Therapeutic combination of capacitib and vinetocart

Abstract

Therapeutic combinations of kapasitinib and vonetog are described. The combination can be used for treating B-cell malignancies. In some embodiments, reducing the dosage (e.g., reducing the frequency and / or reducing the amount) of Venatog may mitigate or eliminate effects such as weight loss that may be experienced in an initial dosing regimen.

Description

Background Art

[0001] B cell malignancies are a class of leukemias and lymphomas caused by the dysregulation of B cell growth. Despite the increased understanding of the biology and genetics of such diseases in recent years, there remains a highly unmet need for treatments to address these cancers.

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

[0003]

[0004] 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 (which is incorporated herein by reference) and is being evaluated in clinical studies for the treatment of cancers including breast cancer and prostate cancer.

[0005] The anti-apoptotic Bcl-2 protein is associated with many diseases including B cell malignancies. In various cancers and immune system disorders, overexpression of the Bcl-2 protein is associated with chemotherapy resistance, clinical outcome, disease progression, overall prognosis, or a combination thereof. Venetoclax, having the following structure:

[0006]

[0007] 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, which is described, for example, in U.S. Patent Nos. 8,546,399 and 9,174,982 (each of which is incorporated herein by reference). Venetoclax is approved for the treatment of chronic lymphocytic leukemia, small lymphocytic leukemia, and acute myeloid leukemia. Summary of the Invention

[0008] In one aspect, there is provided a method of treating a B-cell malignancy in a patient in need thereof, the method comprising: administering to the patient a first amount of capesicitinib 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.

[0009] In one aspect, there is provided a method of treating a B-cell malignancy in a patient in need thereof, the method comprising:

[0010] During a seven-day dosing cycle, administering to the patient:

[0011] A first amount of capesicitinib or a pharmaceutically acceptable salt thereof, for two or four days; and

[0012] A second amount of venetoclax or a pharmaceutically acceptable salt thereof, for seven days; and

[0013] During a subsequent seven-day dosing cycle, administering to the patient:

[0014] A first amount of capesicitinib or a pharmaceutically acceptable salt thereof, for two or four days; and

[0015] A second amount of venetoclax or a pharmaceutically acceptable salt thereof, for one, two, three, four, five, or six days;

[0016] wherein the first amount and the second amount together constitute a therapeutically effective amount.

[0017] In one aspect, there is provided a method of treating a B-cell malignancy in a patient in need thereof, the method comprising:

[0018] During a seven-day dosing cycle, administering to the patient:

[0019] 300 mg to 800 mg of capesicitinib, twice daily on the first and second days and optionally on the third and fourth days; and

[0020] 20 mg to 400 mg of venetoclax, once daily for seven days;

[0021] During a subsequent seven-day dosing cycle, administering to the patient:

[0022] 300 mg to 800 mg of capesicitinib, twice daily on the first and second days and optionally on the third and fourth days of the subsequent seven-day dosing cycle; and

[0023] 20 mg to 400 mg of venetoclax, once daily on the first day and on one additional day, two additional days, or three additional days of the subsequent seven-day dosing cycle.

[0024] In one aspect, capesicitinib is provided for use in any of the methods described herein.

[0025] In one aspect, venetoclax is provided for use in any of the methods described herein.

[0026] In one aspect, a kit is provided that comprises: (i) capesicitinib; and (ii) instructions for using capesicitinib in any of the methods described herein.

[0027] In one aspect, a combination of capesicitinib and venetoclax is provided for use in any of the methods described herein, wherein the combination is for simultaneous, separate, or sequential administration of capesicitinib and venetoclax.

[0028] In one aspect, use of a combination of capesicitinib and venetoclax in any of the methods described herein is provided, the combination comprising: a first amount of capesicitinib 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; wherein the combination is for simultaneous, separate, or sequential administration of capesicitinib and venetoclax.

[0029] Other features, objects, and advantages will be apparent from the description and drawings and from the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 Shows the change in body weight after the following dosing schedule: capesicitinib 130 mg / kg BID 10 / 14, 4 days on / 3 days off; venetoclax 100 mg / kg QD, in the morning (15 minutes after capesicitinib).

[0031] Figure 2 Shows the plasma levels of capesicitinib after the following dosing schedule: capesicitinib 130 mg / kg BID 10 / 14, 4 days on / 3 days off; venetoclax 100 mg / kg QD, in the morning (15 minutes after capesicitinib).

