Combinations of ioa-244, a pd-1 or pd-l1 inhibitor and a chemotherapeutic agent to treat cancer

Abstract

A compound of Formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in a subject, wherein said treatment comprises the separate, sequential or simultaneous administration of i) said Compound 1, or a pharmaceutically acceptable salt thereof, ii) a PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, and iii) a chemotherapeutic agent, or a pharmaceutically acceptable salt thereof to said subject.

Description

[0001] COMBINATIONS OF IOA-244, A PD-1 OR PD-L1 INHIBITOR AND A CHEMOTHERAPEUTIC AGENT TO TREAT CANCER

[0002] Field of the Invention

[0003] The present disclosure relates to methods of treating solid and haematological tumours which are refractory or relapsed after checkpoint blockade inhibitor therapy.

[0004] Background

[0005] Checkpoint blockade inhibitors represent a form of immunotherapy that has revolutionized the field of cancer treatment.

[0006] The immune system has built-in checkpoints, which are regulatory mechanisms that prevent overactivation of immune cells and maintain self-tolerance. Cancer cells can exploit these checkpoints to evade immune detection and attack. Checkpoint inhibitors are designed to block these inhibitory signals and restore the immune system's ability to recognize and eliminate cancer cells. The most widely studied and utilized checkpoint inhibitors target two main immune checkpoint proteins: cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1), along with its ligand, programmed death-ligand 1 (PD-L1). When these checkpoint proteins bind to their respective ligands, they transmit inhibitory signals that suppress immune responses against cancer cells.

[0007] Checkpoint inhibitor therapy works by blocking the interaction between checkpoint proteins and their ligands, thus unleashing the immune system to mount a robust attack against cancer cells. By doing so, these therapies can enhance the body's natural ability to recognize and destroy cancer cells.

[0008] There are several checkpoint inhibitor drugs approved for the treatment of various cancers. Some examples include:

[0009] 1. Ipilimumab: It is a monoclonal antibody that targets CTLA-4 and was the first FDA- approved checkpoint inhibitor. It is primarily used for the treatment of advanced melanoma.

[0010] 2. Pembrolizumab and nivolumab: These drugs target PD-1 and have been approved for the treatment of various cancers, including melanoma, non-small cell lung cancer, renal cell carcinoma, bladder cancer, and Hodgkin's lymphoma.

[0011] 3. Atezolizumab, durvalumab, and avelumab: These drugs target PD-L1 and have approvals for treating specific cancers, such as non-small cell lung cancer, bladder cancer, and Merkel cell carcinoma. Checkpoint inhibitors in monotherapy and / or in combination with chemotherapy have demonstrated remarkable success in some patients, leading to long-lasting responses and improved survival rates in various cancers. However, not all patients respond to these treatments and most importantly some types of tumours are completely unresponsive to immunotherapy. Resistance to checkpoint inhibitors can occur through multiple mechanisms, including:

[0012] 1. Lack of tumour-infiltrating lymphocytes (TILs): Checkpoint inhibitors rely on the presence of TILs, immune cells that recognize and attack cancer cells. Some tumours have a low number of TILs or lack the specific TILs necessary to mount an effective immune response, leading to resistance.

[0013] 2. Upregulation of alternative immune checkpoints: Tumours can upregulate alternative immune checkpoint molecules, such as TIM-3, LAG-3, and VISTA, which can counteract the effects of checkpoint inhibitors. These alternative checkpoints provide additional inhibitory signals to immune cells, dampening the immune response.

[0014] 3. Loss of antigen presentation: Cancer cells may downregulate major histocompatibility complex (MHC) molecules or components of the antigen presentation machinery, making it difficult for immune cells to recognize and attack the tumor. Without effective antigen presentation, checkpoint inhibitors may be less effective.

[0015] 4. Tumour microenvironment factors: The tumour microenvironment can create an immunosuppressive milieu that hampers the efficacy of checkpoint inhibitors. Factors such as tumour-associated fibroblasts, regulatory T cells, myeloid-derived suppressor cells, and cytokines like transforming growth factor-beta (TGF-P) can contribute to immune suppression and resistance.

[0016] 5. Genetic alterations: Genetic alterations within tumours can lead to resistance. For example, mutations in the JAK1 / JAK2 or beta-2-microglobulin (B2M) genes can impair the interferon signalling pathway, which is crucial for the activity of checkpoint inhibitors.

[0017] Overcoming resistance to checkpoint inhibitors is an active area of research. Some strategies being explored include combination therapies with other immunotherapies, targeted therapies, chemotherapy, and radiation therapy.

[0018] The present invention has been devised in light of the above considerations.

[0019] Summary of the Invention

[0020] The present invention is directed to a new treatment for cancer. In some embodiments disclosed in a method of treating cancer in a subject in need thereof, comprising administering to the subject a first amount of a compound of formula I:

[0021] (Compound 1) or a pharmaceutically acceptable salt thereof, and a second amount of a PD1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, and a third amount of a chemotherapeutic agent, or a pharmaceutically acceptable salt thereof wherein the first amount, the second amount and the third amount together comprise a therapeutically effective amount.

[0022] In some embodiments, disclosed is Compound 1, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in a subject, wherein said treatment comprises the separate, sequential or simultaneous administration of i) said Compound 1, or a pharmaceutically acceptable salt thereof, ii) a PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, and iii) a chemotherapeutic agent, or a pharmaceutically acceptable salt thereof, to said subject.

[0023] In some embodiments, disclosed is a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in a subject, wherein said treatment comprises the separate, sequential or simultaneous administration of i) said PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, ii) Compound 1 or a pharmaceutically acceptable salt thereof, and iii) a chemotherapeutic agent, or a pharmaceutically acceptable salt thereof to said subject.

[0024] In some embodiments, disclosed is the use of Compound 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of cancer, wherein said treatment comprises the separate, sequential or simultaneous administration of i) said medicament comprising Compound 1, or a pharmaceutically acceptable salt thereof, ii) a PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, and iii) a chemotherapeutic agent, or a pharmaceutically acceptable salt thereof to said subject.

[0025] In some of the above embodiments, the PD-1 or PD-L1 inhibitor is a PD-1 inhibitor.

[0026] In other of the above embodiments, the PD-1 or PD-L1 inhibitor is a PD-L1 inhibitor. In some of the above embodiments, there is only a single chemotherapeutic agent, i.e. there are no further chemotherapeutic agents. Therefore the treatment may consist of the separate, sequential or simultaneous administration of i) said Compound 1, or a pharmaceutically acceptable salt thereof, ii) a PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, and iii) a single chemotherapeutic agent, or a pharmaceutically acceptable salt thereof.

[0027] In the above embodiments, the cancer may be breast cancer, bladder cancer, cervical cancer, colon cancer, head and neck cancer, haematological cancer, liver cancer, lung cancer, kidney cancer, skin cancer including melanoma, uveal melanoma, stomach cancer, rectal cancer, mesothelioma, endometrial cancer, small intestinal cancer, biliary tract cancer, ovarian cancer, brain cancer, testicular cancer, pancreatic cancer, bone cancer and any solid tumour that is not able to repair errors in its DNA that occur when the DNA is copied.

[0028] In the above embodiments the cancer may be breast cancer, bladder cancer, cervical cancer, colon cancer, head and neck cancer, haematological cancer, liver cancer, lung cancer, kidney cancer, skin cancer including melanoma, uveal melanoma, stomach cancer, rectal cancer, mesothelioma, endometrial cancer, small intestinal cancer, biliary tract cancer, ovarian cancer, brain cancer, testicular cancer, pancreatic cancer or bone cancer.

[0029] In the above embodiments, the cancer may be a malignancy that is refractory to or relapsed after treatment with a checkpoint inhibitor, optionally along with another chemotherapeutic agent.

[0030] In the above embodiments, the subject may have been previously treated with a chemotherapeutic agent and / or a PD-1 or PD-L1 inhibitor and the cancer is refractory or resistant to these treatments. In some embodiments the subject has previously been treated with a chemotherapeutic agent and / or a PD-1 or PD-L1 inhibitor and has not responded to or is resistant to treatment. In some embodiments the subject is a patient with malignancies that are refractory to or relapsed after checkpoint inhibitor plus chemotherapy.

[0031] In some embodiments, disclosed is a pharmaceutical product comprising i) Compound 1 or a pharmaceutically acceptable salt thereof, ii) a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, and iii) a chemotherapeutic agent or a pharmaceutically acceptable salt thereof.

[0032] In some embodiments, disclosed is a kit comprising: a first pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, a second pharmaceutical composition comprising a PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof; and a third pharmaceutical composition comprising a chemotherapeutic agent or a pharmaceutically acceptable salt thereof - and instructions for using the first and second pharmaceutical compositions in combination.

[0033] Inhibition of PI3K5 via treatment with Compound 1, reshapes the tumour immunosuppressive microenvironment to increase antitumor immune response and responsiveness to the combination of checkpoint inhibitors with chemotherapy. This helps to fill a high unmet clinical need in the field of immunotherapy.

[0034] It has surprisingly been found that the combination of Compound 1 with checkpoint inhibitors and chemotherapy has synergistic effects on enhancing antitumoral immune response and cytotoxicity towards tumour cells. Thus, a combination therapy with improved anti-tumoral activity can be provided. Surprisingly these synergistic effects are present already at sub- therapeutic doses. Thus, a combination with improved tolerability may be provided.

[0035] It has also surprisingly been found that the synergistic anti-tumour activity of the combination of Compound 1 with checkpoint inhibitors and chemotherapy is not limited to a specific malignancy. Thus, a combination therapy with improved therapeutic activity across multiple malignancies can be provided.

[0036] Additionally, surprisingly the combination of Compound 1 with checkpoint inhibitors and chemotherapy results in tumour cell killing that is not observed with either inhibitor alone. Thus, a triple combination that can reduce tumour burden can be provided.

[0037] It has also surprisingly been found that the combination of Compound 1 with checkpoint inhibitors and chemotherapy treats patients with malignancies that are refractory to or relapsed after treatment with a checkpoint inhibitor plus another chemotherapeutic agent.

[0038] The present invention therefore is an improved method of treating cancer.

[0039] The invention includes the combination of the aspects and preferred features described except where such a combination is clearly impermissible or expressly avoided.

[0040] Summary of the Figures

[0041] Embodiments and experiments illustrating the principles of the invention will now be discussed with reference to the accompanying figures in which:

[0042] Figure 1 shows the change in immunophenotype driven by the combination of Compound 1 with immunotherapy and chemotherapy in mesothelioma; and

[0043] Figure 2 shows the change in immunophenotype driven by the combination of Compound 1 with immunotherapy and chemotherapy in NSCLC. Detailed Description of the Invention

[0044] Aspects and embodiments of the present invention will now be discussed with reference to the accompanying figures. Further aspects and embodiments will be apparent to those skilled in the art. All documents mentioned in this text are incorporated herein by reference.

[0045] Compound 1 is example 339 in WO2011 / 058149, which document is incorporated herein by reference in its entirety. Its structure is according to Formula I: Formula I

[0046] In IIIPAC nomenclature, the above Compound 1 may be referred to as 6-Fluoro-3-(morpholin-4- ylcarbonyl)-1-[4-(morpholin-4-ylmethyl)phenyl]-1,4-dihydrothiochromeno[4,3-c]pyrazole 5,5- dioxide. Alternatively, the structural formula shown above may be described as [6-fluoro-1-(4- morpholin-4-yl-methylphenyl)-5,5-dioxo-4,5-dihydro-1H-5A6-thiochromeno[4,3-C]pyrazol-3-yl]- morpholin-4-yl-methanone.

[0047] Compound 1 can be prepared and characterized as described in published patent application WO 2011 / 058149 A1 (see compound 339 on p. 69; the preparation on p. 303-307; and the characterization on p. 481 with p. 414-418), which information is specifically incorporated herein by reference.

[0048] Based on the process disclosed in WO 2011 / 058149 A1 , the authors of Haselmayer 2014 describe a five-step preparation procedure for the compound. This procedure starts with reaction of 8-fluoro-2,3-dihydro-4Hthiochromen-4-one with diethyl oxalate in the presence of sodium ethoxide. The intermediate is cyclized with 4-(4-hydrazinylbenzyl)morpholine to form a pyrazole ring. The thioether is then oxidized to the corresponding sulfone by reaction with metachloroperbenzoic acid, followed by saponification of the ethyl ester into the corresponding acid and subsequent coupling with morpholine to yield the compound of formula I. Alternatively, the intermediate of the reaction of 8-fluoro-2,3-dihydro-4H-thiochromen-4-one with diethyl oxalate in the presence of sodium ethoxide is cyclized with 4-hydrazinobenzoic acid. The benzoic acid is reduced using borane-THF complex and the thioether is oxidized to the corresponding sulfone by reaction with meta-chloroperbenzoic acid. Saponification of the ethyl ester into the corresponding acid and chlorination of both the acid and alcohol with excess thionyl chloride in the presence of dimethylformamide and subsequent coupling with morpholine then yields Compound 1.

