the patient’s sample compared to that threshold(s) to determine whether the patient should be classified as a responder or a non-responder. In some embodiments, the patient’s plasma level of the marker protein (or proteins) can be compared to an established threshold that is known to represent responders. In some embodiments, the patient’s plasma level of the marker protein (or proteins) can be compared to an established threshold that is known to represent non-responders. In some embodiments, the patient’s plasma level of the marker protein (or proteins) can be compared to a threshold that is known to represent responders and also to a threshold that is known to represent non-responders. Based on the comparison to one or more known thresholds, an assessment can be made as to whether the test sample is likely to represent a responder or a non-responder.

[0236] The threshold may define the upper limit of normal (ULN) or the lower limit of normal (LLN) for that particular biomarker. In some embodiments, the baseline level is the threshold level. In some embodiments, the threshold level is defined as the baseline level in the individual or in a population of individuals. In some embodiments, the threshold is defined for a population or group, such as responders or non-responders.

[0237] In one embodiment, the change in level of the marker protein is measured before or up to 24 hours after the patient has been administered a first dose of the IAP antagonist and after dosing with the IAP antagonist. In this embodiment, the plasma level of the marker protein is assessed before or up to 24 hours after dosing the patient with the IAP antagonist and the plasma level of the marker protein is assessed three to five weeks after dosing the patient with the IAP antagonist, typically approximately four weeks after dosing the patient, for example 26, 27, 28 or 29 or 30 days after the initial dose, typically four weeks after the first dose. This may be following an off-treatment period. Typically, the biomarker assessed at this time is one (or more) of IL-2Ra, VCAM-1 , PAI-1 , TIMP-1 , IgA, RANTES, IL-1 (3, CD27, MIP-3 (3, MIP-3 a, TNFR2, TN-C, VEGF, Cathepsin D, BDNF, MPO, HB-EGF, OPG, MMP-2, ANG-2, Myoglobin, IL-16, ICAM-1 , TNF Rl, IL-12p40, MMP-1 , and B2M; or one (or more) of Tweak, FAS, TNFR2, VCAM-1 , E-Selectin, CD40, IL-6r, MPO, FRTN, C3, CD27, PSA-f, EGFR, IL-1 RI, YKL-40, IL-17, Eotaxin-2, IL-1 ra, ENA-78, AXL, MCP-4, TIMP-1 , Myoglobin, MMP-3, IL-8, MIP-3 , IL-16, HGF, BDNF, IL-2Ra.

[0238] In some embodiments, the patient’s plasma level of the marker protein (or proteins) after dosing can be compared to the patient’s plasma level of the marker protein (or proteins) at baseline. In some embodiments, the change in the patient’s plasma level of the marker protein (or proteins) can be compared to an established threshold level of change (Delta value) that is known to represent non- responders. In some embodiments, the change in the level of the patient’s plasma level of the marker protein (or proteins) can be compared to a threshold level of change (Delta value) that is known to represent responders and also to a threshold level of change that is known to represent non-responders. Based on the comparison to one or more known thresholds, an assessment can be made as to whether the test sample is likely to represent a responder or a non-responder.

[0239] A decreased level of a biomarker may refer to a relative decrease in the level of the biomarker over time or as compared to a control sample, as described above. An increased level of a biomarker may refer to a relative increase in the level of the biomarker over time or as compared to a control sample, as described above. The threshold for determining whether a biomarker or biomarkers is increased or decreased may be determined by reference to relative increase or decrease in a population. For example, a biomarker may be considered to be increased if the level is higher than 50%, 60%, 70%, 80%, 90%, 95% or 99% of the population. For example, a biomarker may be considered to be decreased if the level is lower than 50%, 60%, 70%, 80%, 90%, 95% or 99% of the population.

[0240] The threshold for determining whether a biomarker or biomarkers is increased or decreased may be determined by reference to relative increase or decrease of the same biomarker or biomarkers in a population when compared to the level of that biomarker or biomarkers in a patient or patient population that does not respond to IAP antagonism.

[0241] The threshold for determining whether a Delta value for a biomarker or biomarkers is increased or decreased may be determined by reference to the Delta value for the same biomarker or biomarkers in a population when compared to the level of that biomarker or biomarkers in a patient or patient population that does not respond to IAP antagonism.

[0242] For example, a biomarker or Delta value may be considered to be increased if the level is higher than 50%, 60%, 70%, 80%, 90%, 95% or 99% of the population that does not respond to IAP antagonism. For example, a biomarker or Delta value may be considered to be decreased if the level is lower than 50%, 60%, 70%, 80%, 90%, 95% or 99% of the population that does not respond to IAP antagonism.

[0243] For the disclosed biomarkers, protein is typically measured. This can be achieved using, for example, immunohistochemistry (IHC). The protein is typically measured in a sample from the patient, typically a sample of blood or a fraction thereof, most typically from a plasma sample. Measuring the amount of a specific protein in a plasma sample from a patient is well-known in the art.

[0244] The biomarkers of the invention may be measured directly or indirectly. Indirect measurement typically involves detection of a molecule that is functionally upstream or downstream of the biomarker and the level of which correlates with the level of the biomarker. For example, a substrate upon which the biomarker acts can be used as an indirect measurement of the biomarker.

[0245] The data in the Examples below indicate that depletion of one or more biomarker proteins activities is typically predictive of sensitivity of cancer cells to an IAP antagonist. Accordingly, low levels of one or more of the biomarkers can be used to identify a cancer suitable for treatment with an IAP antagonist.

[0246] In some embodiments, decreased levels of the biomarker or biomarkers of the invention are determined relative to the level in a patient or patients known to respond, or known not to respond, wherein the known level was determined in substantially the same way as the test sample. In this way, the biomarker level e.g. expression or activity can be compared relative to control levels determined in responders or relative to control levels determined in non-responders.

[0247] In some embodiments, the patient can be identified as a candidate for treatment with an IAP antagonist when the expression or activity level of the one or more biomarkers is low relative to the upper limit of normal (ULN) or low relative to the lower limit of normal (LLN).

[0248] Optionally, the method may comprise the step of administering a therapeutically effective amount of an IAP antagonist to the patient. In one embodiment, the invention provides an IAP antagonist for use in the treatment of cancer, wherein the cancer is characterised by one or more of the biomarkers of the invention within a biological sample obtained from the patient, typically a plasma sample.

[0249] According to another embodiment of the invention, there is provided a method of treating cancer in a patient wherein said method comprises the steps of selecting a patient based on the presence or level of one more of the biomarkers of the invention. The presence or level may be assessed at one or more time points. In certain embodiments, the patient is selected based on: having a decreased level, expression or activity of one or more biomarkers within a biological sample obtained from said patient, typically a plasma sample; and / or having an increased level, expression or activity of one or more biomarkers within a biological sample obtained from said patient, typically a plasma sample and optionally then administering a therapeutically effective amount of an IAP antagonist to said patient.

[0250] According to a further embodiment of the invention, there is provided an IAP antagonist for use in the treatment of cancer in a patient, characterised in that said patient has been selected for having decreased or low level of one or more biomarkers within a biological sample obtained from said patient, when compared to the level of that biomarker or biomarkers in a patient or patient population that does not respond to IAP antagonism.

[0251] According to a further embodiment of the invention, there is provided an IAP antagonist for use in the treatment of cancer in a patient, characterised in that said patient has been selected for having an increased or high level of one or more biomarkers within a biological sample obtained from said patient, when compared to the level of that biomarker or biomarkers in a patient or patient population that does not respond to IAP antagonism.

[0252] In certain embodiments a sample of patient tissue is tested prior to treatment, to determine the cancer biomarker expression profile. The sample may typically comprise one or more blood cells. The sample may be a blood sample or sample of a fraction of blood, for example blood plasma. The testing may comprise an assay to detect protein, mRNA and / or DNA. Typically, the testing comprises an assay to detect protein.

[0253] In certain embodiments a sample of patient tissue is tested prior to and shortly after treatment (e.g. 3 to 5 weeks after treatment, typically approximately 4 weeks e.g. 26 days, 27 days, 28 days, 29 days or 30 days), to determine the change in the cancer biomarker expression profile. The sample may typically comprise one or more blood cells. The sample may be a blood sample or sample of a fraction of blood, for example blood plasma. The testing may comprise an assay to detect protein, mRNA and / or DNA. Typically, the testing comprises an assay to detect protein. In another aspect, the invention provides the use of the expression levels of one or more biomarkers of the invention in a plasma sample of a human cancer patient, as biomarkers for assessing whether the cancer is susceptible to treatment with an IAP antagonist. In another aspect, the invention provides the use of the change in expression levels of one or more biomarkers of the invention in a plasma sample of a human cancer patient after exposure to an IAP antagonist, as biomarkers for assessing whether the cancer is susceptible to treatment with an IAP antagonist. In all aspects of the invention where the level of one or more biomarkers of the invention is determined, such determination may take place at one or more time points. The level of the biomarker at various time points may be compared to provide a change in level of the biomarker over time. In particular, one time point may be before treatment with an IAP antagonist, and one time point may be after treatment with an IAP antagonist. The change in the level of the biomarker from baseline to a time point following treatment with an IAP antagonist is given as a Delta value.

[0254] As set out in Example 2, the Delta value may be greater in in responders or in non-responders. If the Delta value is higher in responders, the biomarker is said to be an upregulated Delta marker. If the Delta value is higher in non-responders, the biomarker is said to be a downregulated Delta marker.

[0255] In a further aspect, the invention provides a method for prognosing or assessing the responsiveness of a human cancer patient to treatment with an IAP antagonist, comprising assessing the level in a sample from a cancer patient of one or more biomarkers of the invention and determining whether the tested expression level indicates that the cancer should be treated with an IAP antagonist.

[0256] In a further aspect, the invention provides a method for continuing or discontinuing treatment with an IPA antagonist based on the responsiveness of a human cancer patient to treatment with an IAP antagonist, comprising assessing the level in a sample from a cancer patient of one or more biomarkers of the invention and determining whether the tested expression level indicates that the cancer should continue to be treated with an IAP antagonist. In this aspect, any patient that is classed as a “responder” by any means described herein should continue treatment with an IPA antagonist. Treatment should be discontinued in any patient classes as a “non-responder” by any means disclosed herein. In a particular embodiment, patients classed as responders based on Delta value should continue to be treated with an IAP antagonist.

[0257] In some embodiments, the one or more biomarkers of the invention indicate that the cancer is likely to be necroptosed. Therefore, in some embodiments the invention is able to identify those patients for whom treatment will be particularly effective.

[0258] In some embodiments, the assessment step comprises an in vitro assay to determine the level of the biomarker or biomarkers in a sample.

[0259] In some embodiments, the assessment step comprises comparing the expression level with the expression level known to be associated with responsiveness or non-responsiveness to treatment with an IAP antagonist. In some embodiments, the assessment step comprises comparing the observed expression level with a threshold value reflecting in the same manner the expression level associated with susceptibility to treatment with an IAP antagonist, to assess whether the tested expression level indicates that the cancer can be treated with an IAP antagonist. In some embodiments, the patient is classified into a group based on the biomarker profile. This may include classifying the patient as likely to respond well (or strongly), or not, to treatment with an IAP antagonist.

[0260] In a further aspect, the invention provides a method of determining whether a human cancer patient is suitable for treatment with an IAP antagonist, comprising detecting in a sample from the patient the level, amount, expression or activity of one or more biomarkers of the invention; and assessing whether the cancer in the patient is likely to be treated with an IAP antagonist on the basis of the level, change in level, amount, change in amount, expression, change in expression, activity level, or change in activity level of the biomarkers in the sample. Optionally, the method of this aspect comprises the further step of treating the cancer in the patient using an IAP antagonist.

[0261] In a further aspect, the invention provides a method of determining whether a human cancer patient is suitable for continued treatment with an IAP antagonist, comprising detecting in a sample from the patient the level, amount, expression or activity of one or more biomarkers of the invention after administering an IAP antagonist; and assessing whether the cancer in the patient is likely to be treated with an IAP antagonist on the basis of the level, change in level, amount, change in amount, expression, change in expression, activity level, or change in activity level of the biomarkers in the sample. Optionally, the method of this aspect comprises the further step of continuing to treat the cancer in the patient using an IAP antagonist. Optionally, the method of this aspect comprises the further step of continuing to treat the cancer in the patient using an IAP antagonist when the change in level of the biomarker (Delta value) is upregulated.

[0262] In a further embodiment the invention provides an IAP antagonist for use in the treatment of cancer in a patient in combination with an anticancer compound, characterised in that i.e. the patient has been selected for having one or more biomarkers of the invention.

[0263] In a further embodiment the invention provides a method of treating cancer in a patient, wherein the patient has been selected as having one or more biomarkers of the invention at a level that indicates that IAP antagonist treatment will be effective; and administering a therapeutically effective amount of an IAP antagonist and optionally another anticancer agent to the selected patient.

[0264] In a further embodiment the invention provides a method of identifying a patient suffering from cancer suitable for treatment with an IAP antagonist wherein said method comprises detecting, and optionally quantifying, the expression, the change in expression, the level, the change in level, the amount or the change in amount of one or more biomarkers of the invention.

[0265] In a further embodiment the invention provides a method of selecting a patient (e.g. suffering from cancer) wherein said method comprises the steps of selecting a patient by detecting, and optionally quantifying, the expression of one or more biomarkers of the invention. The detecting, and optionally quantifying, may take place at more than one time point. In a further embodiment the invention provides a method of selecting a patient (e.g. suffering from cancer) wherein said method comprises the steps of selecting a patient by detecting, and optionally quantifying, the plasma level of one or more biomarkers of the invention. The detecting, and optionally quantifying, may take place at more than one time point.

[0266] In a further embodiment the invention provides a method of determining the likelihood that a cancer patient will respond to therapy with an IAP antagonist, the method comprising: obtaining a measurement of decreased and / or increased expression of one or more of the biomarkers in a plasma or blood sample from the patient, compared to a corresponding non-responder blood sample or plasma sample; and determining that the patient is likely to respond to therapy with an IAP antagonist on the basis of that measurement.

[0267] In a further embodiment the invention provides a drug administration process comprising: determining one or more biomarkers of the invention administering a therapeutically effective amount of an IAP antagonist to a patient with one or more biomarkers of the invention at a level that indicates likely successful treatment by IAP antagonism.

[0268] In yet a further aspect, the invention provides a method of detecting the expression of one or more biomarkers of the invention in a human patient suffering from cancer. This method typically comprises:

[0269] (a) obtaining a sample from a human patient, typically a blood sample or a plasma sample; and

[0270] (b) detecting whether said biomarker(s) are expressed in the sample by contacting the sample with one or more reagents for detecting (i) expression of the biomarker(s) or (ii) the level, concentration or amount of the biomarker(s).

[0271] Optionally, the detecting may take place at more than one time point. In one embodiment, the time points are before and after treatment with an IPA antagonist. The detecting may include detecting the change in expression of the biomarker(s) or the change in the level, concentration or amount of the biomarker(s).

[0272] In a still further aspect, the invention provides a kit or device for detecting the expression level of at least one biomarker for sensitivity to IAP antagonism in a sample from a human patient, said kit or device comprising a detection reagent or detection reagents for detecting one or more biomarkers of the invention.

[0273] In a further aspect, the invention resides in a system for assessing whether a human cancer patient is susceptible to treatment with an IAP antagonist, the system comprising: detection means able and adapted to detect in a sample of from the human patient one or more biomarkers of the invention; a processor able and adapted to determine from the determined biomarker or biomarkers an indication of the likelihood of the patient being treatable with an IAP antagonist. The system optionally contains a data connection to an interface, particularly a graphical user interface, capable of presenting information, preferably also capable of putting in information such as the age of the subject, as well as optionally other patient information such as sex and / or medical history information, said interface being either a part of the system or a remote interface. Optionally one or more of the foregoing items, particularly the processor, are enabled to function "in the cloud”, i.e., not on a fixed machine, but by means of an internet-based application.

[0274] The invention also provides methods of identifying and screening patients, combinations, and kits.

[0275] In a further embodiment, the invention provides a method of screening or identifying a patient for treatment with an IAP antagonist comprising determining whether said patient has: decreased expression of one or more biomarkers within a biological sample obtained from said patient, compared to the level in a non-responder; and / or increased expression of one or more biomarkers within a biological sample obtained from said patient, compared to the level in a non-responder.

[0276] In a further embodiment, the invention provides a method of identifying a patient responder comprising testing a patient for: decreased expression of one or more biomarkers within a biological sample obtained from said patient, compared to the level in a non-responder; and / or increased expression of one or more biomarkers within a biological sample obtained from said patient, compared to the level in a non-responder.

[0277] In a further embodiment, the invention provides a method of treatment comprising:

[0278] (a) identifying a patient in need of treatment for cancer, optionally a blood cancer such as PTCL or CTCL;

[0279] (b) determining that the patient has decreased or increased expression of one or more biomarkers within a biological sample obtained from said patient; and treating the patient with a therapeutically effective amount of an IAP antagonist.

[0280] In a further embodiment, the invention provides a method of treatment comprising:

[0281] (a) identifying a patient in need of treatment for cancer, optionally blood cancer, optionally TCL, optionally PTCL or CTCL;

[0282] (b) determining that the patient has decreased or increased expression of one or more biomarkers within a biological sample obtained from said patient, wherein the decrease or increase is compared to the level in a non-responder; and treating the patient with a therapeutically effective amount of an IAP antagonist.

[0283] In a further embodiment, the invention provides a method of treatment comprising:

[0284] (a) identifying a patient in need of treatment for cancer, optionally TCL e.g. PTCL or CTCL;

[0285] (b) determining one or more biomarkers of the invention in the patient in a blood sample or plasma sample, (c) selecting an IAP antagonist (e.g. tolinapant) as a treatment for the patient, based on the recognition that IAP antagonists are effective in patients who have one or more biomarkers of the invention;

[0286] (d) treating the patient with a therapeutically effective amount of an IAP antagonist.

[0287] In a further embodiment, the invention provides a method of treatment comprising:

[0288] (a) identifying a patient in need of treatment for cancer, blood cancer, optionally TCL, optionally PTCL or CTCL;

[0289] (b) determining one or more biomarkers of the invention in the patient;

[0290] (c) selecting an IAP antagonist as a treatment for the patient, based on the recognition that IAP antagonists are effective in patients who have one or more biomarkers of the invention;

[0291] (d) treating the patient with a therapeutically effective amount of an IAP antagonist.

[0292] Optionally, the determining may take place at more than one time point. The determining may include detecting the change in expression of the biomarker(s) or the change in the level, concentration or amount of the biomarker(s).

[0293] In a further embodiment, the invention provides a method of selecting a treatment for a cancer patient comprising:

[0294] (a) assaying one or more biological samples thereby determining one or more biomarkers of the invention in the patient;

[0295] (b) based on that determination selecting that patient for treatment with a therapeutically effective amount of an IAP antagonist.

[0296] Optionally, the determining may take place at more than one time point. The determining may include detecting the change in expression of the biomarker(s) or the change in the level, concentration or amount of the biomarker(s).

[0297] In a further embodiment, the invention provides a process for selecting a patient (e.g. suffering from cancer) for treatment with an IAP antagonist, characterised in that said patient has been selected for having: decreased or low expression of one or more biomarkers within a biological sample obtained from said patient; and / or increased or high expression of one or more biomarkers within a biological sample obtained from said patient.

[0298] In a further embodiment, the invention provides an IAP antagonist for use in the treatment of cancer in a patient, characterised in that said patient is known to have decreased expression or activity of one or more biomarkers of the invention within a biological sample obtained from said patient. In a further embodiment, the invention provides an IAP antagonist for use in the treatment of cancer in a patient, characterised in that said patient is known to have increased expression or activity of one or more biomarkers of the invention within a biological sample obtained from said patient. Optionally, the detecting may take place at more than one time point. The detecting may include detecting the change in expression of the biomarker(s) or the change in the activity of the biomarker(s).

[0299] In a further embodiment, the invention provides a kit for treating cancer in a patient, wherein said kit comprises a biosensor for detection and / or quantification of one or more biomarkers of the invention, and / or reagents for the detection of one or more biomarkers of the invention, optionally together with instructions for use of the kit in accordance with the methods as defined herein.

[0300] In a further embodiment, the invention provides a method of determining responsiveness of an individual with cancer to treatment with an IAP antagonist comprising detecting decreased expression or activity of one or more biomarkers within a biological sample obtained from said patient. In a further embodiment, the invention provides a method of determining responsiveness of an individual with cancer to treatment with an IAP antagonist comprising detecting increased expression or activity of one or more biomarkers within a biological sample obtained from said patient.

[0301] Optionally, the detecting may take place at more than one time point. The detecting may include detecting the change in expression of the biomarker(s) or the change in the activity of the biomarker(s). In a further embodiment, the invention provides a method of determining responsiveness of an individual with cancer to treatment with an IAP antagonist comprising identifying a patient: having decreased expression or activity of one or more biomarkers within a biological sample obtained from said patient; and / or having increased expression or activity of one or more biomarkers within a biological sample obtained from said patient and then administering a therapeutically effective amount of an IAP antagonist to said patient.

[0302] In a further embodiment, the invention provides a method of treating cancer in a patient wherein said method comprises the steps of selecting a patient having decreased expression or activity of one or more biomarkers within a biological sample obtained from said patient, typically a plasma sample.

[0303] In a further embodiment, the invention provides a drug administration process comprising:

[0304] (i) ordering determination of expression, activity, level, amount or concentration of one or more biomarkers; and

[0305] (ii) administering a therapeutically effective amount of an IAP antagonist to a patient with decreased levels of one or more biomarkers, wherein the decrease is compared to the expression, activity, level, amount or concentration in a non-responder.

[0306] Optionally, the ordering determination of expression, activity, level, amount or concentration of one or more biomarkers may take place at more than one time point. The determination may include detecting the change in expression, activity, level, amount or concentration of one or more biomarkers.

[0307] In a further embodiment, the invention provides a packaged pharmaceutical product comprising: (i) an IAP antagonist;

[0308] (ii) patient insert detailing instructions for use of the IAP antagonist in the treatment of patients identified using the biomarker profile described herein.

[0309] In a further embodiment, the invention provides a method of treating cancer in a patient wherein said method comprises:

[0310] (i) contacting a sample from a patient with a primer, antibody, substrate or probe, to determine the expression or activity levels of one or more biomarkers;

[0311] (ii) selecting a patient having decreased and / or increased levels of one or more biomarkers in a biological sample obtained from said patient;

[0312] (iii) followed by administering a therapeutically effective amount of an IAP antagonist to said patient selected in step (ii).

[0313] In a further embodiment, the invention provides a method for identifying a patient for treatment with an IAP antagonist, the method comprising:

[0314] (a) contacting a sample from the patient with a plurality of oligonucleotide primers, said plurality of primers comprising at least one pair of oligonucleotide primers for any one or more biomarkers;

[0315] (b) performing PCR on said sample to amplify gene expression products / transcripts in the sample;

[0316] (c) determining the level of an expression product of at least one of said genes; and

[0317] (d) identifying the patient as a candidate for treatment with an IAP antagonist when the expression level of said at least one gene is low relative to the upper limit of normal (ULN); or

[0318] (e) identifying the patient as a candidate for treatment with an IAP antagonist when the expression level of said at least one gene is high relative to the lower limit of normal (LLN).

[0319] The patient may optionally be identified as a candidate for treatment with an IAP antagonist when the expression level of one or more biomarkers is low relative to (e.g. below) the upper limit of normal (ULN).

[0320] The patient may optionally be identified as a candidate for treatment with an IAP antagonist when the expression level of one or more biomarkers is high relative to (e.g. above) the lower limit of normal (LLN).

[0321] In a further embodiment, the invention provides a method for identifying a patient for treatment with an IAP antagonist, the method comprising:

[0322] (a) contacting a sample from the patient with an antibody against one or more biomarkers of the invention;

[0323] (b) performing an assay on said sample;

[0324] (c) determining the level of one or more biomarkers of the invention; and

[0325] (d) identifying the patient as a candidate for treatment with an IAP antagonist when the level of one or more biomarkers of the invention is elevated or reduced relative to the upper limit of normal (ULN).

[0326] The assay in part (b) may be or comprise an immunohistochemical assay. In some embodiments, the assay may be or comprise an ELISA. When the sample from the patient is contacted with an antibody against one or more biomarkers, an immunohistochemical assay is typically performed on said sample, and the patient is identified as a candidate for treatment with an IAP antagonist when the level of one or more biomarkers is (a) low (or absent) relative to the upper limit of normal (ULN); or (b) high relative to the lower limit of normal (LLN).

[0327] Once a patient has been identified for treatment, the methods described herein can further comprise treating cancer in the patient with an IAP antagonist.

[0328] In a further embodiment, the invention provides a method of selecting a cancer patient for receiving an IAP antagonist therapy for a cancer, comprising:

[0329] (a) determining the level of one or more biomarkers in a biological sample from the patient; and

[0330] (b) selecting the patient who has a level of one or more biomarkers in the biological sample from the patient that is lower than a predetermined value in the biological sample from the patient that is equal to or greater than a predetermined value.

[0331] In a further embodiment, the invention provides a method for predicting efficacy of IAP antagonist for a cancer in a patient, or for predicting response of a cancer patient to an IAP antagonist for a cancer, comprising determining the level of one or more biomarkers in a biological sample from the patient, where a biological sample level of the one or more biomarkers equal to or typically less than a predetermined value is predictive of efficacy in the patient. In a further embodiment, the invention provides a method for predicting efficacy of IAP antagonist for a cancer in a patient, or for predicting response of a cancer patient to an IAP antagonist for a cancer, comprising determining the level of one or more biomarkers in a biological sample from the patient, where a biological sample level of the one or more biomarkers equal to or typically greater than a predetermined value is predictive of efficacy in the patient.

[0332] In a further embodiment, the invention provides a method of selecting a patient having cancer in need of treatment with an IAP antagonist which comprises testing a blood sample or a plasma sample obtained from the patient for low level of one or more biomarkers of the invention and / or a high level of one or more biomarkers of the invention.

[0333] Typically, in the methods of the invention that comprise a step of detecting, determining or measuring the level or activity of a biomarker, that step comprises measuring, detecting or determining an increase in the level or activity of upregulated biomarkers of the invention and / or comprises measuring, detecting or determining a decrease in the level or activity of downregulated biomarkers of the invention.

[0334] In a further embodiment, the invention provides a method of treating cancer comprising (i) testing a sample e.g. plasma sample obtained from a patient suffering from or likely to suffer from cancer for loss of one or more of the downregulated biomarkers and (ii) administering an IAP antagonist to the patient from which the sample was taken.

[0335] In a further embodiment, the invention provides a method of identifying a patient having cancer most likely to benefit from treatment with an IAP antagonist comprising measuring the level of one or more of the biomarkers of the invention in a sample e.g. plasma sample obtained from the patient and identifying whether or not the patient is likely to benefit from treatment with an IAP antagonist according to the levels present. The tumour is typically a liquid tumour, more typically TCL e.g. PTCL or CTCL. The IAP inhibitor is typically tolinapant.

[0336] The invention variously provides: a method of determining if a cancer patient is amenable to treatment with an IAP antagonist; a method of predicting the sensitivity of tumour cell growth to inhibition by a IAP antagonist; a method of predicting responsiveness of a cancer in a subject to a cancer therapy including an IAP antagonist; a method of developing a treatment plan for a subject with cancer; an in vitro method for the identification of a patient responsive to or sensitive to treatment with an IAP antagonist regimen. The methods typically comprise comparing the levels of one or more biomarkers of the invention in the sample, typically a tumour sample, to a reference level and predicting the responsiveness of the cancer to treatment with the cancer therapy including an IAP antagonist. In one embodiment the methods comprise analysing one or more, for example, two or more, or three or more, or four or more, or five or more, or six or more, or seven or more biomarkers described herein. In one embodiment the methods comprise analysing only one biomarker described herein, i.e. the biomarker consists of single biomarker.

[0337] In a further embodiment, the invention provides an in vitro method for predicting the likelihood that a patient suffering from a tumour, who is a candidate for treatment with an IAP antagonist, will respond to the treatment with the compound, comprising the step of: (a) determining the levels of one or more downregulated biomarkers in one or more tissue samples taken from the patient, wherein (i) loss of one or more biomarkers (e.g compared to a reference value of at least one non-responder tissue) indicates that the patient is likely to respond to the treatment and / or (ii) normal or high levels of one or more biomarkers indicates that the patient is less likely to respond to the treatment. The tissue is typically blood or blood plasma. The cancer is typically a TCL e.g. PTCL or CTCL. The IAP antagonist is typically tolinapant.

[0338] In a further embodiment, the invention provides an in vitro method for predicting the likelihood that a patient suffering from a tumour, who is a candidate for treatment with an IAP antagonist, will respond to the treatment with the compound, comprising the step of: (a) determining the levels of one or more upregulated biomarkers in one or more tissue samples taken from the patient, wherein normal or high levels of one or more biomarkers indicates that the patient is likely to respond to the treatment. The tissue is typically blood or blood plasma. The cancer is typically a TCL e.g. PTCL or CTCL. The IAP antagonist is typically tolinapant.

[0339] In a further embodiment, the invention provides an assay comprising: (a) measuring or quantifying the level of one or more biomarkers; (b) comparing the level of said one or more biomarkers (e.g. relative to control levels determined in responders or non-responders or relative to a different timepoint), and if there is a decrease or loss in one or more downregulated biomarkers (e.g. relative to control levels determined in non-responder tissue or relative to a different timepoint) identifying the patient as suitable for treatment with an IAP antagonist.

[0340] In a further embodiment, the invention provides an assay comprising: (a) measuring or quantifying the level of one or more biomarkers; (b) comparing the level of said one or more biomarkers (e.g. relative to control levels determined in responders or non-responders or relative to a different timepoint), and if there is an increase in one or more upregulated biomarkers (e.g. relative to control levels determined in non-responder tissue or relative to a different timepoint) identifying the patient as suitable for treatment with an IAP antagonist.

[0341] In a further embodiment, the invention provides an assay comprising:

[0342] (i) contacting a biological sample obtained from a patient with an antibody (e.g. antibody specific against one or more biomarkers);

[0343] (ii) washing the sample to remove unbound antibody;

[0344] (iii) measuring the intensity of the signal from the bound antibody;

[0345] (iv) comparing the measured intensity of the signal with a reference value and if the measured intensity is altered relative to the reference value;

[0346] (v) contacting a biological sample obtained from a patient with a. a primer (e.g. at least one oligonucleotide primer pairs for any one or more biomarkers), b. an antibody (e.g. antibody specific against one or more biomarkers), and / or c. a primer for a gene or mutant indicative of loss of one or more downregulated biomarkers;

[0347] (vi) performing PCR, RT-PCR or next generation sequencing on said sample to amplify gene expression products / transcripts in the sample;

[0348] (vii) determining the level of an expression product of at least one of said genes; and

[0349] (viii) identifying the subject as having an increased probability of being suitable for treatment with an IAP antagonist.

[0350] In a further embodiment, the invention provides a method of treating cancer comprising administering an IAP antagonist to a subject with loss of one or more downregulated biomarkers in a tumour sample as determined by sequencing or immunoassay.

[0351] In a further embodiment, the invention provides a method of administering an IAP antagonist to a patient in need thereof comprising:

[0352] (1 ) determining the patient levels of one or more biomarkers;

[0353] (2) assigning a phenotype to the patient based on the levels of the biomarker(s) as determined in (1 ), wherein the phenotype is selected from poor (P), intermediate (I), and sensitive (S), and said phenotype is assigned based upon the level of the genes in the tumour; and

[0354] (3) administering to the patient with phenotype S an IAP antagonist.

[0355] IHC is widely available with the advantage of not requiring a molecular laboratory, and the ability to identify the affected gene by detecting loss of its protein product. In a further embodiment, the invention provides use of an IAP antagonist in the manufacture of a medicament for use in the treatment of cancer in a patient wherein the patient’s blood plasma has loss of one or more downregulated biomarkers of the invention.

[0356] In a further embodiment, the invention provides use of an IAP antagonist in the manufacture of a medicament for use in the treatment of cancer in a patient identified as likely to be responsive to treatment with an IAP antagonist according to the method described herein.

[0357] In a further embodiment, the invention provides an article of manufacture comprising, packaged together, an IAP antagonist medicament in a pharmaceutically acceptable carrier and a package insert indicating that the cancer (e.g. blood cancer, TCL, CTCL or PTCL) medicament is for treating a patient with cancer based on levels of a biomarker or biomarkers identified herein as determined by an assay method used to measure the levels.

[0358] In a further embodiment, the invention provides a method for advertising an IAP antagonist medicament comprising promoting, to a target audience, the use of the IAP antagonist medicament for treating a cancer patient with loss of or decrease in one or more biomarkers as described herein.

[0359] In a further embodiment, the invention provides apparatus configured to identify a tumour (e.g. PTCL or CTCL) of a cancer patient as being likely to benefit from treatment with a therapeutic agent or a combination of therapeutic agents targeting IAP or not likely to benefit from treatment with the therapeutic agent or combination of therapeutic agents. The apparatus may comprise a storage device storing assay data e.g. immunoassay data from blood-based (e.g. plasma-based) samples for the levels of one or more biomarker proteins, and / or loss of or decrease in one or more biomarkers to identify the patient as being either likely or not likely to benefit from the therapeutic agent or a combination of therapeutic agents targeting IAP.

[0360] In one embodiment of the method described here when the levels of one or more downregulated biomarkers are low then the patient is administered an IAP antagonist. In one embodiment of the method described here when the levels of one or more upregulated biomarkers are high then the patient is administered an IAP antagonist. Reference is typically made to the level in a non-responder.

