Therapeutic combination of capivasertib and venetoclax

Abstract

Therapeutic combinations of capivasertib and venetoclax are described. This combination may be useful for treating B-cell malignancies. In some embodiments, reduced dosing (e.g., reduced frequency and / or reduced amount) of venetoclax can reduce or prevent effects, such as weight loss, that may be experienced with initial dosing regimens.

Description

[Technical Field]

[0001] B-cell malignancies represent a class of leukemias and lymphomas that arise from the dysregulated proliferation of B cells. Although our understanding of the biology and genetics of these diseases has increased in recent years, there remains a high unmet need for therapies to address this class of cancers.

[0002] AKT is a serine / threonine-specific protein kinase that plays a key role in multiple cellular processes, including glucose metabolism, apoptosis, cell proliferation, transcription, and cell migration. Mammalian cells express three closely related AKT isoforms: AKT1, AKT2, and AKT3, encoded by different genes. Structure

[0003] [ka] Capivasertib (also known as AZD5363 or its chemical name (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide) is a selective inhibitor of all three AKT isoforms. Capivasertib is described, for example, in WO 2009 / 047563 (incorporated herein by reference) and is being evaluated in clinical studies for use in the treatment of cancer, including breast and prostate cancer.

[0004] The anti-apoptotic Bcl-2 protein is associated with many diseases, including B-cell malignancies. Overexpression of Bcl-2 protein correlates with resistance to chemotherapy, clinical outcome, disease progression, overall prognosis, or a combination thereof, in various cancers and disorders of the immune system.

[0005] [ka] Venetoclax (also known as ABT-199 or its chemical name 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide) is a selective Bcl-2 inhibitor described, for example, in U.S. Pat. Nos. 8,546,399 and 9,174,982, each of which is incorporated herein by reference. It is approved for the treatment of chronic lymphocytic leukemia, small lymphocytic leukemia, and acute myeloid leukemia. Summary of the Invention

[0006] In one aspect, a method of treating a B-cell malignancy in a patient in need thereof is provided, comprising administering to the patient a first amount of capivasertib or a pharmaceutically acceptable salt thereof, and a second amount of venetoclax or a pharmaceutically acceptable salt thereof, wherein the first amount and the second amount together comprise a therapeutically effective amount.

[0007] In one aspect, there is provided a method of treating a B-cell malignancy in a patient in need thereof, comprising: During a 7-day dosing cycle, patients: administering a first amount of capivasertib or a pharmaceutically acceptable salt thereof for 2 or 4 days; and administering a second amount of venetoclax or a pharmaceutically acceptable salt thereof for 7 days; and In the subsequent 7-day dosing cycle, patients administering a first amount of capivasertib or a pharmaceutically acceptable salt thereof for 2 or 4 days; and administering a second amount of venetoclax or a pharmaceutically acceptable salt thereof on days 1, 2, 3, 4, 5, or 6; Methods are provided wherein the first amount and the second amount together comprise a therapeutically effective amount.

[0008] In one aspect, there is provided a method of treating a B-cell malignancy in a patient in need thereof, comprising: During a 7-day dosing cycle, patients: 300 to 800 mg of capivasertib administered twice daily on days 1, 2, and optionally days 3 and 4; and 20 to 400 mg of venetoclax administered once daily for 7 days, In the subsequent 7-day dosing cycle, patients 300 to 800 mg of capivasertib administered twice daily on days 1, 2, and optionally days 3 and 4 of a subsequent 7-day dosing cycle; and administering 20 to 400 mg of venetoclax once daily on day 1 and for 1, 2, or 3 additional days of a subsequent 7-day dosing cycle.

[0009] In one aspect, there is provided capivasertib for use in any one of the methods described herein.

[0010] In one aspect, there is provided venetoclax for use in any one of the methods described herein.

[0011] In one aspect, a kit is provided that includes (i) capivasertib and (ii) instructions for using capivasertib in any one of the methods described herein.

[0012] In one aspect, there is provided a combination of capivasertib and venetoclax for use in any one of the methods described herein, wherein the combination is for simultaneous, separate, or sequential administration of capivasertib and venetoclax.

[0013] In one aspect, there is provided a use of a combination of capivasertib and venetoclax in any one of the methods described herein, wherein the combination comprises a first amount of capivasertib or a pharmaceutically acceptable salt thereof, and a second amount of venetoclax or a pharmaceutically acceptable salt thereof, wherein the first amount and the second amount together comprise a therapeutically effective amount, and the combination is for simultaneous, separate, or sequential administration of capivasertib and venetoclax.

[0014] Other features, objects, and advantages will be apparent from the description and drawings, and from the claims. [Brief explanation of the drawings]

[0015] [Figure 1] Shown is weight change following a dosing schedule of capivasertib 130 mg / kg BID 10 / 14 4 days on / 3 days off, with venetoclax 100 mg / kg QD in the morning (15 minutes after capivasertib). [Figure 2] Capivasertib plasma levels following a dosing schedule of capivasertib 130 mg / kg BID 10 / 14 4 days on / 3 days off with venetoclax 100 mg / kg QD in the morning (15 minutes after capivasertib). [Figure 3] Venetoclax plasma levels following a dosing schedule of capivasertib 130 mg / kg BID 10 / 14 4 days on / 3 days off, venetoclax 100 mg / kg QD in the AM (15 minutes after capivasertib). [Figure 4] Shown is weight change following a dosing schedule of capivasertib 130 mg / kg BID 10 / 14 4 days on / 3 days off, with venetoclax 100 mg / kg QD in the morning (4 hours after capivasertib). [Figure 5] Capivasertib plasma levels following a dosing schedule of capivasertib 130 mg / kg BID 10 / 14 4 days on / 3 days off with venetoclax 100 mg / kg QD in the morning (4 hours after capivasertib). [Figure 6]Venetoclax plasma levels following a dosing schedule of capivasertib 130 mg / kg BID 10 / 14 4 days on / 3 days off with venetoclax 100 mg / kg QD in the morning (4 hours after capivasertib). [Figure 7] Shows weight change following an extended dosing schedule of capivasertib 130 mg / kg BID 10 / 14 4 days on / 3 days off with venetoclax 100 mg / kg QD in the morning (4 hours after capivasertib). [Figure 8] Venetoclax plasma concentrations following administration of venetoclax 100 mg / kg QD monotherapy and capivasertib 130 mg / kg BID 10 / 14 4 days on / 3 days off with venetoclax 100 mg / kg QD in the AM (4 hours after capivasertib). [Figure 9] Figure 1 shows weight change after chronic treatment with capivasertib 130mg / kg BID 10 / 14 4 days on / 3 days off and venetoclax 100mg / kg QD 4 days on / 3 days off in the morning (+4 hours). [Figure 10] Tumor volume over time for capivasertib 130 mg / kg BID 10 / 14 4 days on / 3 days off with venetoclax 100 mg / kg QD 4 days on / 3 days off in the morning (4 hours after capivasertib) compared to vehicle and individual drugs administered on the same schedule. [Figure 11] Shows weight change after long-term treatment with capivasertib 130 mg / kg BID 10 / 14 4 days on / 3 days off and venetoclax 100 mg / kg QD 4 days off / 3 days on. [Figure 12] Tumor volume over time for capivasertib 130 mg / kg BID 10 / 14 4 days on / 3 days off, venetoclax 100 mg / kg QD 4 days off / 3 days on compared to vehicle and individual drugs administered on the same schedule. [Figure 13] Shows weight change after long-term treatment with capivasertib 130 mg / kg BID 10 / 14 4 days on / 3 days off and venetoclax 100 mg / kg QW or 2QW. [Figure 14] Tumor volume over time for capivasertib 130 mg / kg BID 10 / 14 4 days on / 3 days off, 100 mg / kg venetoclax QW or 2QW compared to vehicle and individual drugs administered on the same schedule. [Figure 15] Tumor volume over time compared to vehicle for capivasertib 45 mg / kg BID 10 / 14 4 days on / 3 days off, venetoclax 100 mg / kg QD 5 days on / 2 days off (AM, 15 minutes after capivasertib). [Figure 16] Shown is weight change after dosing with capivasertib 45 mg / kg BID 10 / 14 4 days on / 3 days off and venetoclax 100 mg / kg QD 5 days on / 2 days off (morning, 15 minutes after capivasertib). [Figure 17] Tumor volume over time compared to vehicle for capivasertib 130 mg / kg BID 10 / 14 4 days on / 3 days off, venetoclax 30 mg / kg QD 5 days on / 2 days off (AM, 15 minutes after capivasertib). [Figure 18] Shown is weight change after dosing with capivasertib 130 mg / kg BID 10 / 14 4 days on / 3 days off and venetoclax 30 mg / kg QD 5 days on / 2 days off (morning, 15 minutes after capivasertib). DETAILED DESCRIPTION OF THE INVENTION

