Therapeutic combinations of an AKT inhibitor, a BCL-2 inhibitor, and a glucocorticoid

Abstract

Therapeutic combinations of an AKT inhibitor and a BCL-2 inhibitor; an AKT inhibitor and a glucocorticoid; and an AKT inhibitor, a BCL-2 inhibitor and a glucocorticoid are described. The combinations can be useful in the treatment of acute lymphoblastic leukemia (ALL).

Description

[0001] THERAPEUTIC COMBINATIONS OF AN AKT INHIBITOR, A BCL-2 INHIBITOR, AND A GLUCOCORTICOID

[0002] Cross-reference to related applications

[0003] This application claims priority to United States Provisional Patent Application No. 63 / 692,940, filed 10 September 2024, the disclosure of which is incorporated by reference herein.

[0004] Background

[0005] Acute lymphoblastic leukemia (ALL) is the most common blood cancer of children and the most frequent cause of cancer related death before 20 years of age. Although the survival rate of paediatric patients with ALL is -90% due to innovative chemotherapy regimens, treatment options for relap se / refractory ALL patients continue to be challenging.

[0006] The PI3K / AKT / mTOR axis is often constitutively activated in relapsed or refractory ALL (Gutierrez, A. et al. Blood, 2009, 114, 647-650). For example, loss of the tumor suppressor PTEN leads to hyperactivation of AKT signaling. Despite the importance of PI3K-AKT signaling in ALL, clinically effective treatment strategies to target PI3K-AKT signaling have had limited success. Inhibiting AKT signaling with capivasertib, a first in class pan AKT-inhibitor recently approved in the treatment of ER+ breast cancer (Turner, N.C. et al. N Engl J Med, 2023, 388, 2058-2070), exhibits monotherapy anti -proliferative activity in paediatric T-cell acute lymphoblastic leukemia (T-ALL) and B-cell precursor acute lymphoblastic leukemia (B-ALL) cell lines (Lynch, J.T. et al. Oncotarget, 2016, 7, 22128-22139; Gruninger, P.K. et al. Cancer Gene Ther, 2022, 29, 1751-1760). However, only modest anti -proliferative activity was observed using monotherapy capivasertib treatment.

[0007] Accordingly, there remains a need for further options for the treatment of ALL (such as T-ALL and B-ALL), particularly for relapsed or refractory T-ALL and B-ALL.

[0008] Brief Description of the Drawings

[0009] Figure 1 shows the growth inhibition (%) scores after 72 hours of treatment with varying concentrations of capivasertib, venetoclax and dexamethasone in the REH B-ALL cell line.

[0010] Figure 2 shows the growth inhibition (%) scores after 72 hours of treatment with varying concentrations of capivasertib, venetoclax and dexamethasone in the SEM B-ALL cell line. Figure 3 shows the growth inhibition (%) scores after 72 hours of treatment with varying concentrations of capivasertib, venetoclax and dexamethasone in the KOPN-8 B-ALL cell line.

[0011] Figure 4 shows the growth inhibition (%) scores after 72 hours of treatment with varying concentrations of capivasertib, venetoclax and dexamethasone in the NALM-6 B-ALL cell line.

[0012] Figure 5 shows the growth inhibition (%) scores after 72 hours of treatment with varying concentrations of capivasertib, venetoclax and dexamethasone in the RCH-ACV B-ALL cell line.

[0013] Figure 6 shows the growth inhibition (%) scores after 72 hours of treatment with varying concentrations of capivasertib, venetoclax and dexamethasone in the KARPAS-45, MOLT-4 and JURKAT T-ALL cell lines.

[0014] Figure 7 shows the growth inhibition (%) scores after 72 hours of treatment with varying concentrations of capivasertib and dexamethasone in the LOUCY and KE-37 T-ALL cell lines.

[0015] Figure 8 shows the cell viability of the REH B-ALL cell line after 72 hour treatment with various combinations of capivasertib, venetoclax and dexamethasone.

[0016] Figure 9 shows the cell viability of the MOLT-4 T-ALL cell line after 72 hour treatment with various combinations of capivasertib, venetoclax and dexamethasone, and staurosporine positive control.

[0017] Figure 10 shows luminescence in the Caspase 3 / 7 assay for the REH B-ALL cell line when treated with various combinations of capivasertib, venetoclax and dexamethasone.

[0018] Figure 11 shows luminescence in the Caspase 3 / 7 assay for the MOLT-4 T-ALL cell line when treated with various combinations of capivasertib, venetoclax and dexamethasone.

[0019] Figure 12 shows tumour volume over time in a MOLT-4 T-ALL xenograft model when dosed with capivasertib, venetoclax or dexamethasone monotherapy.

[0020] Figure 13 shows tumour volume over time in a MOLT-4 T-ALL xenograft model when dosed with doublet combinations of capivasertib, venetoclax and dexamethasone.

[0021] Figure 14 shows tumour volume over time in a MOLT-4 T-ALL xenograft model when dosed with a combination of capivasertib, venetoclax and dexamethasone.

[0022] Figure 15 shows tumour volume over time in a MOLT-4 T-ALL xenograft model when dosed with a combination of capivasertib, venetoclax and dexamethasone with a capivasertib QD and BID dosing schedule. Figure 16 shows survival in the CBAT-93917 paediatric T-ALL PDX model when dosed with capivasertib, venetoclax or dexamethasone monotherapy.

[0023] Figure 17 shows survival in the CBAT-93917 paediatric T-ALL PDX model when dosed with doublet combinations of capivasertib, venetoclax and dexamethasone.

[0024] Figure 18 shows survival in the CBAT-93917 paediatric T-ALL PDX model when dosed with a combination of capivasertib, venetoclax and dexamethasone.