[0361] In another embodiment of the method described here when the levels of one or more biomarkers are high (or present) then the patient is not administered an IAP antagonist. Reference is typically made to the level in a non-responder.

[0362] In certain embodiments, an IAP antagonist may be administered to a patient in combination with an additional cancer treatment that is not an IAP antagonist. In one embodiment the at least one biomarker of the invention can be used to select a patient to treat with an IAP antagonist in combination with an agent described in (i) — (xlix) below. In some embodiments, the combination is with a hypomethylating agent, for example decitabine. Decitabine is often administered in combination with cedazuridine, so the combination of IAP antagonist + decitabine + cedazuridine is also provided to treat a patient identified as having a biomarker profile as described herein. In some embodiments, the IAP antagonist is tolinapant and is administered once a day for 7 consecutive days every other week of each 28-day cycle. In some embodiments, the dose of tolinapant is 30 mg or 90 mg daily.

[0363] Pathways

[0364] The biomarkers identified in the present invention may be extrinsic cell death pathway genes and their gene products, and intrinsic cell death pathway genes and their gene products. These proteins and the genes encoding them are all known in the art. As used herein, these biomarkers are referred to as the “pathway biomarkers of the invention” and / or “extrinsic cell death biomarkers” or “intrinsic cell death biomarkers”. These pathways are known in the art, for example in Meier, P., et al., Nat Rev Cancer 24, 299-315 (2024). Reduced function in a cancer cell in the extrinsic cell death pathway or the intrinsic cell death pathway contributes to cancer cell survival. Perturbation of one or more genes or gene products in these pathways therefore has the potential to affect sensitivity to IAP antagonism.

[0365] In one aspect the invention provides an IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of their plasma level of one or more of the pathway biomarkers of the invention and / or extrinsic cell death biomarkers of the invention and / or intrinsic cell death biomarkers of the invention.

[0366] In one embodiment the extrinsic cell death pathway or the intrinsic cell death pathway gene(s) are selected from one or more of the following genes: DIABLO, XIAP, BIRC3, MAP3K7, CYLD, BIRC2, TRAF2, MAP3K14, BAX, UBE2N, IKBKB, HTRA2, BCL2, IKBKG, BAK1 , CASP3, RIPK1 , BCL2L1 , TBK1 , and RIPK2; or HTRA2, CD27, CYCS, BCL2, BIK, CRP, BAK1 , AIFM1 , ENDOG, USP13, USP10, BECN1 , BCL2L1 , PENK, APAF1 , REST, HIP1 , BAX, XIAP, and IL-10.

[0367] The “pathway biomarkers” identified herein may be used in any of the uses or methods described hereinabove relating to the “biomarkers” or “Delta biomarkers” of the invention.

[0368] According to another embodiment of the invention, there is provided a method of treating cancer in a patient wherein said method comprises the steps of selecting a patient based on the expression profile of one more of the pathway biomarkers of the invention. In certain embodiments, the patient is selected based on: having decreased expression or activity of one or more extrinsic cell death biomarkers and / or intrinsic cell death biomarkers within a biological sample obtained from said patient, wherein said biomarkers are selected from the group consisting of DIABLO, XIAP, BIRC3, MAP3K7, CYLD, BIRC2, TRAF2, MAP3K14, BAX, UBE2N, IKBKB, HTRA2, BCL2, IKBKG, BAK1 , CASP3, RIPK1 , BCL2L1 , TBK1 , and RIPK2; or HTRA2, CD27, CYCS, BCL2, BIK, CRP, BAK1 , AIFM1 , ENDOG, USP13, USP10, BECN1 , BCL2L1 , PENK, APAF1 , REST, HIP1 , BAX, XIAP, and IL-10; and optionally then administering a therapeutically effective amount of a IAP antagonist to said patient.

[0369] According to another embodiment of the invention, there is provided the use of the expression or activity level of one or more extrinsic cell death pathway and / or one or more intrinsic cell death pathway genes or gene products in a cancer cell sample of a human patient, wherein the one or more pathway genes or gene products are selected from the list consisting of (a) DIABLO, XIAP, BIRC3, MAP3K7, CYLD, BIRC2, TRAF2, MAP3K14, BAX, UBE2N, IKBKB, HTRA2, BCL2, IKBKG, BAK1 , CASP3, RIPK1 , BCL2L1 , TBK1, and RIPK2; or (b) HTRA2, CD27, CYCS, BCL2, BIK, CRP, BAK1 , AIFM1 , ENDOG, USP13, USP10, BECN1 , BCL2L1 , PENK, APAF1 , REST, HIP1 , BAX, XIAP, and IL-10 as a biomarker or biomarkers for assessing whether the cancer is susceptible to treatment with an IAP antagonist.

[0370] The invention also provides a method for prognosing or assessing the responsiveness of a human cancer patient to treatment with an IAP antagonist, comprising assessing the expression or activity level in a sample from a cancer patient of one or more extrinsic cell death pathway and / or one or more intrinsic cell death pathway genes, wherein said one or more extrinsic cell death pathway and / or one or more intrinsic cell death pathway genes are selected from the group consisting of DIABLO, XIAP, BIRC3, MAP3K7, CYLD, BIRC2, TRAF2, MAP3K14, BAX, UBE2N, IKBKB, HTRA2, BCL2, IKBKG, BAK1 , CASP3, RIPK1 , BCL2L1 , TBK1 , and RIPK2; or HTRA2, CD27, CYCS, BCL2, BIK, CRP, BAK1 , AIFM1 , ENDOG, USP13, USP10, BECN1 , BCL2L1 , PENK, APAF1 , REST, HIP1 , BAX, XIAP, and IL-10., and determining whether the tested expression or activity level indicates that the cancer should be treated with an IAP antagonist.

[0371] In a particular embodiment, the cancer is PTCL and the biomarker is assessed before dosing the patient with the IAP antagonist, wherein the biomarker is one or more of HTRA2, CD27, CYCS, BCL2, BIK, CRP, BAK1 , AIFM1 , ENDOG, USP13, USP10, BECN1 , BCL2L1 , PENK, APAF1 , REST, HIP1 , BAX, XIAP, and IL-10. In another embodiment, the cancer is PTCL and the biomarker is assessed after three to five weeks after dosing the patient with the IAP antagonist, wherein the biomarker is one or more of DIABLO, XIAP, BIRC3, MAP3K7, CYLD, BIRC2, TRAF2, MAP3K14, BAX, UBE2N, IKBKB, HTRA2, BCL2, IKBKG, BAK1 , CASP3, RIPK1 , BCL2L1 , TBK1 , and RIPK2.

[0372] As described above, the assessment step may comprise comparing the expression or activity level with the expression or activity level (i) associated with responsiveness or non-responsiveness to treatment with an IAP antagonist or (ii) from a healthy non-cancer cell of the same type.

[0373] As described herein, the patient may be classified into a group based on the biomarker profile, optionally wherein the groups comprise or consist of responders and non-responders. The pathway biomarkers (a) DIABLO, XIAP, BIRC3, MAP3K7, CYLD, BIRC2, TRAF2, MAP3K14, BAX, UBE2N, IKBKB, HTRA2, BCL2, IKBKG, BAK1 , CASP3, RIPK1 , BCL2L1 , TBK1 , and RIPK2; or (b) HTRA2, CD27, CYCS, BCL2, BIK, CRP, BAK1 , AIFM1 , ENDOG, USP13, USP10, BECN1 , BCL2L1 , PENK, APAF1 , REST, HIP1 , BAX, XIAP, and IL-10 are associated with non-responders.

[0374] The expression or activity level of one or more extrinsic cell death pathway and / or one or more intrinsic cell death pathway genes may be determined by any of the methods described herein.

[0375] BRIEF DESCRIPTION OF THE FIGURES

[0376] Figure 1 : Dosing of tolinapant in the ASTX660-01 trial.

[0377] Figure 2: Visual separation for the three C2Early biomarkers, PTCL.

[0378] Figure 3: ROC curve for the three protein biomarkers at C2Early. Figure 4: The performance distribution of the top ML models.

[0379] Figure 5: Top 7 protein levels (C1 Early biomarkers) separate Response and Non-Response in PTCL.

[0380] Figure 6: Top C1 Early markers in CTCL using ROCAUC separate Response and Non-Response.

[0381] Figure 7: Top C2Early markers in CTCL using ROCAUC separate Response and Non-Response.

[0382] Figure 8: Top C2Early markers in PTCL using ROCAUC separate Response and Non-Response.

[0383] Figure 9: Top Delta markers and their Delta levels in PTCL.

[0384] Figure 10: Top Delta markers and their Delta levels in CTCL.

[0385] Figure 11 : Representation of the ASTX660 knowledge graph.

[0386] DEFINITIONS

[0387] By “IAP” we mean any of the IAP family members XIAP, clAP (clAP1 and / or clAP2), NAIP, ILP2, ML- IAP, survivin and / or BRUCE, in particular XIAP, clAP1 , clAP2, ML-IAP, more particularly XIAP, clAP1 and / or clAP2, most particularly XIAP and / or clAP1 . In particular we mean the BIR domains of IAP, in particular the BIR domains of XIAP, clAP1 , or clAP2.

[0388] By “one or more IAP family members” we mean any of the IAP family members in particular XIAP, clAP1 and / or clAP2, more particularly XIAP and / or clAP1 .

[0389] The term “IAP inhibitor” and “IAP antagonist” are used as synonyms and define IAP compounds or analogues of IAP compounds as described herein, including the ionic, salt, solvate, isomers, tautomers, N-oxides, ester, prodrugs, isotopes and protected forms thereof (preferably the salts or tautomers or isomers or N-oxides or solvates thereof, and more preferably, the salts or tautomers or N-oxides or solvates thereof), as described herein and above.

[0390] “IAP antagonist” means an antagonist of one or more IAP family members. The term “antagonist” refers to a type of receptor ligand or drug that blocks or dampens agonist-mediated biological responses. Antagonists have affinity but no agonistic efficacy for their cognate receptors, and binding will disrupt the interaction and inhibit the function of any ligand (e.g. endogenous ligands or substrates, an agonist or inverse agonist) at receptors. The antagonism may arise directly or indirectly, and may be mediated by any mechanism and at any physiological level. As a result, antagonism of ligands may under different circumstances manifest itself in functionally different ways. Antagonists mediate their effects by binding to the active site or to allosteric sites on receptors, or they may interact at unique binding sites not normally involved in the biological regulation of the receptor's activity. Antagonist activity may be reversible or irreversible depending on the longevity of the antagonist-receptor complex, which, in turn, depends on the nature of antagonist receptor binding. “Potency” is a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity. A highly potent drug evokes a larger response at low concentrations. Potency is proportional to affinity and efficacy. Affinity is the ability of the drug to bind to a receptor. Efficacy is the relationship between receptor occupancy and the ability to initiate a response at the molecular, cellular, tissue or system level.

[0391] As used herein, the term “mediated”, as used e.g. in conjunction with IAP as described herein (and applied for example to various physiological processes, diseases, states, conditions, therapies, treatments or interventions) is intended to operate limitatively so that the various processes, diseases, states, conditions, treatments and interventions to which the term is applied are those in which the protein plays a biological role. In cases where the term is applied to a disease, state or condition, the biological role played by the protein may be direct or indirect and may be necessary and / or sufficient for the manifestation of the symptoms of the disease, state or condition (or its aetiology or progression). Thus, the protein function (and in particular aberrant levels of function, e.g. over- or under-expression) need not necessarily be the proximal cause of the disease, state or condition: rather, it is contemplated that the mediated diseases, states or conditions include those having multifactorial aetiologies and complex progressions in which the protein in question is only partially involved. In cases where the term is applied to treatment, prophylaxis or intervention, the role played by the protein may be direct or indirect and may be necessary and / or sufficient for the operation of the treatment, prophylaxis or outcome of the intervention. Thus, a disease state or condition mediated by a protein includes the development of resistance to any particular cancer drug or treatment.

[0392] The term "treatment" as used herein in the context of treating a condition i.e. state, disorder or disease, pertains generally to treatment and therapy, whether for a human or an animal (e.g. in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, amelioration of the condition, diminishment or alleviation of at least one symptom associated or caused by the condition being treated and cure of the condition. For example, treatment can be diminishment of one or several symptoms of a disorder or complete eradication of a disorder.

[0393] The term “prophylaxis” (i.e. use of a compound as prophylactic measure) as used herein in the context of treating a condition i.e. state, disorder or disease, pertains generally to the prophylaxis or prevention, whether for a human or an animal (e.g. in veterinary applications), in which some desired preventative effect is achieved, for example, in preventing occurrence of a disease or guarding from a disease. Prophylaxis includes complete and total blocking of all symptoms of a disorder for an indefinite period of time, the mere slowing of the onset of one or several symptoms of the disease, or making the disease less likely to occur.

[0394] References to the prophylaxis or treatment of a disease state or condition such as cancer include within their scope alleviating or reducing the incidence e.g. of cancer.

[0395] The combinations of the invention may produce a therapeutically efficacious effect relative to the therapeutic effect of the individual compounds / agents when administered separately. The term ‘efficacious’ includes advantageous effects such as additivity, synergism, reduced side effects, reduced toxicity, increased time to disease progression, increased time of survival, sensitization or resensitization of one agent to another, or improved response rate. Advantageously, an efficacious effect may allow for lower doses of each or either component to be administered to a patient, thereby decreasing the toxicity of chemotherapy, whilst producing and / or maintaining the same therapeutic effect. A “synergistic” effect in the present context refers to a therapeutic effect produced by the combination which is larger than the sum of the therapeutic effects of the agents of the combination when presented individually. An “additive” effect in the present context refers to a therapeutic effect produced by the combination which is larger than the therapeutic effect of any of the agents of the combination when presented individually. The term “response rate” as used herein refers, in the case of a solid tumour, to the extent of reduction in the size of the tumour at a given time point, for example 12 weeks. Thus, for example, a 50% response rate means a reduction in tumour size of 50%. References herein to a “clinical response” refer to response rates of 50% or greater. A “partial response” is defined herein as being a response rate of less than 50%.

[0396] As used herein, the term “combination”, as applied to two or more compounds and / or agents, is intended to define material in which the two or more agents are associated. The terms “combined” and “combining” in this context are to be interpreted accordingly.

[0397] The association of the two or more compounds / agents in a combination may be physical or non-physical. Examples of physically associated combined compounds / agents include:

[0398] • compositions (e.g. unitary formulations) comprising the two or more compounds / agents in admixture (for example within the same unit dose);

[0399] • compositions comprising material in which the two or more compounds / agents are chemically / physicochemically linked (for example by crosslinking, molecular agglomeration or binding to a common vehicle moiety);

[0400] ® compositions comprising material in which the two or more compounds / agents are chemically / physicochemically co-packaged (for example, disposed on or within lipid vesicles, particles (e.g. micro- or nanoparticles) or emulsion droplets);

[0401] • pharmaceutical kits, pharmaceutical packs or patient packs in which the two or more compounds / agents are co-packaged or co-presented (e.g. as part of an array of unit doses);

[0402] Examples of non-physically associated combined compounds / agents include:

[0403] ® material (e.g. a non-unitary formulation) comprising at least one of the two or more compounds / agents together with instructions for the extemporaneous association of the at least one compound to form a physical association of the two or more compounds / agents;

[0404] • material (e.g. a non-unitary formulation) comprising at least one of the two or more compounds / agents together with instructions for combination therapy with the two or more compounds / agents; • material comprising at least one of the two or more compounds / agents together with instructions for administration to a patient population in which the other(s) of the two or more compounds / agents have been (or are being) administered;

[0405] • material comprising at least one of the two or more compounds / agents in an amount or in a form which is specifically adapted for use in combination with the other(s) of the two or more compounds / agents.

[0406] As used herein, the term “combination therapy” is intended to define therapies which comprise the use of a combination of two or more compounds / agents (as defined above). Thus, references to “combination therapy”, “combinations” and the use of compounds / agents “in combination” in this application may refer to compounds / agents that are administered as part of the same overall treatment regimen. As such, the posology of each of the two or more compounds / agents may differ: each may be administered at the same time or at different times. It will therefore be appreciated that the compounds / agents of the combination may be administered sequentially (e.g. before or after) or simultaneously, either in the same pharmaceutical formulation (i.e. together), or in different pharmaceutical formulations (i.e. separately). Simultaneously in the same formulation is as a unitary formulation whereas simultaneously in different pharmaceutical formulations is non-unitary. The posologies of each of the two or more compounds / agents in a combination therapy may also differ with respect to the route of administration.

[0407] As used herein, the term “pharmaceutical kit” defines an array of one or more unit doses of a pharmaceutical composition together with dosing means (e.g. measuring device) and / or delivery means (e.g. inhaler or syringe), optionally all contained within common outer packaging. In pharmaceutical kits comprising a combination of two or more compounds / agents, the individual compounds / agents may unitary or non-unitary formulations. The unit dose(s) may be contained within a blister pack. The pharmaceutical kit may optionally further comprise instructions for use.

[0408] As used herein, the term “pharmaceutical pack” defines an array of one or more unit doses of a pharmaceutical composition, optionally contained within common outer packaging. In pharmaceutical packs comprising a combination of two or more compounds / agents, the individual compounds / agents may unitary or non-unitary formulations. The unit dose(s) may be contained within a blister pack. The pharmaceutical pack may optionally further comprise instructions for use.

[0409] The term 'optionally substituted’ as used herein refers to a group which may be unsubstituted or substituted by a substituent as herein defined.

[0410] The term ‘n-butyl’ as used herein refers to a linear alkyl group containing 4 carbon atoms.

[0411] The term ‘oxo’ as used herein refers to the group =0.

[0412] Dashed bond ( - ) represents a single or double bond as required to complete the valencies of the atoms being linked by the bond. It will be understood that in some instances the bond has aromatic character. Dashed bond ( - ) represents a single or double bond such that the ring containing X and

[0413] U contains at least two double bonds. DETAILED DESCRIPTION OF THE INVENTION

[0414] The invention is based on the identification of biomarkers that allow the determination of a cancer patient's likely response to IAP antagonist therapy. This provides for precision therapy of cancer using an IAP antagonist.

[0415] In certain embodiments, the invention provides a companion diagnostic for treatment of cancer using an IAP antagonist. As used herein, the term companion diagnostic is used to refer both to a test that is required to determine whether or not a patient will respond to a drug (i.e. a necessary companion diagnostic) and a test that is intended to identify whether the patient will respond favourably or optimally (which is sometimes referred to as a complementary diagnostic). In certain embodiments, the biomarkers identify a patient that will respond, and so discriminates responders from non-responders. In another embodiment, the biomarkers identify patients that will respond optimally, whereby the physician can then select the optimal treatment for that patient.

[0416] In some embodiments, the invention provides assays for determining the expression or activity level of 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more of the biomarkers identified herein. Often, only one biomarker needs to be assessed. This may be determined directly or indirectly, as discussed above. This assay may or may not include a step of deducing a prognostic outcome. The assay is typically an in vitro assay carried out on a sample from the patient, such as a blood sample or plasma sample (whether or not the cancer is a blood cancer).

[0417] Biomarkers for effective cancer treatment

[0418] The present disclosure provides biomarkers that indicate increased sensitivity of cancer cells to treatment with an IAP antagonist. The identification of one or more of the identified biomarkers therefore allows a cancer patient to be selected for IAP antagonist treatment.

[0419] The biomarkers of the invention include:

[0420] • C2Early (e.q. 4 weeks after first dose): o IL-2 receptor alpha (lnterleukin-2 receptor alpha): Swiss-Prot accession number: P01589 o IL-6r (lnterleukin-6 receptor): Swiss-Prot accession number: P08887 o CRP (C-Reactive Protein): Swiss-Prot accession number: P02741

[0421] • C2Early ROCAUC biomarkers (e.q. 4 weeks after first dose): o TECK (Thymus-Expressed Chemokine): Swiss-Prot accession number: 015444 o PLGF (Placenta Growth Factor): Swiss-Prot accession number: P49763 o FAS (FASLG Receptor): Swiss-Prot accession number: P25445 o 03 (Complement 03): Swiss-Prot accession number: P01024 MMP-2 (Matrix Metalloproteinase-2): Swiss-Prot accession number: P08253 HGF (Hepatocyte Growth Factor): Swiss-Prot accession number: P14210 FasL (Fas Ligand): Swiss-Prot accession number: P48023 VCAM-1 (Vascular Cell Adhesion Molecule-1): Swiss-Prot accession number: P19320 Tweak (Tumor necrosis factor ligand superfamily member 12): Swiss-Prot accession number: 043508 IL-1 ra (Interleukin-1 receptor antagonist): Swiss-Prot accession number: P18510 IL-6R beta (lnterleukin-6 receptor subunit beta): Swiss-Prot accession number: P40189 VEGF (Vascular Endothelial Growth Factor): Swiss-Prot accession number: P15692 6Ckine (6Ckine): Swiss-Prot accession number: 000585 Haptoglobin (Haptoglobin): Swiss-Prot accession number: P00738 Eotaxin-2 (Eotaxin-2): Swiss-Prot accession number: 000175 MCP-1 (Monocyte Chemotactic Protein 1): Swiss-Prot accession number: P13500 TRAIL-R3 (TNF-Related Apoptosis-Inducing Ligand Receptor 3): Swiss-Prot accession number: 014798 PSA-f (Prostate-Specific Antigen, Free): Swiss-Prot accession number: P07288 IL-1 beta (lnterleukin-1 beta): Swiss-Prot accession number: P01584 IL-2 receptor alpha (lnterleukin-2 receptor alpha): Swiss-Prot accession number: P01589 TN-C (tenascin-C): Swiss-Prot accession number: P24821 Cathepsin D (Cathepsin D): Swiss-Prot accession number: P07339 CD27 (CD27 antigen): Swiss-Prot accession number: P26842 IL-6r (lnterleukin-6 receptor): Swiss-Prot accession number: P08887 MMP-7 (Matrix Metalloproteinase-7): Swiss-Prot accession number: P09237 CRP (C-Reactive Protein): Swiss-Prot accession number: P02741 G-CSF (Granulocyte Colony-Stimulating Factor): Swiss-Prot accession number: P09919 ICAM-1 (Intercellular Adhesion Molecule 1 ): Swiss-Prot accession number: P05362 TNFR2 (Tumor necrosis factor receptor 2): Swiss-Prot accession number: P20333 HB-EGF (Heparin-Binding EGF-Like Growth Factor): Swiss-Prot accession number: Q99075 IL-6 (lnterleukin-6): Swiss-Prot accession number: P05231 IL-1 RII (lnterleukin-1 receptor type 2): Swiss-Prot accession number: P27930 MIP-3 alpha (Macrophage Inflammatory Protein-3 alpha): Swiss-Prot accession number: P78556 FGF-21 (Fibroblast Growth Factor 21): Swiss-Prot accession number: Q9NSA1 IL-10 (Interleukin-10): Swiss-Prot accession number: P22301 CD40 (CD 40 antigen): Swiss-Prot accession number: Q6P2H9 SCF (Stem Cell Factor): Swiss-Prot accession number: P21583 o TIMP-1 (Tissue Inhibitor of Metalloproteinases 1): Swiss-Prot accession number: P01033 o B2M (Beta-2-Microglobulin): Swiss-Prot accession number: P61769 o IL-1 RI (lnterleukin-1 receptor type 1): Swiss-Prot accession number: P14778 o YKL-40 (YKL-40): Swiss-Prot accession number: P36222 o vWF (von Willebrand Factor): Swiss-Prot accession number: P04275 o PARC (Pulmonary and Activation-Regulated Chemokine): Swiss-Prot accession number: P55774

[0422] • C1 Early (e.q. before first dose): o EPO (Erythropoietin): Swiss-Prot accession number: P01588 o CD27 (CD27 antigen): Swiss-Prot accession number: P26842 o CD40 (CD40 antigen): Swiss-Prot accession number: Q6P2H9 o TN-C (Tenascin-C): Swiss-Prot accession number: P24821 o IL-18 (Interleukin-18): Swiss-Prot accession number: Q14116 o PLGF (Placenta Growth Factor): Swiss-Prot accession number: P49763 o TNF Rl (Tumor Necrosis Factor Receptor I): Swiss-Prot accession number: P19438 o I L-6r (lnterleukin-6 receptor): Swiss-Prot accession number: P08887 o MCP-4 (Monocyte Chemotactic Protein 4): Swiss-Prot accession number: Q99616 o TECK (thymus-expressed chemokine): Swiss-Prot accession number: 015444 o IL-8 (lnterleukin-8): Swiss-Prot accession number: P10145 o Alpha-1 -Antitrypsin: Swiss-Prot accession number: P01009 o IL-6R p (lnterleukin-6 receptor beta subunit): Swiss-Prot accession number: P40189 o FRTN: Swiss-Prot accession number: P02794, P02792 o Cathepsin D: Swiss-Prot accession number: P07339

[0423] • Delta C1 Early / C2Early (e.q. change between before first dose and 4 weeks after first dose): o IL-2 receptor alpha (lnterleukin-2 receptor alpha): Swiss-Prot accession number: P01589 o I L-6r (lnterleukin-6 receptor): Swiss-Prot accession number: P08887 o VCAM-1 (Vascular cell adhesion protein 1 : Swiss-Prot accession number: P19320 o PAI-1 (Plasminogen activator inhibitor-1): Swiss-Prot accession number: P05121 o TIMP-1 (TIMP metallopeptidase inhibitor 1): Swiss-Prot accession number: P01033 o IgA (Immunoglobulin A): Swiss-Prot accession number: P01876, P01877 o RANTES (regulated on activation, normal T-cell expressed and secreted): Swiss-Prot accession number: P13501 o IL-1 (lnterleukin-1 beta): Swiss-Prot accession number:P01584 CD27 (CD27 antigen): Swiss-Prot accession number: P26842 MIP-3P (Macrophage Inflammatory Protein 3 beta): Swiss-Prot accession number: Q99731 MIP-3a (Macrophage Inflammatory Protein 3 alpha): Swiss-Prot accession number: P78556 TNFR2 (Tumor necrosis factor receptor type 2): Swiss-Prot accession number: P20333 TN-C (Tenascin-C): Swiss-Prot accession number: P24821 VEGF (Vascular endothelial growth factor): Swiss-Prot accession number: P15692 Cathepsin D: Swiss-Prot accession number: P07339 BDNF (Brain-derived neurotrophic factor): Swiss-Prot accession number: P23560 MPO (Myeloperoxidase): Swiss-Prot accession number: P05164 HB-EGF (Heparin-binding EGF-like growth factor): Swiss-Prot accession number: Q99075 OPG (Osteoprotegerin): Swiss-Prot accession number: 000300 MMP-2 (matrix metalloproteinase-2): Swiss-Prot accession number: P08253 ANG-2 (Angiopoietin-2): Swiss-Prot accession number: 015123 Myoglobin: Swiss-Prot accession number: P02144 IL-16 (lnterleukin-16):Swiss-Prot accession number: Q14005 ICAM-1 (Intercellular Adhesion Molecule 1): Swiss-Prot accession number: P05362 TNF R1 (Tumor Necrosis Factor Receptor 1): Swiss-Prot accession number: P19438 IL-12p40 (Interleukin-12 subunit beta): Swiss-Prot accession number: P29460 MMP-1 (matrix metalloproteinase-1): Swiss-Prot accession number: P03956 B2M ([32 microglobulin): Swiss-Prot accession number: P61769 Tweak (Tumor necrosis factor ligand superfamily member 12): Swiss-Prot accession number: 043508 FAS (apoptosis antigen 1 ): Swiss-Prot accession number: P25445 E-Selectin: Swiss-Prot accession number: P16581 CD40 (CD 40 antigen): Swiss-Prot accession number: Q6P2H9 FRTN (ferritin): Swiss-Prot accession number: P02794, P02792 C3 (Complement component 3): Swiss-Prot accession number: P01024 PSA-f (Prostate-Specific Antigen, Free): Swiss-Prot accession number: P07288 EGFR (epidermal growth factor receptor: Swiss-Prot accession number: P00533 IL-1 Rl (Interleukin 1 receptor, type l)Swiss-Prot accession number: P14778 YKL-40 (Chitinase-3-like protein 1): Swiss-Prot accession number: P36222 IL-17 (Interleukin 17): Swiss-Prot accession number: Q16552 Eotaxin-2 (eosinophil chemotactic protein 2): Swiss-Prot accession number: 000175 IL-1 Ra (interleukin-1 receptor antagonist): Swiss-Prot accession number: P18510 ENA-78 (C-X-C motif chemokine 5): Swiss-Prot accession number: P42830 AXL (Tyrosine-protein kinase receptor UFO): Swiss-Prot accession number: P30530 MCP-4 (Monocyte chemotactic protein 4): Swiss-Prot accession number: Q99616 o MMP-3 (matrix metalloproteinase-3): Swiss-Prot accession number: P08254 o IL-8 (Interleukin 8): Swiss-Prot accession number: P10145 o HGF (Hepatocyte growth factor): Swiss-Prot accession number: P14210

[0424] • Pathway Biomarkers: o DIABLO (Diablo lAP-binding mitochondrial protein): Swiss-Prot accession number: Q9NR28 o XIAP (X-linked inhibitor of apoptosis ): Swiss-Prot accession number: P98170 o BIRC3 (baculoviral IAP repeat containing 3): Swiss-Prot accession number: Q13489 o MAP3K7 (mitogen-activated protein kinase kinase kinase 7): Swiss-Prot accession number: 043318 o CYLD (CYLD lysine 63 deubiquitinase): Swiss-Prot accession number: Q9NQC7 o BIRC2 (baculoviral IAP repeat containing 2): Swiss-Prot accession number: Q13490 o TRAF2 (TNF receptor associated factor 2): Swiss-Prot accession number: Q12933 o MAP3K14 (mitogen-activated protein kinase kinase kinase 14): Swiss-Prot accession number: Q99558 o BAX (BCL2 associated X, apoptosis regulator): Swiss-Prot accession number: Q07812 o UBE2N (ubiquitin conjugating enzyme E2 N): Swiss-Prot accession number: P61088 o IKBKB (inhibitor of nuclear factor kappa B kinase subunit beta): Swiss-Prot accession number: 014920 o HTRA2 (HtrA serine peptidase 2): Swiss-Prot accession number: 043464 o BCL2 (BCL2 apoptosis regulator): Swiss-Prot accession number: P10415 o IKBKG (inhibitor of nuclear factor kappa B kinase regulatory subunit gamma): Swiss- Prot accession number: Q9Y6K9 o BAK1 (BCL2 antagonist / killer 1): Swiss-Prot accession number: Q16611 o CASP3 (caspase 3): Swiss-Prot accession number: P42574 o RIPK1 (receptor interacting serine / threonine kinase 1): Swiss-Prot accession number: Q 13546 o BCL2L1 (BCL2 like 1 ): Swiss-Prot accession number: Q07817 o TBK1 (TANK binding kinase 1): Swiss-Prot accession number: Q9UHD2 o RIPK2 (receptor interacting serine / threonine kinase 2): Swiss-Prot accession number: 043353 o CD27 (CD27 molecule): Swiss-Prot accession number: P26842 o CYCS (cytochrome c, somatic): Swiss-Prot accession number: P99999 o BIK (BCL2 interacting killer): Swiss-Prot accession number: Q13323 o CRP (C-reactive protein): Swiss-Prot accession number: P02741 o AIFM1 (apoptosis inducing factor mitochondria associated 1): Swiss-Prot accession number: 095831 o ENDOG (endonuclease G): Swiss-Prot accession number: Q14249 o USP13 (ubiquitin specific peptidase 13): Swiss-Prot accession number: Q92995 o USP10 (ubiquitin specific peptidase 10): Swiss-Prot accession number: Q14694 o BECN1 (beclin 1 ): Swiss-Prot accession number: Q14457 o PENK (proenkephalin): Swiss-Prot accession number: P01210 o APAF1 (apoptotic peptidase activating factor 1 ): Swiss-Prot accession number: 014727 o REST (RE1 silencing transcription factor): Swiss-Prot accession number: Q13127 o HIP1 (huntingtin interacting protein 1 ): Swiss-Prot accession number: 000291 o IL-10 (interleukin 10): Swiss-Prot accession number: P22301

[0425] In some embodiments, the biomarkers are selected from IL-2Ra, IL-6r, CRP, EPO, CD27, CD40, TN-C and IL-18.

[0426] IL-2Ra, IL-6r or CRP are typically each assessed in the patient’s plasma after an off-treatment period. This is typically several weeks after, typically approximately 4 weeks after the first dose of IAP inhibitor. These markers are typically present in the patient’s plasma at a lower level in responders than in nonresponders. One or more may be assessed, with particular benefits coming form the simplicity of testing a single biomarker.

[0427] EPO, CD27, CD40, TN-C, IL-18, PLGF, TNFrl, IL-6r and MCP-4 and TECK, IL-8, Alpha-1 -Antitrypsin, IL-6R p, FRTN, and Cathepsin D are typically each assessed at baseline, i.e. before dosing the patient. These markers are typically present in the patient’s plasma at a lower level in responders than in nonresponders. One or more may be assessed, with particular benefits coming from the simplicity of testing a single biomarker.