[0016] Described herein are methods of treating a patient in need of treatment for a B-cell malignancy. The method can include administering both capivasertib (or a pharmaceutically acceptable salt thereof) and venetoclax (or a pharmaceutically acceptable salt thereof). The method can include administering both capivasertib and venetoclax at respective dosages and on respective dosing schedules that provide a therapeutic effect. Advantageously, the described combinations can provide a therapeutic effect while minimizing the potential for side effects, such as weight loss.

[0017] Some B-cell malignancies that may be treated with the combination of capivasertib and venetoclax described herein include diffuse large B-cell lymphoma (DLBCL), germinal center B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or follicular lymphoma.

[0018] As used herein, the term "combination" refers to the simultaneous, separate, or sequential administration of two or more agents. In one aspect, "combination" can refer to simultaneous administration (e.g., administration of both agents in a single dosage form). In another aspect, "combination" refers to separate administration (e.g., administration of both 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 additional agent).

[0019] As used herein, the term "dosing cycle" refers to the repeating unit of a dosing schedule. For example, a dosing cycle may be repeated every 7 days, every 10 days, every 14 days, or every 28 days, or other lengths of time. As used herein, the term "dosing schedule" or "administration schedule" refers to the schedule, i.e., the time and interval, at which a given drug is administered. The dosing schedule can be continuous or intermittent.

[0020] Intermittent dosing schedules can include drug holidays, i.e., periods when the drug is not administered. For illustrative purposes, in a 7-day dosing cycle, the intermittently administered drug may be given on the first and second days, but not on the third, fourth, fifth, sixth, or seventh days. The dosing cycle is then repeated. This example can be referred to as a 2-on / 5-off schedule, in which the drug is given for two days, followed by a 5-day drug holiday, and then repeated every seven days. Other variations are possible, such as a 2-on / 5-off schedule in which the administration of two days is non-consecutive.

[0021] In contrast, a continuous dosing schedule does not include a drug holiday during the dosing cycle. Thus, for illustration, in a 7-day dosing cycle, consecutively administered drugs are given on days 1, 2, 3, 4, 5, 6, and 7. The dosing cycle is then repeated.

[0022] When two or more drugs are given to a subject, the two drugs can be administered in the same or different dosage schedules.For example, both the first drug and the second drug can be administered continuously, or the first drug can be administered continuously and the second drug can be administered intermittently (or vice versa), or both the first drug and the second drug can be administered in an intermittent schedule.When both drugs are administered in an intermittent schedule, the schedules can be the same or different.When two (or more) drugs are administered on the same day, they can be administered simultaneously, separately, or sequentially.

[0023] When two (or more) agents are given in combination, they may each be administered at the same dose and on the same schedule as when given as monotherapy (i.e., as a single agent, not in combination with other agents). In other cases, the dosage and / or administration schedule of one or more agents may be altered from the amount and schedule used in monotherapy.

[0024] When capivasertib and venetoclax are given in combination, they can act synergistically. For example, both capivasertib and venetoclax have activity against DLBCL cell lines when used individually. In vitro, their effects are greater than additive when used in combination.

[0025] When capivasertib and venetoclax are given as a combination using their respective monotherapy doses and dosing schedules, mouse models have shown the potential for weight loss. For example, mice bearing xenograft tumors (e.g., DLBCL xenograft tumors) experience body weight loss (BWL) when treated with capivasertib and venetoclax at their respective monotherapy doses with a short (e.g., 15-minute) delay between each dose.

[0026] Surprisingly, such weight loss can be attenuated or prevented by altering the dosage and / or schedule of venetoclax. Moreover, weight loss can be attenuated or prevented without altering the dosage and / or schedule of capivasertib. Furthermore, weight loss can be attenuated or prevented while maintaining efficacy.

[0027] When given as monotherapy, capivasertib may be administered intermittently, for example, on day 4 of a 7-day dosing cycle. For example, 50-900 mg of capivasertib may be administered twice daily on days 1, 2, 3, and 4 of the first 7-day dosing cycle. In some embodiments, 300-700 mg of capivasertib may be administered twice daily on days 1, 2, 3, and 4 of the first 7-day dosing cycle. For example, 50-900 mg of capivasertib may be administered twice daily on days 1 and 2 of the first 7-day dosing cycle. In some embodiments, 300-700 mg of capivasertib may be administered twice daily on days 1, 2, 3, and 4 of the first 7-day dosing cycle.

[0028] In some embodiments, the dosing cycle is 7 days, but with a drug holiday during the fourth cycle (i.e., capivasertib is not given during the last week of the 4-week period). Thus, in some embodiments, capivasertib is given 4 days on and 3 days off for 3 weeks, with no dose given during week 4; in other words, capivasertib is given on days 1, 2, 3, 4, 8, 9, 10, 11, 15, 16, 17, and 18 of a 28-day dosing cycle. In some embodiments, capivasertib is given 2 days on and 5 days off for 3 weeks, with no dose given during week 4; in other words, capivasertib is given on days 1, 2, 8, 9, 15, and 16 of a 28-day dosing cycle. Other dosing schedules and dosages of capivasertib may be used.