[0025] Figure 19 shows tumour volume over time in a KARPAS-231 B-ALL xenograft model when dosed with capivasertib, venetoclax or dexamethasone monotherapy.

[0026] Figure 20 shows tumour volume over time in a KARPAS-231 B-ALL xenograft model when dosed with doublet combinations of capivasertib, venetoclax and dexamethasone.

[0027] Figure 21 shows tumour volume over time in a KARPAS-231 B-ALL xenograft model when dosed with a combination of capivasertib, venetoclax and dexamethasone with a capivasertib QD and BID dosing schedule.

[0028] Detailed Description

[0029] Described herein are methods of treating acute lymphoblastic leukemia (ALL) in a patient in need thereof. The methods include administering combinations of an AKT inhibitor (such as capivasertib or a pharmaceutically acceptable salt thereof), a BCL-2 inhibitor (such as venetoclax or a pharmaceutically acceptable salt thereof), and a glucocorticoid (such as dexamethasone).

[0030] In one embodiment, there is provided a method of treating acute lymphoblastic leukemia (ALL) in a patient in need thereof, comprising administering to the patient a combination of: an amount of an AKT inhibitor (such as capivasertib or a pharmaceutically acceptable salt thereof) and an amount of a BCL-2 inhibitor (such as venetoclax or a pharmaceutically acceptable salt thereof), wherein the amount of the AKT inhibitor and the amount of the BCL-2 inhibitor together comprise a therapeutically effective amount.

[0031] In one embodiment, there is provided a method of treating acute lymphoblastic leukemia (ALL) in a patient in need thereof, comprising administering to the patient a combination of: an amount of an AKT inhibitor (such as capivasertib or a pharmaceutically acceptable salt thereof) and an amount of a glucocorticoid (such as dexamethasone), wherein the amount of the AKT inhibitor and the amount of the glucocorticoid together comprise a therapeutically effective amount.

[0032] In one embodiment, there is provided a method of treating acute lymphoblastic leukemia (ALL) in a patient in need thereof, comprising administering to the patient a combination of: an amount of an AKT inhibitor (such as capivasertib or a pharmaceutically acceptable salt thereof), an amount of a BCL-2 inhibitor (such as venetoclax or a pharmaceutically acceptable salt thereof), and an amount of a glucocorticoid (such as dexamethasone), wherein the amount of the AKT inhibitor, the amount of the BCL-2 inhibitor, and the amount of the glucocorticoid together comprise a therapeutically effective amount.

[0033] In one embodiment, there is provided an AKT inhibitor (such as capivasertib or a pharmaceutically acceptable salt thereof) for use in the treatment of acute lymphoblastic leukemia (ALL) in a patient in need thereof, wherein the AKT inhibitor is administered in combination with a BCL-2 inhibitor (such as venetoclax or a pharmaceutically acceptable salt thereof).

[0034] In one embodiment, there is provided an AKT inhibitor (such as capivasertib or a pharmaceutically acceptable salt thereof) for use in the treatment of acute lymphoblastic leukemia (ALL) in a patient in need thereof, wherein the AKT inhibitor is administered in combination with a glucocorticoid (such as dexamethasone).

[0035] In one embodiment, there is provided an AKT inhibitor (such as capivasertib or a pharmaceutically acceptable salt thereof) for use in the treatment of acute lymphoblastic leukemia (ALL) in a patient in need thereof, wherein the AKT inhibitor is administered in combination with a BCL-2 inhibitor (such as venetoclax or a pharmaceutically acceptable salt thereof) and a glucocorticoid (such as dexamethasone).

[0036] In one embodiment, there is provided the use of an AKT inhibitor (such as capivasertib or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for the treatment of acute lymphoblastic leukemia (ALL) in a patient in need thereof, wherein the AKT inhibitor is administered in combination with a BCL-2 inhibitor (such as venetoclax or a pharmaceutically acceptable salt thereof).

[0037] In one embodiment, there is provided the use of an AKT inhibitor (such as capivasertib or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for the treatment of acute lymphoblastic leukemia (ALL) in a patient in need thereof, wherein the AKT inhibitor is administered in combination with a glucocorticoid (such as dexamethasone).

[0038] In one embodiment, there is provided the use of an AKT inhibitor (such as capivasertib or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for the treatment of acute lymphoblastic leukemia (ALL) in a patient in need thereof, wherein the AKT inhibitor is administered in combination with a BCL-2 inhibitor (such as venetoclax or a pharmaceutically acceptable salt thereof) and a glucocorticoid (such as dexamethasone).

[0039] In one embodiment, there is provided a kit comprising (i) an AKT inhibitor (such as capivasertib or a pharmaceutically acceptable salt thereof), and (ii) instructions for the use of the AKT inhibitor in combination with a BCL-2 inhibitor (such as venetoclax or a pharmaceutically acceptable salt thereof), in the treatment of acute lymphoblastic leukemia (ALL) in a patient in need thereof.

[0040] In one embodiment, there is provided a kit comprising (i) an AKT inhibitor (such as capivasertib or a pharmaceutically acceptable salt thereof), and (ii) instructions for the use of the AKT inhibitor in combination with a glucocorticoid (such as dexamethasone), in the treatment of acute lymphoblastic leukemia (ALL) in a patient in need thereof.

[0041] In one embodiment, there is provided a kit comprising (i) an AKT inhibitor (such as capivasertib or a pharmaceutically acceptable salt thereof), and (ii) instructions for the use of the AKT inhibitor in combination with a BCL-2 inhibitor (such as venetoclax or a pharmaceutically acceptable salt thereof) and a glucocorticoid (such as dexamethasone), in the treatment of acute lymphoblastic leukemia (ALL) in a patient in need thereof.