[0032] Figure 3 Shows the plasma levels of venetoclax after the following dosing schedule: capesicitinib 130 mg / kg BID 10 / 14, 4 days on / 3 days off; venetoclax 100 mg / kg QD, in the morning (15 minutes after capesicitinib).

[0033] Figure 4Shows the weight changes after the following dosing schedule: capesicitinib 130 mg / kg BID 10 / 14, 4 days on / 3 days off; venetoclax 100 mg / kg QD, in the morning (4 hours after capesicitinib).

[0034] Figure 5 Shows the capesicitinib plasma levels after the following dosing schedule: capesicitinib 130 mg / kg BID 10 / 14, 4 days on / 3 days off; venetoclax 100 mg / kg QD, in the morning (4 hours after capesicitinib).

[0035] Figure 6 Shows the venetoclax plasma levels after the following dosing schedule: capesicitinib 130 mg / kg BID 10 / 14, 4 days on / 3 days off; venetoclax 100 mg / kg QD, in the morning (4 hours after capesicitinib).

[0036] Figure 7 Shows the weight changes after the following extended dosing schedule: capesicitinib 130 mg / kg BID 10 / 14, 4 days on / 3 days off; venetoclax 100 mg / kg QD, in the morning (4 hours after capesicitinib).

[0037] Figure 8 Shows the venetoclax plasma concentration after the following dosing: venetoclax 100 mg / kg QD monotherapy, and capesicitinib 130 mg / kg BID 10 / 14, 4 days on / 3 days off; venetoclax 100 mg / kg QD, in the morning (4 hours after capesicitinib).

[0038] Figure 9 Shows the weight changes after the following extended dosing: capesicitinib 130 mg / kg BID 10 / 14, 4 days on / 3 days off; venetoclax 100 mg / kg QD, in the morning (+4 hours), 4 days on / 3 days off.

[0039] Figure 10 Shows the tumor volume over time for the following dosing: capesicitinib 130 mg / kg BID 10 / 14, 4 days on / 3 days off; venetoclax 100 mg / kg QD, in the morning (4 hours after capesicitinib), 4 days on / 3 days off, compared to vehicle and single drug dosed on the same schedule.

[0040] Figure 11 Shows the weight changes after the following extended dosing: capesicitinib 130 mg / kg BID 10 / 14, 4 days on / 3 days off; venetoclax 100 mg / kg QD, 4 days off / 3 days on.

[0041] Figure 12 Shows the tumor volume over time for the following administrations: capesicitinib 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 single drugs administered on the same schedule.

[0042] Figure 13 Shows the weight change after the following extended administrations: capesicitinib 130 mg / kg BID 10 / 14, 4 days on / 3 days off; venetoclax 100 mg / kg QW or 2QW.

[0043] Figure 14 Shows the tumor volume over time for the following administrations: capesicitinib 130 mg / kg BID 10 / 14, 4 days on / 3 days off; venetoclax 100 mg / kg QW or 2QW, compared to vehicle and single drugs administered on the same schedule.

[0044] Figure 15 Shows the tumor volume over time for the following administrations: capesicitinib 45 mg / kg BID 10 / 15, 4 days on / 3 days off; venetoclax 100 mg / kg QD, 5 days on / 2 days off (in the morning, 15 minutes after capesicitinib), compared to vehicle.

[0045] Figure 16 Shows the weight change after the following administrations: capesicitinib 45 mg / kg BID 10 / 14, 4 days on / 3 days off; venetoclax 100 mg / kg QD, 5 days on / 2 days off (in the morning, 15 minutes after capesicitinib).

[0046] Figure 17 Shows the tumor volume over time for the following administrations: capesicitinib 130 mg / kg BID 10 / 17, 4 days on / 3 days off; venetoclax 30 mg / kg QD, 5 days on / 2 days off (in the morning, 15 minutes after capesicitinib), compared to vehicle.

[0047] Figure 18 Shows the weight change after the following administrations: capesicitinib 130 mg / kg BID 10 / 14, 4 days on / 3 days off; venetoclax 30 mg / kg QD, 5 days on / 2 days off (in the morning, 15 minutes after capesicitinib). Detailed Description

[0048] The present text describes a method for treating B-cell malignancies in patients in need thereof. The method may comprise administering both capesertinib (or a pharmaceutically acceptable salt thereof) and venetoclax (or a pharmaceutically acceptable salt thereof). The method may comprise administering both capesertinib and venetoclax at corresponding doses and corresponding dosing schedules so as to provide a therapeutic effect. Advantageously, the described combination may provide a therapeutic effect while minimizing potential side effects such as weight loss.