[0049] Compound 1 may be provided as a pharmaceutically acceptable salt. Suitable pharmaceutically acceptable salts are known in the art. Some pharmaceutically acceptable salts of Compound 1 are described in W02014 / 121901, which is incorporated by reference in its entirety.

[0050] As used herein, Compound 1 is provided as an anhydrous hemifumarate salt (formula illustrated). Its synthesis and characterisation are described in W02014 / 121901 (page 4). It is referred to as solid form A1. A hemifumarate hydrate (H1) has also been identified. The anhydrous hemifumarate salt used is crystalline and has a powder X-ray peak list as described in W02014 / 121901. It will be appreciated that the findings of the invention are not limited to use of this solid form, although it is preferred.

[0051] Accordingly, in some cases Compound 1 is administered as the hemifumarate salt (Formula la). However, it will be understood that the invention is not so limited, and other solid forms (for example, other pharmaceutically acceptable salts) are envisaged.

[0052] Formula la

[0053] Haselmayer 2014 also describes the characterisation of the compound as highly selective PI3K5 inhibitor. Johnson 2023 describes the use of the compound in treating solid tumour cell lines and references ongoing clinical trials.

[0054] Compound 1 can be used to treat cancer. PD-1 and PD-L1 inhibitors

[0055] PD-1 inhibitors and PD-L1 inhibitors are a group of checkpoint inhibitor anticancer drugs that block the activity of PD-1 and PD-L1 immune checkpoint proteins present on the surface of cells. Immune checkpoint inhibitors are emerging as a treatment for several types of cancer. PD-1 and PD-L1 inhibitors act to inhibit the association of the programmed death-ligand 1 (PD- L1) with its receptor, programmed cell death protein 1 (PD-1). The interaction of these cell surface proteins is involved in the suppression of the immune system and occurs following infection to limit the killing of bystander host cells and prevent autoimmune disease.

[0056] Immune checkpoint inhibitors can be used to treat a wide variety of cancer types including breast cancer, bladder cancer, cervical cancer, colon cancer, head and neck cancer, Hodgkin lymphoma, liver cancer, lung cancer, renal cell cancer, skin cancer including melanoma, uveal melanoma, stomach cancer, rectal cancer and any solid tumour that is not able to repair errors in its DNA that occur when the DNA is copied.

[0057] Approved checkpoint inhibitors that block PD-1 include nivolumab (Opdivo), pembrolizumab (Keytruda), cemiplimab (Libtayo), dostarlimab (Jemperli), retifanlimab (Zynyz) and toripalimab (Loqtorzi). Approved checkpoint inhibitors that block PD-L1 include atezolizumab (Tecentriq), avelumab (Bavencio) and durvalumab (Imfinzi).

[0058] In some embodiments the PD-1 or PD-L1 inhibitor is a PD-1 inhibitor.

[0059] In some embodiments the PD-1 inhibitor is an antibody, such as a monoclonal antibody.

[0060] In some embodiments the PD-1 or PD-L1 inhibitor is a PD-L1 inhibitor.

[0061] In some embodiments, the PDL-1 inhibitor is an antibody, such as a monoclonal antibody.

[0062] In some embodiments, the PDL-1 inhibitor is a peptide or macrocycle.

[0063] In some embodiments the PD-1 or PD-L1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, retifanlimab, toripalimab, atezolizumab, avelumab and durvalumab.

[0064] In some embodiments the PD-1 or PD-L1 inhibitor is selected from nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab and cemiplimab.

[0065] In some embodiments the PD-1 inhibitor is nivolumab. Nivolumab (sold under the name Opdivo) is a PD-1 inhibitor used to treat a variety of cancers including: advanced melanoma, melanoma, non-small cell lung cancer, advanced non-small cell lung cancer, malignant pleural mesothelioma, renal cell carcinoma, classical Hodgkin lymphoma, cancer of the head and neck in adults, advanced urothelial carcinoma (bladder and urinary tract cancer), urothelial carcinoma, advanced colorectal cancer (colon or rectal cancer), advanced oesophageal cancer (gullet cancer), oesophageal (gullet) or gastro-oesophageal junction cancer, advanced gastric, gastro-oesophageal junction or oesophageal adenocarcinoma (stomach or gullet cancer).

[0066] Nivolumab, is a monoclonal antibody, a type of protein designed to recognise and attach to a specific target substance in the body. Nivolumab attaches to a target protein called programmed death-1 receptor (PD-1) that can switch off the activity of T cells. By attaching to PD-1 , nivolumab blocks its action and prevents it from switching off T cells. This helps increase their activity against the melanoma, lung, kidney, lymphoid, head and neck, bladder, colon, rectal, stomach, oesophageal or gastro-oesophageal junction cancer cells. Nivolumab can be used in combination with other anti-cancer medicines and radiotherapy.

[0067] In some embodiments the PD-1 inhibitor is pembrolizumab. Pembrolizumab (also sold under the name Keytruda) is a PD-1 inhibitor used to treat a variety of cancers including: melanoma, non-small cell lung cancer, classical Hodgkin lymphoma, bladder cancer (urothelial carcinoma), head and neck squamous cell carcinoma, renal cell carcinoma, colorectal cancer, uterus (endometrial cancer), stomach (gastric cancer), small bowel (small intestine cancer), or bile duct or gallbladder (biliary tract cancer), oesophageal carcinoma, triple-negative breast cancer, endometrial carcinoma and cervical cancer.

[0068] Pembrolizumab is a humanised monoclonal antibody which binds to the programmed cell death-1 (PD-1) receptor and blocks its interaction with ligands PD-L1 and PD-L2. Pembrolizumab potentiates T-cell responses, including anti-tumour responses, through blockade of PD-1 binding to PD-L1 and PD-L2, which are expressed in antigen presenting cells and may be expressed by tumours or other cells in the tumour microenvironment. Pembrolizumab can be used in combination with other anti-cancer medicines and radiotherapy.

[0069] In some embodiments the PD-1 inhibitor is cemiplimab (sold under the name Libtayo). Cemiplimab is a monoclonal antibody used for the treatment of cutaneous squamous cell carcinoma, basal cell carcinoma, lung cancer or cervical cancer.

[0070] In some embodiments the PD-1 inhibitor is dostarlimab. Dostarlimab (sold under the name Jemperli) is a PD-1 inhibitor used to treat endometrial cancer. Dostarlimab is in particular used for the treatment of adults with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer. Dostarlimab is described in US9815897 and US10738117, and its use, including dose, is described in US 11407830. In some embodiments the PD-1 inhibitor is retifanlimab. Retifanlimab (sold under the name Zynyz, and also known as INCMGA00012) is a PD-1 inhibitor used to treat Merkel cell carcinoma. Retifanlimab is a humanized lgG4 monoclonal antibody developed by Incyte and MacroGenics.

[0071] In some embodiments the PD-1 inhibitor is toripalimab. Toripalimab (sold under the name Loqtorzi, and also known as JS 001) is a PD-1 inhibitor used to treat metastatic or recurrent, locally advanced nasopharyngeal carcinoma. Toripalimab is a humanized lgG4 monoclonal antibody against PD-1.

[0072] There are currently many other PD-1 inhibitors under development such as the following: Vopratelimab (JTX-4014) by Jounce Therapeutics as of 2020 entered Phase I trial;

[0073] Spartalizumab (PDR001) is a PD-1 inhibitor developed by Novartis to treat both solid tumors and lymphomas, which as of 2018 has entered Phase III trials;

[0074] Camrelizumab (SHR1210) is an anti-PD-1 monoclonal antibody introduced by Jiangsu HengRui Medicine Co., Ltd. That recently received conditional approval in China for the treatment of relapsed or refractory classical Hodgkin lymphoma;

[0075] Sintilimab (IBI308), a human anti-PD-1 antibody developed by Innovent and Eli Lilly for patients with non-small cell lung cancer (NSCLC);

[0076] Tislelizumab (BGB-A317) is a humanized lgG4 anti-PD-1 monoclonal antibody in pivotal Phase 3 and Phase 2 clinical trials in solid tumors and hematologic cancers;

[0077] Pidilizumab (CT-011) by Medication;

[0078] Cetrelimab (JNJ-63723283) by Johnson and Johnson;

[0079] Serplulimab (HLX10) by Shanghai Henlius Biotech;

[0080] Sasanlimab (PF-06801591) by Pfizer;

[0081] Zimberelimab (GLS-010) by Arcus Biosciences, Gloria Pharmaceuticals and WuXi Biologies;

[0082] Penpulimab (ANNIKO) by Akeso Biopharma / SinoBiopharm;

[0083] Sintilimab (IBI308) by Innovent Biologies;

[0084] Geptanolimab (APL-501, GB226) by Genor BioPharma / Apolomics

[0085] AMP-110 by AstraZeneca;

[0086] AMP-224 by AstraZeneca / Medlmmune and GlaxoSmithKline;

[0087] AMP-514 (MEDI0680) by AstraZeneca; and

[0088] Acrixolimab (YBL-006) by Y-Biologics.

[0089] In some embodiments the PD-L1 inhibitor is atezolizumab (Tecentriq). Atezolizumab is a monoclonal antibody medication used to treat Urothelial carcinoma, lung cancer, breast cancer or hepatocellular carcinoma. It is a fully humanized, engineered monoclonal antibody of IgG 1 isotype against PD-L1. In some embodiments the PD-L1 inhibitor is avelumab (Bavencio). Avelumab is a fully human monoclonal antibody medication used for the treatment of Merkel cell carcinoma, urothelial carcinoma, and renal cell carcinoma.

[0090] In some embodiments the PD-L1 inhibitor is durvalumab (Imfinzi). Durvalumab is a human immunoglobulin G1 kappa (IgGlK) monoclonal antibody that blocks the interaction of programmed cell death ligand 1 (PD-L1) and is an approved immunotherapy for the treatment of cancer. Durvalumab is used to treat lung cancer, bladder cancer or biliary tract cancer.

[0091] There are currently many other PDL-1 inhibitors under development such as the following: Envafolimab (KN035) by Alphamab, 3DMed;

[0092] Sugemalimab (Cejemly, CS1001) by CStone Pharmaceuticals;

[0093] BAT-1306 by BioThera Solutions;

[0094] Cosibelimab (CK-301) by Dana Farber;

[0095] ALINP12 (29-mer peptide) by Aurigene and Laboratoires Pierre Fabre;

[0096] CA-170 (PD-L1 and VISTA SMI antagonist) by Aurigene / Curis; and BMS-986189 (macrocyclic peptide) by Bristol-Myers Squibb.

[0097] Some of these are described in Guzik 2019.

[0098] The chemotherapeutic agent may be selected from those which are currently the standard of care for treating the particular cancers.

[0099] There are various types of chemotherapy drugs including DNA damaging agents, folate antimetabolites, alkylating agents, nitrosoureas, plant alkaloids and natural products, antitumour antibiotics, hormonal agents or biological response modifiers. In some embodiments the chemotherapy drug is a DNA damaging agent.

[0100] In some embodiments, the chemotherapeutic agent may be selected from carboplatin, gemcitabine, cisplatin, docetaxel, doxorubicin, mitoxantrone, 5-fluorouracil (5-Fll), capecitabine, irinotecan, oxaliplatin, pemetrexed, trifluridine and tipiracil.

[0101] In some embodiments, the chemotherapeutic agent may be selected from carboplatin, gemcitabine, cisplatin, doxorubicin, mitoxantrone, 5-fluorouracil (5-Fll), capecitabine, irinotecan, oxaliplatin, pemetrexed, trifluridine and tipiracil. In some embodiments the chemotherapeutic agent is carboplatin. Carboplatin is also sold under the trade name Paraplatin among others. It is used to treat a number of forms of cancer. This includes ovarian cancer, lung cancer, head and neck cancer, brain cancer, and neuroblastoma. It may be used for some types of testicular cancer. It has also been used to treat triple-negative breast cancer. Carboplatin is particularly used in the treatment of some types of lung cancer and ovarian cancer. Carboplatin can be used in combination with other anti-cancer medicines including radiotherapy. Carboplatin is in the alkylating agent class of cytotoxic medicines. Carboplatin has the following structure:

[0102] In some embodiments the chemotherapeutic agent is gemcitabine. Gemcitabine is sold under the name Gemzar among others. It is used to treat cancers including testicular cancer, breast cancer, ovarian cancer, non-small cell lung cancer, pancreatic cancer, and bladder cancer. It is administered by intravenous infusion. It acts against neoplastic growth, and it inhibits the replication of Orthohepevirus A, the causative agent of Hepatitis E, through upregulation of interferon signalling. Gemcitabine has the following structure:

[0103] Gemcitabine can be used in combination with other anti-cancer medicines including radiotherapy. Gemcitabine can be used in as a monotherapy or in combination with cisplatin to treat a variety of cancers including bladder cancer and non-small cell lung cancer. Gemcitabine can be used as a monotherapy or in combination with carboplatin to treat ovarian carcinoma. Gemcitabine can be used as a monotherapy or in combination with paclitaxel to treat breast cancer. Gemcitabine is also approved as a monotherapy to treat adenocarcinoma of the pancreas. Gemcitabine is an antimetabolite.