[0042] Advantageously, the combinations for the treatment of ALL described herein may provide improved therapeutic effects (such as improvement in efficacy or enabling lower doses of each component to be used) compared to monotherapy or dual combination therapy.

[0043] Other features, objects, and advantages will be apparent from the description, drawings, and claims.

[0044] General

[0045] The terms “treat,” “treating,” and “treatment” refer to at least partially alleviating and / or inhibiting a condition, disorder, or disease, such as acute lymphoblastic leukemia (ALL), in a patient in need thereof. The term “treatment” includes both in vitro and in vivo treatments, including in warm-blooded animals such as humans. The effectiveness of treatment of cancer can be assessed in a variety of ways, including but not limited to: inhibiting cancer cell proliferation (including the reversal of cancer growth); promoting cancer cell death (e.g., by promoting apoptosis or another cell death mechanism); improvement in symptoms; duration of response to the treatment; delay in progression of disease; and prolonging survival. Treatments can also be assessed with regard to the nature and extent of side effects associated with the treatment. Furthermore, effectiveness can be assessed with regard to biomarkers, such as levels of expression or phosphorylation of proteins known to be associated with particular biological phenomena. Other assessments of effectiveness are known to those of skill in the art.

[0046] In some embodiments, the patient is an adult patient.

[0047] In some embodiments, the patient is a paediatric patient. In some embodiments, the patient is an infant patient. In some embodiments, the patient is a child patient. In some embodiments, the patient is an adolescent patient.

[0048] In some embodiments, the patient is 18 years or older. In some embodiments, the patient is 21 years or older.

[0049] In some embodiments, the patient is younger than 21 years. In some embodiments, the patient is younger than 18 years. In some embodiments, the patient is younger than 16 years.

[0050] In some embodiments, the patient is a human patient or animal (e.g. mammalian) patient.

[0051] In some embodiments, the patient is a human patient.

[0052] The term “therapeutically effective amount” refers to that amount of a compound or combination of compounds as described herein that is sufficient to effect the intended application including, but not limited to, disease treatment. A therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the patient and disease condition being treated (e.g., the weight, age and gender of the patient), the severity of the disease condition, the manner of administration, etc. which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells (e.g. the amount of apoptosis). The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether the compound is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which the compound is carried. The term "pharmaceutically acceptable" is used to specify that an object (for example a salt, dosage form [such as a tablet or capsule] or excipient [such as a diluent or carrier]) is suitable for use in patients. An example list of pharmaceutically acceptable salts can be found in the “Handbook of Pharmaceutical Salts: Properties, Selection and Use”, P. H. Stahl and C. G. Wermuth, editors, Weinheim / Zurich:Wiley-VCH / VFiCA, 2002 or subsequent editions.

[0053] Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese and aluminium. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins. Examples include isopropylamine, trimethylamine, diethylamine, tri ethyl amine, tripropylamine, and ethanolamine.

[0054] AKT Inhibitors

[0055] In one embodiment, the AKT inhibitor is any molecule which binds to and inhibits the activity of one or more AKT isoforms (for example having a pICso of >4.5, >5, >6, >7, >8 or >9 vs. the isoform in question when tested in a standard potency assay, for example as described in W02009 / 047563). In one embodiment, the AKT inhibitor is any AKT inhibitor known in the art.

[0056] In one embodiment, the AKT inhibitor is selected from miransertib (ARQ-092) or a pharmaceutically acceptable salt thereof, BAY1125976 or a pharmaceutically acceptable salt thereof, borussertib or a pharmaceutically acceptable salt thereof, AT7867 or a pharmaceutically acceptable salt thereof, CCT128930 or a pharmaceutically acceptable salt thereof, A-674563 or a pharmaceutically acceptable salt thereof, PHT-427 or a pharmaceutically acceptable salt thereof, Akti-1 / 2 or a pharmaceutically acceptable salt thereof, AT13148 or a pharmaceutically acceptable salt thereof, SC79 or a pharmaceutically acceptable salt thereof, capivasertib or a pharmaceutically acceptable salt thereof, miltefosine or a pharmaceutically acceptable salt thereof, perifosine or a pharmaceutically acceptable salt thereof, MK-2206 or a pharmaceutically acceptable salt thereof, RX-0201 or a pharmaceutically acceptable salt thereof, erucylphosphocholine or a pharmaceutically acceptable salt thereof, PBI-05204 or a pharmaceutically acceptable salt thereof, GSK690693 or a pharmaceutically acceptable salt thereof, afuresertib (GSK2110183) or a pharmaceutically acceptable salt thereof, uprosertib (GSK2141795) or a pharmaceutically acceptable salt thereof, XL-418 or a pharmaceutically acceptable salt thereof and ipatasertib (GDC-0068) or a pharmaceutically acceptable salt thereof.

[0057] In one embodiment, the AKT inhibitor is selected from capivasertib or a pharmaceutically acceptable salt thereof, perifosine or a pharmaceutically acceptable salt thereof, MK-2206 or a pharmaceutically acceptable salt thereof, RX-0201 or a pharmaceutically acceptable salt thereof, erucylphosphocholine or a pharmaceutically acceptable salt thereof, PBI- 05204 or a pharmaceutically acceptable salt thereof, GSK690693 or a pharmaceutically acceptable salt thereof, uprosertib (GSK2141795) or a pharmaceutically acceptable salt thereof, XL-418 or a pharmaceutically acceptable salt thereof and ipatasertib or a pharmaceutically acceptable salt thereof.