[0049] Some B-cell malignancies that can be treated by the combination of capesertinib 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.

[0050] As used herein, the term "combination" refers to the administration of two or more agents simultaneously, separately, or sequentially. In one aspect, "combination" may refer to simultaneous administration (e.g., administering the two agents in a single dosage form). In another aspect, "combination" refers to separate administration (e.g., in separate dosage forms, but administering the two agents substantially simultaneously). In yet another aspect, "combination" refers to sequential administration (e.g., where the first agent is administered, followed by a delay, and then the second or additional agent is administered).

[0051] As used herein, the term "dosing cycle" refers to the repeating unit of a dosing schedule. For example, the dosing cycle may repeat every seven days, every 10 days, every 14 days, or every 28 days, or at other time lengths. As used herein, the term "dosing schedule" refers to the plan, i.e., the times and intervals at which a given drug is administered. The dosing schedule may be continuous or intermittent.

[0052] An intermittent dosing schedule may include a dosing holiday, i.e., a period of time during which the agent is not administered. For illustrative purposes, within a seven-day dosing cycle, an agent administered intermittently may be administered on the first and second days, and not on the third, fourth, fifth, sixth, or seventh days. Then the dosing cycle is repeated. This illustration is referred to as a 2-day dosing / 5-day drug holiday schedule, where the drug is administered for two days, followed by a five-day holiday, and then repeated every seven days. Other variations are possible, e.g., a 2-day dosing / 5-day drug holiday schedule where the two days of administration are non-consecutive.

[0053] In contrast, a continuous dosing schedule does not include a holiday during the dosing cycle. Thus, for illustration, within a seven-day dosing cycle, an agent administered continuously will be administered on the first, second, third, fourth, fifth, sixth, and seventh days. Then the dosing cycle is repeated.

[0054] When more than one agent is administered to a subject, the two agents can be administered according to the same or different dosing schedules. For example, both the first agent and the second agent can be administered continuously; or the first agent is administered continuously while the second agent is administered intermittently (or vice versa); or both the first agent and the second agent can be administered according to an intermittent schedule. If both agents are administered according to an intermittent schedule, these schedules can be the same or different. In the case where two (or more) agents are administered on the same day, they can be administered simultaneously, separately, or sequentially.

[0055] When two (or more) agents are administered in combination, they can each be administered at the same dose and according to the same schedule as when administered as monotherapy (i.e., as a single agent, not in combination with other agents). In other cases, the dose and / or dosing schedule of one or more agents can be different from the amounts and schedules used in monotherapy.

[0056] When capesicitinib and venetoclax are administered in combination, they can act synergistically. For example, when used alone, both capesicitinib and venetoclax have activity against DLBCL cell lines. In vitro, when used in combination, their effect is greater than additive.

[0057] When capesicitinib and venetoclax are administered in combination using their respective monotherapy doses and dosing schedules, mouse models have shown a likelihood of weight loss. For example, mice bearing xenograft tumors (e.g., DLBCL xenograft tumors) experience body weight loss (BWL) when treated with capesicitinib and venetoclax at their respective monotherapy doses and with a short (e.g., 15-minute) delay between the respective doses.

[0058] Surprisingly, such weight loss can be mitigated or eliminated by changing the dose and / or schedule of venetoclax. In addition, weight loss can be mitigated or eliminated without changing the dose and / or schedule of capesicitinib. Furthermore, weight loss can be mitigated or eliminated while maintaining efficacy.

[0059] When administered as monotherapy, capesicitinib can be administered intermittently, for example, on four days in a seven-day dosing cycle. For example, 50 mg to 900 mg of capesicitinib can be administered twice daily on the first, second, third, and fourth days of the first seven-day dosing cycle. In some embodiments, 300 mg to 700 mg of capesicitinib can be administered twice daily on the first, second, third, and fourth days of the first seven-day dosing cycle. For example, 50 mg to 900 mg of capesicitinib can be administered twice daily on the first and second days of the first seven-day dosing cycle. In some embodiments, 300 mg to 700 mg of capesicitinib can be administered twice daily on the first, second, third, and fourth days of the first seven-day dosing cycle.