[0428] In some embodiments, the biomarkers are selected from TN-C, IL-2Ra, Cathepsin D, CD27, 1 L-6r, MMP- 7, CRP, HGF, C3, G-CSF, VCAM-1 , ICAM-1 , haptoglobin, TNFR2, HB-EGF, IL-6, IL-1 RII, IL-1 Ra, MIP- 3 alpha, FGF-21 , PLGF, IL-10, CD40, SCF, TIMP-1 , B2M, IL-1 R1 , IL-1 beta, YKL-40, vWF, VEGF, and PARC; or TECK, PLGF, FAS, C3, MMP-2, HGF, FasL, VCAM-1 , Tweak, IL-1 ra, IL-6R beta, VEGF, 6Ckine, Haptoglobin, Eotaxin-2, MCP-1 , TRAIL-R3, PAS-f, IL-1 beta, and IL-2Ra. In some embodiments, the biomarkers are selected from IL-2Ra, VCAM-1 , PAI-1 , TIMP-1 , IgA, RANTES, IL-1 p, CD27, MIP- 3p, MIP-3a, TNFR2, TN-C, VEGF, Cathepsin D, BDNF, MPO, HB-EGF, OPG, MMP-2, ANG-2, Myoglobin, IL-16, ICAM-1 , TNF Rl, IL-12p40, MMP-1, and B2M; or Tweak, FAS, TNFR2, VCAM-1 , E- Selectin, CD40, IL-6r, MPO, FRTN, C3, CD27, PSA f, EGFR, IL-1 RI, YKL-40, IL-17, Eotaxin-2, IL-1 ra, ENA-78, AXL, MCP-4, TIMP-1 , Myoglobin, MMP-3, IL-8, MIP-3 p, IL-16, HGF, BDNF, and IL-2Ra.

[0429] In some embodiments, the biomarkers are selected from DIABLO, XIAP, BIRC3, MAP3K7, CYLD, BIRC2, TRAF2, MAP3K14, BAX, UBE2N, IKBKB, HTRA2, BCL2, IKBKG, BAK1 , CASP3, RIPK1 , BCL2L1 , TBK1 , and RIPK2; or HTRA2, CD27, CYCS, BCL2, BIK, CRP, BAK1 , AIFM1 , ENDOG, USP13, USP10, BECN1 , BCL2L1 , PENK, APAF1 , REST, HIP1 , BAX, XIAP, and IL-10.

[0430] Biomarkers and combinations

[0431] For ease of reference, the biomarkers of the disclosure may be characterised into groups: a. C2 Early, which are typically tested around 4 weeks (e.g. 26, 27, 28, 29 or 30 days, typically around 28 days) after the first dose of IAP inhibitor. b. C1 Early, which are typically assessed before administering the first dose of IAP inhibitor to the patient. c. Delta C1 Early / C2Early, _which are typically assessed before administering the first dose of IAP inhibitor to the patient and around 4 weeks (e.g. 26, 27, 28, 29 or 30 days, typically around 28 days) after the first dose of IAP inhibitor. d. Pathway Biomarkers, which were determined as described in Example 3 to identify proteins / pathways that were not directly measured in patients

[0432] In some embodiments, one biomarker is determined. This may be from group a), b), c) or d).

[0433] In some embodiments, multiple biomarkers are determined, for example 2, 3, 4, 5, 6, 7, or more biomarkers. These may comprise or consist of multiple biomarkers from a single group (i.e. group a, b or c), or may comprise or consist of one more biomarkers from one or more different groups, for example: 0, 1 , 2 or more from group a; and / or 0, 1 , 2 or more from group b), and / or 0, 1 , 2 or more from group c) and / or more or more from group d).

[0434] When multiple biomarkers are determined, the combination of biomarkers may be referred to as a biomarker panel. The biomarker panel can comprise or consist of the identified biomarkers.

[0435] In addition to the biomarkers of the invention, other biomarkers and or data, such as demographic data (e.g., age, sex) can be included in a set of data applied for the determination of suitability for IAP inhibition. When other biomarkers are optionally included, the total number of biomarkers (i.e. the biomarker panel of the invention plus other biomarkers) may be 3, 4, 5, 6 or more. In some embodiments, a predictive biomarker panel with fewer components can simplify the testing required.

[0436] The terms “loss” and “decreased” as used herein are to be given their usual meanings. The terms “increased” and “enhanced” as used herein are to be given their usual meanings.

[0437] The biomarkers can be determined by appropriate techniques that will be apparent to one skilled in the art. The biomarkers can be determined by direct or indirect techniques. Gene expression can be detected by detecting mRNA transcripts. Protein biomarkers can be detected by immunohistochemistry.

[0438] In some embodiments, depletion of one or more of the biomarkers of the invention may be determined by evaluating the function of the one or more biomarkers. The biomarker expression level may be directly proportional to the level of function. The function of the one or more biomarkers may be determined directly or indirectly.

[0439] In some embodiments, the expression or activity level can be compared to a threshold value reflecting in the same manner the expression or activity level known to be associated with sensitivity to treatment, to assess whether the tested value is indicative of sensitivity to IAP inhibition treatment in the patient.

[0440] A patient that is assessed according to the present disclosure is known or suspected to have a cancer. The sample that is tested may be known or suspected to comprise cancer cells. In typical embodiments, the sample that is tested will be a biopsy of cancer tissue. The biopsy may be a liquid biopsy or a solid tissue (e.g. solid tumour) biopsy.

[0441] Biomarker levels

[0442] The invention provides one or more biomarkers. These are typically present at a decreased level in responders than in non-responders. Typically, the level is assessed in a blood sample, typically a plasma sample

[0443] The biomarker level is typically assessed by determining the amount or concentration of the protein biomarker in the blood plasma.

[0444] In some embodiments, biomarker levels are determined and compared to the level in the same sample (e.g. plasma) from a responder and / or non-responder, i.e. to a positive and / or negative control.

[0445] In some embodiments, biomarker levels are determined and compared to the level in the sample (e.g. plasma) from the same subject at a different timepoint, i.e. before and after treatment with an IAP antagonist. In further embodiments, biomarker levels are determined relative to laboratory standards and values based on a known population value. The known levels may be taken from a non-responder or population thereof. The known levels may be taken from a responder or population thereof. The known levels may be taken from a non-responder or population thereof and from a responder or population thereof.

[0446] In some embodiments, biomarker levels are assessed relative to the level determined in samples from IAP inhibitor non-responsive subjects, or in a sample from an IAP inhibitor responsive subject.

[0447] In one embodiment, the protein level of one or more biomarkers is decreased relative to the amount of said protein in a control sample obtained from a non-responder.

[0448] In one embodiment it is decreased relative to normal levels (e.g. “Upper limit of Normal” or ULN).

[0449] In some embodiments, the level of at least one of the biomarkers is at least one standard deviation from (e.g. below) the control relative to the level of the one or more biomarkers in a sample from a tissue or person not responsive to IAP antagonism.

[0450] In some embodiments, the control for comparison is a sample obtained from a responder or non- responder. In some embodiments, the control is a historical control or standard value (i.e., a previously tested control sample or group of samples that represent baseline or normal values).

[0451] Controls or standards for comparison to a sample, for the determination of differential expression, include samples believed to represent responders or non-responders as well as laboratory values, even though possibly arbitrarily set. Laboratory standards and values may be set based on a known or determined population value and can be supplied in the format of a graph or table that permits comparison of measured, experimentally determined values.

[0452] In such embodiments, a reference score for biomarker or biomarkers is based on response or nonresponse. In another embodiment, the decreased expression is measured as a decrease or an increase in expression over time. For example, the change in level of the marker protein is measured before and after dosing with the IAP antagonist. In this embodiment, the plasma level of the marker protein is assessed before dosing the patient with the IAP antagonist and the plasma level of the marker protein is assessed three to five weeks after dosing the patient with the IAP antagonist, typically approximately four weeks after dosing the patient. The level before and after dosing is compared. The change in level may be compared between responders and non-responders.

[0453] IAP family

[0454] The family of inhibitor of apoptosis (IAP) proteins comprises 8 members, XIAP, clAP1 , clAP2, NAIP, ILP2, ML-IAP, survivin and BRUCE (also known as apollon). Members of the IAP family have been shown to inhibit programmed cell death through their ability to directly inhibit members of the caspase family of apoptotic enzymes, although the precise role of all 8 members is yet to be fully defined. The common structural feature of all IAP family members is a ~70 amino acid zinc-binding fold termed the baculovirus IAP repeat (BIR) domain, which is present in one to three copies.

[0455] Many interactions between lAPs and other proteins are mediated via a surface groove on the BIR domain. BIR domains may be classified by their peptide-binding specificity. There are three types of BIR domains; type III domains (capable of binding caspase (and caspase-like) peptides with a specificity for proline in the third (P3) position (e.g. XIAP BIR3), type II domains (like type III domains but lacking the proline requirement e.g. XIAP BIR2) and type I domains (which do not bind caspases or similar peptides, e.g. XIAP BIR1 ) (Eckelman et al. Cell Death and Differentiation 2008; 15: 920-928). BIRs are small (~70 amino acids) Zn-coordinated domains and a variety of proteins use their N-terminal to interact with the BIR domains grooves. BIR antagonists prevent caspases binding to BIRs and hence result in increased caspase activity thereby inducing auto-ubiquitination and proteasomal degradation of lAPs. lAPs are overexpressed in many cancers including renal, melanoma, colon, lung, breast, ovarian and prostate cancers (Tamm et al., Clin. Cancer Research 2000; 6(5): 1796-803), and have been implicated in tumour growth, pathogenesis and resistance to chemo- and radio-therapy (Tamm 2000).

[0456] XIAP

[0457] XIAP is a 57kDa protein with three BIR domains, the second and third of which bind caspases and a RING-type zinc finger (E3 ligase). XIAP binds several proteins in addition to caspases, including ligation substrates such as TAK1 and cofactor TAB1 , MURR1 involved in copper homeostasis (Burstein et al., EMBO 2004; 23: 244-254), endogenous inhibitors such as second mitochondria-derived activator of caspases (SMAC), and those of less clear function such as MAGE-D1 , NRAGE (Jordan et al., J. Biol. Chem. 2001 ; 276: 39985-39989).

[0458] The BIR3 domain binds and inhibits caspase-9, an apical caspase in the mitochondrial pathway of caspase activation. A groove on the surface of the BIR3 domain interacts with the N-terminus of the small subunit of caspase-9, locking capsase-9 in its inactive monomeric form with an incompetent catalytic site (Shiozaki et al., Mol. Cell 2003; 11 : 519-527).

[0459] In addition to caspase-binding, XIAP also inhibits apoptosis through other mechanisms. XIAP forms a complex with TAK1 kinase and its cofactor TAB1 that leads to activation of JNK and MAPK signal transduction pathways, in turn leading to activation of NF-KB (Sanna et al., Mol Cell Biol 2002; 22: 1754- 1766). XIAP also activates NF-KB by promoting NF-KB translocation to the nucleus and degradation of IKB (Hofer-Warbinek et al., J. Biol. Chem. 2000; 275: 22064-22068, Levkau et al., Circ. Res. 2001 ; 88: 282-290).

[0460] Cells transfected with XIAP are able to block programmed cell death in response to a variety of apoptotic stimuli (Duckett et al., EMBO 1996; 15: 2685-2694, Duckett et al., MCB 1998; 18: 608-615, Bratton, Lewis, Butterworth, Duckett and Cohen, Cell Death and Differentiation 2002; 9: 881-892).

[0461] XIAP is ubiquitously expressed in all normal tissues, but it is pathologically elevated in many acute and chronic leukaemias, prostate, lung, renal, and other types of tumours (Byrd et al., 2002; Ferreira et al., 2001 ; Hofmann et al., 2002; Krajewska et al., 2003; Schimmer et al., 2003; Tamm et al., 2000). In de novo acute myeloid leukaemia (AML), XIAP expression correlates with myelomonocytic French- American-British (FAB) subtypes M4 / M5 (P < 0.05) and expression of monocytic markers in AML blasts. In addition, XIAP was found to be overexpressed in normal monocytes but undetectable in granulocytes. In AML, XIAP expression was significantly lower in patients with favourable rather than intermediate or poor cytogenetics (n = 74; P < 0.05) (Tamm et al., HematoL J. 2004; 5(6): 489-95).

[0462] Overexpression renders cells resistant to multi-agent therapy and is associated with poor clinical outcome in disease including AML, renal cancer, melanoma (Tamm et al., Clin. Cancer Research 2000; 6: 1796-1803) and lung cancer (Hofmann et al., J. Cancer Res. Clin. Oncology 2002; 128(10): 554-60).

[0463] XIAP is translated by a cap-independent mechanism of translation initiation that is mediated by a unique internal ribosome entry site (IRES) sequence element located in its 5' untranslated region. This allows XIAP mRNA to be actively translated during conditions of cellular stress when the majority of cellular protein synthesis is inhibited. Translational upregulation of XIAP in response to stress increases resistance to radiation induced cell death (Holcik et al., Oncogene 2000; 19: 4174-4177).

[0464] XIAP inhibition has been investigated in vitro via several techniques including RNA silencing, gene knockout, peptidic ligand mimetics and small molecule antagonists, and has been shown to promote apoptosis as a monotherapy and to sensitise many tumour types to chemotherapy, including bladder (Kunze et al., 2008; 28(4B): 2259-63). XIAP knockout mice are born at the expected Mendelian frequency, with no obvious physical or histological defects, and normal life spans (Harlin et al., Mol. Cell Biol. 2001 ; 21 (10): 3604-3608). This indicates that lacking XIAP activity is not toxic in normal tissues and suggests a therapeutic window over tumour cells. Further studies have shown XIAP is a critical discriminator between apoptosis in type 1 and type 2 cells including hepatocytes and therefore should be used with caution in patients with underlying liver conditions (Jost et al., Nature, 2009, 460, 1035- 1041 ). It was noted that the clAP1 and clAP2 levels are upregulated in the XIAP knockout mouse and may protect from pathology via a compensatory mechanism, suggesting pan-inhibition may be required for functional knockout. Similarly, clAP1 and clAP2 knockout mice are also asymptomatic (Conze et al., Mol. Biol. Cell 2005; 25(8): 3348-56). While lack of any one of the lAPs produced no overt phenotype in mice, deletion of clAP1 with c!AP2 or XIAP resulted in mid embryonic lethality (Moulin, EMBO J., 2012).

[0465] Endogenous IAP antagonists such as SMAC have been used to validate members of this family as targets for therapeutic agents. SMAC peptides chemosensitise tumour cells, and in combination with platins and Tumour Necrosis Factor a-related apoptosis inducing ligand (TRAIL) in xenografts, results in tumour growth delay (Fulda et al., Nat. Med. 2002; 808-815; Yang et al., Cancer Res. 2003; 63: 831- 837).

[0466] A natural product, embellin, was identified as binding at the surface groove of the BIR3 domain of XIAP with similar affinity to the natural SMAC peptide. Embellin induces apoptosis in cell lines in vitro and results in tumour growth delay in xenografts (Nikolovska-Coleska et al., J. Med. Chem. 2004; 47(10): 2430-2440; Chitra et al., Chemotherapy 1994; 40: 109-113).

[0467] XIAP antisense oligonucleotides have been developed as therapeutic agents for solid tumour and haematological malignancies. In vitro these antisense oligonucleotides have been shown to knockdown protein expression levels by -70%, induce apoptosis and sensitise cells to chemotherapy and delay tumour growth in vivo. One of these agents, AEG351156, has been studied in clinical trials (Hu et al., Clin. Cancer Res. 2003; 9: 2826-2836; Cummings et al., Br. J. Cancer 2005; 92: 532-538).

[0468] Small molecule antagonists of XIAP developed include peptidomimetics as well as synthetic agents. The peptidomimetics target the BIR3 domain, mimicking SMAC disruption of caspase-9 binding to XIAP, have shown induction of apoptosis in a variety of tumour cell lines as a single agent, as well as chemosensitisers and are being further investigated clinically (Oost et al., J. Med. Chem. 2004; 47: 4417-4426; Sun et al., Bioorg. Med. Chem. Lett. 2005; 15: 793-797).

[0469] Synthetic small molecule antagonists of BIR3 and BIR2 domains also demonstrate anti-tumour activity in several different models, including induction of apoptosis by annexin-V staining and IC50s of <10pM against over one-third of the NCI60 cell line panel. XIAP antagonists also induced dose-dependent cell death of primary-cultured leukaemia cells in 5 out of 5 chronic lymphocytic leukaemia cell lines and 4 out of 5 acute myeloid leukaemia cell lines (Schimmer et al., Cancer Cell 2004; 5: 25-35; Berezovskaya et al., Cancer Res. 2005; 65(6): 2378-86).

[0470] High levels of XIAP protein in tumour cell lines were inversely correlated with sensitivity to some anticancer drugs, particularly cytarabine and other nucleosides (Tamm et al., Clin. Cancer Research 2000; 6: 1796-1803). XIAP inhibition potentiates TRAIL-induced antitumor activity in two preclinical models of pancreatic cancer in vivo (Vogler 2008). Gene expression and transfection studies suggest that the increased expression of apoptosis suppressor XIAP plays an important role in anoikis resistance and in the survival of circulating human prostate carcinoma cells, thereby promoting metastasis. Small molecule antagonists were found to be anti-metastatic in these models (Berezovskaya et al., Cancer Res. 2005; 65(6): 2378-86). XIAP has also been found to be involved in other pathways associated with cancer and other diseases and these may also benefit from XIAP targeted agents. The E3 ligase activity of the RING finger domain of XIAP is able to bind both to TAB1 and to an upstream BMP receptor (type 1 ), suggesting that XIAP may signal in a TGF-p-mediated pathway (Yamaguchi et al., EMBO 1999; 179-187). Focal adhesion kinase (FAK) overexpression has been shown to result in upregulated XIAP expression (Sonoda et al., J. Biol. Chem. 2000; 275: 16309-16315). E3 ligases are attractive therapeutic targets and molecules which target this activity in other proteins such as MDM2 are being developed (Vassilev et al., Science 2004; 303: 844-848). Direct or indirect inhibition of the XIAP ligase activity may also be useful in the treatment of cancer and other diseases. Dysregulated apoptotic signalling, which would result from inhibition of IAP function in controlling programmed cell death, has also been implicated in many diseases, including disorders associated with cell accumulation (e.g. cancer, autoimmunity, inflammation and restenosis) or disorders where excessive apoptosis results in cell loss (e.g. stroke, heart failure, neurodegeneration such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, AIDS, ischaemia (stroke, myocardial infarction) and osteoporosis).

[0471] XIAP is an important apoptotic regulator in experimental autoimmune encephalomyelitis and a potential pharmacological target for treating autoimmune diseases such as multiple sclerosis (MS) (Moore et al., 2004; 203(1 ): 79-93). Antisense-mediated knockdown of XIAP reverses paralysis in an animal model of MS suggesting that treatments targeting XIAP, and perhaps other lAPs, may have utility in the treatment of MS (Hebb et al., Curr. Drug Disc. Tech. 2008; 5(1 ): 75-7). clAP1 , clAP-2, XIAP and survivin are overexpressed in malignant pleural mesothelioma and are responsible for a large degree of the resistance of cultured mesothelioma cells to cisplatin. Levels of circulating TNF-ct are significantly higher in mesothelioma patients prior to surgical tumor debulking compared with those after surgery. TNF-a increases mRNA and protein levels of IAP-1 , IAP-2 and XIAP (Gordon et al., 2007). NF-KB upregulation plays an important survival role in mesotheliomas in response to the inflammatory effects of exposure to asbestos fibres (Sartore-Bianchi et al., 2007). IAP antagonists have the potential to reverse the pro-survival effect of TNF-a.

[0472] The ability of cell lines to upregulate TNF-alpha expression sufficiently to act in an autocrine fashion and kill the cells, once clAP1 & 2 are depleted, is believed to be important for IAP activity (Nature Reviews Cancer (2010), 10(8), 561-74, Gryd-Hansen, M). In vivo, however, certain tumour types are surrounded by a pro-inflammatory cytokine network and hence the tumour cells which, on depletion of clAP1 / 2 are switched towards cell killing by apoptosis, may be triggered to apoptose by TNF-alpha (or other Death Receptor cytokine agonists) already being produced by surrounding cells in the tumour microenvironment, such as tumour-associated macrophages, or indeed by the tumour cells themselves. Certain tumour types such as breast, ovarian and melanoma display this "inflammatory phenotype" which could potentially be targeted by IAP antagonists. clAP1 and clAP2

[0473] Cellular IAP (clAP) 1 and 2 are closely related members of the IAP family with three BIR domains, a RING domain and a caspase-recruitment (CARD) domain. A functional nuclear export signal exists within the CARD domain of clAP1 which appears to be important for cell differentiation (Plenchette et al., Blood 2004; 104: 2035-2043). The presence of this CARD domain is unique to clAP1 and clAP2 within the IAP family of proteins. These two genes reside in tandem on chromosome 11 q22 and given their high degree of similarity are thought to have arisen via gene duplication. clAP1 , like XIAP and survivin, is widely expressed in tumour cell lines, and has been found to be expressed at high levels in colorectal cancers in particular, as well as lung, ovarian, renal, CNS and breast cancers (Tamm et al., Clin. Cancer Res. 2000; 6: 1796-1803). clAP2 expression is generally more restricted and is thought to be regulated though constitutive ubiquitination and degradation by clAP1 (Conze et al., Mol. Biol. Cell 2005; 25(8): 3348-56; Mahoney et al., PNAS 2008; 105: 11778- 11783). Immunohistochemistry and western blot analysis identified clAP1 and clAP2 as potential oncogenes as both are overexpressed in multiple lung cancers with or without higher copy numbers (Dia et al., Human Mol. Genetics 2003; 12(7): 791 -801 ). clAP1 expression level preferentially seems to play an important role in low-stage adenocarcinoma (Hofmann et al., J. Cancer Res. Clin. Oncology 2002; 128(10): 554-60).

[0474] Increased levels of clAP1 and clAP2 and reduced levels of endogenous inhibitors are associated with chemoresistance as has been seen for XIAP. clAP overexpression has been found to correlate in vitro to resistance to DNA alkylating agents such as carboplatin, cisplatin and topoisomerase inhibitor VP-16 (Tamm et al., Clin. Cancer Res. 2000; 6: 1796-1803). Levels of clAP1 and survivin were found to be high in thyroid cancer cells after cisplatin and doxorubicin treatment. Cells resistant to chemotherapy such as taxol showed reduced expression of SMAC and released minimal amounts of this protein from the mitochondria. Down-regulation of clAP1 and survivin has been found to increase the cytotoxicity of cisplatin and doxorubicin, whereas overexpression of SMAC improved the efficacy of taxol. However, silencing of clAP1 and survivin by RNA interference restored sensitivity to doxorubicin and cisplatin (Tirrb et al.; Cancer Res. 2006; 66(8): 4263-72).

[0475] SMAC mimetics such as LBW242 were originally thought to primarily target XIAP. However studies have shown that clAP1 was targeted for degradation by autoubiquitination in cells (Yang et al., J. Biol. Chem. 2004; 279(17): 16963-16970) and may have contributed to the apoptotic effects that resulted. SiRNA of clAP1 and Tumour Necrosis Factor (TNF)-alpha induction (or stimulation) were found to combine synergistically and render cell lines more sensitive (Gaither et al. Cancer Res. 2007; 67 (24): 11493- 11498). clAP1 and clAP2 have been demonstrated to be critical regulators of the NF-KB signalling pathway which is involved in a diverse range of biological processes, particularly in innate and adaptive immunity as well as in proliferation and survival. NF- B pathway deregulation is associated with inflammation and cancers including hepatitis and ulcerative colitis, gastritis, hepatocellular carcinoma colorectal cancer and gastric cancers, as well as angiogenesis and metastasis (Shen et al., Apoptosis 2009; 14: 348-363).

[0476] On ligand binding, the TNF Receptor (TNF-R) recruits TNFR-associated Death Domain (TRADD) and receptor-interacting protein (RIP) 1. TRAF2 and clAP1 / clAP2 are then recruited to form a large membrane complex. RIP1 is ubiquitinated and these polyubiquitin chains serve as a docking site for downstream kinases, resulting in NF-KB pathway signalling effects (Ea et al., Mol. Cell 2006; 22: 245- 257; Wu et al., Nat. Cell Biol. 2006; 8: 398-406). The extended roles are complex and yet to be fully defined but clAP1 and clAP2 are identified as key components of TNF-alpha mediated NF-KB signalling regulation as well as constitutive (ligand-independent / classical) NF-KB signalling (Varfolomeev et al., Cell 2007; 131 (4): 669-81 ). clAP1 and clAP2 have been shown to bind TRAF2, an adapter protein that functions in both the classical and alternative NF-KB pathways as well as MAPK pathway signalling pathway (Rothe et al., Cell 2005; 83: 1243-1252). clAP1 and clAP2 directly target RIP1 for ubiquitination in vitro (Betrand et al., Mol. Cell 2008; 30: 689-700).

[0477] TNF-alpha regulates many cellular functions, including apoptosis, inflammation, immune response, and cell growth and differentiation (Trace et al., Annu. Rev. Med. 1994; 45: 491-503) and therapeutic IAP antagonists may be of benefit in conditions where these functions are affected.

[0478] Production of TNF-alpha is seen in many malignant tumours, and is one of the key drivers of cancer- related inflammation that drives tumour development and / or progression. clAPs protect cancer cells from the lethal effects of TNF-alpha.

[0479] NAIP

[0480] NAIP was the first IAP to be discovered (Roy et al., Cell 1995; 80: 167-178). NAIP is unique among the lAPs in that it possesses a nucleotide-binding and oligomerisation domain, as well as leucine rich repeats which are similar to those contained in proteins normally involved in innate immunity. There are indications that NAIP may also be over expressed in some cancers including breast and oesophageal cancer (Nemoto et al., Exp. Mol. Pathol. 2004; 76(3): 253-9) as well as MS (Choi et al., J. Korean Med. 2007; 22 Suppl: S17-23; Hebb et al., Mult. Sclerosis 2008; 14(5): 577-94).

[0481] ML-IAP

[0482] Melanoma inhibitor of apoptosis protein (ML-IAP) contains a single BIR and RING finger motif. ML-IAP is a powerful inhibitor of apoptosis induced by death receptors and chemotherapeutic agents, probably functioning as a direct inhibitor of downstream effector caspases (Vucic et al., Curr. Biol. 2000; 10(21 ): 1359-66). ML-IAP is also known as Baculoviral IAP repeat-containing protein 7 (BIRC7), Kidney inhibitor of apoptosis protein (KIAP), RING finger protein 50 (RNF50) and Livin. The BIR domain of ML-IAP possesses an evolutionarily conserved fold that is necessary for anti-apoptotic activity. It has been found that the majority of melanoma cell lines express high levels of ML-IAP in contrast to primary melanocytes, which expressed undetectable levels. These melanoma cells were significantly more resistant to drug- induced apoptosis. Elevated expression of ML-IAP renders melanoma cells resistant to apoptotic stimuli and thereby potentially contributes to the pathogenesis of this malignancy.

[0483] ILP-2

[0484] ILP-2, also known as BIRC8, has a single BIR domain and a RING domain. ILP-2 is expressed only in testis in normal cells, and binds to caspase 9 (Richter et al, Mol. Cell. Biol. 2001 ; 21 : 4292-301 ). Survivin

[0485] Survivin, also known as BIRC5, inhibits both caspase 3 and caspase 7, but its primary function is mitotic progression regulation, rather than the regulation of apoptosis. Survivin promotes formation of microtubules in the mitotic spindle, counteracting apoptosis during cell cycle. Apoptosis inhibition by survivin is predictive of poor outcome in colorectal cancer (Kawasaki et al., Cancer Res. 1998; 58(22): 5071-5074) and stage III gastric cancer (Song et al, Japanese J. Clin. Oncol. 2009; 39(5): 290-296).

[0486] BRUCE

[0487] BRUCE (BIR repeat-containing ubiquitin-conjugating enzyme) is a peripheral membrane protein in the trans-Golgi network with a single BIR domain, most similar to that of survivin. BRUCE is inhibited via three mechanisms: (i) SMAC binding, (ii) HtrA2 protease and (iii) caspase-mediated cleavage. In addition, BRUCE acts as a E2 / E3 ubiquitin ligase via ubiquitin-conjugating (UBC) domain.

[0488] IAP ANTAGONISTS

[0489] IAP antagonists are known in the art. Any suitable IAP antagonist can be used according to the present disclosure.

[0490] Known IAP antagonists include, but are not limited to:

[0491] Xevinapant (AT-406, Debio-1143)

[0492] Dasminapant (APG-1387)

[0493] BGB-24714 (BeiGene)

[0494] Birinapant (IGM-9427)

[0495] BI-891065 (Boehringer Ingelheim)

[0496] LCL-161 (Novartis)

[0497] GDC-0152 (RG-7419) (Roche / Genentech)

[0498] HGS-1029 (AEG-40826) (Aegera / HGS)

[0499] CUDC-427 (GDC-0917 / RG7459) (Curis)

[0500] CUDC-427 (GDC-0917 / RG7459)

[0501] Birinapant (TL-32711 )

[0502] ASTX-660 (tolinapant)

[0503] TQB-3728 (Chia Tai Tianging Pharmaceutical Group)

[0504] In certain embodiments, the IAP antagonist is Debio 1 143, LCL161 or Birinapant.

[0505] In one embodiment the IAP antagonist is LCL-161 (Novartis), Debio-1143 (Debiopharma I Ascenta), AZD5582, Birinapant / TL-32711 (TetraLogic), CUDC-427 / GDC-0917 / RG-7459 (Genentech), JP1201 (Joyant), T-3256336 (Takeda), GDC-0152 (Genentech) or HGS-1029 / AEG-40826 (HGS / Aegera).

[0506] In one embodiment the IAP antagonist is ASTX660, LCL-161 (Novartis), Debio-1143 (Debiopharma I Ascenta), AZD5582, Birinapant I TL-32711 (TetraLogic), CUDC-427 / GDC-0917 I RG-7459 (Genentech), JP1201 (Joyant), T-3256336 (Takeda), GDC-0152 (Genentech), HGS-1029 / AEG-40826 (HGS / Aegera), Debio-4028 or Ascentage IAP inhibitor, APG-1387. Particularly suitable IAP antagonists are described in WO-A-2015 / 092420, which is incorporated by reference in its entirety for all purposes.

[0507] In one embodiment the IAP antagonist is ASTX660 (tolinapant).

[0508] Tolinapant is described in U.S. Patent No. 9,783,538 and has a structure as follows: and is named 1-(6-(4-fluorobenzyl)-5-(hydroxymethyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2- b]pyri.din-1-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)ethan-1-one (or alternatively 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2- b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one).

[0509] Examples of IAP antagonists

[0510] In one embodiment the IAP antagonist is an agent that modulates IAP, for example, a small molecule, antisense nucleic acid, antibody or nucleic acid that inhibits expression of IAP. In one embodiment the IAP agent is a small molecule. In one embodiment the IAP agent is a small molecule as detailed herein.

[0511] In some embodiments, the IAP antagonist antagonises the cellular inhibitor of apoptosis proteins clAPI / 2. In some embodiments, the IAP antagonist antagonises the X-linked inhibitor of apoptosis proteins (XIAP). In some embodiments, the IAP antagonist antagonises the cellular and X-linked inhibitors of apoptosis proteins (clAP1 / 2 and XIAP).

[0512] In some embodiments, the IAP antagonist is non-peptidomimetic.

[0513] In some embodiments, the IAP antagonist is a non-peptidomimetic antagonist of the cellular and X- linked inhibitors of apoptosis proteins (clAP1 / 2 and XIAP).

[0514] In some embodiments, the IAP antagonist is a compound of formula (I). The compounds of formula (I) may be antagonists of the IAP family of proteins (IAP), and especially XIAP, and / or clAP (such as clAP1 and / or clAP2) and may be useful in the treatment of lAP-mediated conditions.

[0515] In some embodiments, the IAP antagonist is a compound of formula (I):

[0516] or a tautomeric or a stereochemicaliy isomeric form, a pharmaceutically acceptable salt or a solvate thereof; wherein

[0517] X is CR4, N or NR3; wherein

[0518] ■ when X is CR4, then U represents nitrogen and R6represents oxo; or

[0519] ■ when X is N, then U represents carbon and R6represents hydroxymethyl or - CH(ORX)CH2ORZ; or

[0520] • when X is NR3, then U represents carbon and R6represents oxo; dashed bond ( - ) represents a single or double bond wherein at least two of said dashed bonds represent a double bond;

[0521] R1and R2independently represent hydrogen or methyl;

[0522] R3represents hydrogen, methyl or -NH2;

[0523] R4represents hydrogen, methyl, hydroxymethyl, -NH2or fluorine;

[0524] R5represents unsubstituted n-butyl or benzyl substituted on the phenyl group by one or two fluorines; and

[0525] Rxand Rzindependently represent hydrogen or methyl.

[0526] It will be understood from formula (I) that the compounds of the invention can be represented as follows: wherein Q represents any of A, B or C below:

[0527]

[0528] In one embodiment Q represents A. In one embodiment Q represents B. In one embodiment Q represents C.

[0529] In one embodiment, X represents CR4or N. In an alternative embodiment, X represents CR4or NR3. In an alternative embodiment, X represents N or NR3. In a further embodiment, X represents CR4. In a further alternative embodiment, X represents N. In a yet further alternative embodiment, X represents NR3.

[0530] In one embodiment, one of R1and R2represents hydrogen and the other represents methyl, or R1and R2both represent hydrogen. In one embodiment, one of R1and R2represents hydrogen and the other represents methyl. In a further embodiment, R1represents methyl and R2represents hydrogen. In an alternative embodiment, R1represents hydrogen and R2represents methyl. In a further alternative embodiment, R1and R2both represent hydrogen.