[0058] In one embodiment, the AKT inhibitor is selected from capivasertib or a pharmaceutically acceptable salt thereof, perifosine or a pharmaceutically acceptable salt thereof, MK-2206 or a pharmaceutically acceptable salt thereof, GSK690693 or a pharmaceutically acceptable salt thereof, afuresertib (GSK2110183) or a pharmaceutically acceptable salt thereof, uprosertib (GSK2141795) or a pharmaceutically acceptable salt thereof and ipatasertib (GDC- 0068) or a pharmaceutically acceptable salt thereof.

[0059] In one embodiment, the AKT inhibitor is capivasertib or a pharmaceutically acceptable salt thereof. In one embodiment, the AKT inhibitor is capivasertib.

[0060] Capivasertib has the following chemical structure:

[0061]

[0062] The chemical name of capivasertib is (S)-4-amino-N-(l-(4-chlorophenyl)-3- hydroxypropyl)-l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide). Capivasertib is disclosed in Example 9 of W02009 / 047563, which also describes its synthesis.

[0063] BCL-2 Inhibitors

[0064] In one embodiment, the BCL-2 inhibitor is any BCL-2 inhibitor known in the art. In one embodiment, the BCL-2 inhibitor is a selective BCL-2 inhibitor. In this regard, a selective BCL- 2 inhibitor is one which selectively binds to the BCL-2 protein over other proteins within the BCL-2 protein family (such as BCL-XL and BCL-w). In one embodiment, the BCL-2 inhibitor is any selective BCL-2 inhibitor known in the art. In one embodiment, the BCL-2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof. In one embodiment, the BCL-2 inhibitor is venetoclax.

[0065] Venetoclax, having the structure also referred to as ABT-199 or its chemical name 4-(4-{[2-(4-chlorophenyl)-4,4- dimethylcyclohex-l-en-l-yl]methyl}piperazin-l-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4- ylmethyl)amino]phenyl}sulfonyl)-2-(lH-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide) is a selective BCL-2 inhibitor, described in, e.g., U.S. Patent Nos. 8,546,399 and 9,174,982 (each of which is incorporated herein by reference). Anti-apoptotic BCL-2 proteins are associated with a number of diseases including B-cell malignancies. Overexpression of BCL-2 proteins correlates with resistance to chemotherapy, clinical outcome, disease progression, overall prognosis or a combination thereof in various cancers and disorders of the immune system. Venetoclax is approved for treatment of chronic lymphocytic leukemia, small lymphocytic lymphoma, and acute myeloid leukemia.

[0066] Glucocorticoids

[0067] Glucocorticoids (such as dexamethasone, prednisone and prednisolone) are drugs that are useful in the treatment of ALL (Inaba et al., Lancet Oncol. 2010, 11, 1096-1106).

[0068] In one embodiment, the glucocorticoid is selected from dexamethasone, dexamethasone sodium phosphate, prednisone and prednisolone. In one embodiment, the glucocorticoid is dexamethasone.

[0069] Dexamethasone is also referred to by its chemical name 9-fluoro-l 13,17,21 -trihydroxy- 16a-methylpregna-l,4-diene-3, 20-dione, and has the structure

[0070] In one embodiment, dexamethasone may be administered in the form of dexamethasone sodium phosphate.

[0071] Certain Combinations

[0072] In some embodiments, the AKT inhibitor is capivasertib or a pharmaceutically acceptable salt thereof, the BCL-2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof, and the glucocorticoid is dexamethasone. In some embodiments, the AKT inhibitor is capivasertib, the BCL-2 inhibitor is venetoclax, and the glucocorticoid is dexamethasone. In some embodiments, the treatment of ALL comprises administering to the patient a combination of: capivasertib or a pharmaceutically acceptable salt thereof, a BCL-2 inhibitor, and a glucocorticoid. In some embodiments, the treatment of ALL comprises administering to the patient a combination of: capivasertib or a pharmaceutically acceptable salt thereof, venetoclax or a pharmaceutically acceptable salt thereof, and a glucocorticoid. In some embodiments, the treatment of ALL comprises administering to the patient a combination of: capivasertib or a pharmaceutically acceptable salt thereof, venetoclax or a pharmaceutically acceptable salt thereof, and dexamethasone. In some embodiments, the treatment of ALL comprises administering to the patient a combination of: capivasertib, venetoclax and dexamethasone.

[0073] Acute Lymphoblastic Leukemia (ALL)

[0074] The combinations described herein are useful for the treatment of acute lymphoblastic leukemia (ALL). In one embodiment, the ALL is T-cell acute lymphoblastic leukemia (T-ALL) or B-cell precursor acute lymphoblastic leukemia (B-ALL). In one embodiment, the ALL is T- ALL. In one embodiment, the ALL is B-ALL.

[0075] In one embodiment, the ALL (such as B-ALL or T-ALL) is PTEN-deficient (for example, comprises a cancerous cell (for example, a population of cancerous cells, such as the majority of cancerous cells in a given population) with a reduction in the normal amount [for example compared to a non-cancerous cell of the same patient] or function of the PTEN tumour suppression protein). PTEN status can be determined by methods known in the art. In one embodiment, the ALL (such as B-ALL or T-ALL) is PTEN-null.

[0076] In one embodiment, the ALL (such as B-ALL or T-ALL) comprises one or more PTEN gene alterations.

[0077] In one embodiment, the ALL (such as B-ALL or T-ALL) comprises one or more AKT1, PIK3CA and / or PTEN gene alterations.

[0078] The human wild-type PIK3CA, AKT1 and PTEN genes are identified in Table 1.