[0060] In some embodiments, the dosing cycle is 7 days, but there is a drug holiday during the fourth cycle (i.e., capmatinib is not dosed during the last week of the 4-week period). Thus, in some embodiments, capmatinib is dosed for 4 days within three weeks, with a 3-day drug-free period, and is not dosed during the fourth week; in other words, capmatinib is dosed on the first, second, third, fourth, eighth, ninth, tenth, eleventh, fifteenth, sixteenth, seventeenth, and eighteenth days of a 28-day dosing cycle. In some embodiments, capmatinib is dosed for 2 days within three weeks, with a 5-day drug-free period, and is not dosed during the fourth week; in other words, capmatinib is dosed on the first, second, eighth, ninth, fifteenth, and sixteenth days of a 28-day dosing cycle. Other dosing schedules and doses of capmatinib may be used.

[0061] In some embodiments, capmatinib is administered to a subject according to an intermittent dosing schedule. Administering capmatinib according to an intermittent dosing schedule may, for example, have greater efficacy and / or tolerability than a continuous dosing schedule. In one aspect, capmatinib is administered intermittently according to a 1-day dosing / 6-day drug-free schedule (i.e., capmatinib is administered for one day, followed by a six-day holiday). In another aspect, capmatinib is administered intermittently according to a 2-day dosing / 5-day drug-free schedule (i.e., capmatinib is administered for two days, followed by a five-day holiday). In another aspect, capmatinib is administered intermittently according to a 3-day dosing / 4-day drug-free schedule (i.e., capmatinib is administered for three days, followed by a four-day holiday). In another aspect, capmatinib is administered intermittently according to a 4-day dosing / 3-day drug-free schedule (i.e., capmatinib is administered for four days, followed by a three-day holiday). In another aspect, capmatinib is administered intermittently according to a 5-day dosing / 2-day drug-free schedule (i.e., capmatinib is administered for five days, followed by a two-day holiday). In another aspect, capmatinib is administered intermittently according to a 6-day dosing / 1-day drug-free schedule (i.e., capmatinib is administered for six days, followed by a one-day holiday).

[0062] The dosing cycle of such embodiments is then repeated as long as it is tolerable and beneficial for the subject. In some embodiments, the dosing cycle is 7 days. In some embodiments, the dosing cycle is 28 days.

[0063] In some embodiments, capmatinib is administered twice daily (BID) on an intermittent dosing schedule. In one aspect, capmatinib is administered twice daily at a dose of about 50 mg to about 900 mg on an intermittent dosing schedule. In another aspect, capmatinib is administered twice daily at a dose of about 150 mg to about 750 mg on an intermittent dosing schedule. In another aspect, capmatinib is administered twice daily at a dose of about 200 mg to about 700 mg on an intermittent dosing schedule. In another aspect, capmatinib is administered twice daily at a dose of about 225 mg to about 675 mg on an intermittent dosing schedule. In another aspect, capmatinib is administered twice daily at a dose of about 250 mg to about 650 mg on an intermittent dosing schedule. In another aspect, capmatinib is administered twice daily at a dose of about 300 mg to about 625 mg on an intermittent dosing schedule. In another aspect, capmatinib is administered twice daily at a dose of about 200 mg to about 300 mg on an intermittent dosing schedule. In another aspect, capmatinib is administered twice daily at a dose of about 300 mg to about 400 mg on an intermittent dosing schedule. In another aspect, capmatinib is administered twice daily at a dose of about 400 mg to about 500 mg on an intermittent dosing schedule. In another aspect, capmatinib is administered twice daily at a dose of about 500 mg to about 600 mg on an intermittent dosing schedule. In another aspect, capmatinib is administered twice daily at a dose of about 600 mg to about 700 mg on an intermittent dosing schedule. In another aspect, capmatinib is administered twice daily at a dose of about 700 mg to about 800 mg on an intermittent dosing schedule. In another aspect, capmatinib is administered twice daily at a dose of about 160 mg on an intermittent dosing schedule. In another aspect, capmatinib is administered twice daily at a dose of about 200 mg on an intermittent dosing schedule. In another aspect, capmatinib is administered twice daily at a dose of about 240 mg on an intermittent dosing schedule. In another aspect, capmatinib is administered twice daily at a dose of about 280 mg on an intermittent dosing schedule. In another aspect, capmatinib is administered twice daily at a dose of about 320 mg on an intermittent dosing schedule. In another aspect, capmatinib is administered twice daily at a dose of about 360 mg on an intermittent dosing schedule. In another aspect, capmatinib is administered twice daily at a dose of about 400 mg on an intermittent dosing schedule. In another aspect, capmatinib is administered twice daily at a dose of about 440 mg on an intermittent dosing schedule. In another aspect, capmatinib is administered twice daily at a dose of about 480 mg on an intermittent dosing schedule. In another aspect, capmatinib is administered twice daily at a dose of about 520 mg on an intermittent dosing schedule. In another aspect, capmatinib is administered twice daily at a dose of about 580 mg on an intermittent dosing schedule. In another aspect, capmatinib is administered twice daily at a dose of about 600 mg on an intermittent dosing schedule.In another aspect, capmatinib is administered twice daily at a dose of about 640 mg under an intermittent dosing schedule. In another aspect, capmatinib is administered twice daily at a dose of about 680 mg under an intermittent dosing schedule. In another aspect, capmatinib is administered twice daily at a dose of about 720 mg under an intermittent dosing schedule. In another aspect, capmatinib is administered twice daily at a dose of about 760 mg under an intermittent dosing schedule. In another aspect, capmatinib is administered twice daily at a dose of about 800 mg under an intermittent dosing schedule.