[0104] In some embodiments the chemotherapeutic agent is cisplatin. Cisplatin is used to treat a number of cancers including testicular cancer, ovarian cancer, cervical cancer, bladder cancer, head and neck cancer, lung cancer and brain tumours. Cisplatin is indicated in the treatment of cervical carcinoma in combination with other chemotherapeutics or with radiotherapy. Cisplatin can be used in combination with other anti-cancer medicines including radiotherapy. Cisplatin is administered by intravenous infusion. Cisplatin is in the alkylating agent class of cytotoxic medicines. Cisplatin has the following structure:

[0105] In some embodiments the chemotherapeutic agent is pemetrexed. Pemetrexed is sold under the name Alimta among others. Pemetrexed is used to treat a number of cancers including mesothelioma and lung cancer. Pemetrexed is indicated for the treatment of mesothelioma and non-small cell lung cancer in combination with cis-platin. Pemetrexed is also recommended in combination with carboplatin and pembrolizumab for the first-line treatment of advanced non- small cell lung cancer. Pemetrexed is administered by intravenous infusion. Pemetrexed is a folate antimetabolite. Pemetrexed has the following structure:

[0106] In some embodiments the chemotherapeutic agent is docetaxel. Docetaxel is sold under the name Taxotere among others. Docetaxel is used to treat a number of cancers including breast cancer, head and neck cancer, stomach cancer, prostate cancer and lung cancer. Docetaxel is indicated for the treatment of breast cancer in combination with doxorubicin, trastuzumab or capecitabine. Docetaxel is also recommended in combination with cis-platin for the first-line treatment of advanced non-small cell lung cancer. Docetaxel is also recommended in combination with cis-platin and 5-fluorouracil (5-Fll) for the treatment of stomach cancer. Docetaxel is administered by intravenous infusion. Docetaxel is a taxane. Docetaxel has the following structure:

[0107] In some embodiments the chemotherapeutic agent selected from carboplatin, gemcitabine, doxorubicin, docetaxel, mitoxantrone, 5-fluorouracil (5-Fll), capecitabine, irinotecan, oxaliplatin, trifluridine and tipiracil.

[0108] In some embodiments the chemotherapeutic agent selected from carboplatin, gemcitabine, doxorubicin, mitoxantrone, 5-fluorouracil (5-Fll), capecitabine, irinotecan, oxaliplatin, trifluridine and tipiracil.

[0109] In some embodiments Compound 1 is administered in combination with a PD-1 or PD-L1 inhibitor selected from nivolumab, pembrolizumab, atezolizumab, durvalumab and cemiplimab, and a chemotherapeutic agent selected from carboplatin, gemcitabine, doxorubicin, docetaxel, mitoxantrone, 5-fluorouracil (5-Fll), capecitabine, irinotecan, oxaliplatin, trifluridine and tipiracil.

[0110] In some embodiments Compound 1 is administered in combination with a PD-1 or PD-L1 inhibitor selected from nivolumab, pembrolizumab, atezolizumab, durvalumab and cemiplimab, and a chemotherapeutic agent selected from carboplatin, gemcitabine, doxorubicin, mitoxantrone, 5-fluorouracil (5-Fll), capecitabine, irinotecan, oxaliplatin, trifluridine and tipiracil.

[0111] In some embodiments the present invention relates to a method of treating cancer comprising administering to the subject a first amount of a compound of formula 1, a second amount of a PD-1 or PD-L1 inhibitor selected from nivolumab, pembrolizumab, atezolizumab, durvalumab and cemiplimab, and a third amount of a chemotherapeutic agent selected from carboplatin, gemcitabine, doxorubicin, docetaxel, mitoxantrone, 5-fluorouracil (5-Fll), capecitabine, irinotecan, oxaliplatin, trifluridine and tipiracil.

[0112] In some embodiments the present invention relates to a method of treating cancer comprising administering to the subject a first amount of a compound of formula 1, a second amount of a PD-1 or PD-L1 inhibitor selected from nivolumab, pembrolizumab, atezolizumab, durvalumab and cemiplimab, and a third amount of a chemotherapeutic agent selected from carboplatin, gemcitabine, doxorubicin, mitoxantrone, 5-fluorouracil (5-Fll), capecitabine, irinotecan, oxaliplatin, trifluridine and tipiracil.

[0113] In some embodiments the present invention relates to a method of treating cancer comprising administering to the subject a first amount of a compound of formula 1, a second amount of a PD-1 inhibitor and a third amount of a chemotherapeutic agent selected from carboplatin, gemcitabine, doxorubicin, docetaxel, mitoxantrone, 5-fluorouracil (5-Fll), capecitabine, irinotecan, oxaliplatin, trifluridine and tipiracil.

[0114] In some embodiments the present invention relates to a method of treating cancer comprising administering to the subject a first amount of a compound of formula 1, a second amount of a PD-1 inhibitor and a third amount of a chemotherapeutic agent selected from carboplatin, gemcitabine, doxorubicin, mitoxantrone, 5-fluorouracil (5-FU), capecitabine, irinotecan, oxaliplatin, trifluridine and tipiracil.

[0115] In some embodiments Compound 1 is administered in combination with nivolumab and carboplatin. In some embodiments Compound 1 is administered in combination with nivolumab and cisplatin. In some embodiments Compound 1 is administered in combination with nivolumab and gemcitabine. In some embodiments Compound 1 is administered in combination with atezolizumab and docetaxel. In some embodiments Compound 1 is administered in combination with pembrolizumab and docetaxel.

[0116] In some embodiments the present invention relates to a method of treating cancer comprising administering to the subject a first amount of a compound of formula 1, a second amount of nivolumab and a third amount of carboplatin.

[0117] In some embodiments the present invention relates to a method of treating cancer comprising administering to the subject a first amount of a compound of formula 1, a second amount of nivolumab and a third amount of cisplatin.

[0118] In some embodiments the present invention relates to a method of treating cancer comprising administering to the subject a first amount of a compound of formula 1, a second amount of nivolumab and a third amount of gemcitabine. In some embodiments the present invention relates to a method of treating cancer comprising administering to the subject a first amount of a compound of formula 1, a second amount of atezolizumab and a third amount of docetaxel.

[0119] In some embodiments the present invention relates to a method of treating cancer comprising administering to the subject a first amount of a compound of formula 1, a second amount of pembrolizumab and a third amount of docetaxel.

[0120] Definitions

[0121] The language “pharmaceutical composition” includes compositions comprising an active ingredient and a pharmaceutically acceptable excipient, carrier or diluent, wherein the active ingredient is Compound 1 or a pharmaceutically acceptable salt thereof, or a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, or the further chemotherapeutic agent. The language “pharmaceutically acceptable excipient, carrier or diluent” includes compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, as ascertained by one of skill in the art. In some embodiments, the pharmaceutical compositions are in solid dosage forms, such as capsules, tablets, granules, powders or sachets. In some embodiments, the pharmaceutical compositions are in the form of a sterile injectable solution in one or more aqueous or non-aqueous non-toxic parenterally acceptable buffer systems, diluents, solubilizing agents, co-solvents, or carriers. A sterile injectable preparation may also be a sterile injectable aqueous or oily suspension or suspension in a non-aqueous diluent, carrier or co-solvent, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents. The pharmaceutical compositions could be a solution for iv bolus / infusion injection or a lyophilized system (either alone or with excipients) for reconstitution with a buffer system with or without other excipients. The lyophilized freeze-dried material may be prepared from non-aqueous solvents or aqueous solvents. The dosage form could also be a concentrate for further dilution for subsequent infusion.

[0122] The language “treat,” “treating” and “treatment” includes the reduction or inhibition of tumour cells of a haematological malignancy in a subject, amelioration of one or more symptoms of a haematological malignancy in a subject, or the slowing or delaying of progression of a haematological malignancy in a subject. The language “treat,” “treating” and “treatment” also includes the reduction or inhibition of the growth of a tumor or proliferation of cancerous cells in a subject. The language “inhibit”, “inhibition” or “inhibiting” includes a decrease in the baseline activity of a biological activity or process.

[0123] The term “subject” includes warm-blooded mammals, for example, primates, dogs, cats, rabbits, rats, and mice. In some embodiments, the subject is a primate, for example, a human.

[0124] The language “therapeutically effective amount” includes that amount of Compound 1 and that amount of a PD-1 or PD-L1 inhibitor and that amount of chemotherapeutic agent which together will elicit a biological or medical response in a subject, for example, the reduction or inhibition of cancer cells or tumour cells; amelioration of symptoms cancer; or the slowing or delaying of progression of a cancer. In some embodiments, the language “therapeutically effective amount” includes the amount of Compound 1 and the PD-1 or PD-L1 inhibitor and the chemotherapeutic agent together that is effective to at least partially alleviate, inhibit, and / or ameliorate cancer or inhibit tumour cells and / or reduce or inhibit the proliferation of cancerous cells in a subject.

[0125] In some embodiments, disclosed is a method of treating cancer in a subject in need thereof, comprising administering to the subject a first amount of Compound 1 or a pharmaceutically acceptable salt thereof, a second amount of a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, and a third amount of a chemotherapeutic agent or a pharmaceutically acceptable salt thereof. In the method, the first amount, the second amount and the third amount together comprise a therapeutically effective amount.

[0126] In some embodiments, disclosed is Compound 1 , or a pharmaceutically acceptable salt thereof, for use in the treatment of a cancer in a subject, wherein said treatment comprises the separate, sequential or simultaneous administration of i) said Compound 1 , or a pharmaceutically acceptable salt thereof, ii) a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, and iii) a chemotherapeutic agent or a pharmaceutically acceptable salt thereof to said subject.

[0127] In some embodiments, disclosed is a PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in a subject, wherein said treatment comprises the separate, sequential or simultaneous administration of i) said PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, and ii) Compound 1 , or a pharmaceutically acceptable salt thereof, and iii) a chemotherapeutic agent to said subject.

[0128] In some embodiments, disclosed is the use of Compound 1 , or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of cancer in a subject, wherein said treatment comprises the separate, sequential or simultaneous administration of i) said medicament comprising Compound 1, or a pharmaceutically acceptable salt thereof, ii) a PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, and iii) a chemotherapeutic agent to said subject.

[0129] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof and a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof and the further chemotherapeutic agent, are administered separately, sequentially or simultaneously in a treatment cycle. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is continuously administered in the treatment cycle and a PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt is also continuously administered in the treatment cycle and a chemotherapeutic agent is continuously administered in the treatment cycle. In some embodiments Compound 1 or a pharmaceutically acceptable salt thereof and a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof and the further chemotherapeutic agent, are administered sequentially.

[0130] In some embodiments the PD-1 or PD-L1 inhibitor is Nivolumab or Pembrolizumab. In further embodiments the PD-1 or PD-L1 inhibitor is Nivolumab.

[0131] The term “continuous” or “continuously” refers to administration of a therapeutic agent, e.g. Compound 1, at regular intervals without stopping or interruption, i.e. , no void day. By “void day”, it is meant a day when a therapeutic agent is not administered.

[0132] A “cycle”, “treatment cycle” or “dosing schedule”, as used herein, refers to a period of combination treatment that is repeated on a regular schedule. For example, the treatment can be given for one week, two weeks, or three weeks wherein Compound 1, a PD-1 or PD-L1 inhibitor and a chemotherapeutic agent are administered in a coordinated fashion. In some embodiments, a treatment cycle is about 1 week to about 3 months. In some embodiments, a treatment cycle is about 5 days to about 1 month. In some embodiments, a treatment cycle is about 1 week to about 3 weeks. In some embodiments, a treatment cycle is about 1 week, about 10 days, about 2 weeks, about 3 weeks, about 4 weeks, about 2 months, or about 3 months.

[0133] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof and a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof and the further chemotherapeutic agent, or a pharmaceutically acceptable salt thereof are administered to the human subject in one or more treatment cycles, e.g., a treatment course. A “treatment course” comprises multiple treatment cycles, which can be repeated on a regular schedule, or adjusted as a tapered schedule as the patient’s disease progression is monitored. For example, a patient’s treatment cycles can have longer periods of treatment and / or shorter periods of rest at the beginning of a treatment course (e.g., when the patient is first diagnosed), and as the cancer enters remission, the rest period lengthens, thereby increasing the length of one treatment cycle. The period of time for treatment and rest in a treatment cycle, the number of treatment cycles, and the length of time for the treatment course can be determined and adjusted throughout the treatment course by the skilled artisan based on the patient’s disease progression, treatment tolerance, and prognosis. In some embodiments, the method comprises 1 to 10 treatment cycles. In some embodiments, the method comprises 2 to 8 treatment cycles.

[0134] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered for 28 days in a 28-day treatment cycle.

[0135] Dosage

[0136] Compound 1

[0137] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is in tablet dosage form. In some embodiments, Compound 1 as the hemi-fumarate salt is administered in a dose of 40 mg per day. In some embodiments Compound 1 as the hemi- fumarate salt is administered in a dose of 80 mg per day.