[0079] Table 1

[0080] The PIK3CA and AKT1 genes are oncogenes, and activating mutations in these genes lead to activation of the PI3K / AKT signalling pathway. Accordingly, in one embodiment, the ALL (such as B-ALL or T-ALL) comprises one or more AKT1 and / or PIK3CA activating gene mutations. The PIK3CA and AKT1 gene mutation status may be determined by methods known in the art.

[0081] The PTEN gene is a tumour suppressor gene. Alterations to the PTEN gene that result in reduction or loss of function of the encoded PTEN protein result in activation of the PI3K / AKT pathway. Accordingly, in one embodiment, the ALL (such as B-ALL or T-ALL) comprises one or more loss of function PTEN gene alterations. The PTEN gene alteration status may be determined by methods known in the art.

[0082] In one embodiment, the ALL (such as B-ALL or T-ALL) comprises one or more AKT1 and / or PIK3CA activating gene mutations, or one or more loss of function PTEN gene alterations.

[0083] In one embodiment, the ALL (such as B-ALL or T-ALL) comprises an E17K mutation in the AKT1 gene.

[0084] In one embodiment, the ALL (such as B-ALL or T-ALL) comprises one or more mutations in the PIK3CA gene selected from R88Q, N345K, C420R, E542K, E545A, E545D, E545G, E545K, E545Q, Q546E, Q546K, Q546P, Q546R, Ml 043 V, Ml 0431, H1047L, H1047R, H1047Y, and G1049R.

[0085] In one embodiment, the ALL (such as B-ALL or T-ALL) comprises one or more alterations in the PTEN gene selected from (a) one or more mutations in the PTEN gene selected from C124R, C124S, G129E, G129V, G129R, R130Q, R130G, R130L, R130P, C136R, C136Y, S170R, and R173C; (b) any nonsense (including stop codons), frameshift, or splice site alteration, including those that affect the start codon; and (c) any homozygous deletion of one or more exons, regardless of transcript. In one embodiment, the ALL (such as B-ALL or T-ALL) comprises one or more alterations in the PTEN gene selected from (a) one or more mutations in the PTEN gene selected from C124R, C124S, G129E, G129V, G129R, R130Q, R130G, R130L, R130P, C136R, C136Y, S170R, and R173C; (b) any nonsense (including stop codons), frameshift, or splice site alteration, including those that affect the start codon; (c) any homozygous deletion of one or more exons, regardless of transcript; and (d) any rearrangement that disrupts protein function, regardless of transcript; intragenic events including duplications of only part of the gene, deletions, or inversions; and / or translocations, deletions, or inversions where one breakpoint is in PTEN and the other breakpoint is in another gene or intergenic region.

[0086] In one embodiment, the ALL (such as B-ALL or T-ALL) comprises one or more AKT1, PIK3CA, and / or PTEN alterations described herein.

[0087] In one embodiment, the ALL is relapsed or refractory ALL. In one embodiment, the ALL is relapsed ALL. In one embodiment, the ALL is refractory ALL.

[0088] In one embodiment, the ALL is relapsed or refractory T-ALL. In one embodiment, the ALL is relapsed T-ALL. In one embodiment, the ALL is refractory T-ALL.

[0089] In one embodiment, the ALL is relapsed or refractory B-ALL. In one embodiment, the ALL is relapsed B-ALL. In one embodiment, the ALL is refractory B-ALL.

[0090] Dosing

[0091] The term “combination” as used herein refers to simultaneous, separate, or sequential administration of two, three, or more agents. In one aspect, “combination” can refer to simultaneous administration (e.g., administration of multiple agents in a single dosage form). In another aspect, “combination” refers to separate administration (e.g., administration of multiple agents in separate dosage forms, but at substantially the same time). In a further aspect, “combination” refers to sequential administration (e.g., where a first agent is administered, followed by a delay, followed by administration of a second or further agent).

[0092] In some embodiments, the AKT inhibitor, such as capivasertib or a pharmaceutically acceptable salt thereof, is administered orally, for example in the form of a capsule or a tablet.

[0093] In some embodiments, the BCL-2 inhibitor, such as venetoclax or a pharmaceutically acceptable salt thereof, is administered orally, for example in the form of a capsule or a tablet. In some embodiments, the glucocorticoid, such as dexamethasone, is administered orally, for example in the form of a capsule or a tablet.

[0094] Further Embodiments

[0095] Embodiment 1. An AKT inhibitor for use in the treatment of acute lymphoblastic leukemia (ALL) in a patient in need thereof, wherein the AKT inhibitor is administered in combination with a BCL-2 inhibitor.

[0096] Embodiment 2. An AKT inhibitor for use in the treatment of acute lymphoblastic leukemia (ALL) in a patient in need thereof, wherein the AKT inhibitor is administered in combination with a glucocorticoid.

[0097] Embodiment 3. An AKT inhibitor for use in the treatment of acute lymphoblastic leukemia (ALL) in a patient in need thereof, wherein the AKT inhibitor is administered in combination with a BCL-2 inhibitor and a glucocorticoid.

[0098] Embodiment 4. The AKT inhibitor for use of any one of embodiments 1 to 3, wherein the AKT inhibitor is capivasertib or a pharmaceutically acceptable salt thereof.

[0099] Embodiment 5. The AKT inhibitor for use of any one of embodiments 1 to 4, wherein the AKT inhibitor is capivasertib.

[0100] Embodiment 6. The AKT inhibitor for use of any one of embodiments 1 and 3 to 5, wherein the BCL-2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof.

[0101] Embodiment 7. The AKT inhibitor for use of any one of embodiments 1 and 3 to 6, wherein the BCL-2 inhibitor is venetoclax.

[0102] Embodiment 8. The AKT inhibitor for use of any one of embodiments 2 to 7, wherein the glucocorticoid is dexamethasone.