[0531] In one embodiment, R3represents hydrogen or methyl. In an alternative embodiment, R3represents hydrogen or -NH2. In a further alternative embodiment, R3represents methyl or -NH2. In a further embodiment, R3represents hydrogen. In a further alternative embodiment, R3represents methyl. In a yet further alternative embodiment, R3represents -NH2.

[0532] In one embodiment, R4represents hydrogen or methyl. In a further embodiment, R4represents hydrogen In an alternative embodiment, R4represents methyl.

[0533] In one embodiment, R5represents unsubstituted n-butyl or benzyl substituted by one or two fluorines on the 2, 3 and / or 4 positions of the phenyl group. In one embodiment, R5represents unsubstituted n- butyl. In an alternative embodiment, R5represents benzyl substituted on the phenyl group by one or two fluorines. In a further embodiment, R5represents benzyl substituted by one or two fluorines on the 2, 3 and / or 4 positions of the phenyl group. In a further embodiment, R5represents benzyl substituted by one fluorine on the 2, 3 or 4 position of the phenyl group (i.e. R5represents 2-fluorobenzyl, 3-fluorobenzyl or 4-fluorobenzyl). In a further embodiment, R5represents benzyl substituted by one fluorine on the 4 position of the phenyl group (i.e. R5represents 4-fluorobenzyl). In a further embodiment, R5represents benzyl substituted by two fluorines on the 2,3, 3,4 or 2,4 positions of the phenyl group (i.e. R5represents 2,3-difluorobenzyl, 3,4-difluorobenzyl or 2,4-difluorobenzyl). In a yet further embodiment, R5represents benzyl substituted by two fluorines on the 2,4 positions of the phenyl group (i.e. R5represents 2,4- difluorobenzyl).

[0534] In a further embodiment, R5represents unsubstituted n-butyl, 4-fluorophenyl or 2,4-difluorophenyl. In a yet further embodiment, R5represents 4-fluorophenyl.

[0535] In one embodiment R6represents hydroxymethyl or -CH(ORX)CH2ORZ. In one embodiment R6represents hydroxymethyl.

[0536] In one embodiment R6represents -CH(ORX)CH2ORZ. In one embodiment, one of Rxand Rzrepresents hydrogen and the other represents methyl or Rxand Rzboth represent hydrogen. In a further embodiment, Rxrepresents methyl and Rzrepresents hydrogen. In an alternative embodiment, Rxrepresents hydrogen and Rzrepresents methyl. In a further alternative embodiment, Rxand Rzboth represent hydrogen. In a further embodiment, Rxrepresents hydrogen or methyl and Rzrepresents hydrogen. In a further alternative embodiment, Rxand Rzboth represent methyl.

[0537] In one embodiment, R6represents hydroxymethyl, -CH(OH)CH2OH, -CH(OMe)cH2OH or - CH(OH)CH2OMe. In a further embodiment, R6represents hydroxymethyl, -cH(OH)CH2OH or - CH(OMe)CH2OH. In a yet further embodiment, R6represents hydroxymethyl.

[0538] In one embodiment R6represents oxo (i.e. =0).

[0539] Sub-Formulae

[0540] In one embodiment the compound of formula (I) is wherein:

[0541] X is CR4, N or NR3; wherein

[0542] • when X is CR4, then U represents nitrogen and R6represents oxo; or

[0543] • when X is N, then U represents carbon and R6represents hydroxymethyl or -CH(ORX)CH2ORZ; or

[0544] • when X is NR3, then U represents carbon and R6represents oxo; dashed bond ( - ) represents a single or double bond wherein at least two of said dashed bonds represent a double bond; one of R1and R2represents hydrogen and the other represents methyl or R1and R2both represent hydrogen;

[0545] R3represents hydrogen, methyl or -NH2;

[0546] R4represents hydrogen or methyl;

[0547] R5represents unsubstituted n-butyl or benzyl substituted by one or two fluorines on the 2, 3 and / or 4 positions of the phenyl group; and one of Rxand Rzrepresents hydrogen and the other represents methyl or Rxand Rzboth represent hydrogen.

[0548] In a further embodiment the compound of formula (I) is wherein:

[0549] X is CR4, N or NR3; wherein

[0550] ’ when X is CR4, then U represents nitrogen and R6represents oxo; or

[0551] • when X is N, then U represents carbon and R6represents hydroxymethyl or -CH(ORX)CH2ORZ; or

[0552] ’ when X is NR3, then U represents carbon and R6represents oxo; dashed bond ( - ) represents a single or double bond wherein at least two of said dashed bonds represent a double bond; one of R1and R2represents hydrogen and the other represents methyl or R1and R2both represent hydrogen;

[0553] R3represents hydrogen, methyl or -NH2;

[0554] R4represents hydrogen or methyl;

[0555] R5represents unsubstituted n-butyl, 4-fluorobenzyl or 2,4-fluorobenzyl;

[0556] Rxrepresents hydrogen or methyl; and

[0557] Rzrepresents hydrogen.

[0558] In one embodiment, the compound of formula (I) is a compound of formula (la):

[0559] (la) or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof; wherein R1, R2, R4and R5are as defined in any of the embodiments.

[0560] In one embodiment of the compound of formula (la), one of R1and R2represents hydrogen and the other represents methyl or R1and R2both represent hydrogen. In a further embodiment of the compound of formula (la), R1represents hydrogen and R2represents methyl or R1and R2both represent hydrogen.

[0561] In a further embodiment of the compound of formula (la), R1represents methyl and R2represents hydrogen. In an alternative embodiment of the compound of formula (la), R1represents hydrogen and R2represents methyl. In one embodiment of the compound of formula (la), R4represents hydrogen or methyl.

[0562] In one embodiment of the compound of formula (la), R5represents unsubstituted n-butyl or benzyl substituted by one or two fluorines on the 2, 3 and / or 4 positions of the phenyl group. In one embodiment of the compound of formula (la), R5represents unsubstituted n-butyl. In an alternative embodiment of the compound of formula (la), R5represents benzyl substituted on the phenyl group by one or two fluorines. In a further embodiment of the compound of formula (la), R5represents benzyl substituted by one or two fluorines on the 2, 3 and / or 4 positions of the phenyl group. In a further embodiment of the compound of formula (la), R5represents benzyl substituted by one fluorine on the 4 position of the phenyl group (i.e. R5represents 4-fluorobenzyl). In a further embodiment of the compound of formula (la), R5represents benzyl substituted by two fluorines on the 2,4 positions of the phenyl group (i.e. R5represents 2,4-difluorobenzyl).

[0563] In one embodiment, the compound of formula (I) is a compound of formula (lb):

[0564] (lb) or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof; wherein R1, R2, R5, R6, Rxand Rzare as defined in any of the embodiments. In one embodiment Rsrepresents hydroxymethyl or -CH(ORX)CH2ORZ.

[0565] In one embodiment of the compound of formula (lb), R1represents methyl and R2represents hydrogen or R1and R2both represent hydrogen.

[0566] In a further embodiment of the compound of formula (lb), R1and R2both represent hydrogen.

[0567] In one embodiment of the compound of formula (lb), R5represents unsubstituted n-butyl or benzyl substituted by one or two fluorines on the 2, 3 and / or 4 positions of the phenyl group. In one embodiment of the compound of formula (lb), R5represents unsubstituted n-butyl. In an alternative embodiment of the compound of formula (lb), R5represents benzyl substituted on the phenyl group by one or two fluorines. In a further embodiment of the compound of formula (lb), R5represents benzyl substituted by one or two fluorines on the 2, 3 and / or 4 positions of the phenyl group. In a further embodiment of the compound of formula (lb), R5represents benzyl substituted by one fluorine on the 2, 3 or 4 position of the phenyl group (i.e. R5represents 2-fluorobenzyl, 3-fluorobenzyl or 4-fluorobenzyl). In a further embodiment of the compound of formula (lb), R5represents benzyl substituted by two fluorines on the 2,4 positions of the phenyl group (i.e. R5represents 2,4-difluorobenzyl). In a yet further embodiment of the compound of formula (lb), R5represents benzyl substituted by one fluorine on the 4 position of the phenyl group (i.e. R5represents 4-fluorobenzyl).

[0568] In one embodiment of the compound of formula (lb), R6represents hydroxymethyl, -CH(OH)CH2OH, - CH(OMe)cH2OH or -CH(OH)CH2OMe.

[0569] In a further embodiment of the compound of formula (lb), R6represents hydroxymethyl, -cH(OH)CH2OH or -CH(OMe)CH2OH.

[0570] In a yet further embodiment of the compound of formula (lb), R6represents hydroxymethyl.

[0571] In one embodiment, the compound of formula (I) is a compound of formula (Ic):

[0572] (Ic) or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof; wherein R1, R2, R3and R5are as defined in any of the embodiments.

[0573] In one embodiment of the compound of formula (Ic), one of R1and R2represents hydrogen and the other represents methyl or R1and R2both represent hydrogen. In a further embodiment of the compound of formula (Ic), R1represents methyl and R2represents hydrogen or R1and R2both represent hydrogen.

[0574] In one embodiment of the compound of formula (Ic), R3represents hydrogen or methyl. In an alternative embodiment of the compound of formula (Ic), R3represents hydrogen or -NH2. In a further alternative embodiment of the compound of formula (Ic), R3represents methyl or -NH2. In a further embodiment of the compound of formula (Ic), R3represents hydrogen. In a further alternative embodiment of the compound of formula (Ic), R3represents methyl. In a yet further alternative embodiment of the compound of formula (Ic), R3represents -NH2.

[0575] In one embodiment of the compound of formula (Ic), R5represents unsubstituted n-butyl or benzyl substituted by one or two fluorines on the 2, 3 and / or 4 positions of the phenyl group. In one embodiment of the compound of formula (Ic), R5represents unsubstituted n-butyl. In an alternative embodiment of the compound of formula (Ic), R5represents benzyl substituted on the phenyl group by one or two fluorines. In a further embodiment of the compound of formula (Ic), R5represents benzyl substituted by one or two fluorines on the 2, 3 and / or 4 positions of the phenyl group. In a further embodiment of the compound of formula (Ic), R5represents benzyl substituted by one fluorine on the 2 or 4 position of the phenyl group (i.e. R5represents 2-fluorobenzyl or 4-fluorobenzyl). In a further embodiment of the compound of formula (Ic), R5represents benzyl substituted by one fluorine on the 4 position of the phenyl group (i.e. R5represents 4-fluorobenzyl). In a further embodiment of the compound of formula (Ic), R5represents benzyl substituted by two fluorines on the 2,4 positions of the phenyl group (i.e. R5represents 2,4-difluorobenzyl).

[0576] In one embodiment, the compound of formula (I) is a compound of formula (Id):

[0577] (Id) or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof; wherein R5is as defined in any of the embodiments.

[0578] In one embodiment of the compound of formula (Id), R5represents unsubstituted n-butyl or benzyl substituted by one or two fluorines on the 2, 3 and / or 4 positions of the phenyl group. In one embodiment of the compound of formula (Id), R5represents unsubstituted n-butyl. In an alternative embodiment of the compound of formula (Id), R5represents benzyl substituted on the phenyl group by one or two fluorines. In a further embodiment of the compound of formula (Id), R5represents benzyl substituted by one or two fluorines on the 2, 3 and / or 4 positions of the phenyl group. In a further embodiment of the compound of formula (Id), R5represents benzyl substituted by one fluorine on the 2, 3 or 4 position of the phenyl group (i.e. R5represents 2-fluorobenzyl, 3-fluorobenzyl or 4-fluorobenzyl). In a further embodiment of the compound of formula (Id), R5represents benzyl substituted by two fluorines on the 2,4 positions of the phenyl group (i.e. R5represents 2,4-difluorobenzyl). In a yet further embodiment of the compound of formula (Id), R5represents benzyl substituted by one fluorine on the 4 position of the phenyl group (i.e. R5represents 4-fluorobenzyl).

[0579] In one embodiment, the compound of formula (I) is a compound of formula (I), (la), (lb) or (Ic) wherein R1represents methyl and R2represents hydrogen. In one embodiment, the compound of formula (I) is a compound of formula (I), (la), (lb) or (Ic) wherein R1and R2both represent hydrogen.

[0580] In one embodiment, the compound of formula (I) is a compound of formula (I), (la), (lb) or (Ic) wherein R1represents hydrogen and R2represents methyl.

[0581] In one embodiment, the compound of formula (I) is a compound of formula (I), (la), (lb), (Ic) or (Id) wherein R5represents unsubstituted n-butyl.

[0582] In one embodiment, the compound of formula (I) is a compound of formula (I), (la), (lb), (Ic) or (Id) wherein R5represents benzyl substituted by one or two fluorines on the 2, 3 and / or 4 positions of the phenyl group.

[0583] In one embodiment, the compound of formula (I) is a compound of formula (I), (la), (lb), (Ic) or (Id) wherein R5represents benzyl substituted on the phenyl group by one or two fluorines.

[0584] In one embodiment, the compound of formula (I) is a compound of formula (I), (la), (lb), (Ic) or (Id) wherein R5represents benzyl substituted on the phenyl group by two fluorines, e.g. 2,3 disubstituted, 2,4 disubstituted, 2,5 disubstituted, 3,5 disubstituted, 2,6 disubstituted or 3,4 disubstituted.

[0585] In one embodiment, the compound of formula (I) is a compound of formula (I), (la), (lb), (Ic) or (Id) wherein R5represents benzyl substituted by one or two fluorines on the 2, 3 and / or 4 positions of the phenyl group.

[0586] In one embodiment, the compound of formula (I) is a compound of formula (I), (la), (lb), (Ic) or (Id) wherein R5represents benzyl substituted by one fluorine on the 2, 3 or 4 position of the phenyl group (i.e. R5represents 2-fluorobenzyl, 3-fluorobenzyl or 4-fluorobenzyl).

[0587] In one embodiment, the compound of formula (I) is a compound of formula (I), (la), (lb), (Ic) or (Id) wherein R5represents benzyl substituted by two fluorines on the 2,3, 3,4 or 2,4 positions of the phenyl group (i.e. R5represents 2,3-difluorobenzyl, 3,4-difluorobenzyl or 2,4-difluorobenzyl).

[0588] In one embodiment, the compound of formula (I) is a compound of formula (I), (la), (lb), (Ic) or (Id) wherein R5represents benzyl substituted by two fluorines on the 2,4 positions of the phenyl group (i.e. R5represents 2,4-difluorobenzyl).

[0589] In one embodiment, the compound of formula (I) is a compound of formula (I), (la), (lb), (Ic) or (Id) wherein R5represents 2,4-difluorobenzyl or 4-fluorobenzyl. In one embodiment, the invention provides the use of a compound of formula (I) which comprises the free base of a compound of Examples 1-37 of WO-A-2015 / 092420 or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof.

[0590] In one embodiment, the invention provides the use of a compound of formula (I) which is the free base of a compound of Examples 1 -37 of WO-A-2015 / 092420 or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof.

[0591] In one embodiment, the invention provides the use of a compound of formula (I) which comprises a compound of Examples 1-37 of WO-A-2015 / 092420 or a tautomeric or a stereochemically isomeric form or a solvate thereof.

[0592] In a further embodiment, the compound is selected from the free base of Examples 1 to 34 of WO-A- 2015 / 092420 or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof.

[0593] In a further embodiment, the invention provides a compound of formula (I) which comprises a compound selected from: 1-{6-[(4-Fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2- [(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one;

[0594] 6-[(4-Fluorophenyl)methyl]-3,3,4-trimethyl-1 -{2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]acetyl}-1 H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-5-one;

[0595] 6-[(2,4-Difluorophenyl)methyl]-3,3-dimethyl-1-{2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]acetyl}-1 H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-5-one;

[0596] 6-[(2,4-Difluorophenyl)methyl]-3,3,4-trimethyl-1 -{2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]acetyl}-1 H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-5-one;

[0597] 1-[5-((R or S)-1 ,2-Dihydroxyethyl)-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2- b]pyridin-1-yl]-2-[(2R,5R)-2-{[(3R,5R)-3,5-dimethylmorpholin-4-yl]methyl}-5-methylpiperazin-1 -yl]ethan- 1-one;

[0598] 6-[(2,4-Difluorophenyl)methyl]-1 -{2-[(2R,5R)-2-{[(2S,5R)-2,5-dimethylmorpholin-4-yl]methyl}-5- methylpiperazin-1-yl]acetyl}-3,3-dimethyl-1 H,2H,3H,5H,6H-pyrrolo[2,3-c]pyridin-5-one; 4-Amino-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-1-{2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]acetyl}-1 H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-5-one;

[0599] 1-{6-[(4-Fluorophenyl)methyl]-5-((R or S)-2-hydroxy-1-methoxyethyl)-3,3-dimethyl-1 H,2H,3H- pyrrolo[3,2-b]pyridin-1 -yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1- yl]ethan-1-one; 4-Amino-6-butyl-1-{2-[(2R,5R)-2-{[(3R,5R)-3,5-dimethylmorpholin-4-yl]methyl}-5-methylpiperazin-1- yl]acetyl}-3,3-dimethyl-1 H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-5-one;

[0600] 6-[(2,4-Difluorophenyl)methyl]-3,3,4-trimethyl-1-{2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]acetyl}-1 H,2H,3H,5H,6H-pyrrolo[2,3-c]pyridin-5-one; 6-Butyl-1-{2-[(2R,5R)-2-{[(3R,5R)-3,5-dimethylmorpholin-4-yl]methyl}-5-methylpiperazin-1-yl]acetyl}-

[0601] 3.3-dimethyl-1 H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-5-one; and

[0602] 6-Butyl-1-{2-[(2R,5R)-2-{[(2S,5R)-2,5-dimethylmorpholin-4-yl]methyl}-5-methylpiperazin-1-yl]acetyl}-

[0603] 3.3-dimethyl-1 H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-5-one; or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof.

[0604] In a further embodiment, the invention provides a compound selected from:

[0605] 1-{6-[(4-Fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1 -yl}-2-

[0606] [(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one dihydrochloride (E2);

[0607] 6-[(4-Fluorophenyl)methyl]-3,3,4-trimethyl-1-{2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]acetyl}-1 H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-5-one dihydrochloride (E6); 6-[(2,4-Difluorophenyl)methyl]-3,3-dimethyl-1-{2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]acetyl}-1 H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-5-one dihydrochloride (E8);

[0608] 6-[(2,4-Difluorophenyl)methyl]-3,3,4-trimethyl-1-{2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]acetyl}-1 H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-5-one dihydrochloride (E19);

[0609] 1-[5-((R or S)-1,2-Dihydroxyethyl)-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2- b]pyridin-1-yl]-2-[(2R,5R)-2-{[(3R,5R)-3,5-dimethylmorpholin-4-yl]methyl}-5-methylpiperazin-1-yl]ethan- 1-one dihydrochloride (E21);

[0610] 6-[(2,4-Difluorophenyl)methyl]-1-{2-[(2R,5R)-2-{[(2S,5R)-2,5-dimethylmorpholin-4-yl]methyl}-5- methylpiperazin-1-yl]acetyl}-3,3-dimethyl-1 H,2H,3H,5H,6H-pyrrolo[2,3-c]pyridin-5-one dihydrochloride (E22);

[0611] 4-Amino-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-1-{2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]acetyl}-1 H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-5-one dihydrochloride (E24);

[0612] 1-{6-[(4-Fluorophenyl)methyl]-5-((R or S)-2-hydroxy-1-methoxyethyl)-3,3-dimethyl-1 H,2H,3H- pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1- yl]ethan-1-one trihydrochloride (E27);

[0613] 4-Amino-6-butyl-1-{2-[(2R,5R)-2-{[(3R,5R)-3,5-dimethylmorpholin-4-yl]methyl}-5-methylpiperazin-1- yl]acetyl}-3,3-dimethyl-1 H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-5-one dihydrochloride (E30);

[0614] 6-[(2,4-Difluorophenyl)methyl]-3,3,4-trimethyl-1-{2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]acetyl}-1 H,2H,3H,5H,6H-pyrrolo[2,3-c]pyridin-5-one dihydrochloride (E31);

[0615] 6-Butyl-1-{2-[(2R,5R)-2-{[(3R,5R)-3,5-dimethylmorpholin-4-yl]methyl}-5-methylpiperazin-1-yl]acetyl}-

[0616] 3.3-dimethyl-1 H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-5-one dihydrochloride (E32) and 6-Butyl-1-{2-[(2R,5R)-2-{[(2S,5R)-2,5-dimethylmorpholin-4-yl]methyl}-5-methylpiperazin-1-yl]acetyl}-

[0617] 3.3-dimethyl-1 H,2H,3H,4H,5H-pyrrolo[3,2-b]pyridin-5-one dihydrochloride (E37) or a tautomeric or a stereochemically isomeric form, or a solvate thereof. In a further embodiment, the compound is selected from the free base of Examples 2, 6, 19, 21 , 22, 24, 27, 30, 31 and 32 of WO-A-2015 / 092420, or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof.

[0618] In a yet further embodiment, the invention provides a compound of formula (I) which comprises 1-{6-[(4- Fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)- 5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof.

[0619] In a yet further embodiment, the invention provides a compound of formula (I) which comprises 1 -{6-[(4- Fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)- 5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1 -yl]ethan-1-one hydrochloride salt or a tautomeric or a stereochemically isomeric form, or a solvate thereof.

[0620] In a yet further embodiment, the invention provides 1-{6-[(4-Fluorophenyl)methyl]-5-(hydroxymethyl)-

[0621] 3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1 -one dihydrochloride (E2).

[0622] In a yet further embodiment, the invention provides 1-{6-[(4-Fluorophenyl)methyl]-5-(hydroxymethyl)-

[0623] 3.3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one lactate salt or a tautomeric or a stereochemically isomeric form, or a solvate thereof.

[0624] In a yet further embodiment, the invention provides 1-{6-[(4-Fluorophenyl)methyl]-5-(hydroxymethyl)-

[0625] 3.3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorphoIin-4- yl]methyl}piperazin-1-yl]ethan-1 -one L-(+)-lactate salt or a tautomeric or a stereochemically isomeric form, or a solvate thereof.

[0626] In a yet further embodiment, the compound is selected from Examples 38 - 42 of WO-A-2015 / 092420.

[0627] In a yet further embodiment, the invention provides 1-{6-[(4-Fluorophenyl)methyl]-5-(hydroxymethyl)-

[0628] 3.3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1 -one L-(+)-lactate (Form A) (E39).

[0629] In a yet further embodiment, the invention provides 1-{6-[(4-Fluorophenyl)methyl]-5-(hydroxymethyl)-

[0630] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1 -one L-(+)-lactate (Form B) (E40). In a yet further embodiment, the invention provides 1-{6-[(4-Fluorophenyl)methyl]-5-(hydroxymethyl)-

[0631] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate (Form C) (E43).

[0632] In a yet further embodiment, the invention provides 1-{6-[(4-Fluorophenyl)methyl]-5-(hydroxymethyl)-

[0633] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one sulfate salt or a tautomeric or a stereochemically isomeric form, or a solvate thereof.

[0634] In a yet further embodiment, the invention provides 1-{6-[(4-Fluorophenyl)methyl]-5-(hydroxymethyl)-

[0635] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one sulfate (Form F) (E41 ).

[0636] In a yet further embodiment, the invention provides 1-{6-[(4-Fluorophenyl)methyl]-5-(hydroxymethyl)-

[0637] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one mesylate salt or a tautomeric or a stereochemically isomeric form, or a solvate thereof.

[0638] In a yet further embodiment, the invention provides 1-{6-[(4-Fluorophenyl)methyl]-5-(hydroxymethyl)-

[0639] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one mesylate (Form B) (E42).

[0640] For the avoidance of doubt, it is to be understood that each general and specific preference, embodiment and example for one substituent may be combined with each general and specific preference, embodiment and example for one or more, particularly, all other substituents as defined herein and that all such embodiments are embraced by this application.

[0641] In one embodiment, the IAP antagonist is tolinapant, also known as ASTX660 or 1-(6-(4-fluorobenzyl)- 5-(hydroxymethyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridin-1-yl)-2-((2R,5R)-5-methyl-2-(((R)- 3-methylmorpholino)methyl)piperazin-1 -yl)ethan-1 -one (or alternatively 1 -{6-[(4-fluorophenyl)methyl]-5- (hydroxymethyl)-3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3- methylmorpholin-4-yl]methyl}piperazin-1 -yl]ethan-1 -one).

[0642] As is known in the art, tolinapant is an orally bioavailable, non-peptidomimetic antagonist of both X chromosome-linked inhibitor of apoptosis protein (XIAP), cellular IAP 1 (clAP1 ) and cellular IAP 2 (clAP2), with potential antineoplastic and pro-apoptotic activities. Upon administration, tolinapant selectively binds to and inhibits the activity of XIAP and clAP1 . This restores and promotes the induction of apoptotic signaling pathways in cancer cells, and inactivates the nuclear factor-kappa B (NF-kB)- mediated survival pathway. XIAP and clAP1 are overexpressed by many cancer cell types and suppress apoptosis by inhibiting the activity of certain caspases; they promote both cancer cell survival and chemotherapy resistance. Tolinapant has the CAS Number 1799328-86-1 .

[0643] In an ongoing phase 2 trial (NCT02503423), tolinapant showed activity against extensively pre-treated peripheral and cutaneous T-cell lymphomas (PTCL and CTCL) (Samaniego F, Hollebecque A, Foss F, Lister J, Mita M, Wagner-Johnston N, et al.. Hematological Oncology 2019;37:527-; Mita MM, LoRusso PM, Papadopoulos KP, Gordon MS, Mita AC, Ferraldeschi R, et al. Clinical cancer research : an official journal of the American Association for Cancer Research 2020;26:2819-26 ), and patient samples from this trial have demonstrated some preliminary evidence of immune modulation (Ferrari N, Ward G, Gewinner C, Davis MP, Jueliger S, Saini H, et al. Antagonism of inhibitors of apoptosis proteins reveals a novel, immune response-based therapeutic approach for T-cell lymphoma. Blood advances 2021 ;5:4003-16).

[0644] SALTS, SOLVATES, TAUTOMERS, ISOMERS, N-OXIDES, ESTERS, PRODRUGS AND ISOTOPES A reference to a compound of the formula (I) and sub-groups thereof also includes ionic forms, salts, solvates, isomers (including geometric and stereochemical isomers), tautomers, N-oxides, esters, prodrugs, isotopes and protected forms thereof, for example, as discussed below; particularly, the salts or tautomers or isomers or N-oxides or solvates thereof; and more particularly, the salts or tautomers or N-oxides or solvates thereof, even more particularly the salts or tautomers or solvates thereof.

[0645] Salts

[0646] Many compounds of the formula (I) can exist in the form of salts, for example acid addition salts or, in certain cases salts of organic and inorganic bases such as carboxylate, sulfonate and phosphate salts. All such salts are within the scope of this invention, and references to compounds of the formula (I) include the salt forms of the compounds.

[0647] The salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods such as methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639- 026-8, Hardcover, 388 pages, August 2002. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.

[0648] Acid addition salts (mono- or di-salts) may be formed with a wide variety of acids, both inorganic and organic. Examples of acid addition salts include mono- or di-salts formed with an acid selected from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (e.g. L-ascorbic), L-aspartic, benzenesulfonic, benzoic, 4-acetamidobenzoic, butanoic, (+) camphoric, camphor-sulfonic, (+)-(1S)- camphor-10-sulfonic, capric, caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulfuric, ethane-1,2- disulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, formic, fumaric, galactaric, gentisic, glucoheptonic, D-gluconic, glucuronic (e.g. D-glucuronic), glutamic (e.g. L-glutamic), a-oxoglutaric, glycolic, hippuric, hydrohalic acids (e.g. hydrobromic, hydrochloric, hydriodic), isethionic, lactic (e.g. (+)-L-lactic, (±)-DL- lactic), lactobionic, maleic, malic, (-)-L-malic, malonic, (±)-DL-mandelic, methanesulfonic, naphthalene- 2-sulfonic, naphthalene-1 ,5-disulfonic, 1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, pyruvic, L-pyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulfuric, tannic, (+)-L-tartaric, thiocyanic, p-toluenesulfonic, undecylenic and valeric acids, as well as acylated amino acids and cation exchange resins.

[0649] One particular group of salts consists of salts formed from acetic, hydrochloric, hydriodic, phosphoric, nitric, sulfuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulfonic, toluenesulfonic, methanesulfonic (mesylate), ethanesulfonic, naphthalenesulfonic, valeric, acetic, propanoic, butanoic, malonic, glucuronic and lactobionic acids. One particular, sub group of salts consists of salts formed from hydrochloric, lactic (e.g. (+)-L-lactic, (-)-D-lactic or (±)-DL-lactic), sulfuric and methanesulfonic (mesylate) acids. One particular, further sub group of salts consists of salts formed from lactic (e.g. (+)- L-lactic, (-)-D-lactic or (±)-DL-lactic), sulfuric and methanesulfonic (mesylate) acids. One particular, further sub group of salts consists of salts formed from lactic (e.g. (+)-L-lactic, (-)-D-lactic or (±)-DL-lactic) and sulfuric acids. One particular salt is the hydrochloride salt. One further particular salt is the lactate salt (such as the compound of Examples 39, 40 and 43 of WO-A-2015 / 092420). One further particular salt is the sulfate salt (such as the compound of Example 41 of WO-A-2015 / 092420). One further particular salt is the mesylate salt (such as the compound of Example 42 of of WO-A-2015 / 092420). One particular salt is the lactate salt (such as the compound of Examples 39, 40 and 43, in particular the compound of Example 43 of WO2015 / 092420), e.g. the L-(+)-lactate salt.

[0650] If the compound is anionic, or has a functional group which may be anionic (e.g., -COOH may be -COO-), then a salt may be formed with an organic or inorganic base, generating a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Li+, Na+and K+, alkaline earth metal cations such as Ca2+and Mg2+, and other cations such as Al3+or Zn+. Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH4+) and substituted ammonium ions (e.g., NH3R+, NHzR2+, NHRs -, NR4+). Examples of some suitable substituted ammonium ions are those derived from: methylamine, ethylamine, diethylamine, propylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH3)4+.

[0651] Where the compounds of the formula (I) contain an amine function, these may form quaternary ammonium salts, for example by reaction with an alkylating agent according to methods well known to the skilled person. Such quaternary ammonium compounds are within the scope of formula (I).

[0652] The compounds of the invention may exist as mono-, di- or tri- salts, in particular mono- or di-salts, depending upon the pKa of the acid from which the salt is formed. The salt forms of the compounds of the invention are typically pharmaceutically acceptable salts, and examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceuticaly Acceptable Salts," J. Pharm. Sci., Vol. 66, pp. 1-19. However, salts that are not pharmaceutically acceptable may also be prepared as intermediate forms which may then be converted into pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salt forms, which may be useful, for example, in the purification or separation of the compounds of the invention, also form part of the invention.

[0653] In one embodiment of the invention, there is provided a pharmaceutical composition comprising a solution (e.g. an aqueous solution) containing a compound of the formula (I) and sub-groups and examples thereof as described herein in the form of a salt in a concentration of greater than 10 mg / mL, typically greater than 15 mg / mL and particularly greater than 20 mg / mL.

[0654] N-Oxides

[0655] Compounds of the formula (I) containing an amine function may also form N-oxides. A reference herein to a compound of the formula (I) that contains an amine function also includes the N-oxide.

[0656] Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.

[0657] N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4thEdition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.

[0658] Geometric isomers and tautomers

[0659] Compounds of the formula (I) may exist in a number of different geometric isomeric, and tautomeric forms and references to compounds of the formula (I) include all such forms. For the avoidance of doubt, where a compound can exist in one of several geometric isomeric or tautomeric forms and only one is specifically described or shown, all others are nevertheless embraced by formula (I).

[0660] For example, in compounds of the formula (I), the phenyl ring of compounds when X represents NH and U represents carbon can exist in a tautomeric form as illustrated below. For simplicity, the general formula (I) illustrates one form 1 but the formula is to be taken as embracing both tautomeric forms (1 and 2).

[0661] Other examples of tautomeric forms include, for example, keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / imino alcohol, -nitro. keto enol enolate

[0662] Stereoisomers

[0663] Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms.

[0664] Stereocentres are illustrated in the usual fashion, using ‘hashed’ or ‘wedged’ lines, e.g.

[0665] Boc-N-Methyl alanine (S)-(+)-2-hydroxy-2-phenylpropionic acid

[0666] Where a compound is described as a mixture of two diastereoisomers / epimers, the configuration of the stereocentre is not specified and is represented by straight lines.

[0667] Unless otherwise mentioned or indicated, where compounds of the formula (I) contain one or more chiral centres, and can exist in the form of two or more optical isomers, references to compounds of the formula (I) include all optical isomeric forms thereof (e.g. enantiomers, epimers and diastereoisomers), either as individual optical isomers, or mixtures (e.g. racemic mixtures) or two or more optical isomers, unless the context requires otherwise.

[0668] The optical isomers may be characterised and identified by their optical activity (i.e. as + and - isomers, or d and I isomers) or they may be characterised in terms of their absolute stereochemistry using the “R and S” nomenclature developed by Cahn, Ingold and Prelog, see Advanced Organic Chemistry b Jerry March, 4thEdition, John Wiley & Sons, New York, 1992, pages 109-114, and see also Cahn, Ingold & Prelog, Angew. Chem. Int. Ed. Engl., 1966, 5, 385-415. Optical isomers can be separated by a number of techniques including chiral chromatography (chromatography on a chiral support) and such techniques are well known to the person skilled in the art.