[0138] PD-1 or PD-L1 inhibitor

[0139] In some embodiments, the PD-1 or PD-L1 inhibitor is administered orally. In some embodiments, the PD-1 or PD-L1 inhibitor is in tablet dosage form. In some embodiments, the PD-1 or PD-L1 inhibitor is in capsule dosage form. In some embodiments, the PD-1 or PD-L1 inhibitor is administered by injection. In some embodiments the PD-1 or PD-L1 inhibitor is administered by intravenous (IV) infusion. In some embodiments, the PD-1 or PD-L1 inhibitor is administered in a dose between 10 mg and 1 g.

[0140] In some embodiments, a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof is administered as an intravenous (IV) infusion. In some embodiments the PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof is nivolumab and is administered as an intravenous (IV) infusion.

[0141] In some embodiments the PD-1 or PD-L1 inhibitor is nivolumab or a pharmaceutically acceptable salt thereof and is administered as an intravenous (IV) infusion wherein each mL of concentrate for solution contains approximately 10 mg of nivolumab. In some embodiments the nivolumab is administered as an intravenous (IV) infusion at a dose of 40 mg, 100 mg, 120 mg or 240 mg. In some embodiments nivolumab is administered at a dose of 240 mg every 2 weeks over 30 minutes or 480 mg every 4 weeks over 60 minutes.

[0142] In some embodiments the PD-1 or PD-L1 inhibitor is pembrolizumab or a pharmaceutically acceptable salt thereof is and is administered as an intravenous (IV) infusion. In further embodiments the pembrolizumab is administered at a dose of 200 mg every three weeks or 400 mg every 6 weeks. In some embodiments pembrolizumab is administered via intravenous infusion over 15-60 minutes. In further embodiments Pembrolizumab is administered via intravenous infusion over approximately 30 minutes. In some embodiments Pembrolizumab is administered at a dose of 200mg via intravenous infusion over approximately 30 minutes every three weeks. In some embodiments Pembrolizumab is administered at a dose of 400 mg via intravenous infusion over approximately 30 minutes every six weeks.

[0143] In some embodiments the PD-L1 inhibitor is atezolizumab (Tecentriq), or a pharmaceutically acceptable salt thereof and is administered as an intravenous infusion. In some embodiments the atezolizumab is administered via intravenous infusion at a dose of 840 mg every 2 weeks. In some embodiments the atezolizumab is administered via intravenous infusion at a dose of 1200 mg every 3 weeks. In some embodiments the atezolizumab is administered via intravenous infusion at a dose of 1680 mg every 4 weeks.

[0144] In some embodiments the PD-L1 inhibitor is avelumab or a pharmaceutically acceptable salt thereof and is administered as an intravenous infusion. In some embodiments the avelumab is administered via intravenous infusion at a dose of 600-1000 mg every 2 weeks. In some embodiments the avelumab is administered via intravenous infusion at a dose of 800 mg over 60 minutes every 2 weeks.

[0145] In some embodiments the PD-L1 inhibitor is durvalumab or a pharmaceutically acceptable salt thereof and is administered as an intravenous infusion. In some embodiments the durvalumab is administered via intravenous infusion at a dose of 10 mg / kg every 2 weeks or 1500 mg every 4 weeks. In some embodiments the durvalumab is administered via intravenous infusion at a dose of 1500 mg in combination with chemotherapy every 3 weeks (21 days), for up to 8 cycles followed by 1500 mg every 4 weeks as monotherapy.

[0146] In some embodiments the PD-1 inhibitor is cemiplimab or a pharmaceutically acceptable salt thereof and is administered as an intravenous infusion. In some embodiments the cemiplimab is administered via intravenous infusion at a dose of 150-500 mg every 1-3 weeks. In some embodiments the cemiplimab is administered via intravenous infusion at a dose of 350 mg every 3 weeks. In some embodiments, the further chemotherapeutic agent is administered orally. In some embodiments, the further chemotherapeutic agent is in tablet dosage form. In some embodiments, the further chemotherapeutic agent is in capsule dosage form. In some embodiments, the further chemotherapeutic agent is administered by injection. In some embodiments the further chemotherapeutic agent is administered by intravenous (IV) infusion. In some embodiments, the further chemotherapeutic agent is administered in a dose between 10 mg and 2 g per day.

[0147] In some embodiment, there is only a single chemotherapeutic agent, i.e. no more than one chemotherapeutic agent is administered.

[0148] In some embodiments the chemotherapeutic agent is carboplatin. In some embodiments the carboplatin is administered by intravenous (IV) infusion. The recommended dose will depend on the patients’ medical condition, size and how well their kidneys are working. The doctor will test how well the patients’ kidneys are working using blood or urine samples. There is likely to be about 4 weeks between each dose of carboplatin. Calvert’s formula (Dose(mg)=AUC-(GFR+25)) is used to calculate the dose of carboplatin. It takes under consideration the creatinine clearance and the desired area under curve. After 24 hours, close to 70% of carboplatin is excreted in the urine unchanged. This means that the dose of carboplatin must be adjusted for any impairment in kidney function.

[0149] In some embodiments the chemotherapeutic agent is gemcitabine. In some embodiments the gemcitabine is administered by intravenous (IV) infusion. In some embodiments the gemcitabine is administered at 10 mg / ml solution for infusion allow delivery of 120 ml / 130 ml / 140 ml / 150 ml / 160 ml / 170 ml / 180 ml / 200 ml / 220 ml of solution (equivalent to 1200 mg / 1400 mg / 1600 mg / 1700 mg / 1800 mg / 2000 mg / 2200 mg, respectively). Gemcitabine can also be provided as a concentrate or as powder for solution for infusion.

[0150] In some embodiments the chemotherapeutic agent is cisplatin. In some embodiments the cisplatin is administered by intravenous (IV) infusion. In some embodiments the cisplatin is administered at a concentration of 1 mg / ml. In some embodiments the cisplatin is administered intravenously at a dose of 10 mg / 10 ml, 50 mg / 50 ml or 100 mg / 100 ml. In some embodiments, cisplatin is administered at a single dose of 50-120 mg / m2body surface every 3 to 4 weeks. In some embodiments cisplatin is administered at a dose of 15-20 mg / m2per day over a 5-day period, every 3 to 4 weeks. In some embodiments cisplatin is administered at a dose of 20mg / m2or more once every 3 to 4 weeks. In some embodiments cisplatin is administered at a dose of 40 mg / m2weekly for 6 weeks. In some embodiments the chemotherapeutic agent is docetaxel. In some embodiments the docetaxel is administered by intravenous (IV) infusion. In some embodiments the docetaxel is administered at a concentration <0.74 mg / ml. In some embodiments, docetaxel is administered at a single dose of 65-100 mg / m2body surface every 3 to 4 weeks. In some embodiments docetaxel is administered at a dose of 75 mg / m2once every 3 weeks. In some embodiments docetaxel is administered at a dose of 100 mg / m2once every 3 weeks.

[0151] In some embodiments the chemotherapeutic agent is pemetrexed or a pharmaceutically acceptable salt thereof and is administered as an intravenous infusion. In some embodiments the pemetrexed is administered via intravenous infusion at a dose of 500 mg / m2of body surface area (BSA). In some embodiments the pemetrexed is administered via intravenous infusion at a dose of 500 mg / m2of body surface area (BSA) administered as an intravenous infusion over 10 minutes on the first day of each 21 -day cycle.

[0152] Methods of the invention

[0153] As described in more detail below, the present inventors have surprisingly found that the combination of Compound 1 with checkpoint inhibitors and chemotherapy has synergistic effects on enhancing antitumoral immune response and cytotoxicity towards tumor cells. Thus, a combination therapy with improved anti-tumoral activity can be provided.

[0154] Secondly, the present inventors surprisingly found that the synergistic anti-tumour activity of the combination of Compound 1 with checkpoint inhibitors and chemotherapy is not limited to a specific malignancy. Thus, a combination therapy with improved therapeutic activity across multiple malignancies can be provided.

[0155] Additionally, the present inventors surprisingly found that the combination of Compound 1 with checkpoint inhibitors and chemotherapy results in tumour cell killing that is not observed with either inhibitor alone. Thus, a triple combination that can reduce tumour burden can be provided.

[0156] Furthermore, the present inventors surprisingly found that the combination of Compound 1 with checkpoint inhibitors and chemotherapy has synergistic effects already at sub-therapeutic doses. Thus, a combination with improved tolerability may be provided.

[0157] The present inventors have surprisingly found that the combination of Compound 1 with checkpoint inhibitors and chemotherapy treats patients with malignancies that are refractory to or relapsed after checkpoint inhibitor plus chemotherapy. This combination therefore can be used to treat a wide variety of cancers including breast cancer, bladder cancer, cervical cancer, colon cancer, head and neck cancer, haematological cancer, liver cancer, lung cancer, kidney cancer, skin cancer including melanoma, uveal melanoma, stomach cancer, rectal cancer, mesothelioma, endometrial cancer, small intestinal cancer, biliary tract cancer, ovarian cancer, brain cancer, testicular cancer, pancreatic cancer, bone cancer and any solid tumour that is not able to repair errors in its DNA that occur when the DNA is copied.

[0158] In some embodiments the cancer is breast cancer, bladder cancer, cervical cancer, colon cancer, head and neck cancer, haematological cancer, liver cancer, lung cancer, kidney cancer, skin cancer including melanoma, uveal melanoma, stomach cancer, rectal cancer, mesothelioma, endometrial cancer, small intestinal cancer, biliary tract cancer, ovarian cancer, brain cancer, testicular cancer, pancreatic cancer or bone cancer.

[0159] In some embodiments the cancer is lung cancer. In further embodiments the cancer is nonsmall cell lung cancer or small cell lung cancer.

[0160] In some embodiments the cancer is mesothelioma.

[0161] In some embodiments the cancer is bladder cancer.

[0162] In some embodiments the cancer is melanoma. In further embodiments the cancer is cutaneous melanoma or uveal melanoma.

[0163] In some embodiments the cancer is a malignancy that is refractory to or relapsed after checkpoint inhibitor plus chemotherapy.

[0164] In some embodiments the present invention relates to a method of treating cancer in a subject in need thereof, comprising administering to the subject a first amount of a Compound 1 or a pharmaceutically acceptable salt thereof, and a second amount of a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, and a third amount of a chemotherapeutic agent, wherein the first amount, the second amount and the third amount together comprise a therapeutically effective amount wherein the subject has previously been treated with chemotherapy and / or a PD-1 or PD-L1 inhibitor and the cancer is refractory or resistant.

[0165] In further embodiments the subject has previously been treated with chemotherapy and / or a PD-1 or PD-L1 inhibitor and has not responded or is resistant to treatment. In further embodiments the subject has previously been treated with chemotherapy selected from carboplatin, cisplatin or gemcitabine alone or in combination with a Nivolumab and the cancer is refractory or resistant.

[0166] In further embodiments the subject has previously been treated with chemotherapy selected from carboplatin, cisplatin or gemcitabine alone or in combination with nivolumab over 1 to 12 months and the subject has not responded to the treatment and / or the cancer is refractory or resistant.

[0167] In some embodiments the subject has previously been treated with carboplatin alone or in combination with Nivolumab over 1 to 12 months and the subject has not responded well to the treatment and / or the cancer is refractory or resistant.

[0168] In some embodiments the subject has previously been treated with gemcitabine alone or in combination with Nivolumab over 1 to 12 months and the subject has not responded well to the treatment and / or the cancer is refractory or resistant.

[0169] In some embodiments the subject has previously been treated with nivolumab alone or in combination with carboplatin over 1 to 12 months and the subject has not responded well to the treatment and / or the cancer is refractory or resistant.

[0170] In some embodiments the subject has previously been treated with nivolumab alone or in combination with Gemcitabine over 1 to 12 months and the subject has not responded well to the treatment and / or the cancer is refractory or resistant.

[0171] In some embodiments the subject has not been treated previously with chemotherapy and / or a PD-1 or PD-L1 inhibitor.

[0172] The features disclosed in the foregoing description, or in the following claims, or in the accompanying drawings, expressed in their specific forms or in terms of a means for performing the disclosed function, or a method or process for obtaining the disclosed results, as appropriate, may, separately, or in any combination of such features, be utilised for realising the invention in diverse forms thereof.

[0173] While the invention has been described in conjunction with the exemplary embodiments described above, many equivalent modifications and variations will be apparent to those skilled in the art when given this disclosure. Accordingly, the exemplary embodiments of the invention set forth above are considered to be illustrative and not limiting. Various changes to the described embodiments may be made without departing from the spirit and scope of the invention.

[0174] For the avoidance of any doubt, any theoretical explanations provided herein are provided for the purposes of improving the understanding of a reader. The inventors do not wish to be bound by any of these theoretical explanations.