[0103] Embodiment 9. The AKT inhibitor for use of any one of embodiments 3 to 8, wherein the AKT inhibitor is capivasertib, the BCL-2 inhibitor is venetoclax, and the glucocorticoid is dexamethasone.

[0104] Embodiment 10. The AKT inhibitor for use of any one of embodiments 1 to 9, wherein the ALL is T-cell acute lymphoblastic leukemia (T-ALL).

[0105] Embodiment 11. The AKT inhibitor for use of any one of embodiments 1 to 9, wherein the ALL is B-cell precursor acute lymphoblastic leukemia (B-ALL). Embodiment 12. The AKT inhibitor for use of any one of embodiments 1 to 11, wherein the ALL comprises one or more AKT1, PIK3CA and / or PTEN gene alterations.

[0106] Embodiment 13. The AKT inhibitor for use of any one of embodiments 1 to 12, wherein the ALL is PTEN-deficient.

[0107] Embodiment 14. The AKT inhibitor for use of any one of embodiments 1 to 13, wherein the ALL is relapsed or refractory ALL.

[0108] Embodiment 15. The AKT inhibitor for use of any one of embodiments 1 to 14, wherein the patient is an adult patient.

[0109] Embodiment 16. The AKT inhibitor for use of any one of embodiments 1 to 14, wherein the patient is a paediatric patient.

[0110] Embodiment 17. The use of an AKT inhibitor in the manufacture of a medicament for the treatment of acute lymphoblastic leukemia (ALL) in a patient in need thereof, wherein the AKT inhibitor is administered in combination with a BCL-2 inhibitor.

[0111] Embodiment 18. The use of an AKT inhibitor in the manufacture of a medicament for the treatment of acute lymphoblastic leukemia (ALL) in a patient in need thereof, wherein the AKT inhibitor is administered in combination with a glucocorticoid.

[0112] Embodiment 19. The use of an AKT inhibitor in the manufacture of a medicament for the treatment of acute lymphoblastic leukemia (ALL) in a patient in need thereof, wherein the AKT inhibitor is administered in combination with a BCL-2 inhibitor and a glucocorticoid.

[0113] Embodiment 20. The use of any one of embodiments 17 to 19, wherein the AKT inhibitor is capivasertib or a pharmaceutically acceptable salt thereof.

[0114] Embodiment 21. The use of any one of embodiments 17 to 20, wherein the AKT inhibitor is capivasertib.

[0115] Embodiment 22. The use of any one of embodiments 17 and 19 to 21, wherein the BCL-2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof.

[0116] Embodiment 23. The use of any one of embodiments 17 and 19 to 22, wherein the BCL-2 inhibitor is venetoclax.

[0117] Embodiment 24. The use of any one of embodiments 18 to 23, wherein the glucocorticoid is dexamethasone.

[0118] Embodiment 25. The use of any one of embodiments 19 to 24, wherein the AKT inhibitor is capivasertib, the BCL-2 inhibitor is venetoclax, and the glucocorticoid is dexamethasone. Embodiment 26. The use of any one of embodiments 17 to 25, wherein the ALL is T-cell acute lymphoblastic leukemia (T-ALL).

[0119] Embodiment 27. The use of any one of embodiments 17 to 25, wherein the ALL is B-cell precursor acute lymphoblastic leukemia (B-ALL).

[0120] Embodiment 28. The use of any one of embodiments 17 to 27, wherein the ALL comprises one or more AKT1, PIK3CA and / or PTEN gene alterations.

[0121] Embodiment 29. The use of any one of embodiments 17 to 28, wherein the ALL is PTEN- deficient.

[0122] Embodiment 30. The use of any one of embodiments 17 to 29, wherein the ALL is relapsed or refractory ALL.

[0123] Embodiment 31. The use of any one of embodiments 17 to 30, wherein the patient is an adult patient.

[0124] Embodiment 32. The use of any one of embodiments 17 to 30, wherein the patient is a paediatric patient.

[0125] Embodiment 33. A kit comprising (i) an AKT inhibitor, and (ii) instructions for the use of the

[0126] AKT inhibitor in combination with a BCL-2 inhibitor, in the treatment of acute lymphoblastic leukemia (ALL) in a patient in need thereof.

[0127] Embodiment 34. A kit comprising (i) an AKT inhibitor, and (ii) instructions for the use of the AKT inhibitor in combination with a glucocorticoid, in the treatment of acute lymphoblastic leukemia (ALL) in a patient in need thereof.

[0128] Embodiment 35. A kit comprising (i) an AKT inhibitor, and (ii) instructions for the use of the AKT inhibitor in combination with a BCL-2 inhibitor and a glucocorticoid, in the treatment of acute lymphoblastic leukemia (ALL) in a patient in need thereof.

[0129] Embodiment 36. The kit of any one of embodiments 33 to 35, wherein the AKT inhibitor is capivasertib or a pharmaceutically acceptable salt thereof.

[0130] Embodiment 37. The kit of any one of embodiments 33 to 36, wherein the AKT inhibitor is capivasertib.

[0131] Embodiment 38. The kit of any one of embodiments 33 and 35 to 37, wherein the BCL-2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof.

[0132] Embodiment 39. The kit of any one of embodiments 33 and 35 to 38, wherein the BCL-2 inhibitor is venetoclax. Embodiment 40. The kit of any one of embodiments 34 to 39, wherein the glucocorticoid is dexamethasone.

[0133] Embodiment 41. The kit of any one of embodiments 35 to 40, wherein the AKT inhibitor is capivasertib, the BCL-2 inhibitor is venetoclax, and the glucocorticoid is dexamethasone.

[0134] Embodiment 42. The kit of any one of embodiments 33 to 41, wherein the ALL is T-cell acute lymphoblastic leukemia (T-ALL).