[0029] In some embodiments, capivasertib is administered to a subject on an intermittent dosing schedule. Administering capivasertib on an intermittent dosing schedule may, for example, have greater efficacy and / or tolerability than a continuous dosing schedule. In one aspect, capivasertib is administered intermittently on a 1-day-on / 6-day-off schedule (i.e., capivasertib is administered on one day followed by a 6-day drug holiday). In another aspect, capivasertib is administered intermittently on a 2-day-on / 5-day-off schedule (i.e., capivasertib is administered on two days followed by a 5-day drug holiday). In another aspect, capivasertib is administered intermittently on a 3-day-on / 4-day-off schedule (i.e., capivasertib is administered on three days followed by a 4-day drug holiday). In another embodiment, capivasertib is administered intermittently on a 4-day-on / 3-day-off schedule (i.e., capivasertib is administered for 4 days followed by a 3-day drug holiday). In another embodiment, capivasertib is administered intermittently on a 5-day-on / 2-day-off schedule (i.e., capivasertib is administered for 5 days followed by a 2-day drug holiday). In another embodiment, capivasertib is administered intermittently on a 6-day-on / 1-day-off schedule (i.e., capivasertib is administered for 6 days followed by a 1-day drug holiday).

[0030] The administration cycle of such embodiments is then repeated as long as tolerated and beneficial to the subject. In some embodiments, the administration cycle is 7 days. In some embodiments, the administration cycle is 28 days.

[0031] In some embodiments, capivasertib is administered twice daily (BID) on an intermittent dosing schedule. In one aspect, capivasertib is administered twice daily at a dosage of about 50 mg to about 900 mg. In another aspect, capivasertib is administered twice daily at a dosage of about 150 mg to about 750 mg. In another aspect, capivasertib is administered twice daily at a dosage of about 200 mg to about 700 mg. In another aspect, capivasertib is administered twice daily at a dosage of about 225 mg to about 675 mg. In another aspect, capivasertib is administered twice daily at a dosage of about 250 mg to about 650 mg. In another embodiment, capivasertib is administered twice daily at a dosage of about 300 mg to about 625 mg on an intermittent dosing schedule. In another embodiment, capivasertib is administered twice daily at a dosage of about 200 mg to about 300 mg on an intermittent dosing schedule. In another embodiment, capivasertib is administered twice daily at a dosage of about 300 mg to about 400 mg on an intermittent dosing schedule. In another embodiment, capivasertib is administered twice daily at a dosage of about 400 mg to about 500 mg on an intermittent dosing schedule. In another embodiment, capivasertib is administered twice daily at a dosage of about 500 mg to about 600 mg on an intermittent dosing schedule. In another embodiment, capivasertib is administered twice daily at a dosage of about 600 mg to about 700 mg on an intermittent dosing schedule. In another embodiment, capivasertib is administered twice daily at a dosage of about 700 mg to about 800 mg on an intermittent dosing schedule. In another embodiment, capivasertib is administered twice daily at a dosage of about 160 mg on an intermittent dosing schedule. In another embodiment, capivasertib is administered twice daily at a dosage of about 200 mg on an intermittent dosing schedule. In another embodiment, capivasertib is administered twice daily at a dosage of about 240 mg on an intermittent dosing schedule. In another embodiment, capivasertib is administered twice daily at a dosage of about 280 mg on an intermittent dosing schedule.In another embodiment, capivasertib is administered on an intermittent dosing schedule at a dosage of about 320 mg twice daily. In another embodiment, capivasertib is administered on an intermittent dosing schedule at a dosage of about 360 mg twice daily. In another embodiment, capivasertib is administered on an intermittent dosing schedule at a dosage of about 400 mg twice daily. In another embodiment, capivasertib is administered on an intermittent dosing schedule at a dosage of about 440 mg twice daily. In another embodiment, capivasertib is administered on an intermittent dosing schedule at a dosage of about 480 mg twice daily. In another embodiment, capivasertib is administered on an intermittent dosing schedule at a dosage of about 520 mg twice daily. In another embodiment, capivasertib is administered on an intermittent dosing schedule at a dosage of about 580 mg twice daily. In another embodiment, capivasertib is administered on an intermittent dosing schedule at a dosage of about 600 mg twice daily. In another embodiment, capivasertib is administered on an intermittent dosing schedule at a dosage of about 640 mg twice daily. In another embodiment, capivasertib is administered on an intermittent dosing schedule at a dosage of about 680 mg twice daily. In another embodiment, capivasertib is administered on an intermittent dosing schedule at a dosage of about 720 mg twice daily. In another embodiment, capivasertib is administered on an intermittent dosing schedule at a dosage of about 760 mg twice daily. In another embodiment, capivasertib is administered under an intermittent dosing schedule at a dosage of about 800 mg twice daily.

[0032] When given as monotherapy, venetoclax may be administered continuously, e.g., every 7 days of a 7-day dosing cycle. For example, 20 mg to 400 mg of venetoclax may be administered once daily in a 7-day dosing cycle. In some embodiments, 400 mg of venetoclax may be administered once daily in a 7-day dosing cycle. In some embodiments, increasing dosages of venetoclax are given over several dosing cycles (i.e., a ramp-up dosing schedule) up to the recommended daily dose. The recommended daily dose may be 400 mg, with lower doses being used in monotherapy only as part of the ramp-up schedule. The ramp-up schedule may be 20 mg daily during week 1, 50 mg daily during week 2, 100 mg daily during week 3, 200 mg daily during week 4, and 400 mg daily during week 5 and beyond. Additional information may be found in the approved labeling for venetoclax.

[0033] When given in combination with venetoclax, capivasertib may be administered intermittently, for example, on day 4 of a 7-day dosing cycle or on day 2 of a 7-day dosing cycle. For example, 50-900 mg of capivasertib may be administered twice daily on days 1, 2, 3, and 4 of the first 7-day dosing cycle. In some embodiments, 300-800 mg of capivasertib may be administered twice daily on days 1, 2, 3, and 4 of the first 7-day dosing cycle. In some embodiments, 300-800 mg of capivasertib may be administered twice daily on days 1 and 2 of the first 7-day dosing cycle. In some embodiments, capivasertib is administered for 3 weeks but not during week 4. Other dosing schedules and dosages may be used.