[0175] Any section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0176] Throughout this specification, including the claims which follow, unless the context requires otherwise, the word “comprise” and “include”, and variations such as “comprises”, “comprising”, and “including” will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Ranges may be expressed herein as from “about” one particular value, and / or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent “about,” it will be understood that the particular value forms another embodiment. The term “about” in relation to a numerical value is optional and means for example + / - 10%.

[0177] The compounds of the application will now be further explained by reference to the following nonlimiting examples.

[0178] Examples

[0179] Example 1 - in vitro assay using patient-derived co-culture system that include tumor cells, fibroblasts (MRC-5) and PBMCs in model of NSCLC (non-small cell lung cancer) and mesothelioma

[0180] Proprietary patient-derived mesothelioma (MPM) cell lines 420 and 353 were obtained from the Biological Bank of Mesothelioma, Azienda Ospedaliera (AO) Nazionale Ss. Antonio e Biagio, Alessandria, Italy. For NSCLC cells, patient-derived cell lines #1 , #3, #4, #5, #15, #16, #18, #21 , #26, #34 were obtained from the AOU San Luigi Gonzaga, Orbassano, Italy. 1.1 Tissue processing

[0181] 0.5 g of the tissue was washed twice in 5 ml sterile phosphate buffer saline, containing a sterile aqueous solution of 2 g / l ciprofloxacin. Tissues were manually cut and digested at 37°C 5% CO2 20% O2 for 1 h, in 2 ml RPMI-1640 medium, GlutaMAX™ supplement containing freshly prepared 1 mg / MI collagenase and 0.2 mg / MI hyaluronidase. Digested samples were centrifuged at room temperature at 12,000 x g for 5 minutes, resuspended in 1 ml HAM’s F12 medium containing 1% v / v penicillin-streptomycin (#P4333; Sigma-Aldrich) and 10% v / v fetal bovine serum. Viable cells were counted and plated in 60-mm3diameter Petri dishes at density of 1 x106cells / dish. Every 3 days cells were washed twice with sterile PBS, and fresh complete medium was added. When cells reached 80% confluence, they were sub-cultured. Cells were used between passage 3 and 6 for the experimental procedures described.

[0182] 1.2 Lung fibroblasts cell cultures

[0183] MRC-5 lung fibroblast cell line was purchased from American Type Culture Collection (ATCC) (#CCL-171). Cells were cultured in OptiMEM (#11058021 ; Gibco ThermoFisher Scientific), containing 1% v / v penicillin-streptomycin and 10% v / v FBS, and maintained in 100 mm3-diameter Petri dishes (#P5606; Sigma-Aldrich) at a density of 2.5 x106cells / dish. Every 3 days cells were washed twice with sterile PBS, and complete medium was added. When cells reached 80% confluence, they were sub-cultured and plated in 100-mm3diameter Petri dishes at density of 2.5 x106cells / dish. Cells were used until passage 12-15 for the experimental procedures described.

[0184] 1.3 MPM-fibroblasts or NSCLC-fibroblasts co-cultures

[0185] For cultures of MPM or NSCLC cells alone, 5 x 105patient derived MPM or NSCLC cells, resuspended into 0.5 Ml complete HAM’s F12 medium, were seeded in 24-well plates (#CLS3526; Sigma-Aldrich), on the top of 0.25 Ml coating MaxGel™ ECM (#E0282; Sigma-Aldrich), added 18 h before the cells and maintained in incubator at 37°C, 5% CO2, 20% O2.

[0186] In co-cultures, 1 x 105MRC-5 cells were mixed with 0.25 Ml coating MaxGel™ ECM / well into a 24-well plate and maintained for 18 h in incubator at 37°C. After this incubation time, 5 x 105patient-derived MPM or NSCLC cells, resuspended into 0.5 Ml complete HAM’s F12 medium, were seeded on the top of the MaxGel™ ECM. Cultures of MPM or NSCLC cells, or co-cultures of MPM / MRC-5 or NSCLC / MRC-5 cells were maintained for 48 h in incubator at 37°C, 5% CO2, 20% O2, before proceeding with the viability assays or the co-cultures with peripheral blood mononuclear cells (PBMCs).

[0187] 1.4 Peripheral blood monocyte cells (PBMC) co-cultures

[0188] Four heparinized tubes, each containing 5 ml of whole blood, were collected by patient’s peripheral vein and maintained at room temperature for < 1 h in mild agitation on a mechanical shaker (50 rpm), before further processing. Under biosafety level 2 laminar hood, tubes were wiped off with 70% v / v ethanol. Blood volumes were collected into a 50 ml conic sterile plastic tube (Falcon ®, #734-0448, Avantor), diluted 1 :2 v / v with sterile 0.9% w / v NaCI solution (#S8776, Sigma-Aldrich) and mixed gently with 10 Ml-sterile pipette, up to 10 times. 15 ml of Ficoll®-Paque Premium (#GE17-5442-03, Sigma-Aldrich) were added at the bottom of a new 50 ml conical sterile plastic tube, with a 25 ml sterile pipette. Diluted blood was let to flow down the side of the tube and pool on top of the Ficoll density gradient, without breaking surface plane. Tubes were centrifuged at room temperature at 760 x g for 25 min, selecting “brakes OFF” function. The supernatant (plasma fraction) was removed by gentle pipetting, while the peripheral blood mononuclear cells (PBMCs), at the plasma / Ficoll interface, were transferred with a disposable sterile 1 ml pipet into a new series of 15-ml conical tubes (Falcon ®, #734-0452, Avantor). Each tube was filled with sterile PBS and centrifuged at 350 x g for 8 min, then the supernatant was carefully removed. The pellets were resuspended by gentle pipetting in sterile PBS to fill the tubes. This washing-centrifugation steps was repeated twice. After the second wash, the pellet was resuspended into 3 Ml of Red Blood Cell solution (eBioscience™ 1X RBC Lysis Buffer, # 00-4333- 57; ThermoFisher Scientific) and incubated for 15 min at room temperature in tubes filled with RPMI-1640 medium. Tubes were then centrifuged at 350 x g for 8 min. The supernatant was carefully removed and the PBMCs contained in the pellet were re-suspended in 1 Ml RPMI-1640 medium containing 1 % v / v penicillin-streptomycin and 10% v / v FBS. A 10 pL aliquot, diluted 1 :10 into RPMI-1640 medium, was used to count PBMCs using the automated cell counter Acella 50. For MPM / MRC-5 or NSCLC / MRC-5 co-cultures, PBMCs were added to the co-cultures after 48 h from seeding MPM or NSCLC cells, at 1 :10 (PBMC:MPM or PBMC:NSCLC) ratio (i.e., 5 x104PBMC added to each 24-well plate containing 5 x105MPM or NSCLC cells). PBMC were cocultured with MPM / MRC-5 or NSCLC / MRC-5 for 5 days before performing the immunophenotyping assays.

[0189] 1.5 Pharmacological treatments for IC50 assessment:

[0190] For IC50 evaluation, MPM or NSCLC cultures, MPM / MRC-5 or NSCLC / MRC-5 co-cultures, seeded 48 h before, were incubated for 72 h with the following agents or combinations:

[0191] 1) Compound 1 , dissolved in DMSO (#D2438, Sigma-Aldrich), at a final concentration of 10'9M, 10'8M, 10'7M, 10'6M, 10'5M, 10'4M, 10'3M;

[0192] 2) carboplatin (#C2538, Sigma-Aldrich), dissolved in sterile aqueous solution, at a final concentration of 10’9M, 10’8M, 10’7M, 10’6M, 10’5M, 10’4M, 10’3M;

[0193] 3) gemcitabine (#G6423, Sigma-Aldrich), dissolved in sterile aqueous solution, at a final concentration of 10’9M, 10’8M, 10’7M, 10’6M, 10’5M, 10’4M, 10’3M;

[0194] 3) nivolumab, dissolved in sterile aqueous solution, at a final concentration of 10'9M, 10'8M, 10’7M, 10'6M, 10'5M, 10'4M, 10'3M 4) carboplatin+nivolumab, each at a final concentration of 10'9M, 10'8M, 10'7M, 10'6M, 10'5M, 10’4M, 10'3M;

[0195] 5) gemcitabine+nivolumab, each at a final concentration of 10'9M, 10'8M, 10'7M, 10'6M, 10'5M, 10’4M, 10'3M;

[0196] 6) Compound 1+carboplatin+nivolumab, each at a final concentration of 10'9M, 10'8M, 10'7M, 10'6M, 10'5M, 10'4M, 10'3M for 72 h (concomitant treatment a);

[0197] 7) Compound 1+gemcitabine+nivolumab, each at a final concentration of 10'9M, 10'8M, 10'7M, 10'6M, 10'5M, 10'4M, 10'3M for 72 h (concomitant treatment b);

[0198] 8) carboplatin+nivolumab, each at a final concentration of 10'9M, 10'8M, 10'7M, 10'6M, 10'5M, 10'4M, 10'3M for 72h h, plus Compound 1 added in the last 24 h at a final concentration of 10'9M, 10'8M, 10'7M, 10'6M, 10'5M, 10'4M, 10'3M (sequential treatment a);

[0199] 9) gemcitabine+nivolumab, each at a final concentration of 10'9M, 10'8M, 10'7M, 10'6M, 10'5M, 10'4M, 10'3M for 72h h, plus Compound 1 added in the last 24 h at a final concentration of 10'9M, 10'8M, 10'7M, 10'6M, 10'5M, 10'4M, 10'3M (sequential treatment b).

[0200] 10) Compound 1+docetaxel+pembrolizumab, each at a final concentration of 10'9M, 10'8M, 10'7M, 10-6M, 10'5M, 10-4M, 10'3M for 72 h (concomitant treatment a);

[0201] 11) Compound 1+docetatxel+atezolizumab, each at a final concentration of 10'9M, 10'8M, 10'7M, 10-6M, 10'5M, 10-4M, 10'3M for 72 h (concomitant treatment b);

[0202] 12) docetaxel+pembrolizumab, each at a final concentration of 10'9M, 10'8M, 10'7M, 10'6M, 10'5M, 10-4M, 10'3M for 72h h, plus Compound 1 added in the last 24 h at a final concentration of 10'9M, 10'8M, 10'7M, 10'6M, 10'5M, 10'4M, 10'3M (sequential treatment a);

[0203] 13) docetatxel+atezolizumab, each at a final concentration of 10'9M, 10'8M, 10'7M, 10'6M, 10'5M, 10'4M, 10'3M for 72h h, plus Compound 1 added in the last 24 h at a final concentration of 10'9M, 10'8M, 10'7M, 10'6M, 10'5M, 10'4M, 10-3M (sequential treatment b).

[0204] Cells grown in complete culture medium were considered as control group.

[0205] 1.6 IC50 evaluation

[0206] At the end of the pharmacological treatments, MPM and NSCLC cells, grown on the top of the MaxGel™ ECM coating, containing or not MRC-5 cells, were collected by carefully removing the cell culture medium and adding 0.5 ml Cell Dissociation Solution (#C5914; Sigma-Aldrich) on the tope of MaxGel ECM surface. Samples were maintained 10 min in incubator at 37°C, 5% CO2, 20% O2, then 0.5 ml sterile PBS was added and the soluble phase, containing MPM or NSCLC cells, was transferred into a 1 .5 ml sterile plastic tube. Cells were centrifuged at room temperature at 1 ,200 x g for 2 min, the supernatant was removed and the pellet was re-suspended into 0.45 ml OptiMEM without Phenol Red. 100 pl of cell suspension were seeded into a 96-well plate, in technical quadruplicates for each sample. Plates were maintained in incubator at 37°C, 5% CO2, 20% O2 for 2 h to let cell to adhere. After this time, 10 pl / well of Cell Proliferation Reagent WST- 1 (CELLPRO-RO; Sigma-Aldrich) were added for additional 2 h. Samples were maintained in incubator, then plates were transferred into a Synergy™ HTX Multi-Mode Microplate Reader (Cytation 3; Bio-Tek Agilent) and shook at room temperature for 1 min. The absorbance was read at 450 nm, using the Gene-5 software (Bio-Tek). The absorbance was read also at 650 nm, used as reference length. The absorbance at 650 nm was subtracted from the absorbance at 450 nm from each well. The technical quadruplicate was averaged for each sample. The percentage of cell viability was calculated using the following equation:

[0207] % viable cells = (100 x (absorbance untreated cells-absorbance sample X)) / absorbance untreated cells

[0208] The viability values were plotted against the drug concentrations using the GraphPad PRISM software (v. 9.5.1). IC50 was calculated using the “log(inhibitor) vs. response (three parameters)” function of the same software.

[0209] 1.7 Pharmacological treatments for immunophenotyping assays:

[0210] To evaluate the effects of the pharmacological treatments on PBMC immunophenotype, the 5- days co-cultures of MPM / MRC-5+PBMC or NSCLC / MRC-5+PBMC were incubated in the last 72h with the following agents, each used at their IC50, as determined above

[0211] 1) Compound 1

[0212] 2) carboplatin + nivolumab

[0213] 3) gemcitabine + nivolumab

[0214] 4) Compound 1 + carboplatin + nivolumab (concomitant treatment a):

[0215] 5) Compound 1 + gemcitabine + nivolumab (concomitant treatment b);

[0216] 6) carboplatin + nivolumab, plus Compound 1 added in the last 24 h (seguential treatment a):

[0217] 7) gemcitabine + nivolumab, plus Compound 1 added in the last 24 h (seguential treatment b). Cells grown in complete culture medium were considered as control group.