[0135] Embodiment 43. The kit of any one of embodiments 33 to 41, wherein the ALL is B-cell precursor acute lymphoblastic leukemia (B-ALL).

[0136] Embodiment 44. The kit of any one of embodiments 33 to 43, wherein the ALL comprises one or more AKT1, PIK3CA and / or PTEN gene alterations.

[0137] Embodiment 45. The kit of any one of embodiments 33 to 44, wherein the ALL is PTEN- deficient.

[0138] Embodiment 46. The kit of any one of embodiments 33 to 45, wherein the ALL is relapsed or refractory ALL.

[0139] Embodiment 47. The kit of any one of embodiments 33 to 46, wherein the patient is an adult patient.

[0140] Embodiment 48. The kit of any one of embodiments 33 to 46, wherein the patient is a paediatric patient.

[0141] Examples

[0142] The specific Examples below, with reference to the accompanying Figures, are provided for illustrative purposes only and are not to be construed as limiting the teachings herein.

[0143] Example 1 - In vitro luminescence assay

[0144] An assay -ready plate (ARP) was prepared on the day of the assay by using an ECHO liquid dispenser (BECKMAN COULTER, INC.). In opaque white 384-well assay plate, cells were seeded at the appropriate optimal seeding density (see Table 2) onto the ARP with compounds (capivasertib, venetoclax and / or dexamethasone) for a final assay volume of 60 pL using WELLJET (INTEGRA BIOSCIENCES AG). After an incubation period, 30 pL of CELLTITER-GLO reagent (from PROMEGA CORP, equilibrated to room temperature) was added to the plate equilibrated to room temperature. The plate was then shaken for 30 minutes at room temperature protected from light. The luminescent signal was read on an AGILENT BIOTEK reader. Data was analyzed and plotted as a bar graph using GRAPHPAD PRISM software.

[0145] Table 2 The results for each cell line are shown in Figures 1 to 7. Growth inhibition (%) scores after 72 hours of treatment with varying concentrations of capivasertib, venetoclax and dexamethasone are shown. 0% indicates uninhibited growth, 100% indicates stasis and 200% indicates cell death.

[0146] Highest Single Agent (HSA) synergy scores were calculated for each combination in B- ALL subtypes and are shown in Table 3.

[0147] Table 3

[0148] The percentage of viable cells remaining was calculated using the following formula: The cell viability after 72 hour treatment with various combinations of capivasertib (referred to as capiva or capi), venetoclax (referred to as ven) and dexamethasone (referred to as dex) is shown in Figure 8 (REH cell line) and Figure 9 (MOLT-4 cell line). Staurosporine was used as a positive control.

[0149] Example 2 - In vitro Caspase 3 / 7 assay

[0150] Assay -ready plates (ARP) plates were prepared on the day of the assay by using an ECHO liquid dispenser (BECKMAN COULTER, INC.). In opaque white 384-well assay plates, REH and MOLT-4 cells were seeded at the appropriate optimal seeding density (see Table 2) onto the ARP plate with compounds (capivasertib, venetoclax and / or dexamethasone) for a final assay volume of 60 pL using WELLJET (INTEGRA BIOSCIENCES AG). Staurosporine was used as a positive control. Freshly prepared CASPASE-GLO 3 / 7 reagent (PROMEGA CORP) was equilibrated to room temperature. At each time point (0 hours, 4 hours and 24 hours) 30 pL of the reagent was added to equilibrated room temperature plates. The plate was then shaken for 30 minutes at room temperature while protected from light. The luminescent signal was read on an AGILENT BIOTEK reader. Data was analysed and plotted as relative luminescence values for each treatment group over time using GRAPHPAD PRISM software.

[0151] The assay results are shown in Figure 10 (REH cell line) and Figure 11 (MOLT-4 cell line) with least-squares fit shown. Individual data points at 0, 4 and 24 hours are omitted for clarity. The greatest levels of luminescence (indicating cell apoptosis) were observed for the combination of capivasertib, venetoclax and dexamethasone.

[0152] Example 3 - Mouse xenograft models of ALL cell lines and PDX models

[0153] For in vivo evaluation of ALL xenograft mouse models, 5 million MOLT-4 or KARPAS- 231 cells in PBS mixed with 50:50 with MATRIGEL (BECKTON DICKINSON, Franklin Lakes, NJ, USA) were implanted subcutaneously into the right flank of CB-17 scid female mice in a volume of 0.1 mL. Tumour volumes (measured by caliper), animal body weight, and tumour condition were recorded a minimum of twice weekly for the duration of the study. The tumour volume was calculated (taking length to be the longest diameter across the tumour and width to be the corresponding perpendicular diameter) using the formula: length (mm) x width (mm)2 / 0.52. For efficacy studies, growth inhibition from the start of treatment was assessed by comparison of the differences in tumour volume between control and treated groups. Because the variance in mean tumour volume data increases proportionally with volume (and is therefore disproportionate between groups), data were log transformed to remove any size dependency before statistical evaluation. Statistical significance was evaluated using a one-tailed, 2-sample t test. For efficacy studies, mice were randomized based on tumour volumes using stratified sampling and enrolled into control and treatment groups. Dosing began when mean tumour size reached approximately 200 mm3. Capivasertib was formulated as a solution in 10% DMSO / 25% KLEPTOSE and dosed 130 mg / kg QD or BID and administered by oral gavage. Venetoclax was formulated as a suspension in 60% PHOSAL 50 PG, 30% polyethylene glycol 400, 10% ethanol and administered by oral gavage at a dose of 30 mg / kg QD. Dexamethasone was diluted in 0.09% saline and administered intraperitoneally at a dose of 1 mg / kg QD. Dexamethasone was provided for only the first 5 days of a 21 or 28 -day cycle, whereas capivasertib was given on a 4-day on / 3-day off schedule and venetoclax was given on day 1 and 3 each week. A 4 hour gap was provided between capivasertib and venetoclax + dexamethasone. Dosing holidays were provided along with food supplementation when body weight loss was greater than 10% for an individual mouse. For paediatric T-ALL PDX models CBAT -44179 and CBAT-93917, 1 million cells were injected via tail vein into six- to eight-week-old female NOD.Cg-Prkdc severe combined immunodeficiency I12rgtmlWjl / SzJ (NSG; Jackson Laboratory, Bar Harbor, ME, USA) mice. Dosing was initiated when peripheral blood disease was -5-10%. Mice that exhibited signs of morbidity due to disease progression were humanely euthanized.