[0034] When given in combination with capivasertib, in some embodiments, venetoclax can be administered consecutively, e.g., every 7 days of a 7-day dosing cycle. For example, 20 mg to 400 mg of venetoclax can be administered once daily in a 7-day dosing cycle. In some embodiments, 400 mg of venetoclax can be administered once daily in a 7-day dosing cycle. In some embodiments, increasing dosages of venetoclax are given over several dosing cycles (i.e., an escalating dosing schedule), up to the recommended daily dose of 400 mg.

[0035] When given in combination with capivasertib, in some embodiments, venetoclax may be administered intermittently, e.g., on day 6 of a 7-day dosing cycle, day 5 of a 7-day dosing cycle, day 4 of a 7-day dosing cycle, day 3 of a 7-day dosing cycle, day 2 of a 7-day dosing cycle, or day 1 of a 7-day dosing cycle. In some embodiments, a dose of venetoclax may be given on days when capivasertib is also given, and in other embodiments, a dose of venetoclax may be given on days when capivasertib is not given.

[0036] On days when both capivasertib and venetoclax are given, the two agents can be administered together or separately. Administration together can be in the form of a fixed-dose combination (e.g., a single tablet or capsule containing both agents) or in the form of separate doses given at substantially the same time, i.e., with a delay of less than one hour between administration of the two agents (coadministration). In some embodiments, venetoclax can be administered at least two hours after capivasertib or at least four hours after capivasertib. In other embodiments, capivasertib can be administered at least two hours after venetoclax or at least four hours after venetoclax.

[0037] In some embodiments, capivasertib can be administered on day 4 of a 7-day dosing cycle and venetoclax can be administered on day 4 of a 7-day dosing cycle. In some embodiments, both agents are given on the same 4 days of a 7-day dosing cycle, e.g., days 1, 2, 3, and 4. In some embodiments, the two agents are not given on the same 4 days, but on different days, e.g., capivasertib on days 1, 2, 3, and 4, and venetoclax on days 4, 5, 6, and 7 of a 7-day dosing cycle. Other variations are possible.

[0038] In some embodiments, capivasertib may be administered on day 2 of a 7-day dosing cycle and venetoclax may be administered on day 4 of a 7-day dosing cycle. In some embodiments, both agents are given on overlapping days of a 7-day dosing cycle, e.g., days 1 and 2. In some embodiments, the two agents are not given on the same day, but on different days, e.g., capivasertib on days 1 and 2 and venetoclax on days 3, 4, 5, and 6 of a 7-day dosing cycle. Other variations are possible.

[0039] In some embodiments, capivasertib may be administered on day 4 of a 7-day dosing cycle and venetoclax may be administered on day 3 of a 7-day dosing cycle. In some embodiments, both agents are given on the same day, e.g., capivasertib on days 1, 2, 3, and 4 of a 7-day dosing cycle and venetoclax on days 1, 2, and 3. In some embodiments, the two agents are not given on the same day, but on different days, e.g., capivasertib on days 1, 2, 3, and 4 of a 7-day dosing cycle and venetoclax on days 5, 6, and 7 of a 7-day dosing cycle. Other variations are possible.

[0040] In some embodiments, capivasertib may be administered on day 2 of a 7-day dosing cycle and venetoclax may be administered on day 2 of a 7-day dosing cycle. In some embodiments, both agents are given on the same two days of a 7-day dosing cycle, e.g., days 1 and 2. In some embodiments, the two agents are not given on the same days, but on different days, e.g., capivasertib on days 1 and 2 and venetoclax on days 3 and 4 of a 7-day dosing cycle. Other variations are possible.

[0041] In some embodiments, capivasertib may be administered on day 4 of a 7-day dosing cycle and venetoclax may be administered on day 2 of a 7-day dosing cycle. In some embodiments, both agents are given on the same days, e.g., capivasertib on days 1, 2, 3, and 4 of a 7-day dosing cycle and venetoclax on days 1 and 2. In some embodiments, venetoclax may be given on non-consecutive days of a 7-day dosing cycle, e.g., days 1 and 3. Other variations are possible.

[0042] In some embodiments, capivasertib can be administered on day 2 of a 7-day dosing cycle and venetoclax can be administered on day 2 of a 7-day dosing cycle. In some embodiments, both agents are given on overlapping days, e.g., capivasertib on days 1 and 2 of a 7-day dosing cycle and venetoclax on days 1 and 3 of a 7-day dosing cycle. Other variations are possible.

[0043] In some embodiments, capivasertib may be administered on day 4 of a 7-day dosing cycle and venetoclax may be administered on day 1 of the 7-day dosing cycle. In some embodiments, both agents are given on the same day (e.g., capivasertib on days 1, 2, 3, and 4 of a 7-day dosing cycle and venetoclax on day 1). In other embodiments, the agents are given on different days. Other variations are possible.

[0044] In some embodiments, capivasertib may be administered on day 2 of a 7-day dosing cycle and venetoclax may be administered on day 1 of a 7-day dosing cycle. In some embodiments, both agents are given on the same day (e.g., capivasertib on days 1 and 2 of a 7-day dosing cycle and venetoclax on day 1). In other embodiments, the agents are given on different days. Other variations are possible.

[0045] In some embodiments, venetoclax may be given at a dose lower than the recommended daily dose of 400 mg. This may be during an escalation dosing schedule in accordance with approved labeling, or during continued treatment after escalation is complete. For example, a continued dose lower than the recommended daily dose of venetoclax may be 20 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, or 350 mg.

[0046] Thus, in some embodiments, 50-900 mg, or 300-800 mg, of capivasertib may be administered twice daily on days 1, 2, 3, and 4 of a 7-day dosing cycle, and a dose of venetoclax lower than the recommended daily dose of 400 mg may be administered once daily in a 7-day dosing cycle.

[0047] In some embodiments, 50-900 mg, or 300-800 mg, of capivasertib may be administered twice daily on days 1, 2, 3, and 4 of a 7-day dosing cycle, and a dose of venetoclax lower than the recommended daily dose of 400 mg may be administered on 4 days (e.g., days 1, 2, 3, and 4) of the 7-day dosing cycle. Other variations are possible.

[0048] In some embodiments, 50-900 mg, or 300-800 mg, of capivasertib may be administered twice daily on days 1 and 2 of a 7-day dosing cycle, and a dose of venetoclax lower than the recommended daily dose of 400 mg may be administered on 4 days (e.g., days 1, 2, 3, and 4) of the 7-day dosing cycle. Other variations are possible.

[0049] In some embodiments, 50-900 mg, or 300-800 mg, of capivasertib may be administered twice daily on days 1, 2, 3, and 4 of a 7-day dosing cycle, and a dose of venetoclax lower than the recommended daily dose of 400 mg may be administered on 2 days (e.g., days 1 and 2, or days 1 and 3) of a 7-day dosing cycle. Other variations are possible.