[0218] 1.8 Results

[0219] In co-culture with fibroblasts, immune cells and patient-derived tumour cells, Compound 1 treatment in monotherapy for 72 h impaired the viability of tumour cells, with IC50 values that range between 0.12 and 11.7 micromolar in NSCLC patients, while showing limited monotherapy efficacy in mesothelioma, with IC50 of 46.31 and 49.77 micromolar (Table 1 and Table 2).

[0220] However, when added to the combination of chemotherapy and immunotherapy, Compound 1 strongly decreases the IC50 of the three drugs when combined. This increased cytotoxicity is particularly relevant in NSCLC patients that are refractory to immunotherapy (NR) (Table 1 and Table 2). Table 1. IC50 value (pM) of Compound 1, chemotherapy and nivolumab, used as single, double and triple treatment.

[0221] Table 2. IC50 value (pM) of Compound 1, docetaxel and CPI, used as single, double and triple treatment.

[0222] 1.9 Combination Index (Cl) evaluation

[0223] CompuSyn, a computer program for quantitation of synergism and antagonism in drug combinations, was used to calculate the combination index of the NSCLC patient samples cocultured with fibroblasts and PBMCs in presence of the drugs listed in Table 1. The cell viability data was entered as the average of all patients, and further stratified as responders or nonresponders based on their response to CPI as listed in Table 1, and the Cl was calculated when i) the drugs were administered concomitantly, or ii) when the drugs were applied sequentially. Cl was classified as follows: <0.1 very strong synergism, 0.1 to 0.3 strong synergism, 0.3 to 0.7 synergism, 0.7 to 0.85 moderate synergism, 0.85 to 0.90 slight synergism, 0.90 to 1.10 near additive, 1.10 to 1.20 slight antagonism, 1.20 to 1.45 moderate antagonism, 1.45 to 3.3 antagonism, 3.3 to 10 strong antagonism, >10 very strong antagonism. 1.10 Results

[0224] In the combination assays with nivolumab, where all three drugs were combined concomitantly, an additive effect was observed at the ED50 concentration, and an increasing synergistic effect at higher concentrations when looking at the average over all patient samples. When the patients are stratified into responders and non-responders to CPI, the combination is additive in responders at the ED50 and becomes antagonistic at higher concentrations, while in the non- responders the combination is additive at ED50 and shifts to synergistic at higher concentrations (Table 3). When applying the drugs sequentially, synergy is observed across all patients and at all concentrations with the strongest synergy observed in the CPI non-responders and the synergy shifts to strong synergy with increasing concentrations (Table 3).

[0225] Table 3. Cl of the combination of Compound 1 with chemotherapy and nivolumab, used as triple treatment.

[0226] In the combination assays with atezolizumab, where all three drugs were combined concomitantly, synergistic effects were observed at all concentrations with a tendency to increase at higher concentrations when looking at both responder and non-responder patients (Table 4). When applying the drugs sequentially, synergy is again observed across all patients and at all concentrations, however without a shift to strong synergy with increasing concentrations (Table 4). Table 4. Cl of the combination of Compound 1 with chemotherapy and atezolizumab, used as triple treatment.

[0227] In the combination assays with pembrolizumab, where all three drugs were combined concomitantly or sequentially, synergistic effects were observed at almost all concentrations with a clear shift to stronger synergy at higher concentrations. Only for the non-responder patients in the concomitant combination no synergy was observed at the ED50 (Table 5).

[0228] Table 5. Cl of the combination of Compound 1 with chemotherapy and pembrolizumab, used as triple treatment.

[0229] Example 2. Immunophenotyping assay

[0230] 2.1 Cell collection and counting:

[0231] 0.4 ml of the cell culture medium, containing floating PBMC, was collected by gentle pipetting from the MPM / MRC-5+PBMC or NSCLC / MRC-5+PBMC co-cultured for 5 days, untreated or treated for the last 72 h as indicated in section 1.7 above, and transferred into 1.5 Ml Eppendorf sterile plastic tubes. A further 0.1 ml medium, at the surface of MaxGel ECM, was removed by gently pipetting, avoiding the contact with the Maxgel ECM, and discharged. The exposed MaxGel ECM surface was rinsed with 0.5 ml Cell Dissociation Solution (#C5914; Sigma-Aldrich), to cover the MaxGel ECM surface. Samples were maintained in incubator 10 min at 37°C, 5% CO2, 20% O2, then 0.5 ml sterile PBS was added and the soluble phase, containing MPM or NSCLC cells, was transferred into a separated 1.5 ml Eppendorf sterile plastic tube series. The samples with PBMC, MPM or NSCLC cells were centrifuged at 1 ,200 x g for 5 min at room temperature, washed with 1 ml sterile PBS and resuspended. The centrifugation, washing and resuspension step was repeated once, then cells were re-suspended in 1 ml sterile PBS containing 5% v / v FBS. A 10 pl aliquot was transferred to a new 1.5 Ml Eppendorf sterile plastic tube, the volume was brought to 0.3 Ml with PBS and cell were counted by a Guava EasyCyte flow cytometer (Millipore), equipped with the InCyte software. For PBMC, each sample was divided into 12 aliquots, each containing >3,000 cells; the volume was brought to 0.3 ml with sterile PBS containing 1% v / v FBS. For MPM or NSCLC cells, each sample was divided into 2 aliquots, each containing >3,000 cells; the volume was brought to 0.3 ml with sterile PBS containing 1 % v / v FBS.

[0232] 2.2. PBMC immunophenotyping:

[0233] Each PBMC aliquot was incubated 1 h at room temperature with the combination of antibodies detailed below. All the acquisitions and analyses were performed by a Guava EasyCyte flow cytometer (Millipore), equipped with the InCyte software. A minimum of 3,000 events were counted.

[0234] CD3+CD8+cells

[0235] Antibodies used: anti-CD3 APC (REA613, #130-113-135, Miltenyi; diluted 1 :50); anti-CD8 FITC (clone BW135 / 80, #130-113-157, Miltenyi; diluted 1 :50).

[0236] Acquisition strategies: CD3+(T-lymphocytes) and CD3+CD8+cells (T-cytotoxic lymphocytes) were acquired. Results were expressed as % CD3+CD8+cells over CD3+cells.

[0237] CD8+CD107a+!FNy cells

[0238] Sample treatment: cells were treated with the Inside Stain Kit (#130-090-477, Miltenyi) as per manufacturer’s protocol.

[0239] Antibodies used: anti-CD8 FITC (clone BW135 / 80, #130-113-157, Miltenyi; diluted 1 :50); anti- CD107a APC (REA792, #130-111-847, Miltenyi; diluted 1 :50); anti IFN-y PE (REA600, #130-113- 498, Miltenyi; diluted 1 :50).

[0240] Acquisition strategies: CD8+(T-cytotoxic lymphocytes) and CD8+CD107a+IFNy+(activated T- cytotoxic lymphocytes) were acquired. Results were expressed as % CD107a+IFNy+cells over CD8+cells.

[0241] CD8+PD-1and CD8+TIM-3 cells

[0242] Antibodies used: anti-CD8 FITC (clone BW135 / 80, #130-113-157, Miltenyi; diluted 1 :50); anti CD279 / PD-1 APC (clone PD1.3.1.3, # 130-117-806, Miltenyi; diluted 1 :50); anti-CD366 / TIM-3 PE (REA635, # 130-119-785, Miltenyi; diluted 1 :50).

[0243] Acquisition strategies: strategies: CD8+, CD8+PD-1+and CD8+TIM-3+cells were acquired. Results were expressed as % CD8+PD-1+cells or CD8+TIM-3+cells over CD8+cells.

[0244] CD8+LAG-3+and CD8+CTLA-4+cells

[0245] Antibodies used: anti-CD8 FITC (clone BW135 / 80, #130-113-157, Miltenyi; diluted 1 :50); anti CD233 / LAG-3 APC (REA351 , #130-119-567, Miltenyi; diluted 1 :50); anti-CD152 / CTLA-4 PE (REA1003, #130-116-810, Miltenyi; diluted 1 :50). Acquisition strategies: CD8+, CD8+LAG-3+and CD8+CTLA-4+cells were acquired. Results were expressed as % CD8+LAG-3+cells or CD8+CTLA-4+cells over CD8+cells.

[0246] CD3+CD4+and CD4+FoxP3+cells

[0247] Antibodies used: anti-CD3 APC (REA613, #130-113-135, Miltenyi; diluted 1 :50); anti-CD4 FITC (clone M-T466, #130-113-253, Miltenyi; diluted 1 :50); anti FoxP3 PE (REA1253, #130-125-579, Miltenyi; diluted 1 :50).

[0248] Acquisition strategies: CD3+CD4+cells (T-helper lymphocytes) and CD3+CD4+FoxP3+(T- regulatory -Treg- cells) were acquired. Results were expressed as % CD4+cells over CD3+cells or % FoxP3+cells over CD4+cells.

[0249] CD68+CD86+lnos+cells

[0250] Antibodies used: anti-CD68 APC (clone Y1 / 82A, #130-125-857, Miltenyi; diluted 1 :50); anti-CD86 PE (REA968, #130-116-160, Miltenyi; diluted 1 :50); anti-inducible nitric oxide synthase (Inos) Alexa Fluor 488 (#NBP2-99091AF488, Novus Biological, diluted 1 / 10).

[0251] Acquisition strategies: CD68+(macrophages) and CD68+CD86+lnos+cells (M1 -polarized macrophages) were acquired. Results were expressed as % CD68+CD86+lnos+cells over CD68+cells.

[0252] CD68+CD20 Arg+cells

[0253] Antibodies used: anti-CD68 APC (clone Y1 / 82A, #130-125-857, Miltenyi; diluted 1 :50); anti CD206 FITC (clone DCN228, #130-123-671 , Miltenyi; diluted 1 :50); anti-Arginase PE (clone 14D2C43, #369704, BioLegend, diluted 1 / 100)-

[0254] Acquisition strategies: CD68+(macrophages) and CD68+CD206+arginase+cells (M2-polarized macrophages) were acquired. Results were expressed as % CD68+CD206+arginase+cells over CD68+cells.

[0255] 2.3 Results

[0256] In ex vivo co-culture models of patient-derived mesothelioma cells (n=2) or NSCLC (n=10) with matched PBMC, and fibroblasts the addition of Compound 1 to chemotherapy plus nivolumab specifically increased activated Ki67+ / IFNg+ CD8 T cells and M1-like macrophages, and concomitantly decreased Tregs, exhausted TIM3+ CD8 T cells and MDSCs with an overall effect to increase the antitumoral immune response. These data demonstrate that Compound 1 increase chemo / immunotherapy cytotoxicity by increasing antitumoral immune cells, while decreasing protumoral immune cells (figure 1 and figure 2). Data shown in figure 1 and figure 2 are representative of immune cell changes observed for mesothelioma and lung cancer, respectively. They have been repeated in a total of 2 mesothelioma and 10 lung cancer patients.

[0257] Figure 1 shows BAP1-wild-type (BAP+) MPM cells were co-cultured with peripheral mononuclear cells (PBMCs) and in the presence of fibroblasts (+MRC5) and treated with Compound 1 alone, co-incubated with cisplatin / nivolumab. The immunophenotype of immune cells was analysed by flow cytometry (n = 2, two independent experiments). *p<0.05, **p<0.01 , ***p<0.001.

[0258] Figure 2 shows NSCLC cells from CPI-refractory patient #4 were co-cultured with peripheral mononuclear cells (PBMCs) and in the presence of fibroblasts (+MRC5) and treated with Compound 1 alone, co-incubated with cisplatin / nivolumab. The immunophenotype of immune cells was analysed by flow cytometry (n = 2, two independent experiments). *p<0.05, **p<0.01 , ***p<0.001.

[0259] References

[0260] A number of publications are cited above in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Full citations for these references are provided below. The entirety of each of these references is incorporated herein.

[0261] For standard molecular biology techniques, see Sambrook, J., Russel, D.W. Molecular Cloning, A Laboratory Manual. 3 ed. 2001, Cold Spring Harbor, New York: Cold Spring Harbor Laboratory Press

[0262] Statements

[0263] 1. A method of treating cancer in a subject in need thereof, comprising administering to the subject a first amount of a compound of formula I: Formula I or a pharmaceutically acceptable salt thereof, and a second amount of a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, and a third amount of a chemotherapeutic agent, wherein the first amount, the second amount and the third amount together comprise a therapeutically effective amount.

[0264] 2. The method according to statement 1 , wherein the PD-1 or PD-L1 inhibitor is a PD-1 inhibitor.