[0669] As an alternative to chiral chromatography, optical isomers can be separated by forming diastereoisomeric salts with chiral acids such as (+)-tartaric acid, (-)-pyroglutamic acid, (-)-di-toluoyl-L- tartaric acid, (+)-mandelic acid, (-)-malic acid, and (-)-camphorsulfonic acid, separating the diastereoisomers by preferential crystallisation, and then dissociating the salts to give the individual enantiomer of the free base.

[0670] Additionally enantiomeric separation can be achieved by covalently linking an enantiomerically pure chiral auxiliary onto the compound and then performing diastereisomer separation using conventional methods such as chromatography. This is then followed by cleavage of the aforementioned covalent linkage to generate the appropriate enantiomerically pure product.

[0671] Where compounds of the formula (I) exist as two or more optical isomeric forms, one enantiomer in a pair of enantiomers may exhibit advantages over the other enantiomer, for example, in terms of biological activity. Thus, in certain circumstances, it may be desirable to use as a therapeutic agent only one of a pair of enantiomers, or only one of a plurality of diastereoisomers. Accordingly, the invention provides compositions containing a compound of the formula (I) having one or more chiral centres, wherein at least 55% (e.g. at least 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) of the compound of the formula (I) is present as a single optical isomer (e.g. enantiomer or diastereoisomer). In one general embodiment, 99% or more (e.g. substantially all) of the total amount of the compound of the formula (I) may be present as a single optical isomer (e.g. enantiomer or diastereoisomer).

[0672] Compounds encompassing double bonds can have an E (entgegen) or Z (zusammen) stereochemistry at said double bond. Substituents on bivalent cyclic or (partially) saturated radicals may have either the cis- or frans-configuration. The terms cis and trans when used herein are in accordance with Chemical Abstracts nomenclature (J. Org. Chem. 1970, 35 (9), 2849-2867), and refer to the position of the substituents on a ring moiety.

[0673] Of special interest are those compounds of formula (I) which are stereochemically pure. When a compound of formula (I) is for instance specified as R, this means that the compound is substantially free of the S isomer. If a compound of formula (I) is for instance specified as E, this means that the compound is substantially free of the Z isomer. The terms cis, trans, R, S, E and Z are well known to a person skilled in the art.

[0674] Isotopic variations

[0675] The present invention includes all pharmaceutically acceptable isotopically-labeled compounds of the invention, i.e. compounds of formula (I), wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.

[0676] Examples of isotopes suitable for inclusion in the compounds of the invention comprise isotopes of hydrogen, such as2H (D) and3H (T), carbon, such as11C,13C and14C, chlorine, such as36CI, fluorine, such as18F, iodine, such as123l,125l and131l, nitrogen, such as13N and15N, oxygen, such as15O,17O and18O, phosphorus, such as32P, and sulfur, such as35S.

[0677] Certain isotopically-labelled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The compounds of formula (I) can also have valuable diagnostic properties in that they can be used for detecting or identifying the formation of a complex between a labelled compound and other molecules, peptides, proteins, enzymes or receptors. The detecting or identifying methods can use compounds that are labelled with labelling agents such as radioisotopes, enzymes, fluorescent substances, luminous substances (for example, luminol, luminol derivatives, luciferin, aequorin and luciferase), etc. The radioactive isotopes tritium, i.e.3H (T), and carbon-14, i.e.14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

[0678] Substitution with heavier isotopes such as deuterium, i.e.2H (D), may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be used in some circumstances.

[0679] Substitution with positron emitting isotopes, such as11C,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies for examining target occupancy.

[0680] Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the nonlabeled reagent previously employed.

[0681] Esters

[0682] Esters such as carboxylic acid esters, acyloxy esters and phosphate esters of the compounds of formula

[0683] (I) bearing a carboxylic acid group or a hydroxyl group are also embraced by Formula (I). Examples of esters are compounds containing the group -C(=O)OR, wherein R is an ester substituent, for example, a C1-7 alkyl group, a C3-12 heterocyclyl group, or a C5-12 aryl group, particularly a C1-6 alkyl group.

[0684] Particular examples of ester groups include, but are not limited to -C(=O)OCH3 , - C(=O)OCH2CH3, -C(=O)OC(CH3)3, and -C(=O)OPh. Examples of acyloxy (reverse ester) groups are represented by -OC(=O)R, wherein R is an acyloxy substituent, for example, a C1-6 alkyl group, a C3-12 heterocyclyl group, or a C5-12 aryl group, particularly a C1-6 alkyl group. Particular examples of acyloxy groups include, but are not limited to, -OC(=O)CH3 (acetoxy), -OC(=O)CH2CH3, -OC(=O)C(CH3)3, -OC(=O)Ph, and -OC(=O)CH2Ph. Examples of phosphate esters are those derived from phosphoric acid.

[0685] In one embodiment of the invention, formula (I) includes within its scope esters of compounds of the formula (I) bearing a carboxylic acid group or a hydroxyl group. In another embodiment of the invention, formula (I) does not include within its scope esters of compounds of the formula (I) bearing a carboxylic acid group or a hydroxyl group.

[0686] Solvates and Crystalline forms

[0687] Also encompassed by formula (I) are any polymorphic forms of the compounds, and solvates such as hydrates, alcoholates and the like.

[0688] The compounds of the invention may form solvates, for example with water (i.e., hydrates) or common organic solvents. As used herein, the term “solvate” means a physical association of the compounds of the present invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. The term “solvate” is intended to encompass both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include compounds of the invention in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid or ethanolamine and the like. The compounds of the invention may exert their biological effects whilst they are in solution.

[0689] Solvates are well known in pharmaceutical chemistry. They can be important to the processes for the preparation of a substance (e.g. in relation to their purification, the storage of the substance (e.g. its stability) and the ease of handling of the substance and are often formed as part of the isolation or purification stages of a chemical synthesis. A person skilled in the art can determine by means of standard and long used techniques whether a hydrate or other solvate has formed by the isolation conditions or purification conditions used to prepare a given compound. Examples of such techniques include thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray crystallography (e.g. single crystal X-ray crystallography or X-ray powder diffraction) and Solid State NMR (SS-NMR, also known as Magic Angle Spinning NMR or MAS-NMR). Such techniques are as much a part of the standard analytical toolkit of the skilled chemist as NMR, IR, HPLC and MS.

[0690] Alternatively the skilled person can deliberately form a solvate using crystallisation conditions that include an amount of the solvent required for the particular solvate. Thereafter the standard methods described above, can be used to establish whether solvates had formed.

[0691] In one embodiment the salt of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1 H,2H,3H- pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1 - yl]ethan-1-one has <10% solvates present (such as no more than any one of the following amounts 9, 8, 7, 6, 5, 4, 3, 2, 1 , 0.5, 0.1 , 0.05 or 0.01 %), e.g. hydrates, alcoholates, isopropylacetate, methyl acetate or alkanes, such as heptanes.

[0692] In one embodiment the salt of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1 H,2H,3H- pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1 - yl]ethan-1-one is anhydrous. In a further embodiment, the anhydrous salt of 1-{6-[(4- fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)- 5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one contains no more than 5% (such as no more than any one of the following amounts 4, 3, 2, 1, 0.5, 0.1, 0.05 or 0.01 %) by weight of water.

[0693] In one embodiment the salt of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1 H,2H,3H- pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1- yl]ethan-1-one contains a single crystalline form and no more than 5% (such as no more than any one of the following amounts 4, 3, 2, 1 , 0.5, 0.1 , 0.05 or 0.01 %) by weight of other crystalline forms.

[0694] In one embodiment the salt of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1 H,2H,3H- pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1- yl]ethan-1-one is crystalline.

[0695] In one embodiment the salt of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1 H,2H,3H- pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1- yl]ethan-1-one is amorphous.

[0696] Furthermore, the compounds of the present invention may have one or more polymorph or amorphous crystalline forms and as such are intended to be included in the scope of the invention.

[0697] References herein to "polymorph” refer to the existence of more than one crystal structure of a compound of formula (I). The ability of a chemical compound to crystallize in more than one crystal modification can have an effect upon the properties of said compound, such as physicochemical properties, shelf life, solubility, formulation properties, toxicity, bioavailability, hygroscopicity and processing properties. In addition, the therapeutic action of a pharmaceutical compound can be affected by the polymorphism of the drug molecule.

[0698] In one embodiment, the compound of formula (I) comprises a polymorphic form of 1-{6-[(4- fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)- 5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one or salt thereof. In a further embodiment, the compound of formula (I) comprises a polymorphic form of a salt of 1-{6- [(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2- [(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one.

[0699] In a further embodiment, the compound of formula (I) comprises the Form A polymorph of 1-{6-[(4- fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)- 5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1 -yl]ethan-1 -one L-(+)-lactate. This compound may be prepared as defined herein in Example 39 of of WO-A-2015 / 092420.

[0700] In a yet further embodiment, 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1 H,2H,3H- pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1- yl]ethan-1-one L-(+)-lactate is characterised by the1H NMR spectrum depicted in Figure 1 of WO-A- 2015 / 092420.

[0701] A compound’s X-ray powder pattern is characterised by the diffraction angle (29) and interplanar spacing (d) parameters of an X-ray diffraction spectrum. These are related by Bragg's equation, nA=2d Sin 0, (where n=1 ; A=wavelength of the cathode used; d=interplanar spacing; and 9=diffraction angle). Herein, interplanar spacings, diffraction angle and overall pattern are important for identification of crystal in the X-ray powder diffraction, due to the characteristics of the data. The relative intensity should not be strictly interpreted since it may be varied depending on the direction of crystal growth, particle sizes and measurement conditions. In addition, the diffraction angles usually mean ones which coincide in the range of 29±0.2°. The peaks mean main peaks and include peaks not larger than medium at diffraction angles other than those stated above.

[0702] In a yet further embodiment, the Form A polymorph of 1 -{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0703] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1 -one L-(+)-lactate is characterised by an XRPD pattern having peaks at 6.5 ± 0.5°, 7.1 ± 0.5°, 7.9 ± 0.5°, 9.3 ± 0.5°, 10.2 ± 0.5°, 11.0 ± 0.5°, 11.6 ± 0.5°, 13.3 ± 0.5°, 14.4 ± 0.5°, 15.0 ± 0.5°, 16.7 ± 0.5°, 18.0 ± 0.5°, 18.4 ± 0.5°, 20.0 ± 0.5°, 21.0 ± 0.5°, 23.4 ± 0.5°, 25.2 ± 0.5° and 26.1 ± 0.5° (29, 1d.p).

[0704] In a yet further embodiment, the Form A polymorph of 1-{6-[(4-fiuorophenyl)methyl]-5-(hydroxymethyl)-

[0705] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1 -one L-(+)-lactate is characterised by an XRPD pattern having peaks at 6.5 ± 0.2°, 7.1 ± 0.2°, 7.9 ± 0.2°, 9.3 ± 0.2°, 10.2 ± 0.2°, 11.0 ± 0.2°, 11.6 ± 0.2°, 13.3 ± 0.2°, 14.4 ± 0.2°, 15.0 ± 0.2°, 16.7 ± 0.2°, 18.0 ± 0.2°, 18.4 ± 0.2°, 20.0 ± 0.2°, 21.0 ± 0.2°, 23.4 ± 0.2°, 25.2 ± 0.2° and 26.1 ± 0.2° (20, 1d.p).

[0706] In a yet further embodiment, the Form A polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0707] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterised by an XRPD pattern having peaks at 6.5 ± 0.1°, 7.1 ± 0.1°, 7.9 ± 0.1°, 9.3 ± 0.1°, 10.2 ± 0.1 °, 11.0 ± 0.1 °, 11.6 ± 0.1°, 13.3 ± 0.1°, 14.4 ± 0.1°, 15.0 ± 0.1°, 16.7 ± 0.1 °, 18.0 ± 0.1 °, 18.4 ± 0.1°, 20.0 ± 0.1°, 21.0 ± 0.1°, 23.4 ± 0.1°, 25.2 ± 0.1° and 26.1 ± 0.1° (20, 1d.p).

[0708] In a yet further embodiment, the Form A polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0709] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterised by an XRPD pattern having peaks at 6.5°, 7.1°, 7.9°, 9.3°, 10.2°, 11.0°, 11.6°, 13.3°, 14.4°, 15.0°, 16.7°, 18.0°, 18.4°, 20.0°, 21.0°, 23.4°, 25.2° and 26.1° (20, 1d.p).

[0710] In a yet further embodiment, the Form A polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0711] 3.3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterised by an XRPD pattern substantially as shown in Figure 2 of WO-A-2015 / 092420.

[0712] In a yet further embodiment, the Form A polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0713] 3.3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterised by having peaks at the same diffraction angles (20) of the XRPD pattern shown in Figure 2 of WO-A-2015 / 092420 and optionally wherein the peaks have the same relative intensity as the peaks shown in Figure 2 of WO-A- 2015 / 092420.

[0714] It will be appreciated by the skilled person that references herein to “intensity” of peaks with respect to XRPD refer to relative intensities which have taken into account normalisation of background noise and other such parameters.

[0715] In a yet further embodiment, the Form A polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0716] 3.3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterised by having major peaks at diffraction angles (20) and intensities as those shown in the XRPD pattern in Figure 2 of WO-A-2015 / 092420.

[0717] In a yet further embodiment, the Form A polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0718] 3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterised by interplanar spacing (d) values of 13.59 ± 0.5A, 12.44 ± 0.5A, 11.19 ± 0.5A, 9.50 ± 0.5A, 8.67 ± 0.5A, 8.04 ± 0.5A, 7.62 ± 0.5A, 6.65 ± 0.5A, 6.15 ± 0.5A, 5.90 ± 0.5A, 5.31 ± 0.5A, 4.93 ± 0.5A, 4.82 ± 0.5A, 4.44 ± 0.5A, 4.23 ± 0.5A, 3.80 ± 0.5A, 3.53 ± 0.5A and 3.41 ± 0.5A (d, 2d.p.).

[0719] In a yet further embodiment, the Form A polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0720] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1 -yl]ethan-1 -one L-(+)-lactate is characterised by interplanar spacing (d) values of 13.59 ± 0.2A, 12.44 + 0.2A, 11.19 ± 0.2A, 9.50 ± 0.2A, 8.67 + 0.2A, 8.04 ± 0.2A, 7.62 ± 0.2A, 6.65 ± 0.2A, 6.15 ± 0.2A, 5.90 ± 0.2A, 5.31 ± 0.2A, 4.93 ± 0.2A, 4.82 + 0.2A, 4.44 ± 0.2A, 4.23 ± 0.2A, 3.80 ± 0.2A, 3.53 ± 0.2A and 3.41 ± 0.2A (d, 2d.p.).

[0721] In a yet further embodiment, the Form A polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0722] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterised by interplanar spacing (d) values of 13.59 ± 0.1A, 12.44 ± 0.1A, 11.19 ± 0.1A, 9.50 ± 0.1A, 8.67 ± 0.1A, 8.04 ± 0.1A, 7.62 ± 0.1A, 6.65 ± 0.1A, 6.15 ± 0.1A, 5.90 ± 0.1A, 5.31 ± 0.1A, 4.93 ± 0.1A, 4.82 ± 0.1A, 4.44 ± O.lA, 4.23 ± O.lA, 3.80 ± 0.1A, 3.53 ± 0.1A and 3.41 ± 0.1A (d, 2d.p.).

[0723] In a yet further embodiment, the Form A polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0724] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterised by interplanar spacing (d) values of 13.59A, 12.44A, 11.19A, 9.50A, 8.67A, 8.04A, 7.62A, 6.65A, 6.15A, 5.90A, 5.31A, 4.93A, 4.82A, 4.44A, 4.23A, 3.80A, 3.53A and 3.41 A (d, 2d.p.).

[0725] In a further embodiment, the Form A polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3- dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterised by DSC peak temperatures of 78.69°C ± 0.5°C and / or 113.91°C ± 0.5°C (such as 78.69°C + 0.2°C and / or 113.91°C ± 0.2°C, in particular 78.69°C ± 0.1°C and / or 113.91 °C ± 0.1°C, more particularly 78.69°C and / or 113.91°C).

[0726] In a yet further embodiment, the Form A polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0727] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1 -yl]ethan-1 -one L-(+)-lactate is characterised by DSC onset temperatures of 72.3°C ± 0.5°C (endotherm, broad) and / or 102°C ± 0.5°C (endotherm, broad) (such as 72.3°C ± 0.2°C and / or 102°C ± 0.2°C, in particular 72.3°C ± 0.1 °C and / or 102°C ± 0.1°C, more particularly 72.3°C and / or 102°C).

[0728] In a yet further embodiment, the Form A polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0729] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterised by a DSC thermogram as depicted in Figure 3.

[0730] In a further embodiment, the compound of formula (I) comprises the Form B polymorph of 1 -{6-[(4- fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)- 5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate. This compound may be prepared as defined herein in Example 40 of WO-A-2015 / 092420. In a yet further embodiment, 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1 H,2H,3H- pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1- yl]ethan-1-one L-(+)-lactate is characterised by the1H NMR spectrum depicted in Figure 4 of WO-A- 2015 / 092420.

[0731] In a yet further embodiment, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0732] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterised by an XRPD pattern having peaks at

[0733] 6.6 ± 0.5°, 9.4 ± 0.5°, 11.0 ± 0.5°, 13.2 ± 0.5°, 14.3 ± 0.5°, 15.8 ± 0.5°, 17.4 ± 0.5°, 18.4 ± 0.5°, 19.1 ± 0.5°, 20.9 ± 0.5°, 21 .8 + 0.5°, 23.1 ± 0.5°, 24.9 ± 0.5°, 26.7 + 0.5° and 27.8 ± 0.5° (26, 1d.p).

[0734] In a yet further embodiment, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0735] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterised by an XRPD pattern having peaks at

[0736] 6.6 + 0.2°, 9.4 ± 0.2°, 11.0 ± 0.2°, 13.2 ± 0.2°, 14.3 + 0.2°, 15.8 ± 0.2°, 17.4 + 0.2°, 18.4 ± 0.2°, 19.1 ± 0.2°, 20.9 ± 0.2°, 21 .8 ± 0.2°, 23.1 ± 0.2°, 24.9 ± 0.2°, 26.7 ± 0.2° and 27.8 ± 0.2° (26, 1 d.p).

[0737] In a yet further embodiment, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0738] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterised by an XRPD pattern having peaks at

[0739] 6.6 ± 0.1 °, 9.4 ± 0.1°, 11.0 ± 0.1°, 13.2 ± 0.1 °, 14.3 ± 0.1 °, 15.8 ± 0.1 °, 17.4 ± 0.1°, 18.4 ± 0.1°, 19.1 ± 0.1°, 20.9 ± 0.1°, 21.8 ± 0.1 °, 23.1 ± 0.1 °, 24.9 + 0.1 °, 26.7 ± 0.1° and 27.8 ± 0.1° (26, 1d.p).

[0740] In a yet further embodiment, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0741] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterised by an XRPD pattern having peaks at 6.6°, 9.4°, 11.0°, 13.2°, 14.3°, 15.8°, 17.4°, 18.4°, 19.1°, 20.9°, 21.8°, 23.1°, 24.9°, 26.7° and 27.8° (26, 1d.p).

[0742] In a yet further embodiment, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0743] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterised by an XRPD pattern substantially as shown in Figure 5 of WO-A-2015 / 092420.

[0744] In a yet further embodiment, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0745] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterised by having peaks at the same diffraction angles (26) of the XRPD pattern shown in Figure 5 of WO-A-2015 / 092420 and optionally wherein the peaks have the same relative intensity as the peaks shown in Figure 5 of WO-A- 2015 / 092420. In a yet further embodiment, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0746] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterised by having major peaks at diffraction angles (20) and intensities as those shown in the XRPD pattern in Figure 5 of WO-A-2015 / 092420.

[0747] In a yet further embodiment, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0748] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterised by interplanar spacing (d) values of

[0749] 13.39 ± 0.5A, 9.40 ± 0.5A, 8.04 ± 0.5A, 6.70 ± 0.5A, 6.19 ± 0.5A, 5.61 + 0.5A, 5.09 ± 0.5A, 4.82 ± 0.5A,

[0750] 4.64 ± 0.5A, 4.25 ± 0.5A, 4.07 ± 0.5A, 3.85 ± 0.5A, 3.57 + 0.5A, 3.34 ± 0.5A and 3.21 ± 0.5A (d, 2d.p.).

[0751] In a yet further embodiment, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0752] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterised by interplanar spacing (d) values of

[0753] 13.39 ± 0.2A, 9.40 ± 0.2A, 8.04 ± 0.2A, 6.70 + 0.2A, 6.19 ± 0.2A, 5.61 ± 0.2A, 5.09 ± 0.2A, 4.82 ± 0.2A,

[0754] 4.64 ± 0.2A, 4.25 ± 0.2A, 4.07 ± 0.2A, 3.85 ± 0.2A, 3.57 ± 0.2A, 3.34 ± 0.2A and 3.21 ± 0.2A (d, 2d.p.).

[0755] In a yet further embodiment, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0756] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterised by interplanar spacing (d) values of

[0757] 13.39 + 0.1A, 9.40 ± 0.1A, 8.04 ± 0.1A, 6.70 ± 0.1A, 6.19 ± 0.1 A, 5.61 ± O.lA, 5.09 ± O.lA, 4.82 ± 0.1 A,

[0758] 4.64 ± 0.1 A, 4.25 ± 0.1A, 4.07 ± O.lA, 3.85 ± 0.1 A, 3.57 ± 0.1A, 3.34 ± 0.1A and 3.21 + 0.1A (d, 2d.p.).

[0759] In a yet further embodiment, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0760] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterised by interplanar spacing (d) values of 13.39A, 9.40A, 8.04A, 6.70A, 6.19A, 5.61 A, 5.09A, 4.82A, 4.64A, 4.25A, 4.07A, 3.85A, 3.57A, 3.34A and 3.21A (d, 2d.p.).

[0761] In a further embodiment, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3- dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1 -one L-(+)-lactate is characterised by DSC peak temperatures of 85.25°C ± 0.5°C and / or 106.72°C ± 0.5°C (such as 85.25°C ± 0.2°C and / or 106.72°C ± 0.2°C, in particular 85.25°C ± 0.1°C and / or 106.72°C ± 0.1°C, more particularly 85.25°C and / or 106.72°C).

[0762] In a yet further embodiment, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0763] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterised by DSC onset temperatures of 68°C ± 0.5°C (large endotherm, broad) and / or 102°C ± 0.5°C (very small endotherm, broad) (such as 68°C ± 0.2°C and / or 102°C ± 0.2°C, in particular 68°C ± 0.1°C and / or 102°C ± 0.1°C, more particularly 68°C and / or 102°C).

[0764] In a yet further embodiment, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0765] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterised by a DSC thermogram as depicted in Figure 6 of WO-A-2015 / 092420.

[0766] In a further embodiment, the compound of formula (I) comprises the Form F polymorph of 1-{6-[(4- fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)- 5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one sulfate. This compound may be prepared as defined herein in Example 41 of WO-A-2015 / 092420.

[0767] In a yet further embodiment, 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1 H,2H,3H- pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1- yl]ethan-1-one sulfate is characterised by the1H NMR spectrum depicted in Figure 7 of WO-A- 2015 / 092420.

[0768] In a yet further embodiment, the Form F polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0769] 3.3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one sulfate is characterised by an XRPD pattern having peaks at 8.5 + 0.5°, 13.5 ± 0.5°, 13.9 ± 0.5°, 14.3 ± 0.5°, 16.2 ± 0.5°, 17.3 ± 0.5°, 20.1 ± 0.5°, 21 .3 ± 0.5°, 23.3 + 0.5°,

[0770] 24.4 ± 0.5° and 27.9 ± 0.5° (26, 1d.p).

[0771] In a yet further embodiment, the Form F polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0772] 3.3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one sulfate is characterised by an XRPD pattern having peaks at 8.5 ± 0.2°, 13.5 ± 0.2°, 13.9 + 0.2°, 14.3 ± 0.2°, 16.2 ± 0.2°, 17.3 ± 0.2°, 20.1 ± 0.2°, 21 .3 ± 0.2°, 23.3 ± 0.2°,

[0773] 24.4 ± 0.2° and 27.9 ± 0.2° (26, 1d.p).

[0774] In a yet further embodiment, the Form F polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0775] 3.3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one sulfate is characterised by an XRPD pattern having peaks at 8.5 ± 0.1°, 13.5 ± 0.1 °, 13.9 + 0.1°, 14.3 ± 0.1 °, 16.2 ± 0.1 °, 17.3 ± 0.1°, 20.1 ± 0.1 °, 21.3 ± 0.1°, 23.3 ± 0.1°,

[0776] 24.4 ± 0.1° and 27.9 ± 0.1° (26, 1d.p).

[0777] In a yet further embodiment, the Form F polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0778] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one sulfate is characterised by an XRPD pattern having peaks at 8.5°, 13.5°, 13.9°, 14.3°, 16.2°, 17.3°, 20.1 °, 21.3°, 23.3°, 24.4° and 27.9° (26, 1d.p). In a yet further embodiment, the Form F polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0779] 3.3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1 -yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one sulfate is characterised by an XRPD pattern substantially as shown in Figure 8 of WO-A-2015 / 092420.

[0780] In a yet further embodiment, the Form F polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0781] 3.3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1 -yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one sulfate is characterised by having peaks at the same diffraction angles (20) of the XRPD pattern shown in Figure 8 and optionally wherein the peaks have the same relative intensity as the peaks shown in Figure 8 of WO-A-2015 / 092420.

[0782] In a yet further embodiment, the Form F polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0783] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1 -yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one sulfate is characterised by having major peaks at diffraction angles (20) and intensities as those shown in the XRPD pattern in Figure 8 of WO-A-2015 / 092420.

[0784] In a yet further embodiment, the Form F polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0785] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1 -yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one sulfate is characterised by interplanar spacing (d) values of 10.40 ± 0.5A, 6.56 ± 0.5A, 6.37 ± 0.5A, 6.19 ± 0.5A, 5.47 ± 0.5A, 5.12 ± 0.5A, 4.42 ± 0.5A, 4.17 + 0.5A, 3.82 ± 0.5A, 3.65 ± 0.5A and 3.20 ± 0.5A (d, 2d.p.).

[0786] In a yet further embodiment, the Form F polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0787] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1 -yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one sulfate is characterised by interplanar spacing (d) values of 10.40 ± 0.2A, 6.56 ± 0.2A, 6.37 ± 0.2A, 6.19 ± 0.2A, 5.47 ± 0.2A, 5.12 ± 0.2A, 4.42 ± 0.2A, 4.17 ± 0.2A, 3.82 ± 0.2A, 3.65 ± 0.2A and 3.20 ± 0.2A (d, 2d.p.).

[0788] In a yet further embodiment, the Form F polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0789] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1 -yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one sulfate is characterised by interplanar spacing (d) values of 10.40 ± 0.1A, 6.56 ± 0.1A, 6.37 ± 0.1A, 6.19 + 0.1A, 5.47 ± 0.1A, 5.12 ± O.lA, 4.42 ± 0.1A, 4.17 ± O.lA, 3.82 ± 0.1A, 3.65 ± 0.1A and 3.20 ± 0.1A (d, 2d.p.).

[0790] In a yet further embodiment, the Form F polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0791] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1 -yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one sulfate is characterised by interplanar spacing (d) values of 10.40A, 6.56A, 6.37A, 6.19A, 5.47A, 5.12A, 4.42A, 4.17A, 3.82A, 3.65A and 3.20A (d, 2d.p.). In a further embodiment, the Form F polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3- dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yJ}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one sulfate is characterised by DSC peak temperatures of 80.31°C ± 0.5°C and / or 149.07°C ± 0.5°C (such as 80.31°C ± 0.2°C and / or 149.07°C ± 0.2°C, in particular 80.31°C ± 0.1°C and / or 149.07°C ± 0.1°C, more particularly 80.31°C and / or 149.07°C).

[0792] In a yet further embodiment, the Form F polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0793] 3.3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one sulfate is characterised by DSC onset temperatures of 51.2°C ± 0.5°C (endotherm, broad) and / or 136°C ± 0.5°C (endotherm, broad) (such as 51.2°C ± 0.2°C and / or 136°C ± 0.2°C, in particular 51 ,2°C ± 0.1 °C and / or 136°C ± 0.1°C, more particularly 51 ,2°C and / or 136°C).

[0794] In a yet further embodiment, the Form F polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0795] 3.3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one sulfate is characterised by a DSC thermogram as depicted in Figure 9 of WO-A-2015 / 092420.

[0796] In a further embodiment, the compound of formula (I) comprises the Form B polymorph of 1-{6-[(4- fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)- 5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1 -one mesylate. This compound may be prepared as defined herein in Example 42 of WO-A-2015 / 092420.

[0797] In a yet further embodiment, 1 -{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1 H,2H,3H- pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1- yl]ethan-1-one mesylate is characterised by the1H NMR spectrum depicted in Figure 10 of WO-A- 2015 / 092420.

[0798] In a yet further embodiment, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0799] 3.3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one mesylate is characterised by an XRPD pattern having peaks at 6.6 ± 0.5°, 8.0 ± 0.5°, 11.8 ± 0.5°, 13.2 + 0.5°, 14.3 ± 0.5°, 15.0 ± 0.5°, 15.6 ± 0.5°, 17.1 ± 0.5°, 17.4 ± 0.5°, 17.7 ± 0.5°, 19.2 ± 0.5°, 20.3 ± 0.5°, 21 .2 ± 0.5°, 22.3 ± 0.5°, 23.0 ± 0.5°, 24.0 + 0.5°, 25.8 ± 0.5°, 26.8 ± 0.5° and 28.9 ± 0.5° (20, 1 d.p).

[0800] In a yet further embodiment, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0801] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one mesylate is characterised by an XRPD pattern having peaks at 6.6 ± 0.2°, 8.0 ± 0.2°, 11.8 ± 0.2°, 13.2 ± 0.2°, 14.3 + 0.2°, 15.0 ± 0.2°, 15.6 ± 0.2°, 17.1 ± 0.2°, 17.4 ± 0.2°, 17.7 ± 0.2°, 19.2 ± 0.2°, 20.3 ± 0.2°, 21 .2 ± 0.2°, 22.3 ± 0.2°, 23.0 ± 0.2°, 24.0 ± 0.2°, 25.8 ± 0.2°, 26.8 ± 0.2° and 28.9 ± 0.2° (20, 1 d.p). In a yet further embodiment, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0802] 3.3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1 -yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one mesylate is characterised by an XRPD pattern having peaks at 6.6 ± 0.1 °, 8.0 + 0.1°, 11.8 ± 0.1 °, 13.2 ± 0.1°, 14.3 + 0.1 °, 15.0 ± 0.1°, 15.6 ± 0.1 °, 17.1 ± 0.1 °, 17.4 + 0.1 °, 17.7 ± 0.1 °, 19.2 ± 0.1°, 20.3 ± 0.1 °, 21.2 ± 0.1 °, 22.3 ± 0.1 °, 23.0 ± 0.1 °, 24.0 ± 0.1 °, 25.8 ± 0.1 °, 26.8 ± 0.1 ° and 28.9 ± 0.1 ° (26, 1d.p).

[0803] In a yet further embodiment, the Form B polymorph of 1 -{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0804] 3.3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl)-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one mesylate is characterised by an XRPD pattern having peaks at 6.6°, 8.0°, 11.8°, 13.2°, 14.3°, 15.0°, 15.6°, 17.1 °, 17.4°, 17.7°, 19.2°, 20.3°, 21.2°, 22.3°, 23.0°, 24.0°, 25.8°, 26.8° and 28.9° (26, 1d.p).

[0805] In a yet further embodiment, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0806] 3.3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1 -yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one mesylate is characterised by an XRPD pattern substantially as shown in Figure 11 of WO-A-2015 / 092420.

[0807] In a yet further embodiment, the Form B polymorph of 1-{6-[(44luorophenyl)methyl]-5-(hydroxymethyl)-

[0808] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1 -yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one mesylate is characterised by having peaks at the same diffraction angles (26) of the XRPD pattern shown in Figure 11 of WO-A-2015 / 092420 and optionally wherein the peaks have the same relative intensity as the peaks shown in Figure 11 of WO-A-2015 / 092420.

[0809] In a yet further embodiment, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0810] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one mesylate is characterised by having major peaks at diffraction angles (26) and intensities as those shown in the XRPD pattern in Figure 11 of WO-A-2015 / 092420.

[0811] In a yet further embodiment, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0812] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1 -yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one mesylate is characterised by interplanar spacing (d) values of 13.39 ± 0.5A, 1 1.05 ± 0.5A, 7.50 + 0.5A, 6.70 ± 0.5A, 6.19 ± 0.5A, 5.90 ± 0.5A, 5.68 ± 0.5A, 5.18 ± 0.5A, 5.09 ± 0.5A, 5.01 ± 0.5A, 4.62 ± 0.5A, 4.37 ± 0.5A, 4.19 ± 0.5A, 3.98 ± 0.5A, 3.86 ± 0.5A, 3.71 ± 0.5A, 3.45 ± 0.5A, 3.32 ± 0.5A and 3.09 ± 0.5A (d, 2d.p.).

[0813] In a yet further embodiment, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0814] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one mesylate is characterised by interplanar spacing (d) values of 13.39 ± 0.2A, 11 .05 ± 0.2A, 7.50 ± 0.2A, 6.70 ± 0.2A, 6.19 ± 0.2A, 5.90 ± 0.2A, 5.68 ± 0.2A, 5.18 ± 0.2A, 5.09 + 0.2A, 5.01 + 0.2A, 4.62 ± 0.2A, 4.37 + 0.2A, 4.19 ± 0.2A, 3.98 ± 0.2A, 3.86 ± 0.2A, 3.71 ± 0.2A, 3.45 ± 0.2A, 3.32 ± 0.2A and 3.09 ± 0.2A (d, 2d.p.).