[0050] In some embodiments, 50-900 mg, or 300-800 mg, of capivasertib may be administered twice daily on days 1 and 2 of a 7-day dosing cycle, and a dose of venetoclax lower than the recommended daily dose of 400 mg may be administered on 2 days (e.g., days 1 and 2, or days 1 and 3) of the 7-day dosing cycle. Other variations are possible.

[0051] In some embodiments, 50-900 mg, or 300-800 mg, of capivasertib may be administered twice daily on days 1, 2, 3, and 4 of a 7-day dosing cycle, and a dose of venetoclax lower than the recommended daily dose of 400 mg may be administered on one day of the 7-day dosing cycle (e.g., on day 1). Other variations are possible.

[0052] In some embodiments, 50-900 mg, or 300-800 mg, of capivasertib may be administered twice daily on days 1 and 2 of a 7-day dosing cycle, and a dose of venetoclax lower than the recommended daily dose of 400 mg may be administered on one day of the 7-day dosing cycle (e.g., day 1). Other variations are possible.

[0053] In some embodiments, treatment with venetoclax is initiated on an escalation schedule, whereby patients receive a low dose in the first dosing cycle (e.g., a 7-day dosing cycle) and progressively higher doses in subsequent dosing cycles until the recommended daily dose (e.g., 400 mg) is reached. The escalation schedule can be 20 mg daily during week 1, 50 mg daily during week 2, 100 mg daily during week 3, 200 mg daily during week 4, and 400 mg daily during weeks 5 and beyond. Additional information can be found in the approved labeling for venetoclax. When given in combination with capivasertib, the escalation schedule can be initiated prior to, in conjunction with, or after the initiation of capivasertib treatment.

[0054] In some embodiments, the initial target regimen includes target dosages and schedules for each of capivasertib and venetoclax. The initial target regimen is selected by a clinician and can be customized to suit the needs of an individual patient. In some embodiments, the initial target regimen includes 50-900 mg or 300-800 mg of capivasertib administered twice daily on days 1, 2, 3, and 4 of a 7-day dosing cycle, and 400 mg of venetoclax administered daily in a 7-day dosing cycle. In some embodiments, the initial target regimen includes 480 mg of capivasertib administered twice daily on days 1, 2, 3, and 4 of a 7-day dosing cycle, and 400 mg of venetoclax administered daily in a 7-day dosing cycle. In some embodiments, the initial target regimen comprises 400 mg of capivasertib administered twice daily on days 1, 2, 3, and 4 of a 7-day dosing cycle and 400 mg of venetoclax administered daily in a 7-day dosing cycle. In some embodiments, the initial target regimen comprises 640 mg of capivasertib administered twice daily on days 1 and 2 of a 7-day dosing cycle and 400 mg of venetoclax administered daily in a 7-day dosing cycle.

[0055] In some cases, patients being treated with the initial target regimen may experience adverse side effects, including, for example, weight loss or undesirable changes in blood glucose levels. If adverse side effects are actually observed with the initial target regimen, the initial target regimen may be modified. The modified regimen may be selected to reduce or eliminate the adverse side effects while maintaining a high level of efficacy. In some embodiments, the initial target regimen is modified with respect to the capivasertib dosage, the capivasertib dosing schedule, or both, without changing the venetoclax dosage or dosing schedule. In some embodiments, the initial target regimen is modified with respect to the venetoclax dosage, the venetoclax dosing schedule, or both, without changing the capivasertib dosage or dosing schedule. In some embodiments, the initial target regimen is modified with respect to the venetoclax dosage and / or venetoclax dosing schedule, and the capivasertib dosage and / or capivasertib dosing schedule.

[0056] In some embodiments, modified regimens involving reduced dosages of venetoclax, reduced dosing frequency of venetoclax, or both, without changing the dosage or dosing schedule of capivasertib, can reduce or eliminate adverse side effects experienced with the initial target regimen while maintaining a high degree of efficacy.

[0057] In some embodiments, modifications to the initial target plan can include a change to the dosing schedule of venetoclax. For example, the dosing schedule can be changed from administering venetoclax daily to administering it on 6 days of a 7-day dosing cycle, on 5 days of a 7-day dosing cycle, on 4 days of a 7-day dosing cycle, on 3 days of a 7-day dosing cycle, on 2 days of a 7-day dosing cycle, or on 1 day of a 7-day dosing cycle.

[0058] In some embodiments, the initial target regimen may involve administering venetoclax every day in a 7-day dosing cycle, and the modified regimen may involve administering venetoclax on day 4 of the 7-day dosing cycle. The modified regimen may involve administering capivasertib on days 4 or 2 of the 7-day dosing cycle. The modified regimen may involve administering capivasertib on days 1, 2, 3, and 4 of the 7-day dosing cycle and administering venetoclax on days 1, 2, 3, and 4 of the 7-day dosing cycle. The modified regimen may involve administering capivasertib on days 1 and 2 of the 7-day dosing cycle and administering venetoclax on days 1, 2, 3, and 4 of the 7-day dosing cycle.

[0059] In some embodiments, the initial target regimen may involve administering venetoclax every day in a 7-day dosing cycle, and the modified regimen may involve administering venetoclax on day 2 of the 7-day dosing cycle. The modified regimen may involve administering capivasertib on day 4 or day 2 of the 7-day dosing cycle. The modified regimen may involve administering capivasertib on days 1, 2, 3, and 4 of the 7-day dosing cycle, and administering venetoclax on days 1 and 2 or days 1 and 3 of the 7-day dosing cycle. The modified regimen may involve administering capivasertib on days 1 and 2 of the 7-day dosing cycle, and administering venetoclax on days 1 and 2 or days 1 and 3 of the 7-day dosing cycle.

[0060] In some embodiments, the initial target regimen may involve administering venetoclax every day in a 7-day dosing cycle, and the modified regimen may involve administering venetoclax on day 1 of the 7-day dosing cycle. The modified regimen may involve administering capivasertib on day 4 or day 2 of the 7-day dosing cycle. The modified regimen may involve administering capivasertib on days 1, 2, 3, and 4 of the 7-day dosing cycle and administering venetoclax on day 1 of the 7-day dosing cycle. The modified regimen may involve administering capivasertib on days 1 and 2 of the 7-day dosing cycle and administering venetoclax on day 1 of the 7-day dosing cycle.

[0061] In some embodiments, modifications to the initial target plan can include a change to the dosage of venetoclax. For example, the dosage can be changed from administering 400 mg of venetoclax to administering 350 mg, 300 mg, 250 mg, 200 mg, 150 mg, or 50 mg of venetoclax.

[0062] In some embodiments, modifications to the initial target plan can include changes to both the dosing schedule and dosage of venetoclax. For example, the dosing schedule can be changed from administering venetoclax daily to administering it on 6 days of a 7-day dosing cycle, on 5 days of a 7-day dosing cycle, on 4 days of a 7-day dosing cycle, on 3 days of a 7-day dosing cycle, on 2 days of a 7-day dosing cycle, or on 1 day of a 7-day dosing cycle, and the dosage can be changed from administering 400 mg of venetoclax to administering 350 mg, 300 mg, 250 mg, 200 mg, 150 mg, or 50 mg of venetoclax. Combinations of these changes are contemplated as being within the scope of the combinations described herein.