[0265] 3. The method according to statement 1 or 2, wherein the cancer is breast cancer, bladder cancer, cervical cancer, colon cancer, head and neck cancer, haematological cancer, liver cancer, lung cancer, kidney cancer, skin cancer including melanoma, uveal melanoma, stomach cancer, rectal cancer, mesothelioma, endometrial cancer, small intestinal cancer, biliary tract cancer, ovarian cancer, brain cancer, testicular cancer, pancreatic cancer, bone cancer and any solid tumour that is not able to repair errors in its DNA that occur when the DNA is copied.

[0266] 4. The method according to any of statements 1 to 3, wherein the cancer is lung cancer, mesothelioma, bladder cancer, melanoma or uveal melanoma.

[0267] 5. The method according to any of statements 1 to 3, wherein the cancer is a malignancy that is refractory to or relapsed after checkpoint inhibitor plus chemotherapy

[0268] 6. The method according to any of statements 1 to 5, wherein the PD-1 or PD-L1 inhibitor is a PD-1 inhibitor selected from atezolizumab, nivolumab, pembrolizumab, cemiplimab, dostarlimab, retifanlimab and toripalimab. 7. The method according to statement 6, wherein the PD-1 inhibitor is nivolumab.

[0269] 8. The method according to statement 6, wherein the PD-1 inhibitor is pembrolizumab.

[0270] 9. The method according to statement 6, wherein the PD-1 inhibitor is dostarlimab.

[0271] 10. The method according to statement 6, wherein the PD-L1 inhibitor is atezolizumab.

[0272] 11. The method according to any of statements 1 to 10, wherein the chemotherapeutic agent, is selected from carboplatin, gemcitabine, cisplatin, docetaxel, doxorubicin, mitoxantrone, 5-fluorouracil (5-FU), capecitabine, irinotecan, oxaliplatin, pemetrexed, trifluridine and tipiracil.

[0273] 12. The method according to any of statements 1 to 11 , wherein the chemotherapeutic agent, is selected from carboplatin, gemcitabine, cisplatin and docetaxel.

[0274] 13 The method according to any of statements 1 to 11 , wherein the chemotherapeutic agent, is carboplatin.

[0275] 14. The method according to any of statements 1 to 11 , wherein the chemotherapeutic agent, is cisplatin.

[0276] 15. The method according to any of statements 1 to 11 , wherein the chemotherapeutic agent is gemcitabine.

[0277] 16. The method according to any of statements 1 to 11 , wherein the chemotherapeutic agent is docetaxel.

[0278] 17. The method according to any of statements 1 to 7, comprising administering to the subject a first amount of a Compound 1 , a second amount of nivolumab and a third amount of carboplatin.

[0279] 18. The method according to any of statements 1 to 7, comprising administering to the subject a first amount of a Compound 1 , a second amount of nivolumab and a third amount of cisplatin.

[0280] 19. The method according to any of statements 1 to 7, comprising administering to the subject a first amount of a Compound 1 , a second amount of nivolumab and a third amount of gemcitabine. 20. The method according to any of statements 1 to 6, comprising administering to the subject a first amount of a Compound 1 , a second amount of pembrolizumab and a third amount of docetaxel.

[0281] 21. The method according to any of statements 1 to 6, comprising administering to the subject a first amount of a Compound 1 , a second amount of atezolizumab and a third amount of docetaxel.

[0282] 22. The method according to any one of statements 1 to 21, wherein Compound 1 is administered as the hemifumarate salt in a dose of 40 mg or 80 mg per day.

[0283] 23. The method according to any one of statements 1 to 22, wherein the subject has previously been treated with chemotherapy and / or a PD-1 or PD-L1 inhibitor and the cancer is refractory or resistant.

[0284] 24. The method according to any one of statements 1 to 22, wherein the subject has previously been treated with chemotherapy and / or a PD-1 or PD-L1 inhibitor and has not responded to or is resistant to treatment.

[0285] 25. The method according to any one of statements 1 to 22, wherein the subject has previously been treated with chemotherapy selected from carboplatin, cisplatin or gemcitabine alone or in combination with nivolumab and the cancer is refractory or resistant.

[0286] 26. The method according to any one of statements 1 to 22, wherein the subject has previously been treated with Nivolumab alone or in combination with chemotherapy selected from carboplatin, cisplatin or gemcitabine and the cancer is refractory or resistant.

[0287] 27. A compound of Formula I: or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in a subject, wherein said treatment comprises the separate, sequential or simultaneous administration of i) said Compound 1, or a pharmaceutically acceptable salt thereof, ii) a PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, and iii) a chemotherapeutic agent, or a pharmaceutically acceptable salt thereof to said subject.

[0288] 28. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to statement 27, wherein the PD-1 or PD-L1 inhibitor is a PD-1 inhibitor.

[0289] 29. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to statement 27 or 28, wherein the cancer is breast cancer, bladder cancer, cervical cancer, colon cancer, head and neck cancer, haematological cancer, liver cancer, lung cancer, kidney cancer, skin cancer including melanoma, uveal melanoma, stomach cancer, rectal cancer, mesothelioma, endometrial cancer, small intestinal cancer, biliary tract cancer, ovarian cancer, brain cancer, testicular cancer, pancreatic cancer, bone cancer and any solid tumour that is not able to repair errors in its DNA that occur when the DNA is copied.

[0290] 30. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to statement 29, wherein the cancer is lung cancer, mesothelioma, bladder cancer, melanoma or uveal melanoma.

[0291] 31. Compound 1 , or a pharmaceutically acceptable salt thereof, for use according to any one of statements 27 to 30, wherein the cancer is a malignancy that is refractory to or relapsed after checkpoint inhibitor plus chemotherapy.

[0292] 32. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 23-27, wherein the PD-1 or PD-L1 inhibitor is a PD-1 inhibitor selected from atezolizumab, nivolumab, pembrolizumab, cemiplimab, dostarlimab, retifanlimab and toripalimab.

[0293] 33. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to statement 32, wherein the PD-1 inhibitor is nivolumab.

[0294] 34. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to statement 32, wherein the PD-1 inhibitor is pembrolizumab.

[0295] 35. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to statement 32, wherein the PD-1 inhibitor is dostarlimab.

[0296] 36. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to statement 32, wherein the PD-1 inhibitor is atezolizumab.

[0297] 37. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 27 to 36, wherein the chemotherapeutic agent, is selected from carboplatin, gemcitabine, cisplatin, docetaxel, doxorubicin, mitoxantrone, 5-fluorouracil (5-Fll), capecitabine, irinotecan, oxaliplatin, pemetrexed, trifluridine and tipiracil.

[0298] 38. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 27-37, wherein the chemotherapeutic agent, is selected from carboplatin, gemcitabine, cisplatin and docetaxel.

[0299] 39. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 27-38, wherein the chemotherapeutic agent, is carboplatin.

[0300] 40. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 27-38, wherein the chemotherapeutic agent, is cisplatin.

[0301] 41. Compound 1 , or a pharmaceutically acceptable salt thereof, for use according to any one of statements 27-38, wherein the chemotherapeutic agent, is gemcitabine.

[0302] 42. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 27-38, wherein the chemotherapeutic agent, is docetaxel. 43. Compound 1 , or a pharmaceutically acceptable salt thereof, for use according to any one of statements 27-33, comprising administering to the subject a first amount of a Compound 1 , a second amount of nivolumab and a third amount of carboplatin.

[0303] 44. Compound 1 , or a pharmaceutically acceptable salt thereof, for use according to any one of statements 27-33, comprising administering to the subject a first amount of a Compound 1 , a second amount of nivolumab and a third amount of cisplatin.

[0304] 45. Compound 1 , or a pharmaceutically acceptable salt thereof, for use according to any one of statements 27-33, comprising administering to the subject a first amount of a Compound 1 , a second amount of nivolumab and a third amount of gemcitabine.

[0305] 46. Compound 1 , or a pharmaceutically acceptable salt thereof, for use according to any one of statements 27-32, comprising administering to the subject a first amount of a Compound 1 , a second amount of pembrolizumab and a third amount of docetaxel.

[0306] 47. Compound 1 , or a pharmaceutically acceptable salt thereof, for use according to any one of statements 27-32, comprising administering to the subject a first amount of a Compound 1 , a second amount of atezolizumab and a third amount of docetaxel.

[0307] 48. Compound 1 , or a pharmaceutically acceptable salt thereof, for use according to any one of statements 27-47, wherein Compound 1 is administered as the hemifumarate salt in a dose of 40 mg or 80 mg per day.

[0308] 49. Compound 1 , or a pharmaceutically acceptable salt thereof, for use according to any one of statements 27-48, wherein the subject has previously been treated with chemotherapy and / or a PD-1 or PD-L1 inhibitor and the cancer is refractory or resistant.

[0309] 50. Compound 1 , or a pharmaceutically acceptable salt thereof, for use according to any one of statements 27-48, wherein the subject has previously been treated with chemotherapy and / or a PD-1 or PD-L1 inhibitor and has not responded to or is resistant to treatment.

[0310] 51 . Compound 1 , or a pharmaceutically acceptable salt thereof, for use according to any one of statements 27-48, wherein the subject has previously been treated with chemotherapy selected from carboplatin, cisplatin or gemcitabine alone or in combination with Nivolumab and the cancer is refractory or resistant. 52. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 27-48, wherein the subject has previously been treated with Nivolumab alone or in combination with chemotherapy selected from carboplatin, cisplatin or gemcitabine and the cancer is refractory or resistant.

[0311] 53. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 27-52, wherein said treatment comprises the sequential administration of i) said Compound 1, or a pharmaceutically acceptable salt thereof, ii) a PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, and iii) a chemotherapeutic agent, or a pharmaceutically acceptable salt thereof to said subject.

[0312] 54. A PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in a subject, wherein said treatment comprises the separate, sequential or simultaneous administration of i) said PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, ii) a compound of Formula I: Formula I, or a pharmaceutically acceptable salt thereof, and iii) a chemotherapeutic agent, or a pharmaceutically acceptable salt thereof to said subject.

[0313] 55. A PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, for use according to statement 54, wherein the cancer is breast cancer, bladder cancer, cervical cancer, colon cancer, head and neck cancer, haematological cancer, liver cancer, lung cancer, kidney cancer, skin cancer including melanoma, uveal melanoma, stomach cancer, rectal cancer, mesothelioma, endometrial cancer, small intestinal cancer, biliary tract cancer, ovarian cancer, brain cancer, testicular cancer, pancreatic cancer, bone cancer and any solid tumour that is not able to repair errors in its DNA that occur when the DNA is copied. 56. A PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, for use according to statement 55, wherein the cancer is lung cancer, mesothelioma, bladder cancer, melanoma or uveal melanoma.

[0314] 57. A PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, for use according to any of statements 54-56, wherein the cancer is a malignancy that is refractory to or relapsed after checkpoint inhibitor plus chemotherapy.

[0315] 58. A PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 54-57, wherein the PD-1 or PD-L1 inhibitor is a PD-1 inhibitor selected from atezolizumab, nivolumab, pembrolizumab, cemiplimab, dostarlimab, retifanlimab and toripalimab.

[0316] 59. A PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, for use according to statement 58, wherein the PD-1 inhibitor is nivolumab.

[0317] 60. A PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, for use according to statement 58, wherein the PD-1 inhibitor is pembrolizumab.

[0318] 61. A PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, for use according to statement 58, wherein the PD-1 inhibitor is dostarlimab.

[0319] 62. A PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, for use according to statement 58, wherein the PD-1 inhibitor is atezolizumab.

[0320] 63. A PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 54-62, wherein the chemotherapeutic agent, is selected from carboplatin, gemcitabine, cisplatin, docetaxel, doxorubicin, mitoxantrone, 5-fluorouracil (5- Fll), capecitabine, irinotecan, oxaliplatin, pemetrexed, trifluridine and tipiracil.

[0321] 64. A PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 54-63, wherein the chemotherapeutic agent, is selected from carboplatin, gemcitabine, cisplatin and docetaxel.

[0322] 65. A PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 54-64, wherein the chemotherapeutic agent, is carboplatin. 66. A PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 54-64, wherein the chemotherapeutic agent, is cisplatin.

[0323] 67. A PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 54-64, wherein the chemotherapeutic agent, is gemcitabine.

[0324] 68. A PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 54-64, wherein the chemotherapeutic agent, is docetaxel.

[0325] 69. A PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 54-59, comprising administering to the subject a first amount of a Compound 1 , a second amount of nivolumab and a third amount of carboplatin.

[0326] 70. A PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 54-59, comprising administering to the subject a first amount of a Compound 1 , a second amount of nivolumab and a third amount of cisplatin.

[0327] 71 . A PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 54-59, comprising administering to the subject a first amount of a Compound 1 , a second amount of nivolumab and a third amount of gemcitabine.

[0328] 72. A PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 54-58, comprising administering to the subject a first amount of a Compound 1 , a second amount of pembrolizumab and a third amount of docetaxel.

[0329] 73. A PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 54-58, comprising administering to the subject a first amount of a Compound 1 , a second amount of atezolizumab and a third amount of docetaxel.