[0154] Figures 12 to 15 show tumour volume over time in the MOLT -4 T-ALL xenograft model when dosed with various combinations of capivasertib, venetoclax and dexamethasone. Figure 14 indicates that the combination of capivasertib, venetoclax and dexamethasone provides the foremost efficacy in the MOLT-4 T-ALL model relative to the singlets and doublets (Figures 12 and 13). Figure 15 indicates that capivasertib in combination with dexamethasone and venetoclax provides similar efficacy in the MOLT-4 T-ALL model regardless of whether the capivasertib is administered QD or BID. Table 4 shows overall survival of mice in the CBAT-44179 paediatric T-ALL PDX model. The combination of capivasertib and dexamethasone provided an increase in overall survival relative to the individual components.

[0155] Table 4

[0156] Figures 16 to 18 show overall survival in the CBAT-93917 paediatric T-ALL PDX model. Figure 18 shows that capivasertib in combination with dexamethasone and venetoclax provides the best overall survival benefit in the CBAT-93917 paediatric T-ALL PDX model compared to the singlets and doublets (Figures 16 and 17).

[0157] Figures 19 to 21 show tumour volume over time in the KARPAS-231 B-ALL xenograft model when dosed with various combinations of capivasertib, venetoclax and dexamethasone. Figure 21 indicates that the combination of capivasertib, venetoclax and dexamethasone provides the foremost efficacy in the KARPAS-231 B-ALL model relative to the singlets and doublets (Figures 19 and 20). Other embodiments are within the scope of the following claims. All documents cited herein are each entirely incorporated by reference herein.

Claims

CLAIMS1. A method of treating acute lymphoblastic leukemia (ALL) in a patient in need thereof, comprising administering to the patient a combination of: an amount of an AKT inhibitor and an amount of a BCL-2 inhibitor, wherein the amount of the AKT inhibitor and the amount of the BCL-2 inhibitor together comprise a therapeutically effective amount.

2. A method of treating acute lymphoblastic leukemia (ALL) in a patient in need thereof, comprising administering to the patient a combination of: an amount of an AKT inhibitor and an amount of a glucocorticoid, wherein the amount of the AKT inhibitor and the amount of the glucocorticoid together comprise a therapeutically effective amount.

3. A method of treating acute lymphoblastic leukemia (ALL) in a patient in need thereof, comprising administering to the patient a combination of: an amount of an AKT inhibitor, an amount of a BCL-2 inhibitor, and an amount of a glucocorticoid, wherein the amount of the AKT inhibitor, the amount of the BCL-2 inhibitor, and the amount of the glucocorticoid together comprise a therapeutically effective amount.

4. The method of any one of the preceding claims, wherein the AKT inhibitor is capivasertib or a pharmaceutically acceptable salt thereof.

5. The method of any one of the preceding claims, wherein the AKT inhibitor is capivasertib.

6. The method of any one of claims 1 and 3 to 5, wherein the BCL-2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof.

7. The method of any one of claims 1 and 3 to 6, wherein the BCL-2 inhibitor is venetoclax.

8. The method of any one of claims 2 to 7, wherein the glucocorticoid is dexamethasone.

9. The method of any one of claims 3 to 8, wherein the AKT inhibitor is capivasertib, the BCL-2 inhibitor is venetoclax, and the glucocorticoid is dexamethasone.

10. The method of any one of the preceding claims, wherein the ALL is T-cell acute lymphoblastic leukemia (T-ALL).

11. The method of any one of claims 1 to 9, wherein the ALL is B-cell precursor acute lymphoblastic leukemia (B-ALL).

12. The method of any one of the preceding claims, wherein the ALL comprises one or more AKT1, PIK3CA and / or PTEN gene alterations.

13. The method of any one of the preceding claims, wherein the ALL is PTEN- deficient.

14. The method of any one of the preceding claims, wherein the ALL is relapsed or refractory ALL.

15. The method of any one of the preceding claims, wherein the patient is an adult patient.

16. The method of any one of claims 1 to 14, wherein the patient is a paediatric patient.

17. An AKT inhibitor for use in the treatment of acute lymphoblastic leukemia (ALL) in a patient in need thereof, wherein the AKT inhibitor is administered in combination with a BCL-2 inhibitor.

18. An AKT inhibitor for use in the treatment of acute lymphoblastic leukemia (ALL) in a patient in need thereof, wherein the AKT inhibitor is administered in combination with a glucocorticoid.

19. An AKT inhibitor for use in the treatment of acute lymphoblastic leukemia (ALL) in a patient in need thereof, wherein the AKT inhibitor is administered in combination with a BCL-2 inhibitor and a glucocorticoid.

20. A kit comprising (i) an AKT inhibitor, and (ii) instructions for the use of the AKT inhibitor in the method of any one of claims 1 to 16.

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