[0063] The following regimen is an example of a combination therapy using capivasertib and venetoclax.

[0064] Example Scheme 1 Capivasertib was administered at 480 mg twice daily on days 1, 2, 3, and 4 of a 7-day dosing cycle, with optional drug holidays every 4 weeks, and venetoclax was administered at 400 mg daily. Optionally, on days when both were administered, there was a delay of 2 hours or more between administration of the two drugs.

[0065] Example Scheme 2 Capivasertib was administered at 480 mg twice daily on days 1, 2, 3, and 4 of a 7-day dosing cycle, with optional dosing days every 4 weeks, and venetoclax was administered at 400 mg daily on days 1, 2, 3, and 4 of a 7-day dosing cycle. Optionally, on days when both are administered, there is a delay of 2 hours or more between administration of the two drugs.

[0066] Example Scheme 3 Capivasertib was administered at 480 mg twice daily on days 1, 2, 3, and 4 of a 7-day dosing cycle, with optional drug holidays every 4 weeks, and venetoclax was administered at 400 mg daily on days 1 and 2 of a 7-day dosing cycle. Optionally, on days when both are administered, there is a delay of 2 hours or more between administration of the two drugs.

[0067] Example Scheme 4 Capivasertib was administered at 480 mg twice daily on days 1, 2, 3, and 4 of a 7-day dosing cycle, with optional dosing days every 4 weeks, and venetoclax was administered at 400 mg daily on days 1 and 3 of a 7-day dosing cycle. Optionally, on days when both are administered, there is a delay of 2 hours or more between administration of the two drugs.

[0068] Example Scheme 5 Capivasertib was administered at 480 mg twice daily on days 1, 2, 3, and 4 of a 7-day dosing cycle, with optional drug holidays every 4 weeks, and venetoclax was administered at 400 mg daily on day 1 of a 7-day dosing cycle. Optionally, on days when both are administered, there is a delay of 2 hours or more between administration of the two drugs.

[0069] Example Scheme 6 Capivasertib was administered at 480 mg twice daily on days 1, 2, 3, and 4 of a 7-day dosing cycle, with optional drug holidays every 4 weeks, and venetoclax was administered at 300 mg daily. Optionally, on days when both were administered, there was a delay of 2 hours or more between administration of the two drugs.

[0070] Example Scheme 7 Capivasertib was administered at 480 mg twice daily on days 1, 2, 3, and 4 of a 7-day dosing cycle, with optional drug holidays every 4 weeks, and venetoclax was administered at 200 mg daily. Optionally, on days when both were administered, there was a delay of 2 hours or more between administration of the two drugs.

[0071] Example Scheme 8 Capivasertib was administered at 480 mg twice daily on days 1, 2, 3, and 4 of a 7-day dosing cycle, with optional drug holidays every 4 weeks, and venetoclax was administered at 100 mg daily. Optionally, on days when both were administered, there was a delay of at least 2 hours between administration of the two drugs.

[0072] Exemplary Plan 9 Capivasertib was administered at 400 mg twice daily on days 1, 2, 3, and 4 of a 7-day dosing cycle, with optional drug holidays every 4 weeks, and venetoclax was administered at 400 mg daily. Optionally, on days when both were administered, there was a delay of 2 hours or more between administration of the two drugs.

[0073] Exemplary Scheme 10 Capivasertib was administered at 400 mg twice daily on days 1, 2, 3, and 4 of a 7-day dosing cycle, optionally with a drug holiday every 4 weeks, and venetoclax was administered at 400 mg daily on days 1, 2, 3, and 4 of a 7-day dosing cycle. Optionally, on days when both are administered, there is a delay of 2 hours or more between administration of the two drugs.

[0074] Exemplary Scheme 11 Capivasertib was administered at 400 mg twice daily on days 1, 2, 3, and 4 of a 7-day dosing cycle, optionally with a drug holiday every 4 weeks, and venetoclax was administered at 400 mg daily on days 1 and 2 of a 7-day dosing cycle. Optionally, on days when both are administered, there is a delay of 2 hours or more between administration of the two drugs.

[0075] Exemplary Plan 12 Capivasertib was administered at 400 mg twice daily on days 1, 2, 3, and 4 of a 7-day dosing cycle, optionally with a dosing day every 4 weeks, and venetoclax was administered at 400 mg daily on days 1 and 3 of a 7-day dosing cycle. Optionally, on days when both are administered, there is a delay of 2 hours or more between administration of the two drugs.

[0076] Exemplary Plan 13 Capivasertib was administered at 400 mg twice daily on days 1, 2, 3, and 4 of a 7-day dosing cycle, optionally with a drug holiday every 4 weeks, and venetoclax was administered at 400 mg daily on day 1 of a 7-day dosing cycle. Optionally, on days when both are administered, there is a delay of 2 hours or more between administration of the two drugs.

[0077] Exemplary Scheme 14 Capivasertib was administered at 400 mg twice daily on days 1, 2, 3, and 4 of a 7-day dosing cycle, with optional drug holidays every 4 weeks, and venetoclax was administered at 300 mg daily. Optionally, on days when both were administered, there was a delay of 2 hours or more between administration of the two drugs.

[0078] Exemplary Plan 15 Capivasertib was administered at 400 mg twice daily on days 1, 2, 3, and 4 of a 7-day dosing cycle, with optional drug holidays every 4 weeks, and venetoclax was administered at 200 mg daily. Optionally, on days when both were administered, there was a delay of 2 hours or more between administration of the two drugs.

[0079] Exemplary Plan 16 Capivasertib was administered at 400 mg twice daily on days 1, 2, 3, and 4 of a 7-day dosing cycle, with optional drug holidays every 4 weeks, and venetoclax was administered at 100 mg daily. Optionally, on days when both were administered, there was a delay of 2 hours or more between administration of the two drugs.

[0080] Exemplary Plan 17 Capivasertib was administered at 640 mg twice daily on days 1 and 2 of a 7-day dosing cycle, with optional drug holidays every 4 weeks, and venetoclax was administered at 400 mg daily, with optional delay of 2 hours or more between administration of the two drugs on days when both were administered.

[0081] Exemplary Plan 18 Capivasertib was administered at 640 mg twice daily on days 1 and 2 of a 7-day dosing cycle, with optional dosing days every 4 weeks, and venetoclax was administered at 400 mg on days 1, 2, 3, and 4 of a 7-day dosing cycle. Optionally, on days when both are administered, there is a delay of 2 hours or more between administration of the two drugs.