[0330] 74. A PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 54-73, wherein Compound 1 is administered as the hemifumarate salt in a dose of 40 mg or 80 mg per day.

[0331] 75. A PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 54-74, wherein the subject has previously been treated with chemotherapy and / or a PD-1 or PD-L1 inhibitor and the cancer is refractory or resistant. 76. A PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 54-74, wherein the subject has previously been treated with chemotherapy and / or a PD-1 or PD-L1 inhibitor and has not responded to or is resistant to treatment.

[0332] 77. A PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 54-74, wherein the subject has previously been treated with chemotherapy selected from carboplatin, cisplatin or gemcitabine alone or in combination with nivolumab and the cancer is refractory or resistant.

[0333] 78. A PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 54-74, wherein the subject has previously been treated with Nivolumab alone or in combination with chemotherapy selected from carboplatin, cisplatin or gemcitabine and the cancer is refractory or resistant.

[0334] 79. A PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 54-78, wherein said treatment comprises the sequential administration of i) said Compound 1, or a pharmaceutically acceptable salt thereof, ii) a PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, and iii) a chemotherapeutic agent, or a pharmaceutically acceptable salt thereof to said subject.

[0335] 80. The use of a compound of Formula I: Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of cancer, wherein said treatment comprises the separate, sequential or simultaneous administration of i) said medicament comprising Compound 1, or a pharmaceutically acceptable salt thereof, ii) a PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, and iii) a chemotherapeutic agent, or a pharmaceutically acceptable salt thereof to said subject. 81 . The use of Compound 1 , or a pharmaceutically acceptable salt thereof, according to statement 80, wherein the PD-1 or PD-L1 inhibitor is a PD-1 inhibitor.

[0336] 82. The use of Compound 1 , or a pharmaceutically acceptable salt thereof, according to statement 80 or 81 , wherein the cancer is breast cancer, bladder cancer, cervical cancer, colon cancer, head and neck cancer, haematological cancer, liver cancer, lung cancer, kidney cancer, skin cancer including melanoma, uveal melanoma, stomach cancer, rectal cancer, mesothelioma, endometrial cancer, small intestinal cancer, biliary tract cancer, ovarian cancer, brain cancer, testicular cancer, pancreatic cancer, bone cancer and any solid tumour that is not able to repair errors in its DNA that occur when the DNA is copied.

[0337] 83. The use of Compound 1 , or a pharmaceutically acceptable salt thereof, according to any one of statements 80-82, wherein the cancer is lung cancer, mesothelioma, bladder cancer, melanoma or uveal melanoma.

[0338] 84. The use of Compound 1 , or a pharmaceutically acceptable salt thereof, according to any one of statements 80-82, wherein the cancer is a malignancy that is refractory to or relapsed after checkpoint inhibitor plus chemotherapy.

[0339] 85. The use of Compound 1 , or a pharmaceutically acceptable salt thereof, according to any one of statements 80-84, wherein the PD-1 or PD-L1 inhibitor is selected from atezolizumab, nivolumab, pembrolizumab, cemiplimab, dostarlimab, retifanlimab and toripalimab.

[0340] 86. The use of Compound 1 , or a pharmaceutically acceptable salt thereof, according to statement 85, wherein the PD-1 or PD-L1 inhibitor is nivolumab.

[0341] 87. The use of Compound 1 , or a pharmaceutically acceptable salt thereof, according to statement 85, wherein the PD-1 or PD-L1 inhibitor is pembrolizumab.

[0342] 88. The use of Compound 1 , or a pharmaceutically acceptable salt thereof, according to statement 85, wherein the PD-1 or PD-L1 inhibitor is dostarlimab.

[0343] 89. The use of Compound 1 , or a pharmaceutically acceptable salt thereof, according to statement 85, wherein the PD-1 or PD-L1 inhibitor is atezolizumab.

[0344] 90. The use of Compound 1 , or a pharmaceutically acceptable salt thereof, according to any one of statements 80-89, wherein the chemotherapeutic agent, is selected from carboplatin, gemcitabine, cisplatin, docetaxel, doxorubicin, mitoxantrone, 5-fluorouracil (5-Fll), capecitabine, irinotecan, oxaliplatin, pemetrexed, trifluridine and tipiracil.

[0345] 91. The use of Compound 1 , or a pharmaceutically acceptable salt thereof, according to any one of statements 80-90, wherein the chemotherapeutic agent, is selected from carboplatin, gemcitabine, cisplatin and docetaxel.

[0346] 92. The use of Compound 1, or a pharmaceutically acceptable salt thereof, according to any one of statements 80-91, wherein the chemotherapeutic agent, is carboplatin.

[0347] 93. The use of Compound 1, or a pharmaceutically acceptable salt thereof, according to any one of statements 80-91, wherein the chemotherapeutic agent, is cisplatin.

[0348] 94. The use of Compound 1, or a pharmaceutically acceptable salt thereof, according to any one of statements 80-91, wherein the chemotherapeutic agent, is gemcitabine.

[0349] 95. The use of Compound 1, or a pharmaceutically acceptable salt thereof, according to any one of statements 80-91, wherein the chemotherapeutic agent, is docetaxel.

[0350] 96. The use of Compound 1, or a pharmaceutically acceptable salt thereof, according to any one of statements 80-86, comprising administering to the subject a first amount of a Compound 1, a second amount of nivolumab and a third amount of carboplatin.

[0351] 97. The use of Compound 1, or a pharmaceutically acceptable salt thereof, according to any one of statements 80-86, comprising administering to the subject a first amount of a Compound 1, a second amount of nivolumab and a third amount of cisplatin.

[0352] 98. The use of Compound 1, or a pharmaceutically acceptable salt thereof, according to any one of statements 80-86, comprising administering to the subject a first amount of a Compound 1, a second amount of nivolumab and a third amount of gemcitabine.

[0353] 99. The use of Compound 1, or a pharmaceutically acceptable salt thereof, according to any one of statements 80-85, comprising administering to the subject a first amount of a Compound 1, a second amount of pembrolizumab and a third amount of docetaxel.

[0354] 100. The use of Compound 1, or a pharmaceutically acceptable salt thereof, according to any one of statements 80-85, comprising administering to the subject a first amount of a Compound 1, a second amount of atezolizumab and a third amount of docetaxel. 101. The use of Compound 1, or a pharmaceutically acceptable salt thereof, according to any one of statements 80-100, wherein Compound 1 is administered as the hemifumarate salt in a dose of 40 mg or 80 mg per day.

[0355] 102. The use of Compound 1, or a pharmaceutically acceptable salt thereof, according to any one of statements 80-101, wherein the subject has previously been treated with chemotherapy and / or a PD-1 or PD-L1 inhibitor and the cancer is refractory or resistant.

[0356] 103. The use of Compound 1, or a pharmaceutically acceptable salt thereof, according to any one of statements 80-101, wherein the subject has previously been treated with chemotherapy and / or a PD-1 or PD-L1 inhibitor and has not responded to or is resistant to treatment.

[0357] 104. The use of Compound 1, or a pharmaceutically acceptable salt thereof, according to any one of statements 80-101, wherein the subject has previously been treated with chemotherapy selected from carboplatin, cisplatin or gemcitabine alone or in combination with nivolumab and the cancer is refractory or resistant.

[0358] 105. The use of Compound 1, or a pharmaceutically acceptable salt thereof, according to any one of statements 80-101, wherein the subject has previously been treated with Nivolumab alone or in combination with chemotherapy selected from carboplatin, cisplatin or gemcitabine and the cancer is refractory or resistant.

[0359] 106. The use of Compound 1, or a pharmaceutically acceptable salt thereof, according to any one of statements 80-105, wherein said treatment comprises the sequential administration of i) said medicament comprising Compound 1, or a pharmaceutically acceptable salt thereof, ii) a PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, and iii) a chemotherapeutic agent, or a pharmaceutically acceptable salt thereof to said subject.

[0360] 107. A pharmaceutical product comprising i) a compound of Formula I: Formula I, or a pharmaceutically acceptable salt thereof, ii) a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, and iii) a chemotherapeutic agent or a pharmaceutically acceptable salt thereof.

[0361] 108. A kit comprising: a first pharmaceutical composition comprising a compound of Formula Formula I, or a pharmaceutically acceptable salt thereof; a second pharmaceutical composition comprising a PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof; and a third pharmaceutical composition comprising a chemotherapeutic agent, or a pharmaceutically acceptable salt thereof -and instructions for using the first and second pharmaceutical compositions in combination.

Claims

Claims:

1. A compound of Formula I:or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in a subject, wherein said treatment comprises the separate, sequential or simultaneous administration of i) said Compound 1, or a pharmaceutically acceptable salt thereof, ii) a PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, and iii) a chemotherapeutic agent, or a pharmaceutically acceptable salt thereof to said subject.

2. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to claim 1, wherein the PD-1 or PD-L1 inhibitor is a PD-1 inhibitor.

3. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to claim 1 or 2, wherein the cancer is breast cancer, bladder cancer, cervical cancer, colon cancer, head and neck cancer, haematological cancer, liver cancer, lung cancer, kidney cancer, skin cancer including melanoma, uveal melanoma, stomach cancer, rectal cancer, mesothelioma, endometrial cancer, small intestinal cancer, biliary tract cancer, ovarian cancer, brain cancer, testicular cancer, pancreatic cancer, bone cancer and any solid tumour that is not able to repair errors in its DNA that occur when the DNA is copied.

4. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to claim 3, wherein the cancer is lung cancer, mesothelioma, bladder cancer, melanoma or uveal melanoma.

5. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1 to 3, wherein the cancer is a malignancy that is refractory to or relapsed after checkpoint inhibitor plus chemotherapy.

6. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-5, wherein the PD-1 or PD-L1 inhibitor is a PD-1 inhibitor selected from atezolizumab, nivolumab, pembrolizumab, cemiplimab, dostarlimab, retifanlimab and toripalimab.

7. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to claim 6, wherein the PD-1 inhibitor is atezolizumab, nivolumab, pembrolizumab or dostarlimab.

8. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-7, wherein the chemotherapeutic agent, is selected from carboplatin, gemcitabine, cisplatin, docetaxel, doxorubicin, mitoxantrone, 5-fluorouracil (5-Fll), capecitabine, irinotecan, oxaliplatin, pemetrexed, trifluridine and tipiracil.

9. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-8, wherein the chemotherapeutic agent, is selected from carboplatin, gemcitabine, cisplatin and docetaxel.

10. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-9, wherein the chemotherapeutic agent, is carboplatin.

11. Compound 1 , or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-9, wherein the chemotherapeutic agent, is cisplatin.

12. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-9, wherein the chemotherapeutic agent, is gemcitabine.

13. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-9, wherein the chemotherapeutic agent, is docetaxel14. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-9, comprising administering to the subject a first amount of a Compound 1 , a second amount of nivolumab and a third amount of carboplatin.

15. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-9, comprising administering to the subject a first amount of a Compound 1 , a second amount of nivolumab and a third amount of cisplatin.

16. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-9, comprising administering to the subject a first amount of a Compound 1 , a second amount of nivolumab and a third amount of gemcitabine.

17. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of claim 1-9, comprising administering to the subject a first amount of a Compound 1, a second amount of pembrolizumab and a third amount of docetaxel.

18. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of claim 1-9, comprising administering to the subject a first amount of a Compound 1, a second amount of atezolizumab and a third amount of docetaxel.

19. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-18, wherein Compound 1 is administered as the hemifumarate salt in a dose of 40 mg or 80 mg per day.

20. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-19, wherein the subject has previously been treated with:(a) chemotherapy and / or a PD-1 or PD-L1 inhibitor and the cancer is refractory or resistant;(b) chemotherapy and / or a PD-1 or PD-L1 inhibitor and has not responded to or is resistant to treatment;(c) chemotherapy selected from carboplatin, cisplatin or gemcitabine alone or in combination with Nivolumab and the cancer is refractory or resistant; or(d) Nivolumab alone or in combination with chemotherapy selected from carboplatin, cisplatin or gemcitabine and the cancer is refractory or resistant.

21. Compound 1 , or a pharmaceutically acceptable salt thereof, for use according to any one of claim 1-20, wherein said treatment comprises the sequential administration of i) said Compound 1, or a pharmaceutically acceptable salt thereof, ii) a PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, and iii) a chemotherapeutic agent, or a pharmaceutically acceptable salt thereof to said subject.

22. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of claim 1-21, wherein only a single chemotherapeutic agent is administered.

23. A pharmaceutical product comprising i) a compound of Formula I:Formula I, or a pharmaceutically acceptable salt thereof, ii) a PD-1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof, and iii) a chemotherapeutic agent or a pharmaceutically acceptable salt thereof.

24. A kit comprising: a first pharmaceutical composition comprising a compound of Formulaor a pharmaceutically acceptable salt thereof; a second pharmaceutical composition comprising a PD-1 or PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof; and a third pharmaceutical composition comprising a chemotherapeutic agent, or a pharmaceutically acceptable salt thereof -and instructions for using the first and second pharmaceutical compositions in combination.

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