[0815] In a yet further embodiment, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0816] 3.3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methy(morpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one mesylate is characterised by interplanar spacing (d) values of 13.39 ± 0.1A, 11 .05 ± 0.1 A, 7.50 + 0.1 A, 6.70 ± O.lA, 6.19 ± 0.1 , 5.90 ± 0.1 A, 5.68 + 0.1 A, 5.18 ± 0.1 A, 5.09 ± 0.1A, 5.01 ± 0.1A, 4.62 ± 0.1A, 4.37 + 0.1A, 4.19 + 0.1A, 3.98 ± O.lA, 3.86 ± 0.1A, 3.71 + 0.1A, 3.45 ± 0.1 A, 3.32 ± 0.1 A and 3.09 ± 0.1 A (d, 2d.p.).

[0817] In a yet further embodiment, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0818] 3.3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one mesylate is characterised by interplanar spacing (d) values of 13.39A, 11.05A, 7.50A, 6.70A, 6.19A, 5.90A, 5.68A, 5.18A, 5.09A, 5.01A, 4.62A, 4.37A, 4.19A, 3.98A, 3.86A, 3.71 A, 3.45A, 3.32A and 3.09A (d, 2d.p.).

[0819] In a further embodiment, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3- dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one mesylate is characterised by DSC peak temperatures of 98.63°C ± 0.5°C and / or 177.11°C ± 0.5°C (such as 98.63°C ± 0.2°C and / or 177.11°C ± 0.2°C, in particular 98.63°C ± 0.1°C and / or 177.11°C ± 0.1°C, more particularly 98.63°C and / or 177.11°C).

[0820] In a further embodiment, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3- dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one mesylate is characterised by DSC onset temperatures of 73.3°C ± 0.5°C (endotherm, broad) and / or 160.8°C ± 0.5°C (endotherm, broad) (such as 73.3°C ± 0.2°C and / or 160.8°C ± 0.2°C, in particular 73.3°C ± 0.1°C and / or 160.8°C ± 0.1°C, more particularly 73.3°C and / or 160.8°C).

[0821] In a yet further embodiment, the Form B polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0822] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1 -yl]ethan-1-one mesylate is characterised by a DSC thermogram as depicted in Figure 12 of WO-A-2015 / 092420.

[0823] In a further embodiment, the compound of formula (I) comprises the Form C polymorph of 1-{6-[(4- fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)- 5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1 -yl]ethan-1 -one L-(+)-lactate. This compound may be prepared as defined herein in Example 43 of WO-A-2015 / 092420. In a yet further embodiment, 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1 H,2H,3H- pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1- yl]ethan-1-one L-(+)-lactate is characterised by the1H NMR spectrum depicted in Figure 15 of WO-A- 2015 / 092420.

[0824] In a yet further embodiment, the Form C polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0825] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterised by an XRPD pattern having peaks at

[0826] 7.4 ± 0.5°, 7.9 ± 0.5°, 8.3 ± 0.5°, 8.7 ± 0.5°, 9.0 ± 0.5°, 10.4 + 0.5°, 11 .2 ± 0.5°, 11 .6 ± 0.5°, 12.3 ± 0.5°,

[0827] 13.1 ± 0.5°, 13.9 ± 0.5°, 14.7 ± 0.5°, 15.8 + 0.5°, 16.5 ± 0.5°, 17.1 ± 0.5°, 17.9 ± 0.5°, 18.4 ± 0.5°, 18.9 ± 0.5°, 19.6 ± 0.5°, 20.4 ± 0.5°, 21.0 ± 0.5°, 21.8 ± 0.5°, 22.9 ± 0.5°, 23.3 ± 0.5°, 23.6 ± 0.5°, 24.0 ± 0.5°,

[0828] 24.9 ± 0.5° and 26.4 ± 0.5° (20, 1 d.p).

[0829] In a yet further embodiment, the Form C polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0830] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterised by an XRPD pattern having peaks at

[0831] 7.4 ± 0.2°, 7.9 ± 0.2°, 8.3 ± 0.2°, 8.7 ± 0.2°, 9.0 ± 0.2°, 10.4 ± 0.2°, 11 .2 ± 0.2°, 11 .6 ± 0.2°, 12.3 ± 0.2°,

[0832] 13.1 ± 0.2°, 13.9 ± 0.2°, 14.7 ± 0.2°, 15.8 ± 0.2°, 16.5 ± 0.2°, 17.1 ± 0.2°, 17.9 ± 0.2°, 18.4 ± 0.2°, 18.9 ± 0.2°, 19.6 ± 0.2°, 20.4 ± 0.2°, 21 .0 ± 0.2°, 21 .8 ± 0.2°, 22.9 ± 0.2°, 23.3 ± 0.2°, 23.6 ± 0.2°, 24.0 ± 0.2°,

[0833] 24.9 ± 0.2° and 26.4 ± 0.2° (20, 1 d.p).

[0834] In a yet further embodiment, the Form C polymorph of 1-{6-[(4 luorophenyl)methyl]-5-(hydroxymethyl)-

[0835] 3.3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterised by an XRPD pattern having peaks at

[0836] 7.4 ± 0.1 °, 7.9 ± 0.1 °, 8.3 ± 0.1 °, 8.7 ± 0.1 °, 9.0 ± 0.1 °, 10.4 ± 0.1 °, 11.2 ± 0.1 °, 11.6 ± 0.1 °, 12.3 ± 0.1 °,

[0837] 13.1 ± 0.1 °, 13.9 ± 0.1 °, 14.7 ± 0.1 °, 15.8 ± 0.1 °, 16.5 ± 0.1°, 17.1 ± 0.1 °, 17.9 ± 0.1 °, 18.4 ± 0.1 °, 18.9 ± 0.1 °, 19.6 ± 0.1 °, 20.4 ± 0.1 °, 21.0 ± 0.1 °, 21.8 ± 0.1 °, 22.9 ± 0.1 °, 23.3 ± 0.1 °, 23.6 ± 0.1 °, 24.0 ± 0.1 °,

[0838] 24.9 ± 0.1 ° and 26.4 ± 0.1 ° (20, 1d.p).

[0839] In a yet further embodiment, the Form C polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0840] 3.3-dimethyl-1H,2H,3H-pyrrolo[3J2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1 -yl]ethan-1-one L-(+)-lactate is characterised by an XRPD pattern having peaks at 7.4°, 7.9°, 8.3°, 8.7°, 9.0°, 10.4°, 11.2°, 11.6°, 12.3°, 13.1 °, 13.9°, 14.7°, 15.8°, 16.5°, 17.1°, 17.9°, 18.4°, 18.9°, 19.6°, 20.4°, 21.0°, 21.8°, 22.9°, 23.3°, 23.6°, 24.0°, 24.9° and 26.4° (20, 1d.p).

[0841] In a yet further embodiment, the Form C polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0842] 3.3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1 -yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1 -yl]ethan-1-one L-(+)-lactate is characterised by an XRPD pattern substantially as shown in Figure 16 of WO-A-2015 / 092420 labelled as 1. In a yet further embodiment, the Form C polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0843] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterised by having peaks at the same diffraction angles (20) of the XRPD pattern shown in Figure 16 of WO-A-2015 / 092420 labelled as 1 and optionally wherein the peaks have the same relative intensity as the peaks shown in Figure 16 of WO- A-2015 / 092420labelled as 1.

[0844] In a yet further embodiment, the Form C polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0845] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterised by having major peaks at diffraction angles (20) and intensities as those shown in the XRPD pattern in Figure 16 of WO-A-2015 / 092420 labelled as 1.

[0846] In a yet further embodiment, the Form C polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0847] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterised by having major peaks as measured by XRPD at 8.7 ± 0.5°, 17.1 ± 0.5°, 17.9 ± 0.5° and 18.9 ± 0.5° (20, 1 d.p).

[0848] In a yet further embodiment, the Form C polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0849] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterised by having major peaks as measured by XRPD at 8.7 ± 0.2°, 17.1 ± 0.2°, 17.9 ± 0.2° and 18.9 ± 0.2° (20, 1d.p).

[0850] In a yet further embodiment, the Form C polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0851] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterised by having major peaks as measured by XRPD at 8.7 ± 0.1°, 17.1 ± 0.1°, 17.9 ± 0.1° and 18.9 ± 0.1 ° (20, 1d.p).

[0852] In a yet further embodiment, the Form C polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0853] 3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterised by having major peaks as measured by XRPD at 8.7°, 17.1 °, 17.9° and 18.9° (20, 1d.p).

[0854] In a yet further embodiment, the Form C polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0855] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterised by interplanar spacing (d) values of 11.94 ± 0.5A, 11.19 ± 0.5A, 10.65 ± 0.5A, 10.16 ± 0.5A, 9.82 ± 0.5A, 8.50 ± 0.5A, 7.90 ± 0.5A, 7.62 ±

[0856] 0.5A, 7.19 ± 0.5A, 6.75 ± 0.5A, 6.37 ± 0.5A, 6.02 ± 0.5A, 5.61 ± 0.5A, 5.37 ± 0.5A, 5.18 ± 0.5A, 4.95 ±

[0857] 0.5A, 4.82 ± 0.5A, 4.69 ± 0.5A, 4.53 ± 0.5A, 4.35 ± 0.5A, 4.23 ± 0.5A, 4.07 ± 0.5A, 3.88 ± 0.5A, 3.82 ±

[0858] 0.5A, 3.77 ± 0.5A, 3.71 ± 0.5A, 3.57 ± 0.5A and 3.37 ± 0.5A (d, 2d.p.). In a yet further embodiment, the Form C polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0859] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1 -yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterised by interplanar spacing (d) values of 11.94 ± 0.2A, 11.19 ± 0.2A, 10.65 ± 0.2A, 10.16 ± 0.2A, 9.82 ± 0.2A, 8.50 ± 0.2A, 7.90 ± 0.2A, 7.62 ±

[0860] 0.2A, 7.19 ± 0.2A, 6.75 ± 0.2A, 6.37 ± 0.2A, 6.02 ± 0.2A, 5.61 ± 0.2A, 5.37 ± 0.2A, 5.18 ± 0.2A, 4.95 ±

[0861] 0.2A, 4.82 ± 0.2A, 4.69 ± 0.2A, 4.53 ± 0.2A, 4.35 ± 0.2A, 4.23 ± 0.2A, 4.07 ± 0.2A, 3.88 ± 0.2A, 3.82 ±

[0862] 0.2A, 3.77 ± 0.2A, 3.71 ± 0.2A, 3.57 ± 0.2A and 3.37 ± 0.2A (d, 2d.p.).

[0863] In a yet further embodiment, the Form C polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0864] 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1 -yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterised by interplanar spacing (d) values of 11.94 ± 0.1A, 11.19 ± 0.1A, 10.65 ± 0.1A, 10.16 ± 0.1A, 9.82 ± 0.1A, 8.50 + 0.1A, 7.90 ± 0.1A, 7.62 ±

[0865] 0.1A, 7.19 ± 0.1A, 6.75 ± 0.1A, 6.37 ± 0.1A, 6.02 ± 0.1A, 5.61 ± O.lA, 5.37 ± O.lA, 5.18 ± 0.1A, 4.95 ±

[0866] 0.1A, 4.82 ± 0.1A, 4.69 ± O.lA, 4.53 ± O.lA, 4.35 ± 0.1A, 4.23 ± 0.1A, 4.07 ± O.lA, 3.88 ± 0.1A, 3.82 ±

[0867] 0.1A, 3.77 ± 0.1A, 3.71 ± 0.1A, 3.57 ± 0.1 A and 3.37 ± O.lA (d, 2d.p.).

[0868] In a yet further embodiment, the Form C polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0869] 3.3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1 -yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1 -yl]ethan-1-one L-(+)-lactate is characterised by interplanar spacing (d) values of 11.94A, 11.19A, 10.65A, 10.16A, 9.82A, 8.50A, 7.90A, 7.62A, 7.19A, 6.75A, 6.37A, 6.02A, 5.61A, 5.37A, 5.18A, 4.95A, 4.82A, 4.69A, 4.53A, 4.35A, 4.23A, 4.07A, 3.88A, 3.82A, 3.77 , 3.71 A, 3.57A and 3.37A (d, 2d.p.).

[0870] In a further embodiment, the Form C polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3- dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1 -yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterised by a DSC peak temperature of 174.37°C ± 0.5°C (such as 174.37°C ± 0.2°C, in particular 174.37°C ± 0.1°C, more particularly 174.37°C).

[0871] In a yet further embodiment, the Form C polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0872] 3.3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1 -yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterised by a DSC onset temperature of 171.6°C ± 0.5°C (endotherm, sharp) (such as 171.6°C ± 0.2°C, in particular 171.6°C ± 0.1 °C, more particularly 171.6°C).

[0873] In a yet further embodiment, the Form C polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-

[0874] 3.3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1 -yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate is characterised by a DSC thermogram as depicted in Figure 17 of WO-A-2015 / 092420 labelled as 1. In one embodiment, a lactate (e.g. L-(+)-lactate) salt of 1 -{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)- 3,3-dimethyl-1 H,2H,3H-pyrrolo[3,2-b]pyridin-1 -yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one which is crystalline and is characterised by one or more (in any combination) or all of the following parameters:

[0875] (a) the1H NMR spectrum depicted in Figure 15; and / or

[0876] (b) an XRPD pattern having peaks at 7.4 + 0.5°, 7.9 ± 0.5°, 8.3 ± 0.5°, 8.7 ± 0.5°, 9.0 ± 0.5°, 10.4 ± 0.5°, 11.2 ± 0.5°, 11.6 ± 0.5°, 12.3 ± 0.5°, 13.1 ± 0.5°, 13.9 + 0.5°, 14.7 ± 0.5°, 15.8 ± 0.5°, 16.5 ± 0.5°, 17.1 ± 0.5°, 17.9 ± 0.5°, 18.4 ± 0.5°, 18.9 ± 0.5°, 19.6 ± 0.5°, 20.4 ± 0.5°, 21 .0 ± 0.5°, 21.8 ± 0.5°, 22.9 ± 0.5°, 23.3 ± 0.5°, 23.6 ± 0.5°, 24.0 ± 0.5°, 24.9 ± 0.5° and 26.4 ± 0.5° (20, 1 d.p); and / or

[0877] (c) an XRPD pattern substantially as shown in Figure 16 labelled as 1 ; and / or

[0878] (d) having peaks at the same diffraction angles (29) of the XRPD pattern shown in Figure 16 labelled as 1 and optionally wherein the peaks have the same relative intensity as the peaks shown in Figure 16 labelled as 1 ; and / or

[0879] (e) having major peaks at diffraction angles (20) and intensities as those shown in the XRPD pattern in Figure 16 labelled as 1 ; and / or

[0880] (f) having major peaks as measured by XRPD at 8.7 + 0.5°, 17.1 ± 0.5°, 17.9 ± 0.5° and 18.9 ± 0.5° (20, 1 d.p); and / or

[0881] (g) interplanar spacing (d) values of 11.94 ± 0.5 A, 11 .19 ± 0.5 A, 10.65 ± 0.5 A, 10.16 ± 0.5 A, 9.82 ± 0.5 A, 8.50 ± 0.5 A, 7.90 + 0.5 A, 7.62 ± 0.5 A, 7.19 ± 0.5 A, 6.75 ± 0.5 A, 6.37 ± 0.5 A, 6.02 ± 0.5 A, 5.61 ± 0.5 A, 5.37 ± 0.5 A, 5.18 ± 0.5 A, 4.95 ± 0.5 A, 4.82 ± 0.5 A, 4.69 ± 0.5 A, 4.53 ± 0.5 A, 4.35 ± 0.5 A, 4.23 ± 0.5 A, 4.07 ± 0.5 A, 3.88 ± 0.5 A, 3.82 ± 0.5 A, 3.77 ± 0.5 A, 3.71 ± 0.5 A, 3.57 ± 0.5 A and 3.37 ± 0.5 A (d, 2d.p.); and / or

[0882] (h) a DSC peak temperature of 174.37°C ± 0.5°C (such as 174.37°C ± 0.2°C, in particular 174.37°C ± 0.1°C, more particularly 174.37°C); and / or

[0883] (i) a DSC onset temperature of 171 ,6°C ± 0.5°C (endotherm, sharp) (such as 171 .6°C ± 0.2°C, in particular 171.6°C + 0.1°C, more particularly 171.6°C); and / or

[0884] (j) a DSC thermogram as depicted in Figure 17 of WO-A-2015 / 092420 labelled as 1.

[0885] In particular, the Form C polymorph of 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl- 1 H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4- yl]methyl}piperazin-1-yl]ethan-1-one L-(+)-lactate provides advantages with respect to stability and crystallinity.

[0886] Complexes

[0887] Formula (I) also includes within its scope complexes (e.g. inclusion complexes or clathrates with compounds such as cyclodextrins, or complexes with metals) of the compounds. Inclusion complexes, clathrates and metal complexes can be formed by means of methods well known to the skilled person.

[0888] Prod rugs Also encompassed by formula (I) are any pro-drugs of the compounds of the formula (I). By “prodrugs” is meant for example any compound that is converted in vivo into a biologically active compound of the formula (I).

[0889] For example, some prodrugs are esters of the active compound (e.g., a physiologically acceptable metabolically labile ester). During metabolism, the ester group (-C(=O)OR) is cleaved to yield the active drug. Such esters may be formed by esterification, for example, of any of the carboxylic acid groups (- C(=O)OH) in the parent compound, with, where appropriate, prior protection of any other reactive groups present in the parent compound, followed by deprotection if required.

[0890] Examples of such metabolically labile esters include those of the formula -C(=O)OR wherein R is: Ci-7alkyl (e.g., -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, -tBu);

[0891] Ci-7aminoalkyl (e.g., aminoethyl; 2-(N,N-diethylamino)ethyl; 2-(4-morpholino)ethyl); and acyloxy-Cwalkyi (e.g., acyloxymethyl; acyloxyethyl; pivaloyloxymethyl; acetoxymethyl; 1 -acetoxyethyl;

[0892] 1 -(1 -methoxy- 1 -methyl)ethyl-carbonxyloxyethyl; 1 -(benzoyloxy)ethyl; isopropoxy-carbonyloxymethyl;

[0893] 1 -isopropoxy-carbonyloxyethyl; cyclohexyl-carbonyloxymethyl; 1 -cyclohexyl-carbonyloxyethyl; cyclohexyloxy-carbonyloxymethyl; 1 -cyclohexyloxy-carbonyloxyethyl; (4-tetrahydropyranyloxy) carbonyloxymethyl; 1 -(4-tetrahydropyranyloxy)carbonyloxyethyl; (4- tetrahydropyranyl)carbonyloxymethyl; and 1 -(4-tetrahydropyranyl)carbonyloxyethyl).

[0894] Also, some prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound (for example, as in antigen-directed enzyme pro-drug therapy (ADEPT), gene-directed enzyme pro-drug therapy (GDEPT), and ligand-directed enzyme pro-drug therapy (LIDEPT), etc.). For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative. In one embodiment formula (I) does not include pro-drugs of the compounds of the formula (I) within its scope.

[0895] METHODS FOR THE PREPARATION OF COMPOUNDS OF FORMULA (I)

[0896] Compounds of the formula (I) can be prepared in accordance with synthetic methods well known to the skilled person.

[0897] Processes for preparing a compound of formula (I) as hereinbefore defined are provided in WO2015 / 092420.

[0898] The compounds of the invention can be isolated and purified according to standard techniques well known to the person skilled in the art and examples of such methods include chromatographic techniques such as column chromatography (e.g. flash chromatography) and HPLC. One technique of particular usefulness in purifying the compounds is preparative liquid chromatography using mass spectrometry as a means of detecting the purified compounds emerging from the chromatography column.

[0899] Preparative LC-MS is a standard and effective method used for the purification of small organic molecules such as the compounds described herein. The methods for the liquid chromatography (LC) and mass spectrometry (MS) can be varied to provide better separation of the crude materials and improved detection of the samples by MS. Optimisation of the preparative gradient LC method will involve varying columns, volatile eluents and modifiers, and gradients. Methods are well known in the art for optimising preparative LC-MS methods and then using them to purify compounds. Such methods are described in Ros entreter U, Huber U.; Optimal fraction collecting in preparative LC / MS ; J Comb Chem. 2004; 6(2), 159-64 and Leister W, Strauss K, Wisnoski D, Zhao Z, Lindsley C., Development of a custom high-throughput preparative liquid chromatography / mass spectrometer platform for the preparative purification and analytical analysis o f compound lib raries ; J Co mb Chem.' 2003; 5(3); 322-9. An example of such a system for purifying compounds via preparative LC-MS is described below in the Examples section of this application (under the heading “Mass Directed Purification LC-MS System”).

[0900] Methods of recrystallisation of compounds of formula (I) and salt thereof can be carried out by methods well known to the skilled person - see for example (P. Heinrich Stahl (Editor), Camille G. We rmuth (Editor), ISBN: 3-90639-026-8, Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Chapter 8, Publisher Wiley-VCH). Products obtained from an organic reaction are seldom pure when isolated directly from the reaction mixture. If the compound (or a salt thereof) is solid, it may be purified and / or crystallized by recrystallisation from a suitable solvent. A good recrystallisation solvent should dissolve a moderate quantity of the substance to be purified at elevated temperatures but only a small quantity of the substance at lower temperature. It should dissolve impurities readily at low temperatures or not at all. Finally, the solvent should be readily removed from the purified product. This usually means that it has a relatively low boiling point and a person skilled in the art will know recrystallising solvents for a particular substance, or if that information is not available, test several solvents. To get a good yield of purified material, the minimum amount of hot solvent to dissolve all the impure material is used. In practice, 3-5% more solvent than necessary is used so the solution is not saturated. If the impure compound contains an impurity which is insoluble in the solvent it may then be removed by filtration and then allowing the solution to crystallize. In addition, if the impure compound contains traces of coloured material that are not native to the compound, it may be removed by adding a small amount of decolorizing agent e.g. activating charcoal to the hot solution, filtering it and then allowing it to crystallize. Usually crystallization spontaneously occurs upon cooling the solution. If it is not, crystallization may be induced by cooling the solution below room temperature or by adding a single crystal of pure material (a seed crystal). Recrystallisation can also be carried out and / or the yield optimized by the use of an anti-solvent or co-solvent. In this case, the compound is dissolved in a suitable solvent at elevated temperature, filtered and then an additional solvent in which the required compound has low solubility is added to aid crystallization. The crystals are then typically isolated using vacuum filtration, washed and then dried, for example, in an oven or via desiccation.

[0901] Other examples of methods for purification include sublimation, which includes a heating step under vacuum for example using a cold finger, and crystallization from melt (Crystallization Technology Handbook 2nd Edition, edited by A. Mersmann, 2001).

[0902] Biomarker detection

[0903] In some embodiments, a sample of patient tissue is tested. The tissue typically comprises blood or a fraction of blood, and more typically is a plasma sample.

[0904] In some embodiments, the sample is entered into an in vitro diagnostic device, which measures the relevant expression or activity of the biomarker or biomarkers of interest.

[0905] The patient may typically be known or suspected to have cancer when the invention is carried out to confirm whether treatment is likely to be effective. In certain embodiments therefore, the method is for assessing whether a human patient, known or suspected to have cancer, can be treated using an IAP antagonist.

[0906] A method of the invention typically comprises detecting one or more of the identified biomarkers, and optionally further biomarkers, by using one or more detection reagents and / or detection techniques. The detection is typically carried out ex vivo on a sample from the patient, for example in vitro. In one embodiment, the biomarker is measured directly. In another embodiment, a biomarker substrate may be measured to measure biomarker levels indirectly.

[0907] By “detecting” is meant measuring, quantifying, scoring, or assaying the expression or activity level of the biomarkers. Methods of evaluating biological compounds, including biomarker proteins, genes or mRNA transcripts, are known in the art. It is recognized that methods of detecting a biomarker include direct measurements and indirect measurements. One skilled in the art will be able to select an appropriate method of assaying a particular biomarker.

[0908] A “detection reagent” is an agent or compound that specifically (or selectively) binds to, interacts with or detects the biomarker of interest. Such detection reagents may include, but are not limited to, an antibody, polyclonal antibody, or monoclonal antibody that preferentially binds a protein biomarker, or an oligonucleotide that is complementary to and binds selectively to an mRNA or DNA biomarker, typically under stringent hybridising conditions.

[0909] The phrase "specifically (or selectively) binds" or "specifically (or selectively) immunoreactive with," when referring to a detection reagent, refers to a binding reaction that is determinative of the presence of the biomarker in a heterogeneous population of biological molecules. For example under designated immunoassay conditions, the specified detection reagent (e.g. antibody) binds to a particular protein at least two times the background and does not substantially bind in a significant amount to other proteins present in the sample. Specific binding under such conditions may require an antibody that is selected for its specificity for a particular protein. A variety of immunoassay formats may be used to select antibodies specifically immunoreactive with a particular protein. For example, solid-phase ELISA immunoassays (enzyme linked immunosorbent assay) are routinely used to select antibodies specifically immunoreactive with a protein (see, e.g., Harlow & Lane, Antibodies, A Laboratory Manual (1988), for a description of immunoassay formats and conditions that can be used to determine specific immunoreactivity). Typically a specific or selective reaction will be at least twice the background signal or noise and more typically more than 10 to 100 times the background.

[0910] Technologies such as in situ hybridization (ISH), quantitative real-time polymerase reaction (qRT PCR) and immuno-histochemistry (IHC) have been traditionally used for diagnosing or detecting disease biomarkers. However, the emergence of high throughput, sensitive approaches such as next-generation sequencing, single molecule real-time sequencing, digital pathology and quantitative histopathology have created a shift in the enabling technology platform for a companion diagnostic or CDx. Quantitative histopathology and digital pathology are both medical imaging-based diagnostics approaches; they provide localization and measurement of protein biomarkers in a tissue sample. Tissue markers are identified and quantified using an automated, fluorescence-based imaging platform.

[0911] When the biomarker to be detected is a protein, methods for detection include antibody-based assays, protein array assays, mass spectrometry (MS) based assays, and (near) infrared spectroscopy based assays. For example, immunoassays, include but are not limited to competitive and non-competitive assay systems using techniques such as Western blots, radioimmunoassays, ELISA, "sandwich" immunoassays, immunoprecipitation assays, precipitin reactions, gel diffusion precipitin reactions, immunodiffusion assays, fluorescent immunoassays and the like. Such assays are routine and well known in the art.

[0912] To "analyze" includes determining a set of values associated with a sample by measurement of a marker (such as, e.g., presence or absence of a marker or constituent expression or activity levels) in the sample and comparing the measurement against measurement in a sample or set of samples from the same subject or other control subject(s). The markers of the present teachings can be analyzed by any of various conventional methods known in the art. To "analyze" can include performing a statistical analysis to, e.g., determine whether a subject is a responder or a non-responder to a therapy (e.g., an IAP antagonist treatment as described herein).

[0913] A "sample" in the context of the present teachings refers to any biological sample that is isolated from a subject, e.g., a blood sample or a biopsy. A sample can include, without limitation, a single cell or multiple cells, fragments of cells, an aliquot of body fluid, whole blood, platelets, serum, plasma, red blood cells, white blood cells or leucocytes, endothelial cells, tissue biopsies, synovial fluid, lymphatic fluid, ascites fluid, and interstitial or extracellular fluid. The term "sample" also encompasses the fluid in spaces between cells, including gingival crevicular fluid, bone marrow, cerebrospinal fluid (CSF), saliva, mucous, sputum, semen, sweat, urine, or any other bodily fluids. "Blood sample" can refer to whole blood or any fraction thereof, including blood cells, red blood cells, white blood cells or leukocytes, platelets, serum and plasma. Samples can be obtained from a subject by means including but not limited to venipuncture, excretion, ejaculation, massage, biopsy, needle aspirate, lavage, scraping, surgical incision, or intervention or other means known in the art. Analysis techniques

[0914] Prior to administration of a IAP antagonist, a patient may be screened to determine whether a disease or condition from which the patient is or may be suffering is one which would be susceptible to treatment with a compound which inhibits IAP, The term ‘patient’ includes human and veterinary subjects such as primates, in particular human patients.

[0915] For example, a biological sample taken from a patient may be analysed to determine whether a condition or disease, such as cancer, that the patient is or may be suffering from is one which is characterised by a genetic abnormality or abnormal protein expression which leads to up-regulation of the levels of IAP or to upregulation of a biochemical pathway downstream of IAP. Furthermore the biological sample taken from a patient may be analysed to determine whether a condition or disease, such as cancer, that the patient is or may be suffering from is one which is characterised by the biomarkers of the invention.

[0916] Examples of such abnormalities that result in activation or sensitisation of IAP, loss of, or inhibition of regulatory pathways impacting on IAP expression, up-regulation of receptors or their ligands, cytogenetic aberrations or presence of mutant variants of the receptors or ligands. Tumours with upregulation of IAP, in particular over-expression of IAP, may be particularly sensitive to inhibitors of IAP.

[0917] The terms “elevated” and “increased” includes up-regulated expression or over-expression, including gene amplification (i.e. multiple gene copies), cytogenetic aberration and increased expression by a transcriptional effect or post-translational effect. Thus, the patient may be subjected to a diagnostic test to detect a suitable protein or marker characteristic of up-regulation of the biomarkers of the invention. The term diagnosis includes screening.

[0918] The terms “reduced”, “depleted” or “decreased” includes lowered expression or reduced-expression, including down regulation (i.e. reduced gene copies), cytogenetic aberration and decreased expression by a transcriptional effect. Thus, the patient may be subjected to a diagnostic test to detect lower levels of a biomarker of the invention.

[0919] The diagnostic tests and screens are typically conducted on a biological sample (i.e. body tissue or body fluids) selected from tumour biopsy samples, blood samples (isolation and enrichment of shed tumour cells or isolation of circulating tumour DNA), cerebrospinal fluid, plasma, serum, saliva, stool biopsies, sputum, chromosome analysis, pleural fluid, peritoneal fluid, buccal spears, skin biopsy or urine. Typically, the sample is a blood sample, more typically a plasma sample.

[0920] In one embodiment, the sample obtained is a blood sample e.g. a plasma or serum sample, in particular a plasma sample.

[0921] In one embodiment, blood, usually collected in a serum-separating tube, is analysed in a medical laboratory or at the point of care. In a second embodiment the tumour is analysed by biopsy and analysed in a medical laboratory.

[0922] Screening methods could include, but are not limited to, standard methods such as reversetranscriptase polymerase chain reaction (RT-PCR), protein analysis or in-situ hybridization such as fluorescence in situ hybridization (FISH). Methods of identification and analysis of cytogenetic aberration, genetic amplification, deletions, down regulation, mutations and up-regulation of proteins are known to a person skilled in the art. Screening methods could include, but are not limited to, standard methods such as DNA sequence analysis by conventional Sanger or next-generation sequencing methods, reverse-transcriptase polymerase chain reaction (RT-PCR), RNA sequencing (RNAseq), Nanostring hybridisation proximity RNA nCounter assays, or in-situ hybridization such as fluorescence in situ hybridization (FISH) or allele-specific polymerase chain reaction (PCR). In addition, methods for assessing protein levels include immunohistochemistry or other immunoassays. Therefore, in one embodiment protein expression is analysed in the patient sample. In another embodiment gene expression is analysed in the patient sample for example gene aberration, using techniques such as FISH. Methods for assessing gene copy changes include techniques commonly used in cytogenetic laboratories such as MLPA (Multiplex Ligation-dependent Probe Amplification) a multiplex PCR method detecting abnormal copy numbers, or other PCR techniques which can detect gene amplification, gain and deletion.

[0923] In screening by RT-PCR, the level of mRNA in the tumour is assessed by creating a cDNA copy of the mRNA followed by amplification of the cDNA by PCR. Methods of PCR amplification, the selection of primers, and conditions for amplification, are known to a person skilled in the art. Nucleic acid manipulations and PCR are carried out by standard methods, as described for example in Ausubel, F.M. et al., eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc., or Innis, M.A. et al., eds. (1990) PCR Protocols: a guide to methods and applications, Academic Press, San Diego. Reactions and manipulations involving nucleic acid techniques are also describedin Sambrook et al., (2001 ), 3rd Ed, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press. Alternatively a commercially available kit for RT-PCR (for example Roche Molecular Biochemicals) may be used, or methodology as set forth in United States patents 4,666,828; 4,683,202; 4,801 ,531 ; 5,192,659, 5,272,057, 5,882,864, and 6,218,529 and incorporated herein by reference. Mutations, for example in the genes outlined herein, can be determined by PCR. In one embodiment the specific primer pairs are commercially available or as described in the literature.

[0924] An example of an in-situ hybridisation technique for assessing mRNA expression would be fluorescence in-situ hybridisation (FISH) (see Angerer (1987) Meth. EnzymoL, 152: 649).

[0925] Next generation sequencing (NGS), DNA sequencing or Nanostring can be performed.