[0082] Exemplary Plan 19 Capivasertib was administered at 640 mg twice daily on days 1 and 2 of a 7-day dosing cycle, with optional dosing days every 4 weeks, and venetoclax was administered at 400 mg on days 1 and 2 of a 7-day dosing cycle. Optionally, on days when both are administered, there is a delay of 2 hours or more between administration of the two drugs.

[0083] Exemplary Plan 20 Capivasertib was administered at 640 mg twice daily on days 1 and 2 of a 7-day dosing cycle, with optional drug holidays every 4 weeks, and venetoclax was administered at 400 mg on days 1 and 3 of a 7-day dosing cycle. Optionally, on days when both are administered, there is a delay of 2 hours or more between administration of the two drugs.

[0084] Exemplary Plan 21 Capivasertib was administered at 640 mg twice daily on days 1 and 2 of a 7-day dosing cycle, with optional drug holidays every 4 weeks, and venetoclax was administered at 400 mg on day 1 of a 7-day dosing cycle. Optionally, on days when both are administered, there is a delay of 2 hours or more between administration of the two drugs.

[0085] Exemplary Plan 22 Capivasertib was administered at 640 mg twice daily on days 1 and 2 of a 7-day dosing cycle, with optional drug holidays every 4 weeks, and venetoclax was administered at 300 mg daily, with optional delay of 2 hours or more between administration of the two drugs on days when both were administered.

[0086] Exemplary Plan 23 Capivasertib was administered at 640 mg twice daily on days 1 and 2 of a 7-day dosing cycle, with optional drug holidays every 4 weeks, and venetoclax was administered at 200 mg daily, with optional delay of 2 hours or more between administration of the two drugs on days when both were administered.

[0087] Exemplary Plan 24 Capivasertib was administered at 640 mg twice daily on days 1 and 2 of a 7-day dosing cycle, with optional drug holidays every 4 weeks, and venetoclax was administered at 100 mg daily, with optional delay of 2 hours or more between administration of the two drugs on days when both were administered. [Example]

[0088] [Table 1]

[0089] Example 1 - SUDHL4 human GCB-DLBCL tumor cells For the experiments described below, SUDHL4 human GCB-DLBCL tumor cells (10 × 10 6100 mg / kg venetoclax (venetoclax) was subcutaneously implanted into female CB.17 SCID mice. Mice were randomized into groups of 5 for efficacy and tolerability assessment based on tumor volume and treated with either vehicle (10% DMSO / 25% Kleptose pH=5 (Vehicle 1) and 10% ethanol / 30% PEG 400 / 60% Phosal PG-50 (Vehicle 2)), 130 mg / kg or 45 mg / kg capivasertib, 100 mg / kg venetoclax, or a combination of capivasertib and venetoclax. Capivasertib was formulated in 10% DMSO / 25% Kleptose (pH=5), and venetoclax was formulated in 10% ethanol / 30% PEG 400 / 60% Phosal PG-50. All agents were administered by oral gavage at a dose volume of 5 mL / kg according to the schedules listed after tumor cell implantation. The length and width of the tumor were measured with a caliper and calculated using the formula (length × width). 2 )*π / 6 was used to calculate tumor volume.

[0090] Coadministration of both capivasertib and venetoclax at their respective clinically relevant doses and schedules (capivasertib 130 mg / kg BID 10 / 14 4 days on / 3 days off, venetoclax 100 mg / kg QD in the morning (15 minutes after capivasertib)) resulted in weight loss (Figure 1) and drug interactions (Figures 2 and 3). This dosing schedule is shown in the table below.

[0091] [Table 2]

[0092] Separating capivasertib and venetoclax administration by 4 hours (capivasertib 130 mg / kg BID 10 / 14 4 days on / 3 days off, venetoclax 100 mg / kg QD in the morning (4 hours after capivasertib)) reduced weight loss (Figure 4) and improved the exposure profile (Figures 5 and 6). However, weight loss (Figure 7) and drug interactions were observed after prolonged administration. This dosing schedule is shown in the table below.

[0093] [Table 3]

[0094] Figure 8 shows venetoclax plasma concentrations following administration of venetoclax 100 mg / kg QD monotherapy and capivasertib 130 mg / kg BID 10 / 14 4 days on / 3 days off with venetoclax 100 mg / kg QD in the AM (4 hours after capivasertib).

[0095] The table below sets out further dosing schedules as well as the TGI and maximum mean weight loss obtained.

[0096] [Table 4]

[0097] In Study 1, 22 days of treatment with capivasertib monotherapy resulted in an 82% TGI, and venetoclax monotherapy resulted in a 42% TGI. When both drugs were administered on a simultaneous 4-day-on, 3-day-off schedule, 100% tumor regression (5 / 5 CR) was achieved, but was accompanied by a significant 13% weight loss. The dosing schedule is shown in the table below.

[0098] [Table 5]

[0099] Figure 9 shows the resulting weight changes over time. Figure 10 shows tumor volume over time for both drugs (capivasertib BID 10 / 14 4 days on / 3 days off x 22 days, venetoclax QD in the morning (4 hours after capivasertib) 4 days on / 3 days off x 22 days) compared to vehicle and individual drugs administered on the same schedule. By introducing dosing days, weight loss could be controlled.

[0100] To minimize weight loss, alternative dosing regimens were explored. Sequencing capivasertib and venetoclax on separate days resulted in a 95% TGI with a maximum mean weight loss of 5%. The dosing schedule is shown in the table below.

[0101] [Table 6]

[0102] Figure 11 shows the resulting weight change over time. Figure 12 shows tumor volume over time compared to vehicle and individual drugs for both drugs on a sequential dosing schedule (capivasertib BID 10 / 14 4 days on / 3 days off, venetoclax QD 4 days off / 3 days on).

[0103] Reducing the frequency of venetoclax to either once or twice weekly in combination with a clinically relevant dose and schedule of capivasertib resulted in 100% tumor regression with minimal weight loss of 5% or less for either regimen. The dosing schedule is shown in the table below.

[0104] [Table 7]

[0105] [Table 8]

[0106] Figure 13 shows the resulting weight change over time. Figure 14 shows tumor volume over time for both drugs (capivasertib BID 10 / 14 4 days on / 3 days off, venetoclax (QW or 2QW)) compared to vehicle and individual drugs.

[0107] In Study 2, capivasertib at 45 mg / kg BID for 28 days in combination with a clinically relevant dose of venetoclax reduced efficacy in the SUDHL4 xenograft model, resulting in a 36% TGI. This dosing schedule is shown in the table below.

[0108] [Table 9]

[0109] Figure 15 shows the tumor volume over time compared to vehicle. Figure 16 shows the resulting weight change over time. A period of 28 doses is shown in the figure.

[0110] Venetoclax administered at 30 mg / kg QD in combination with a clinically relevant dose and schedule of capivasertib was well tolerated in the SUDHL4 xenograft model and achieved 100% tumor regression, as shown in the table below.

[0111] [Table 10]

[0112] Figure 17 shows tumor volume over time compared to vehicle. Figure 18 shows the resulting weight change over time. A 28 day dosing period is shown in the figure.

[0113] Other embodiments are within the scope of the following claims.

Claims

1. 1. A method of treating a B-cell malignancy in a patient in need thereof, comprising administering to the patient a first amount of capivasertib or a pharmaceutically acceptable salt thereof, and a second amount of venetoclax or a pharmaceutically acceptable salt thereof, wherein the first amount and the second amount together comprise a therapeutically effective amount.

2. 2. The method of claim 1, wherein the B-cell malignancy is diffuse large B-cell lymphoma (DLBCL), germinal center B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or follicular lymphoma.

3. 3. The method of claim 2, wherein the B-cell malignancy is germinal center B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL).

4. The method of any one of claims 1 to 3, wherein the B cell malignancy is PTEN null.

5. The method of any one of claims 1-3, wherein venetoclax is administered at least 2 hours after capivasertib is administered on the days when both are administered.

6. 6. The method of any one of claims 1-5, wherein capivasertib is administered on 4 days in a 7-day dosing cycle.

7. 6. The method of any one of claims 1-5, wherein capivasertib is administered twice daily at a dose of 300-800 mg, optionally twice daily at a dose of about 320 mg, about 400 mg, or about 480 mg on days 1, 2, 3, and 4 of a 7-day dosing cycle.

8. 6. The method of any one of claims 1-5, wherein capivasertib is administered on 2 days in a 7-day dosing cycle.

9. 6. The method of any one of claims 1-5, wherein capivasertib is administered twice daily at a dose of 300-800 mg, optionally twice daily at a dose of about 480 mg, about 560 mg, or about 640 mg on days 1 and 2 of a 7-day dosing cycle.

10. 10. The method of any one of claims 1 to 9, wherein capivasertib is administered for three weeks and not administered during the fourth week.

11. 11. The method of any one of claims 1-10, wherein venetoclax is administered every 7 days in a 7-day dosing cycle.

12. 11. The method of any one of claims 1-10, wherein venetoclax is administered on days 1, 2, 3, 4, 5, or 6 in a 7-day dosing cycle.

13. 11. The method of any one of claims 1-10, wherein venetoclax is administered on 4 days in a 7-day dosing cycle.

14. 11. The method of any one of claims 1-10, wherein venetoclax is administered on 3 days in a 7-day dosing cycle.

15. 11. The method of any one of claims 1-10, wherein venetoclax is administered on 2 days in a 7-day dosing cycle.

16. 11. The method of any one of claims 1-10, wherein venetoclax is administered daily in a 7-day dosing cycle.

17. 11. The method of any one of claims 1-10, wherein venetoclax is administered only on days when capivasertib is administered.

18. 11. The method of any one of claims 1-5 and 10, wherein capivasertib is administered on day 2 or 4 of a 7-day dosing cycle and venetoclax is administered on day 1, 2, 3, 4, 5, 6, or 7 of the 7-day dosing cycle.

19. 19. The method of claim 18, wherein venetoclax is administered on days 1, 2, 4, or 7 of a 7-day dosing cycle.

20. 1. A method of treating a B-cell malignancy in a patient in need thereof, comprising: In a 7-day dosing cycle, the patient administering a first amount of capivasertib or a pharmaceutically acceptable salt thereof for 2 or 4 days; and administering a second amount of venetoclax or a pharmaceutically acceptable salt thereof for 7 days; and In a subsequent 7-day dosing cycle, the patient administering a first amount of capivasertib or a pharmaceutically acceptable salt thereof for 2 or 4 days; and administering a second amount of venetoclax or a pharmaceutically acceptable salt thereof on days 1, 2, 3, 4, 5, or 6; wherein said first amount and said second amount together comprise a therapeutically effective amount.

21. 21. The method of claim 20, wherein capivasertib is administered on days 1, 2, 3, and 4 of a 7-day dosing cycle and venetoclax is administered on day 1 and an additional 1, 2, or 3 days of said 7-day dosing cycle.

22. 21. The method of claim 20, wherein capivasertib is administered on days 1 and 2 of a 7-day dosing cycle and venetoclax is administered on day 1 and an additional 1, 2, or 3 days of said 7-day dosing cycle.

23. 23. The method of any one of claims 20-22, wherein venetoclax is administered on day 1, and either day 2 or day 3 of the 7-day dosing cycle.

24. 1. A method of treating a B-cell malignancy in a patient in need thereof, comprising: In a 7-day dosing cycle, the patient administering a first amount of capivasertib or a pharmaceutically acceptable salt thereof for 2 or 4 days; and administering a second amount of venetoclax or a pharmaceutically acceptable salt thereof for 7 days; and In a subsequent 7-day dosing cycle, the patient administering a first amount of capivasertib or a pharmaceutically acceptable salt thereof for 2 or 4 days; and administering a third amount of venetoclax or a pharmaceutically acceptable salt thereof every 7 days, wherein the third amount is less than the second amount; The method, wherein the first amount and the second amount together comprise a therapeutically effective amount, and the first amount and the third amount together comprise a therapeutically effective amount.

25. 1. A method of treating a B-cell malignancy in a patient in need thereof, comprising: In a 7-day dosing cycle, the patient 300-800 mg of capivasertib administered twice daily on days 1, 2, and optionally days 3 and 4; and 20 to 400 mg of venetoclax administered once daily for 7 days; In a subsequent 7-day dosing cycle, the patient 300-800 mg of capivasertib administered twice daily on days 1, 2, and optionally days 3 and 4 of said subsequent 7-day dosing cycle; and administering 20-400 mg of venetoclax once daily on day 1, and for 1, 2, or 3 additional days, of said subsequent 7-day dosing cycle.

26. Capivasertib for use in the method of any one of claims 1 to 25.

27. Venetoclax for use in the method of any one of claims 1 to 25.

28. 26. A kit comprising: (i) capivasertib; and (ii) instructions for using capivasertib in the method of any one of claims 1 to 25.

29. 26. A combination of capivasertib and venetoclax for use in the method of any one of claims 1 to 25, wherein the combination is for simultaneous, separate or sequential administration of capivasertib and venetoclax.

30. 26. The use of a combination of capivasertib and venetoclax in the method of any one of claims 1 to 25, wherein the combination comprises a first amount of capivasertib or a pharmaceutically acceptable salt thereof, and a second amount of venetoclax or a pharmaceutically acceptable salt thereof, wherein the first amount and the second amount together constitute a therapeutically effective amount, and the combination is for simultaneous, separate, or sequential administration of capivasertib and venetoclax.

31. 31. The combination for use according to claim 29 or the use according to claim 30, wherein the combination is for separate or sequential administration.

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