[0926] Generally, in situ hybridization comprises the following major steps: (1 ) fixation of tissue to be analyzed; (2) prehybridization treatment of the sample to increase accessibility of target nucleic acid, and to reduce nonspecific binding; (3) hybridization of the mixture of nucleic acids to the nucleic acid in the biological structure or tissue; (4) post-hybridization washes to remove nucleic acid fragments not bound in the hybridization, and (5) detection of the hybridized nucleic acid fragments. The probes used in such applications are typically labelled, for example, with radioisotopes or fluorescent reporters. Certain probes are sufficiently long, for example, from about 50, 100, or 200 nucleotides to about 1000 or more nucleotides, to enable specific hybridization with the target nucleic acid(s) under stringent conditions. Standard methods for carrying out FISH are described in Ausubel, F.M. et al., eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc and Fluorescence In Situ Hybridization: Technical Overview by John M. S. Bartlett in Molecular Diagnosis ofCancer, Methods and Protocols, 2nd ed.; ISBN: 1-59259-760-2; March 2004, pps. 077-088; Series: Methods in Molecular Medicine.

[0927] Methods for gene expression profiling are described by (DePrimo et al. (2003), BMC Cancer, 3:3). Briefly, the protocol is as follows: double-stranded cDNA is synthesized from total RNA using a (dT)24 oligomer for priming first-strand cDNA synthesis, followed by second strand cDNA synthesis with random hexamer primers. The double-stranded cDNA is used as a template for in vitro transcription of cRNA using biotinylated ribonucleotides. cRNA is chemically fragmented according to protocols described by Affymetrix (Santa Clara, CA, USA), and then hybridized overnight on Human Genome Arrays. Alternatively, single nucleotide polymorphism (SNP) arrays, a type of DNA microarray, can be used to detect polymorphisms within a population.

[0928] In addition, test kits may use Nanostring technology or ddPCR.

[0929] Alternatively, the protein products expressed from the mRNAs may be assayed by immunohistochemistry of tumour samples (or other immunoassays), solid phase immunoassay with microtitre plates, Western blotting, 2-dimensional SDS-polyacrylamide gel electrophoresis, ELISA, flow cytometry and other methods known in the art for detection of specific proteins e.g. capillary electrophoresis. Detection methods would include the use of site specific antibodies. The skilled person will recognise that all such well-known techniques for detection of upregulation of IAP, detection of IAP variants or mutants, or loss of negative regulators of IAP, or the genes described herein are applicable in the present case. In particular levels of the genes described herein can be measured using immunohistochemistry. Expression in the cytoplasm can be assessed by staining of tumour cells. In some embodiments, one or both of the protein biomarkers of the invention are assayed using these techniques. In some embodiments, one or more biomarker substrates are assayed using these techniques.

[0930] Levels of proteins, in particular increased, decreased or abnormal levels of proteins can be measured using standard protein assays. Elevated or lowered levels, or under- or over-expression could also be detected in a tissue sample, for example, a tumour tissue by measuring the protein levels with an assay such as that from Chemicon International. The protein of interest would be immunoprecipitated from the sample lysate and its levels measured.

[0931] It will be appreciated that there are various analytical methods are available for determination, such as ELISA, immunoturbidimetry, rapid immunodiffusion, and visual agglutination.

[0932] Proximity Extension Assay (O-Link) or Aptamer-based (SomaScan, https: / / doi.org / 10.1371%2Fjournal.pone.0015004) technologies may also be used to determine protein levels in a sample.

[0933] Immunohistochemistry (IHC) is an important technique for biomarker detection. First, it allows direct visualization of biomarker expression in histologically relevant regions of the examined cancer tissue. Second, IHC is run on FFPE tissue sections processed by standard methods, ensuring the biomarker assay can be run on clinically available of specimens. Third, validated IHC assays can be implemented readily into clinical practice. For example, there are multiple validated IHC assays used clinically, such as assays to detect PD-L1 , HER2 and ALK (https: / / www.fda.gov / medical-devices / vitro-diagnostics / list- cleared-or-approved-companion-diagnostic-devices-vitro-and-imaging-tools). Traditionally, pathologists have visually scored IHC data. For example, in the calculation of an HSCORE, a summation of the percentage of area stained at each intensity level multiplied by the weighted intensity (e.g., 1 , 2, or 3; where 0 is no staining, 1 is weak staining, 2 is moderate staining and 3 is strong staining) of staining is generated [McCarty et al: Cancer Res 1986, 46:4244s-4248s], For assay validation purposes these analyses are frequently performed on specimens arrayed on stained TMA sections allowing representation of a sufficiently large number of specimens to for statistically rigorous testing. Tissue specimens are adequately represented by tissue cores on very few slides minimizing IHC cost and tissue usage, and facilitating intra-observer, inter-observer and inter-laboratory studies. Computer aided methods to classify image areas of interest (e.g., carcinomatous areas of tissue specimens) and quantify IHC staining intensity within those areas can also be utilised to generate data.

[0934] Such techniques will find equal applicability in the detection of other genes described herein. In some embodiments, detection of the increased levels of the genes described herein comprises a polymerase chain reaction (PCR) assay, or direct nucleic acid sequencing or hybridization with a nucleic acid probe specific for the genes.

[0935] Therefore all of these techniques could also be used to identify tumours particularly suitable for treatment with the IAP antagonists.

[0936] Ex-vivo functional assays could also be utilised where appropriate, for example measurement of circulating leukemia cells in a cancer patient, to assess the response to challenge with an IAP inhibitor.

[0937] Therefore in a further aspect of the invention includes use of IAP antagonist for the manufacture of a medicament for the treatment or prophylaxis of a disease state or condition in a patient who has been screened and has been determined as suffering from, or being at risk of suffering from, a disease or condition which would be susceptible to treatment with an IAP inhibitor.

[0938] Another aspect of the invention includes an IAP antagonist for use in the prophylaxis or treatment of cancer in a patient selected from a sub-population possessing loss of one or more biomarkers.

[0939] MRI determination of vessel normalization (e.g. using MRI gradient echo, spin echo, and contrast enhancement to measure blood volume, relative vessel size, and vascular permeability) in combination with circulating biomarkers may also be used to identify patients suitable for treatment with a compound of formula (I).

[0940] Thus a further aspect of the invention is a method for the diagnosis and treatment of a disease state or condition mediated by IAP, which method comprises (i) screening a patient to determine whether a disease or condition from which the patient is or may be suffering is one which would be susceptible to treatment with IAP inhibitor; and (ii) where it is indicated that the disease or condition from which the patient is thus susceptible, thereafter administering to the patient a IAP antagonists and sub-groups or examples thereof as defined herein.

[0941] In one embodiment the samples obtained from the patient are contacted with a primer, antibody, substrate or probe to determine the levels of biomarkers described herein. In one embodiment the method comprises: (i) contacting the patient sample with an antibody, substrate or probe, and (ii) determining the levels of genes described herein.

[0942] In one embodiment the method comprises: (i) contacting the patient sample with an antibody, and (ii) determining the levels of one or more biomarkers described herein. In an alternative embodiment, step (i) of the method comprises contacting the patient sample with one or more PCR primers for one or more biomarker substrates.

[0943] Protein levels can be determined using an ELISA Kit. ELISA kits for use on patient samples may be used in a clinical setting to assess blood chemistry. These utilise an antibody specific for the protein for example an anti-biomarker antibody or a conjugated antibody. In particular the antibody to be used is part of an FDA approved in vitro diagnostic kit. In one embodiment, the level is determined using a test that complies with the standard as defined by the Association for Clinical Biochemistry (ACB).

[0944] In one embodiment the method comprises: (i) contacting the patient sample with an antibody, and (ii) determining the levels of proteins described herein.

[0945] In particular, the sample is contacted under conditions to quantify the levels.

[0946] For example, in the contacting step above the sample is contacted with primer, probe, substrate or antibody typically in the presence of a buffer. The substrate may be e.g. a fluorescent probe.

[0947] Patient Selection

[0948] It will be appreciated that the patient selected for treatment with an IAP antagonist according to the invention will be tested for or will be measured for one or more biomarkers in accordance with the methodology described in the previous section.

[0949] For example, such a selected patient will have: decreased or low expression or activity of one or more of the biomarkers.

[0950] In one embodiment, the selected patient exhibits or presents with at least one symptom of cancer.

[0951] In one embodiment, the selected cancer patient has not previously been treated with an IAP antagonist. In one embodiment, the selected patient has not previously responded to therapy with an IAP antagonist.

[0952] In some embodiments, a nucleic acid expression profile is determined by PCR, HTG EdgeSeq or a quantitative gene expression assay such as NanoString nCounter. In some embodiments, a protein expression profile is determined by an immunoassay.

[0953] In one embodiment, the protein level of one or more of the biomarkers is decreased relative to the amount of said protein in a control sample obtained from an IAP antagonist non-responsive subject.

[0954] Upper limit of normal (ULN) refers to those levels that are at 95% of the whole range. It is a set of values within which 95 percent of the normal population falls (that is, 95% prediction interval).

[0955] In one embodiment, the reduced level is a < 1 fold difference relative to the control sample or the upper limit of normal (ULN), such as a fold difference of 0.75, 0.5, 0.4, 0.3, 0.2, 0.15, 0.1 , 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02 or 0.01 or any ranges therebetween. In one embodiment, the reduced level is between 1 and 0.01 fold difference relative to the control sample or ULN. In one embodiment, the reduced level is very low for example a > 0.01 fold difference relative to the control sample, ULN or sample taken from said patient, such as a fold difference of 0.001 or any ranges therebetween. In one embodiment, the reduced level is 0 i.e. completely absent.

[0956] In another embodiment the level of the biomarker or biomarkers is determined by immunohistochemistry.

[0957] Proteins, protein complexes or proteomic markers may be specifically identified and / or quantified by a variety of methods known in the art and may be used alone or in combination. Immunologic- or antibodybased techniques include enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), western blotting, immunofluorescence, microarrays, some chromatographic techniques (i.e. immunoaffinity chromatography), flow cytometry, immunoprecipitation and the like. Such methods are based on the specificity of an antibody or antibodies for a particular epitope or combination of epitopes associated with the protein or protein complex of interest. Non-immunologic methods include those based on physical characteristics of the protein or protein complex itself. Examples of such methods include electrophoresis, some chromatographic techniques (e.g. high performance liquid chromatography (HPLC), fast protein liquid chromatography (FPLC), affinity chromatography, ion exchange chromatography, size exclusion chromatography and the like), mass spectrometry, sequencing, protease digests, and the like. Such methods are based on the mass, charge, hydrophobicity or hydrophilicity, which is derived from the amino acid complement of the protein or protein complex, and the specific sequence of the amino acids.

[0958] In one embodiment there is no expression of the one or more biomarkers. Samples having low levels of one or more biomarkers can be identified as biomarker negative, for example biomarker loss.

[0959] In one embodiment, the expression level of one or more of the biomarkers is reduced by 50%, 60%, 70%, 80%, 90%, 95%, 96, 97%, 98%, 99%, 99.5%, 99.9% or 100%. 100% reduction in expression is completely reduced i.e. total loss. In some embodiments, at least 50% reduction is provided. In some embodiments, at least 75% reduction is provided.

[0960] In some embodiments, at least 80% reduction is provided.

[0961] In some embodiments, at least 95% reduction is provided, for example at least 99%.

[0962] Methods of quantifying

[0963] The invention relates to identifying a patient for treatment with an IAP antagonist. In some embodiments, the methods comprise at least the steps of:

[0964] (a) contacting a sample from the patient with an antibody against one or more biomarkers, (or one or more biomarker substrates);

[0965] (b) performing an ELISA or immunohistochemical assay on said sample; (c) determining the level of one or more biomarkers; and

[0966] (d) identifying the patient as a candidate for treatment with an IAP antagonist when (i) the level of one or more biomarkers is reduced relative to the upper limit of normal (ULN); or (ii) one or more biomarkers are absent; or (iii) the level of one or more biomarkers is low relative to the upper limit of normal (ULN).

[0967] In other embodiments, the method for identifying a patient for treatment with an IAP antagonist comprises:

[0968] (a) contacting a sample from the patient with an antibody against one or more biomarkers (and / or one or more biomarker substrates) to determine the level of protein expression; and / or

[0969] (b) contacting a sample from the patient with an antibody against one or more different biomarkers to (a) (and / or one or more biomarker substrates) to determine the level of protein expression;

[0970] (c) treating the patient with an IAP antagonist when the level of the one or more biomarkers is reduced relative to the upper limit of normal (ULN)

[0971] Also described is a method for identifying or selecting a patient for treatment with an IAP antagonist, the method comprising:

[0972] (a) contacting a sample from the patient with an antibody one or more biomarkers to determine the level of protein expression; and / or

[0973] (b) contacting a sample from the patient with an antibody against one or more biomarkers to determine the level of protein expression; and / or

[0974] (c) contacting a sample from the patient with a plurality of oligonucleotide primers, said plurality of primers comprising at least one pair of oligonucleotide primers for any one or more biomarkers;

[0975] (d) treating the patient with an IAP antagonist when the level of one or more biomarkers is reduced relative to the upper limit of normal (ULN).

[0976] The selected patient is typically a cancer patient. A patient is typically selected when the patient has a level of one or more biomarkers in the biological sample from the patient that is lower than a predetermined value (or is absent).

[0977] A method for predicting efficacy of an IAP antagonist for a cancer in a patient, comprises determining the level of one or more biomarkers in the biological sample from the patient, where a biological sample level of one or more biomarkers is less than a predetermined value is predictive of efficacy in the patient.

[0978] Systems for carrying out the methods

[0979] The methods described herein can make use of a system to assist in the assessment or prognosis of the patient. The system can be a single apparatus having various device components (units) integrated therein. The system can also have its various components, or some of these components, as separate apparatuses. The components can comprise a measurement device, a graphical user interface and a computer-processing unit.

[0980] The system typically comprises a data connection to an interface, whereby the interface itself can be a part of the system or can be a remote interface. The latter refers to the possibility to use a different apparatus, preferably a handheld apparatus such as a smartphone or a tablet computer, for providing the actual interface. The data connection in such cases will preferably involve wireless data transfer such as by Wi-Fi or Bluetooth, or by other techniques or standards.

[0981] In certain embodiments, the measurement device is configured to receive a tissue sample, for example by putting one or more cancer cells or a drop of blood on a cartridge, which can be inserted into the device. The device can be an existing device that is capable to determine, from the same sample, the levels of the biomarker or biomarkers. A processing unit can receive numerical values for the protein concentrations from the measurement device. The processing unit is typically provided with software (typically embedded software) allowing it to calculate a score based on the input data.

[0982] In another embodiment, a system for assessing whether a human cancer patient is suitable for treatment with an IAP antagonist comprises:

[0983] (a) detection means able and adapted to detect in a sample from the human patient the biomarker or biomarkers of the invention. Such means are known, and easily accessible to the skilled person. Typically, there is provided a container for receiving a sample of a subject therein, the container provided with the detection means;

[0984] (b) a processor able and adapted to determine from the determined concentrations of said proteins an indication of the patient’s likelihood of being treated with an IAP antagonist.

[0985] Optionally, the system comprises a user interface (or a data connection to remote interface), particularly a graphical user interface (GUI), capable of presenting information; a GUI is a type of user interface that allows users to interact with electronic devices through graphical icons and visual indicators such as secondary notation, instead of text-based user interfaces, typed command labels or text navigation (none of such interface types being excluded in the present invention); GUIs are generally known, and are used typically in handheld mobile devices such as MP3 players, portable media players, gaming devices, smartphones and smaller household, office and industrial controls; as said, the interface optionally can also be chosen so as to be capable of putting in information, such as, information on the patient.

[0986] In one embodiment, a system for determining the suitability of a human cancer patient for treatment with an IAP antagonist comprises a storage memory for storing data associated with a sample from the patient comprising data associated with a panel of biomarkers indicating biomarker expression levels in the sample from the subject, the panel of biomarkers comprising one or more biomarkers of the invention; and a processor communicatively coupled to the storage memory for classifying the patient. Kits

[0987] The invention also provides, either separately or as part of the aforementioned system, a kit for detecting one or more of the biomarkers of the invention, to assess a patient’s likelihood of responding to IAP inhibition for cancer therapy. The kit typically comprises one or more detection reagents for detecting one or more of the biomarkers of the invention. These reagents may be for direct detection or indirect detection of the biomarker, for example detection of a correlated substrate.

[0988] Typically, the kit comprises two or more, or three or more, detection reagents, each directed to a different biomarker of the invention.

[0989] As discussed above with reference to the methods of the invention, the kit may comprise more detection reagents, such as for other proteins. In a preferred embodiment the detection reagents made available in the kit consist of the detection reagents for the detection of two, three or four proteins making up a biomarker panel of the invention, as mentioned.

[0990] The kit may comprise a solid support, such as a chip, a microtiter plate or a bead or resin comprising said detection reagents. In some embodiments, the kits comprise mass spectrometry probes.

[0991] The kit may also provide washing solutions and / or detection reagents specific for either unbound detection reagent or for said biomarkers (sandwich type assay).

[0992] Such kits will suitably comprise a biosensor for detection and / or quantification of one or more of the biomarkers of the invention, optionally together with instructions for use of the kit in accordance with the methodology as described herein.

[0993] There are well established genetic and biochemical means of characterising the state of one or more of the biomarkers of the invention. There are also well established biochemical means of characterising the amount of proteins in blood e.g. serum samples.

[0994] In one embodiment, the invention includes a packaged cancer treatment. The packaged treatment includes a composition packaged with instructions for using an effective amount of the composition of the invention for an intended use in a patient selected using the present invention. In other embodiments, the present invention provides a use of any of the compositions of the invention for manufacture of a medicament to treat cancer in a subject.

[0995] In one embodiment the invention provides a kit or panel or array for determining the level of one or more of the biomarkers of the invention from a single patient sample.

[0996] BIOLOGICAL EFFECTS

[0997] The compounds described herein, subgroups and examples thereof, may be useful in alleviating or reducing the incidence of cancer in a patient identified as likely to be responsive to treatment based on the biomarkers described herein.

[0998] The compounds described herein may be useful for the treatment of the adult population. The compounds of the present invention may be useful for the treatment of the pediatric population. The compounds described herein are antagonists of inhibitor of apoptosis protein (IAP), and which may be useful in preventing or treating disease states or conditions described herein. The compounds for use in the invention, and subgroups thereof, will be useful in preventing or treating diseases or condition mediated by IAP. References to the preventing or prophylaxis or treatment of a disease state or condition such as cancer include within their scope alleviating or reducing the incidence of cancer.

[0999] More particularly, the compounds of the formula (I) and sub-groups thereof are antagonists of IAP. For example, compounds of the invention have affinity against XIAP, clAP1 and / or clAP2, and in particular an IAP selected from XIAP and clAP1 .

[1000] Particular compounds are compounds that have affinity for one or more IAP selected from XIAP, clAP1 and clAP2. Particular compounds of the invention are those having IC50 values of less than 0.1 pM.

[1001] The antagonist compounds of formula (I) are capable of binding to IAP and exhibiting potency for IAP. In one embodiment the antagonist compounds of formula (I) exhibit selectivity for one or more IAP over other IAP family members, and may be capable of binding to and / or exhibiting affinity for XIAP and / or clAP in preference to binding to and / or exhibiting affinity for other of the IAP family members.

[1002] In addition many of the compounds of the invention exhibit selectivity for the XIAP compared to clAP or vice versa, selectivity for the clAP compared to XIAP (in particular clAP1 ), and such compounds represent one embodiment of the invention. In particular compounds of the invention may have at least 10 times greater affinity against one or more IAP family member in particular XIAP, clAP1 and / or clAP2 than other IAP family members. This can be determined using the methods described herein. In a further embodiment compounds of the invention may have e...

Claims

CLAIMS:1 . An IAP antagonist for use in a method of treating a cancer in a patient, wherein the patient has been selected for IAP antagonist treatment on the basis of a biomarker level in the patient, and wherein the biomarker is one or more of: a. IL-2Ra, IL-6r, CRP, EPO, CD27, CD40, TN-C, IL-18, PLGF, TNFrl, and MCP-4; b. TECK, IL-8, Alpha-1 -Antitrypsin, IL-6R(3, FRTN, and Cathepsin D; or c. TN-C, IL-2Ra, Cathepsin D, CD27, IL-6r, MMP-7, CRP, HGF, C3, G-CSF, VCAM-1 , ICAM-1, haptoglobin, TNFR2, HB-EGF, IL-6, IL-1 RII, IL-1 Ra, MIP-3 alpha, FGF-21 , PLGF, IL-10, CD40, SCF, TIMP-1 , B2M, IL-1R1 , IL-1 beta, YKL-40, vWF, VEGF, and PARC; or d. TECK, PLGF, FAS, C3, MMP-2, HGF, FasL, VCAM-1 , Tweak, IL-1 ra, IL-6R beta, VEGF, 6Ckine, Haptoglobin, Eotaxin-2, MCP-1 , TRAIL-R3, PAS-f, IL-1 beta, and IL- 2Ra; or e. IL-2Ra, VCAM-1 , PAI-1 , TIMP-1 , IgA, RANTES, IL-1 p, CD27, MIP-3p, MIP-3a, TNFR2, TN-C, VEGF, Cathepsin D, BDNF, MPO, HB-EGF, OPG, MMP-2, ANG-2, Myoglobin, IL-16, ICAM-1 , TNF Rl, IL-12p40, MMP-1 , and B2M; or f. Tweak, FAS, TNFR2, VCAM-1 , E-Selectin, CD40, I L-6r, MPO, FRTN, C3, CD27, PSA-f, EGFR, IL-1 RI, YKL-40, IL-17, Eotaxin-2, IL-1ra, ENA-78, AXL, MCP-4, TIMP-1 , Myoglobin, MMP-3, IL-8, MIP-3 (3, IL-16, HGF, BDNF, and IL-2Ra; or g. DIABLO, XIAP, BIRC3, MAP3K7, CYLD, BIRC2, TRAF2, MAP3K14, BAX, UBE2N, IKBKB, HTRA2, BCL2, IKBKG, BAK1 , CASP3, RIPK1 , BCL2L1, TBK1 , and RIPK2; or h. HTRA2, CD27, CYCS, BCL2, BIK, CRP, BAK1 , AIFM1 , ENDOG, USP13, USP10, BECN1 , BCL2L1 , PENK, APAF1 , REST, HIP1 , BAX, XIAP, and IL-10.

2. An IAP antagonist for use in a method according to claim 1 , wherein the patient is selected for treatment on the basis of a single biomarker.

3. An IAP antagonist for use in a method according to claim 1 or claim 2, wherein the patient is selected for treatment on the basis of the biomarker level in their blood plasma.

4. An IAP antagonist for use in a method according to any of claims 1 to 3, wherein the biomarker is assessed in a sample obtained from the patient.

5. An IAP antagonist for use in a method according to any of claims 1 to 4, wherein the patient is selected for treatment on the basis of a comparison to: the biomarker level in a control that is known to represent successful treatment; and / or the biomarker level in a control that is known to represent unsuccessful treatment, optionally wherein the patient is selected for treatment when the biomarker level is less than the level in the control that is known to represent unsuccessful treatment; or the biomarker level at a different time point; optionally where the different time points are before and after the first dose of the IAP antagonist.

6. An IAP antagonist for use in a method according to any of claims 1 to 4, wherein the patient is selected for treatment on the basis of a comparison to an established threshold, wherein the established threshold was determined using: a biomarker level that is known to represent successful treatment; and / or a biomarker level that is known to represent unsuccessful treatment.

7. An IAP antagonist for use according to any of claims 1 to 6, wherein the biomarker is: a. IL-2Ra, I L-6r or CRP; or b. TECK, PLGF, FAS, 03, MMP-2, HGF, FasL, VCAM-1 , Tweak, IL-1 ra, IL-6R beta, VEGF, 6Ckine, Haptoglobin, Eotaxin-2, MCP-1 , TRAIL-R3, PAS-f, IL-1 beta, or IL-2Ra; or c. TN-C, IL-2Ra, Cathepsin D, CD27, IL-6r, MMP-7, CRP, HGF, C3, G-CSF, VCAM-1 , ICAM-1 , haptoglobin, TNFR2, HB-EGF, IL-6, IL-1 RII, IL-1 Ra, MIP-3 alpha, FGF-21, PLGF, IL-10, CD40, SCF, TIMP-1 , B2M, IL-1 R1 , IL-1 beta, YKL-40, vWF, VEGF, or PARC; and wherein the level of the biomarker is assessed 2, 3, 4, 5 or 6 weeks after the first dose of the IAP inhibitor, typically approximately 4 weeks after the first dose, optionally after an off-treatment period, optionally wherein the off-treatment period is one week or more.

8. An IAP antagonist for use according to any of claims 1 to 6, wherein the biomarker is: a. EPO, CD27, CD40, TN-C, IL-18, PLGF, TNFrl, IL-6r or MCP-4; or b. TECK, IL-8, Alpha-1 -Antitrypsin, IL-6R [3, FRTN, or Cathepsin D, and wherein the level of the biomarker is assessed before the first dose of the IAP inhibitor or up to 24 hours after the first dose.

9. An IAP antagonist for use according to claim 8, wherein the level of the biomarker is assessed 14 days or less, 10 days or less, or 7 days or less before the first dose of IAP antagonist.

10. An IAP antagonist for use according to any preceding claim, wherein the cancer is a blood cancer, typically a T-Cell Lymphoma.

11. An IAP antagonist for use according to any preceding claim, wherein the cancer is Peripheral T-Cell Lymphoma (PTCL) or Cutaneous T-Cell Lymphoma (CTCL).

12. An IAP antagonist for use according to claim 10, wherein the biomarker is a protein detected using an immunoassay, a protein-binding assay, an antibody-based assay, an antigen-binding protein-based assay, a protein-based array, an enzyme-linked immunosorbent assay (ELISA), flow cytometry, a protein array, a blot, a Western blot, nephelometry, turbidimetry, chromatography, mass spectrometry, enzymatic activity, a radioimmunoassay, immunofluorescence, immunochemiluminescence, immunoelectrochemiluminescence, immunoelectrophoretic, a competitive immunoassay, immunoprecipitation immunohistochemistry, Proximity Extension Assay or an aptamer-based assay.

13. An IAP antagonist for use according to any preceding claim, wherein the cancer cells undergo necroptosis following the treatment step.

14. An IAP antagonist for use according to any preceding claim, wherein the IAP antagonist is an antagonist of one, two or all three of X chromosome-linked inhibitor of apoptosis protein (XIAP), cellular IAP 1 (clAP1) and cellular IAP 2 (clAP2).

15. An IAP antagonist for use according to any preceding claim, wherein the IAP antagonist is tolinapant or a pharmaceutically acceptable salt or solvate thereof.

16. An IAP antagonist for use according to any preceding claim, wherein the patient has been selected for IAP antagonist treatment on the basis of a change in biomarker level in the patient at different time points.

17. Use of the level or amount of one or more of: a. IL-2Ra, IL-6r, CRP, EPO, EPO, CD27, CD40, TN-C, IL-18, PLGF, TNFrl and MCP-4; or b. TECK, IL-8, Alpha-1 -Antitrypsin, IL-6Rp, FRTN, and Cathepsin D; or c. TN-C, IL-2Ra, Cathepsin D, CD27, IL-6r, MMP-7, CRP, HGF, C3, G-CSF, VCAM-1 , ICAM-1, haptoglobin, TNFR2, HB-EGF, IL-6, IL-1RI1, IL-1Ra, MIP-3 alpha, FGF-21 , PLGF, IL-10, CD40, SCF, TIMP-1 , B2M, IL-1 R1 , IL-1 beta, YKL-40, vWF, VEGF, and PARC; or d. TECK, PLGF, FAS, C3, MMP-2, HGF, FasL, VCAM-1 , Tweak, IL-1 ra, IL-6R beta, VEGF, 6Ckine, Haptoglobin, Eotaxin-2, MCP-1 , TRAIL-R3, PAS-f, IL-1 beta, and IL- 2Ra; or e. IL-2Ra, VCAM-1 , PAI-1 , TIMP-1 , IgA, RANTES, IL-1 p, CD27, MIP-30, MIP-3a, TNFR2, TN-C, VEGF, Cathepsin D, BDNF, MPO, HB-EGF, OPG, MMP-2, ANG-2, Myoglobin, IL-16, ICAM-1 , TNF Rl, IL-12p40, MMP-1 , and B2M; or f. Tweak, FAS, TNFR2, VCAM-1 , E-Selectin, CD40, IL-6r, MPO, FRTN, C3, CD27, PSA-f, EGFR, IL-1 RI, YKL-40, IL-17, Eotaxin-2, IL-1ra, ENA-78, AXL, MCP-4, TIMP-1 , Myoglobin, MMP-3, IL-8, MIP-3 p, IL-16, HGF, BDNF, and IL-2Ra; or g. DIABLO, XIAP, BIRC3, MAP3K7, CYLD, BIRC2, TRAF2, MAP3K14, BAX, UBE2N, IKBKB, HTRA2, BCL2, IKBKG, BAK1 , CASP3, RIPK1 , BCL2L1 , TBK1 , and RIPK2; or h. HTRA2, CD27, CYCS, BCL2, BIK, CRP, BAK1 , AIFM1, ENDOG, USP13, USP10, BECN1 , BCL2L1 , PENK, APAF1 , REST, HIP1 , BAX, XIAP, and IL-10, in a cancer cell sample of a human patient, as a biomarker or biomarkers for assessing whether the cancer is susceptible to treatment with an IAP antagonist, for example wherein the IAP antagonist is tolinapant or a pharmaceutically acceptable salt or solvate thereof.

18. A method for prognosing or assessing the responsiveness of a human cancer patient to treatment with an IAP antagonist, comprising assessing the level or amount in a sample from a cancer patient of one or more of: a. IL-2Ra, IL-6r, CRP, EPO, CD27, CD40, TN-C, IL-18, PLGF, TNFrl and MCP-4; orb. TECK, IL-8, Alpha-1 -Antitrypsin, IL-6R£, FRTN, and Cathepsin D; or c. TN-C, IL-2Ra, Cathepsin D, CD27, IL-6r, MMP-7, CRP, HGF, C3, G-CSF, VCAM-1 , ICAM-1 , haptoglobin, TNFR2, HB-EGF, IL-6, IL-1 RII, IL-1 Ra, MIP-3 alpha, FGF-21 , PLGF, IL-10, CD40, SCF, TIMP-1 , B2M, IL-1 R1 , IL-1 beta, YKL-40, vWF, VEGF, and PARC; or d. TECK, PLGF, FAS, C3, MMP-2, HGF, FasL, VCAM-1 , Tweak, IL-1 ra, IL-6R beta, VEGF, 6Ckine, Haptoglobin, Eotaxin-2, MCP-1 , TRAIL-R3, PAS-f, IL-1 beta, and IL- 2Ra; or e. IL-2Ra, VCAM-1 , PAI-1 , TIMP-1 , IgA, RANTES, IL-1 [3, CD27, MIP-3 , MIP-3a, TNFR2, TN-C, VEGF, Cathepsin D, BDNF, MPO, HB-EGF, OPG, MMP-2, ANG-2, Myoglobin, IL-16, ICAM-1 , TNF Rl, IL-12p40, MMP-1 , and B2M; or f. Tweak, FAS, TNFR2, VCAM-1 , E-Selectin, CD40, 1 L-6r, MPO, FRTN, C3, CD27, PSA-f, EGFR, IL-1 RI, YKL-40, IL-17, Eotaxin-2, IL-1 ra, ENA-78, AXL, MCP-4, TIMP-1 , Myoglobin, MMP-3, IL-8, MIP-3 p, IL-16, HGF, BDNF, and IL-2Ra; or g. DIABLO, XIAP, BIRC3, MAP3K7, CYLD, BIRC2, TRAF2, MAP3K14, BAX, UBE2N, IKBKB, HTRA2, BCL2, IKBKG, BAK1 , CASP3, RIPK1 , BCL2L1 , TBK1 , and RIPK2; or h. HTRA2, CD27, CYCS, BCL2, BIK, CRP, BAK1 , AIFM1 , ENDOG, USP13, USP10, BECN1 , BCL2L1 , PENK, APAF1 , REST, HIP1 , BAX, XIAP, and IL-10, and determining whether the tested amount or level indicates that the cancer should be treated with an IAP antagonist.

19. A method according to claim 18, wherein the assessment step comprises comparing the amount or level with the amount or level associated with responsiveness or non-responsiveness to treatment with an IAP antagonist.

20. A method according to claim 18 or claim 19, wherein the patient is classified into a group based on the biomarker profile, optionally wherein the groups comprise or consist of:(i) responders and non-responders; or(ii) strong responders.21 . A method according to any of claims 18 to 20, wherein the patient is identified for treatment with the IAP antagonist when a decreased level or amount of one or more of the biomarkers is detected, relative to the level or amount associated with non-responsiveness to treatment with an IAP antagonist.

22. A method according to any of claims 18 to 21 , comprising the step of detecting the amount or level of the biomarkers in a sample of plasma from said human patient.

23. A method according to claim 22, wherein the detection is carried out using an in vitro detection assay.

24. A method of determining the susceptibility of a human cancer patient to treatment with an IAP antagonist, comprising detecting in a sample of plasma from the patient the level or amount of one or more of: a. IL-2Ra, IL-6r, CRP, EPO, CD27, CD40, TN-C, IL-18, PLGF, TNFrl and MCP-4; or b. TECK, IL-8, Alpha-1 -Antitrypsin, IL-6R0, FRTN, and Cathepsin D; or c. TN-C, IL-2Ra, Cathepsin D, CD27, IL-6r, MMP-7, CRP, HGF, C3, G-CSF, VCAM-1, ICAM-1, haptoglobin, TNFR2, HB-EGF, IL-6, IL-1RII, IL-1 Ra, MIP-3 alpha, FGF-21 , PLGF, IL-10, CD40, SCF, TIMP-1 , B2M, IL-1 R1 , IL-1 beta, YKL-40, vWF, VEGF, and PARC; or d. TECK, PLGF, FAS, C3, MMP-2, HGF, FasL, VCAM-1 , Tweak, IL-1 ra, IL-6R beta, VEGF, 6Ckine, Haptoglobin, Eotaxin-2, MCP-1 , TRAIL-R3, PAS-f, IL-1 beta, and IL- 2Ra; or e. IL-2Ra, VCAM-1, PAI-1 , TIMP-1 , IgA, RANTES, IL-1 0, CD27, MIP-30, MIP-3a, TNFR2, TN-C, VEGF, Cathepsin D, BDNF, MPO, HB-EGF, OPG, MMP-2, ANG-2, Myoglobin, IL-16, ICAM-1 , TNF Rl, IL-12p40, MMP-1 , and B2M; or f. Tweak, FAS, TNFR2, VCAM-1 , E-Selectin, CD40, IL-6r, MPO, FRTN, C3, CD27, PSA-f, EGFR, IL-1 Rl, YKL-40, IL-17, Eotaxin-2, IL-1ra, ENA-78, AXL, MCP-4, TIMP-1 , Myoglobin, MMP-3, IL-8, MIP-3 0, IL-16, HGF, BDNF, and IL-2Ra; or g. DIABLO, XIAP, BIRC3, MAP3K7, CYLD, BIRC2, TRAF2, MAP3K14, BAX, UBE2N, IKBKB, HTRA2, BCL2, IKBKG, BAK1 , CASP3, RIPK1, BCL2L1 , TBK1 , and RIPK2; or h. HTRA2, CD27, CYCS, BCL2, BIK, CRP, BAK1 , AIFM1 , ENDOG, USP13, USP10, BECN1 , BCL2L1 , PENK, APAF1 , REST, HIP1 , BAX, XIAP, and IL-10, and assessing whether the cancer in the patient is likely to respond to treatment with a IAP antagonist on the basis of the amount or level of the biomarkers in the sample.

25. A method of detecting the amount or level of one or more of: a. IL-2Ra, IL-6r, CRP, EPO, CD27, CD40, TN-C, IL-18, PLGF, TNFrl and MCP-4; or b. TECK, IL-8, Alpha-1 -Antitrypsin, IL-6R0, FRTN, and Cathepsin D; or c. TN-C, IL-2Ra, Cathepsin D, CD27, IL-6r, MMP-7, CRP, HGF, C3, G-CSF, VCAM-1 , ICAM-1 , haptoglobin, TNFR2, HB-EGF, IL-6, IL-1 RII, IL-1Ra, MIP-3 alpha, FGF-21 , PLGF, IL-10, CD40, SCF, TIMP-1 , B2M, IL-1 R1 , IL-1 beta, YKL-40, vWF, VEGF, and PARC; or d. TECK, PLGF, FAS, C3, MMP-2, HGF, FasL, VCAM-1 , Tweak, IL-1 ra, IL-6R beta, VEGF, 6Ckine, Haptoglobin, Eotaxin-2, MCP-1 , TRAIL-R3, PAS-f, IL-1 beta, and IL- 2Ra; or e. IL-2Ra, VCAM-1 , PAI-1 , TIMP-1 , IgA, RANTES, IL-1 0, CD27, MIP-30, MIP-3a, TNFR2, TN-C, VEGF, Cathepsin D, BDNF, MPO, HB-EGF, OPG, MMP-2, ANG-2, Myoglobin, IL-16, ICAM-1 , TNF Rl, IL-12p40, MMP-1 , and B2M; orf. Tweak, FAS, TNFR2, VCAM-1 , E-Selectin, CD40, IL-6r, MPO, FRTN, C3, CD27, PSA-f, EGFR, IL-1 RI, YKL-40, IL-17, Eotaxin-2, IL-1ra, ENA-78, AXL, MCP-4, TIMP-1 , Myoglobin, MMP-3, IL-8, MIP-3 p, IL-16, HGF, BDNF, and IL-2Ra; or g. DIABLO, XIAP, BIRC3, MAP3K7, CYLD, BIRC2, TRAF2, MAP3K14, BAX, UBE2N, IKBKB, HTRA2, BCL2, IKBKG, BAK1 , CASP3, RIPK1 , BCL2L1 , TBK1 , and RIPK2; or h. HTRA2, CD27, CYCS, BCL2, BIK, CRP, BAK1 , AIFM1 , ENDOG, USP13, USP10, BECN1 , BCL2L1 , PENK, APAF1 , REST, HIP1 , BAX, XIAP, and IL-10, in a human patient suffering from cancer.

26. A method according to claim 25, comprising the steps of:(a) obtaining a sample of plasma from a human patient; and(b) detecting the level or amount of said biomarker or biomarkers present in the sampled plasma by contacting the sample with one or more reagents for detecting expression of the biomarker or biomarkers.

27. A method according to any of claims 20 to 26, wherein the IAP antagonist is an antagonist one, two or all three of X chromosome-linked inhibitor of apoptosis protein (XIAP), cellular IAP 1 (clAP1 ) and cellular IAP 2 (clAP2).

28. A method according to any of claims 18 to 27, wherein the IAP antagonist is tolinapant, or a tautomer or a solvate or a pharmaceutically acceptable salt thereof.

29. A method according to any of claims 18 to 28, further comprising the step of treating the cancer in the patient by administering an IAP antagonist.

30. A method according to claim 29, wherein the IAP antagonist is tolinapant or a tautomer, pharmaceutically acceptable salt or solvate thereof.

31. A method according to claim 29 or claim 30, wherein the treatment is provided to the patient based on the outcome of the method.

32. A kit or device for detecting the expression or activity level of at least one biomarker for sensitivity to IAP inhibition in a sample from a human patient, comprising detection reagents for detecting one or more of a. IL-2Ra, IL-6r, CRP, EPO, CD27, CD40, TN-C, IL-18, PLGF, TNFrl and MCP-4; or b. TECK, IL-8, Alpha-1 -Antitrypsin, IL-6Rp, FRTN, and Cathepsin D; or c. TN-C, IL-2Ra, Cathepsin D, CD27, IL-6r, MMP-7, CRP, HGF, C3, G-CSF, VCAM-1 , ICAM-1 , haptoglobin, TNFR2, HB-EGF, IL-6, IL-1 RII, IL-1 Ra, MIP-3 alpha, FGF-21 , PLGF, IL-10, CD40, SCF, TIMP-1 , B2M, IL-1 R1 , IL-1 beta, YKL-40, vWF, VEGF, and PARC; or d. TECK, PLGF, FAS, C3, MMP-2, HGF, FasL, VCAM-1 , Tweak, IL-1 ra, IL-6R beta, VEGF, 6Ckine, Haptoglobin, Eotaxin-2, MCP-1 , TRAIL-R3, PAS-f, IL-1 beta, and IL- 2Ra; ora. IL-2Ra, VCAM-1 , PAI-1 , TIMP-1 , IgA, RANTES, IL-1 p, CD27, MIP-3 , MIP-3a, TNFR2, TN-C, VEGF, Cathepsin D, BDNF, MPO, HB-EGF, OPG, MMP-2, ANG-2, Myoglobin, IL-16, ICAM-1 , TNF Rl, IL-12p40, MMP-1 , and B2M; or f. Tweak, FAS, TNFR2, VCAM-1 , E-Selectin, CD40, IL-6r, MPO, FRTN, C3, CD27, PSA-f, EGFR, IL-1 Rl, YKL-40, IL-17, Eotaxin-2, IL-1 ra, ENA-78, AXL, MCP-4, TIMP-1 , Myoglobin, MMP-3, IL-8, MIP-3 p, IL-16, HGF, BDNF, and IL-2Ra; or g. DIABLO, XIAP, BIRC3, MAP3K7, CYLD, BIRC2, TRAF2, MAP3K14, BAX, UBE2N, IKBKB, HTRA2, BCL2, IKBKG, BAK1 , CASP3, RIPK1 , BCL2L1 , TBK1 , and RIPK2; or h. HTRA2, CD27, CYCS, BCL2, BIK, CRP, BAK1 , AIFM1 , ENDOG, USP13, USP10, BECN1 , BCL2L1 , PENK, APAF1 , REST, H1P1 , BAX, XIAP, and IL-10.

33. A system for determining the suitability of a human cancer patient for treatment with an IAP antagonist, comprising a storage memory for storing data associated with a sample from the patient comprising data associated with a panel of biomarkers indicating biomarker expression or activity levels in the sample from the subject, the panel of biomarkers comprising one or more of: a. IL-2Ra, IL-6r, CRP, EPO, CD27, CD40, TN-C, IL-18, PLGF, TNFrl and MCP-4; or b. TECK, IL-8, Alpha-1 -Antitrypsin, IL-6RP, FRTN, and Cathepsin D; or c. TN-C, IL-2Ra, Cathepsin D, CD27, IL-6r, MMP-7, CRP, HGF, C3, G-CSF, VCAM-1 , ICAM-1 , haptoglobin, TNFR2, HB-EGF, IL-6, IL-1 RII, IL-1 Ra, MIP-3 alpha, FGF-21 , PLGF, IL-10, CD40, SCF, TIMP-1 , B2M, IL-1 R1 , IL-1 beta, YKL-40, vWF, VEGF, and PARC; or d. TECK, PLGF, FAS, C3, MMP-2, HGF, FasL, VCAM-1 , Tweak, IL-1 ra, IL-6R beta, VEGF, 6Ckine, Haptoglobin, Eotaxin-2, MCP-1 , TRAIL-R3, PAS-f, IL-1 beta, and IL- 2Ra; or e. IL-2Ra, VCAM-1 , PAI-1 , TIMP-1 , IgA, RANTES, IL-1 p, CD27, MIP-3P, MIP-3a, TNFR2, TN-C, VEGF, Cathepsin D, BDNF, MPO, HB-EGF, OPG, MMP-2, ANG-2, Myoglobin, IL-16, ICAM-1 , TNF Rl, IL-12p40, MMP-1 , and B2M; or f. Tweak, FAS, TNFR2, VCAM-1 , E-Selectin, CD40, IL-6r, MPO, FRTN, C3, CD27, PSA-f, EGFR, IL-1 Rl, YKL-40, IL-17, Eotaxin-2, IL-1 ra, ENA-78, AXL, MCP-4, TIMP- 1 , Myoglobin, MMP-3, IL-8, MIP-3 p, IL-16, HGF, BDNF, and IL-2Ra, or g. DIABLO, XIAP, BIRC3, MAP3K7, CYLD, BIRC2, TRAF2, MAP3K14, BAX, UBE2N, IKBKB, HTRA2, BCL2, IKBKG, BAK1 , CASP3, RIPK1 , BCL2L1 , TBK1 , and RIPK2; or h. HTRA2, CD27, CYCS, BCL2, BIK, CRP, BAK1 , AIFM1 , ENDOG, USP13, USP10, BECN1 , BCL2L1 , PENK, APAF1 , REST, HIP1 , BAX, XIAP, and IL-10. and a processor communicatively coupled to the storage memory for classifying the patient.

34. An IAP antagonist for use, use, or method according to any of claims 1 to 31 , wherein the IAP antagonist is part of a combination therapy with a second therapeutic agent, optionally a hypomethylating agent such as decitabine.

35. An IAP antagonist for use in a method of treating a cancer, wherein the cancer is in a patient with low plasma levels of one or more of: a. IL-2Ra, IL-6r, CRP, EPO, EPO, CD27, CD40, TN-C, IL-18, PLGF, TNFrl and MCP-4; or b. TECK, IL-8, Alpha-1 -Antitrypsin, IL-6R0, FRTN, and Cathepsin D; or c. TN-C, IL-2Ra, Cathepsin D, CD27, IL-6r, MMP-7, CRP, HGF, C3, G-CSF, VCAM-1 , ICAM-1 , haptoglobin, TNFR2, HB-EGF, IL-6, IL-1 RII, IL-1 Ra, MIP-3 alpha, FGF-21 , PLGF, IL-10, CD40, SCF, TIMP-1 , B2M, IL-1 R1 , IL-1 beta, YKL-40, vWF, VEGF, and PARC; or d. TECK, PLGF, FAS, C3, MMP-2, HGF, FasL, VCAM-1 , Tweak, IL-1 ra, IL-6R beta, VEGF, 6Ckine, Haptoglobin, Eotaxin-2, MCP-1 , TRAIL-R3, PAS-f, IL-1 beta, and IL-2Ra; or e. IL-2Ra, VCAM-1 , PAI-1 , TIMP-1 , IgA, RANTES, IL-1 0, CD27, MIP-30, MIP- 3a, TNFR2, TN-C, VEGF, Cathepsin D, BDNF, MPO, HB-EGF, OPG, MMP- 2, ANG-2, Myoglobin, IL-16, ICAM-1 , TNF Rl, IL-12p40, MMP-1 , and B2M; or f. Tweak, FAS, TNFR2, VCAM-1 , E-Selectin, CD40, IL-6r, MPO, FRTN, C3, CD27, PSA-f, EGFR, IL-1 Rl, YKL-40, IL-17, Eotaxin-2, IL-1 ra, ENA-78, AXL, MCP-4, TIMP-1 , Myoglobin, MMP-3, IL-8, MIP-3 0, IL-16, HGF, BDNF, and IL- 2Ra optionally in combination with a hypomethylating agent for example decitabine.

36. A method of treating cancer in a patient wherein said method comprises the steps of selecting a patient:(a) having a low plasma level of one or more of a. IL-2Ra, IL-6r, CRP, EPO, CD27, CD40, TN-C, IL-18, PLGF, TNFrl and MCP-4; b. TECK, IL-8, Alpha-1 -Antitrypsin, IL-6R0, FRTN, and Cathepsin D; or c. TN-C, IL-2Ra, Cathepsin D, CD27, IL-6r, MMP-7, CRP, HGF, C3, G-CSF, VCAM-1 , ICAM-1 , haptoglobin, TNFR2, HB-EGF, IL-6, IL-1 RII, IL-1Ra, MIP-3 alpha, FGF- 21 , PLGF, IL-10, CD40, SCF, TIMP-1 , B2M, IL-1 R1 , IL-1 beta, YKL-40, vWF, VEGF, and PARC; or d. TECK, PLGF, FAS, C3, MMP-2, HGF, FasL, VCAM-1 , Tweak, IL-1 ra, IL-6R beta, VEGF, 6Ckine, Haptoglobin, Eotaxin-2, MCP-1 , TRAIL-R3, PAS-f, IL-1 beta, and IL-2Ra; or e. IL-2Ra, VCAM-1 , PAI-1 , TIMP-1 , IgA, RANTES, IL-1 0, CD27, MIP-30, MIP-3a, TNFR2, TN-C, VEGF, Cathepsin D, BDNF, MPO, HB-EGF, OPG, MMP-2, ANG-2, Myoglobin, IL-16, ICAM-1 , TNF Rl, IL-12p40, MMP-1 , and B2M; or f. Tweak, FAS, TNFR2, VCAM-1 , E-Selectin, CD40, IL-6r, MPO, FRTN, C3, CD27, PSA-f, EGFR, IL-1 RI, YKL-40, IL-17, Eotaxin-2, IL-1 ra, ENA-78, AXL, MCP-4, TIMP-1 , Myoglobin, MMP-3, IL-8, MIP-3 0, IL-16, HGF, BDNF, and IL-2Ra and(b) administering a therapeutically effective amount of an IAP antagonist and optionally a hypomethylating agent, to said patient selected in step (a).

37. An IAP antagonist according to claim 35 or a method according to claim 36, wherein the hypomethylating agent is decitabine.

38. A pharmaceutical composition comprising an IAP inhibitor, wherein the IAP inhibitor is tolinapant or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of cancer in a patient, wherein the patient, cancer or treatment is as defined in any of claims 1 to 16.

39. An IAP antagonist for use in a method of treating a patient with cancer, wherein the method comprises:(i) determining that a sample from the patient is depleted of one or more proteins selected from a. IL-2Ra, IL-6r, CRP, EPO, CD27, CD40, TN-C, IL-18, PLGF, TNFrl and MCP-4; or b. TECK, IL-8, Alpha-1 -Antitrypsin, IL-6R0, FRTN, and Cathepsin D; or c. TN-C, IL-2Ra, Cathepsin D, CD27, IL-6r, MMP-7, CRP, HGF, C3, G- CSF, VCAM-1 , ICAM-1, haptoglobin, TNFR2, HB-EGF, IL-6, IL-1 RII, IL-1 Ra, MIP-3 alpha, FGF-21 , PLGF, IL-10, CD40, TIMP-1 , B2M, IL- 1 R1 , YKL-40, vWF, VEGF, and PARC; or d. TECK, PLGF, FAS, C3, MMP-2, HGF, VCAM-1 , IL-1 ra, IL-6R beta, VEGF, Haptoglobin, Eotaxin-2, MCP-1, TRAIL-R3, and IL-2Ra; or e. IL-2Ra, VCAM-1 , PAI-1 , TIMP-1 , IgA, RANTES, IL-1 0, CD27, MIP- 30, MIP-3a, TNFR2, TN-C, VEGF, Cathepsin D, BDNF, MPO, HB- EGF, OPG, MMP-2, ANG-2, Myoglobin, IL-16, ICAM-1 , TNF Rl, IL- 12p40, MMP-1 , and B2M; or f. Tweak, FAS, TNFR2, VCAM-1 , E-Selectin, CD40, IL-6r, MPO, FRTN, C3, CD27, PSA-f, EGFR, IL-1 RI, YKL-40, IL-17, Eotaxin-2, IL-1ra, ENA-78, AXL, MCP-4, TIMP-1 , Myoglobin, MMP-3, IL-8, MIP-3 0, IL- 16, HGF, BDNF, and IL-2Ra(ii) administering an effective amount of the IAP antagonist to the patient.

40. An IAP antagonist for use in a method of treating a cancer, wherein the cancer is in a patient with low plasma levels of one or more of: a. IL-2Ra, IL-6r, CRP, EPO, CD27, CD40, TN-C, IL-18, PLGF, TNFrl and MCP- 4; or b. TECK, IL-8, Alpha-1 -Antitrypsin, IL-6R0, FRTN, and Cathepsin D; or c. TN-C, IL-2Ra, Cathepsin D, CD27, IL-6r, MMP-7, CRP, HGF, C3, G-CSF, VCAM-1 , ICAM-1 , haptoglobin, TNFR2, HB-EGF, IL-6, IL-1 RII, IL-1 Ra, MIP-3 alpha, FGF-21 , PLGF, IL-10, CD40, TIMP-1 , B2M, IL-1 R1 , YKL-40, vWF, VEGF, and PARC; ord. TECK, PLGF, FAS, C3, MMP-2, HGF, VCAM-1 , IL-1 ra, IL-6R beta, VEGF, Haptoglobin, Eotaxin-2, MCP-1, TRAIL-R3, and IL-2Ra; or e. IL-2Ra, VCAM-1 , PAI-1 , TIMP-1 , IgA, RANTES, IL-1 (3, CD27, MIP-3p, MIP- 3a, TNFR2, TN-C, VEGF, Cathepsin D, BDNF, MPO, HB-EGF, OPG, MMP- 2, ANG-2, Myoglobin, IL-16, ICAM-1 , TNF Rl, IL-12p40, MMP-1 , and B2M; or f. Tweak, FAS, TNFR2, VCAM-1 , E-Selectin, CD40, IL-6r, MPO, FRTN, C3, CD27, PSA-f, EGFR, IL-1 Rl, YKL-40, IL-17, Eotaxin-2, IL-1 ra, ENA-78, AXL, MCP-4, TIMP-1 , Myoglobin, MMP-3, IL-8, MIP-3 p, IL-16, HGF, BDNF, and IL- 2Ra optionally in combination with an anticancer agent e.g. a hypomethylating agent.41 . A method of treating cancer in a patient wherein said method comprises the steps of selecting a patient:(a) having low levels of a. IL-2Ra, IL-6r, CRP, EPO, CD27, CD40, TN-C, IL-18, PLGF, TNFrl and MCP-4; or b. TECK, IL-8, Alpha-1 -Antitrypsin, IL-6Rp, FRTN, and Cathepsin D; or c. TN-C, IL-2Ra, Cathepsin D, CD27, IL-6r, MMP-7, CRP, HGF, C3, G-CSF, VCAM-1 , ICAM-1 , haptoglobin, TNFR2, HB-EGF, IL-6, IL-1 RII, IL-1 Ra, MIP-3 alpha, FGF- 21 , PLGF, IL-10, CD40, TIMP-1 , B2M, IL-1 R1 , YKL-40, vWF, VEGF, and PARC; or d. TECK, PLGF, FAS, C3, MMP-2, HGF, VCAM-1 , IL-1 ra, IL-6R beta, VEGF, Haptoglobin, Eotaxin-2, MCP-1 , TRAIL-R3, and IL-2Ra; or e. IL-2Ra, VCAM-1 , PAI-1 , TIMP-1 , IgA, RANTES, IL-1 p, CD27, MIP-3 , MIP-3a, TNFR2, TN-C, VEGF, Cathepsin D, BDNF, MPO, HB-EGF, OPG, MMP-2, ANG-2, Myoglobin, IL-16, ICAM-1 , TNF Rl, IL-12p40, MMP-1 , and B2M; or f. Tweak, FAS, TNFR2, VCAM-1 , E-Selectin, CD40, IL-6r, MPO, FRTN, C3, CD27, PSA-f, EGFR, IL-1 RI, YKL-40, IL-17, Eotaxin-2, IL-1 ra, ENA-78, AXL, MCP-4, TIMP-1 , Myoglobin, MMP-3, IL-8, MIP-3 (3, IL-16, HGF, BDNF, and IL-2Ra within a biological sample obtained from said patient, optionally a plasma sample; and(b) administering a therapeutically effective amount of an IAP antagonist and optionally an anticancer agent, optionally a hypomethylating agent, to said patient selected in step (a).

42. An IAP antagonist for use in a method of treating a cancer, wherein the cancer patient is depleted of plasma proteins selected from a. IL-2Ra, IL-6r, CRP, EPO, CD27, CD40, TN-C, IL-18, PLGF, TNFrl and MCP-4; or b. TECK, IL-8, Alpha-1 -Antitrypsin, IL-6RP, FRTN, and Cathepsin D; or c. TN-C, IL-2Ra, Cathepsin D, CD27, IL-6r, MMP-7, CRP, HGF, C3, G-CSF, VCAM-1 , ICAM-1 , haptoglobin, TNFR2, HB-EGF, IL-6, IL-1 RII, IL-1 Ra, MIP-3 alpha, FGF-21 , PLGF, IL-10, CD40, TIMP-1 , B2M, IL-1 R1 , YKL-40, vWF, VEGF, and PARC; or d. TECK, PLGF, FAS, C3, MMP-2, HGF, VCAM-1 , IL-1 ra, IL-6R beta, VEGF, Haptoglobin, Eotaxin-2, MCP-1 , TRAIL-R3, and IL-2Ra; ore. IL-2Ra, VCAM-1, PAI-1, TIMP-1, IgA, RANTES, IL-1 p, CD27, MIP-3p, MIP-3a, TNFR2, TN-C, VEGF, Cathepsin D, BDNF, MPO, HB-EGF, OPG, MMP-2, ANG-2, Myoglobin, IL-16, ICAM-1, TNF Rl, IL-12p40, MMP-1, and B2M; or f. Tweak, FAS, TNFR2, VCAM-1 , E-Selectin, CD40, 1 L-6r, MPO, FRTN, C3, CD27, PSA-f, EGFR, IL-1 RI, YKL-40, IL-17, Eotaxin-2, IL-1ra, ENA-78, AXL, MCP-4, TIMP-1 , Myoglobin, MMP-3, IL-8, MIP-3 p, IL-16, HGF, BDNF, and IL-2Ra.

43. An IAP antagonist for use in a method of treating a cancer, wherein the cancer patient’s plasma is depleted of one or more of the proteins a. IL-2Ra, IL-6r, CRP, EPO, CD27, CD40, TN-C, IL-18, PLGF, TNFrl and MCP-4 b. TECK, IL-8, Alpha-1 -Antitrypsin, IL-6RP, FRTN, and Cathepsin D; or c. TN-C, IL-2Ra, Cathepsin D, CD27, IL-6r, MMP-7, CRP, HGF, C3, G-CSF, VCAM-1 , ICAM-1 , haptoglobin, TNFR2, HB-EGF, IL-6, IL-1RII, IL-1Ra, MIP-3 alpha, FGF-21 , PLGF, IL-10, CD40, TIMP-1 , B2M, IL-1 R1 , YKL-40, vWF, VEGF, and PARC; or d. TECK, PLGF, FAS, C3, MMP-2, HGF, VCAM-1, IL-1 ra, IL-6R beta, VEGF, Haptoglobin, Eotaxin-2, MCP-1, TRAIL-R3, and IL-2Ra; or e. IL-2Ra, VCAM-1 , PAI-1 , TIMP-1 , IgA, RANTES, IL-1 p, CD27, MIP-3p, MIP-3a, TNFR2, TN-C, VEGF, Cathepsin D, BDNF, MPO, HB-EGF, OPG, MMP-2, ANG-2, Myoglobin, IL-16, ICAM-1 , TNF Rl, IL-12p40, MMP-1, and B2M; or f. Tweak, FAS, TNFR2, VCAM-1 , E-Selectin, CD40, IL-6r, MPO, FRTN, C3, CD27, PSA-f, EGFR, IL-1 Rl, YKL-40, IL-17, Eotaxin-2, IL-1ra, ENA-78, AXL, MCP-4, TIMP-1 , Myoglobin, MMP-3, IL-8, MIP-3 p, IL-16, HGF, BDNF, and IL-2Ra.

44. An IAP antagonist for use in a method according to any embodiment herein.

45. An IAP antagonist for use according to claim , wherein the IAP antagonist is tolinapant (ASTX- 660), Xevinapant (AT-406, Debio-1143), Dasminapant (APG-1387), BGB-24714 (BeiGene), Birinapant (IGM-9427), BI-891065 (Boehringer Ingelheim), LCL-161 (Novartis), GDC-0152 (RG-7419) (Roche / Genentech), HGS-1029 (AEG-40826) (Aegera / HGS), CUDC-427 (GDC- 0917 / RG7459) (Curis), Debio 1143, GDC-917 / CUDC-427, TL-32711 / Birinapant, HGS- 1029 / AEG-40826, Bl 891065, or APG-1387.

46. A method of treating a cancer in a subject comprising administering an IAP antagonist to the subject having assessed in the subject the plasma level of: a. IL-2Ra, IL-6r, CRP, EPO, CD27, CD40, TN-C, IL-18, PLGF, TNFrl or MCP-4; or b. TECK, IL-8, Alpha-1 -Antitrypsin, IL-6RP, FRTN, and Cathepsin D; or c. TN-C, IL-2Ro, Cathepsin D, CD27, IL-6r, MMP-7, CRP, HGF, C3, G-CSF, VCAM-1 , ICAM-1 , haptoglobin, TNFR2, HB-EGF, IL-6, IL-1RII, IL-1 Ra, MIP-3 alpha, FGF-21 ,PLGF, IL-10, CD40, SCF, TIMP-1 , B2M, IL-1 R1 , IL-1 beta, YKL-40, vWF, VEGF, and PARC; or d. TECK, PLGF, FAS, C3, MMP-2, HGF, FasL, VCAM-1 , Tweak, IL-1 ra, IL-6R beta, VEGF, 6Ckine, Haptoglobin, Eotaxin-2, MCP-1 , TRAIL-R3, PAS-f, IL-1 beta, and IL- 2Ra; or e. IL-2Ra, VCAM-1 , PAI-1 , TIMP-1 , IgA, RANTES, IL-1 p, CD27, MIP-3p, MIP-3a, TNFR2, TN-C, VEGF, Cathepsin D, BDNF, MPO, HB-EGF, OPG, MMP-2, ANG-2, Myoglobin, IL-16, ICAM-1 , TNF Rl, IL-12p40, MMP-1 , and B2M; or f. Tweak, FAS, TNFR2, VCAM-1 , E-Selectin, CD40, IL-6r, MPO, FRTN, C3, CD27, PSA-f, EGFR, IL-1 RI, YKL-40, IL-17, Eotaxin-2, IL-1ra, ENA-78, AXL, MCP-4, TIMP-1 , Myoglobin, MMP-3, IL-8, MIP-3 p, IL-16, HGF, BDNF, and IL-2Ra.

47. A method of treating cancer in a patient, wherein the patient’s plasma shows loss of one or more of: a. IL-2Ra, IL-6r, CRP, EPO, CD27, CD40, TN-C, IL-18, PLGF, TNFrl, and MCP-4; or b. TECK, IL-8, Alpha-1 -Antitrypsin, IL-6Rp, FRTN, and Cathepsin D; or c. TN-C, IL-2Ra, Cathepsin D, CD27, IL-6r, MMP-7, CRP, HGF, C3, G-CSF, VCAM-1 , ICAM-1 , haptoglobin, TNFR2, HB-EGF, IL-6, IL-1 RII, IL-1 Ra, MIP-3 alpha, FGF-21 , PLGF, IL-10, CD40, TIMP-1 , B2M, IL-1 R1 , YKL-40, vWF, VEGF, and PARC; or d. TECK, PLGF, FAS, C3, MMP-2, HGF, VCAM-1 , IL-1 ra, IL-6R beta, VEGF, Haptoglobin, Eotaxin-2, MCP-1 , TRAIL-R3, and IL-2Ra; or e. f.EGFR, IL-1 RI, YKL-40, IL-17, Eotaxin-2, IL-1 ra, ENA-78, AXL, MCP-4, TIMP-1 , Myoglobin, MMP-3, IL-8, MIP-3 p, IL-16, HGF, BDNF, and IL-2Ra.

48. An IAP antagonist for use in a method of treating a cancer in a patient, wherein the patient has been selected for IAP antagonist treatment on the basis of a change in the biomarker level in the patient, wherein the biomarker is selected from the group consisting of: a. IL-2Ra, VCAM-1 , PAI-1 , TIMP-1 , IgA, RANTES, IL-1 p, CD27, MIP-3 , MIP-3a, TNFR2, TN-C, VEGF, Cathepsin D, BDNF, MPO, HB-EGF, OPG, MMP-2, ANG-2, Myoglobin, IL- 16, ICAM-1 , TNF Rl, IL-12p40, MMP-1 , and B2M; or b. Tweak, FAS, TNFR2, VCAM-1 , E-Selectin, CD40, IL-6r, MPO, FRTN, C3, CD27, PSA-f, EGFR, IL-1 Rl, YKL-40, IL-17, Eotaxin-2, IL-1 ra, ENA-78, AXL, MCP-4, TIMP-1 , Myoglobin, MMP-3, IL-8, MIP-3 p, IL-16, HGF, BDNF, and IL-2Ra.

49. An IAP antagonist for use in a method according to claim 48, wherein the change in the level of the biomarker is determined based on the level of the biomarker:a. before the first dose of the IAP inhibitor or up to 24 hours after the first dose; and b. 2, 3, 4, 5 or 6 weeks after the first dose of the IAP inhibitor, typically approximately 4 weeks after the first dose, optionally after an off-treatment period, optionally wherein the off- treatment period is one week or more.

50. An IAP antagonist for use in a method of treating cancer in a patient, wherein the patient has been selected for treatment based on the assessment of the level of one or more extrinsic cell death biomarkers pathway and / or intrinsic cell death pathway biomarkers, wherein the one or more biomarkers are selected from the list consisting of (a) DIABLO, XIAP, BIRC3, MAP3K7, CYLD, BIRC2, TRAF2, MAP3K14, BAX, UBE2N, IKBKB, HTRA2, BCL2, IKBKG, BAK1 , CASP3, RIPK1 , BCL2L1 , TBK1 , and RIPK2; or (b) HTRA2, CD27, CYCS, BCL2, BIK, CRP, BAK1 , AIFM1 , ENDOG, USP13, USP10, BECN1 , BCL2L1 , PENK, APAF1 , REST, HIP1 , BAX, XIAP, and IL-10.51 . Use of the expression or activity level of one or more extrinsic cell death pathway and / or one or more intrinsic cell death pathway genes or gene products in a cancer cell sample of a human patient, wherein the one or more genes or gene products are selected from the list consisting of (a) DIABLO, XIAP, BIRC3, MAP3K7, CYLD, BIRC2, TRAF2, MAP3K14, BAX, UBE2N, IKBKB, HTRA2, BCL2, IKBKG, BAK1 , CASP3, RIPK1 , BCL2L1 , TBK1 , and RIPK2; or (b) HTRA2, CD27, CYCS, BCL2, BIK, CRP, BAK1 , AIFM1 , ENDOG, USP13, USP10, BECN1 , BCL2L1 , PENK, APAF1 , REST, HIP1 , BAX, XIAP, and IL-10 as a biomarker or biomarkers for assessing whether the cancer is susceptible to treatment with an IAP antagonist.

52. The IAP antagonist of claim 50 or the use is claim 5, wherein the level of the biomarker is assessed before treatment with an IAP antagonist and the biomarker is one or more of HTRA2, CD27, CYCS, BCL2, BIK, CRP, BAK1 , AIFM1 , ENDOG, USP13, USP10, BECN1 , BCL2L1 , PENK, APAF1 , REST, HIP1 , BAX, XIAP, and IL-10; or wherein the level of the biomarker is assessed after treatment with an IAP antagonist and the biomarker is one or more of DIABLO, XIAP, BIRC3, MAP3K7, CYLD, BIRC2, TRAF2, MAP3K14, BAX, UBE2N, IKBKB, HTRA2, BCL2, IKBKG, BAK1 , CASP3, RIPK1 , BCL2L1 , TBK1 , and RIPK2.

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