[0064] When administered as monotherapy, venetoclax can be administered continuously, e.g., for seven days in a seven-day dosing cycle. For example, 20 mg to 400 mg of venetoclax can be administered once daily within a seven-day dosing cycle. In some embodiments, 400 mg of venetoclax can be administered once daily within a seven-day dosing cycle. In some embodiments, an escalating dose of venetoclax (i.e., an escalating dosing schedule) is administered over several dosing cycles to the recommended daily dose. The recommended daily dose can be 400 mg, and the lower doses used in monotherapy are only as part of the escalating schedule. The escalating schedule can be 20 mg daily in the first week, 50 mg daily in the second week, 100 mg daily in the third week, 200 mg daily in the fourth week, and 400 mg daily in the fifth week and above. Additional information can be found in the approved label of venetoclax.

[0065] When administered in combination with venetoclax, capmatinib can be administered intermittently, e.g., for four days in a seven-day dosing cycle or for two days in a seven-day dosing cycle. For example, 50 mg to 900 mg of capmatinib can be administered twice daily on the first, second, third, and fourth days of the first seven-day dosing cycle. In some embodiments, 300 mg to 800 mg of capmatinib can be administered twice daily on the first, second, third, and fourth days of the first seven-day dosing cycle. In some embodiments, 300 mg to 800 mg of capmatinib can be administered twice daily on the first and second days of a seven-day dosing cycle. In some embodiments, capmatinib is administered for three weeks but not in the fourth week. Other dosing schedules and doses can be used.

[0066] When administered in combination with capmatinib, in some embodiments, venetoclax can be administered continuously, e.g., for seven days in a seven-day dosing cycle. For example, 20 mg to 400 mg of venetoclax can be administered once daily within a seven-day dosing cycle. In some embodiments, 400 mg of venetoclax can be administered once daily within a seven-day dosing cycle. In some embodiments, an escalating dose of venetoclax (i.e., an escalating dosing schedule) is administered over several dosing cycles until the recommended daily dose of 400 mg.

[0067] When administered in combination with capesicitinib, in some embodiments, venetoclax can be administered intermittently, e.g., on six days of a seven-day dosing cycle, on five days of a seven-day dosing cycle, on four days of a seven-day dosing cycle, on three days of a seven-day dosing cycle, on two days of a seven-day dosing cycle or on one day of a seven-day dosing cycle. In some embodiments, the dose of venetoclax can be administered on the days when capesicitinib is also administered; in other embodiments, the dose of venetoclax can be administered on the days when capesicitinib is not administered.

[0068] On the days when both capesicitinib and venetoclax are administered, the two agents can be administered together or separately. Administering together can be in the form of a fixed-dose combination (e.g., a single tablet or capsule with both agents), or can be in the form of separate doses administered substantially simultaneously, i.e., with a delay of less than one hour between the administrations of the two agents (simultaneous administration). In some embodiments, venetoclax can be administered at least two hours after capesicitinib or at least four hours after capesicitinib. In other embodiments, capesicitinib can be administered at least two hours after venetoclax or at least four hours after venetoclax.

[0069] In some embodiments, capesicitinib can be administered on four days of a seven-day dosing cycle, and venetoclax can be administered on four days of a seven-day dosing cycle. In some embodiments, the two agents are administered on the same four days, e.g., on the first, second, third, and fourth days of a seven-day dosing cycle. In some embodiments, the two agents are not administered on the same four days, but on different days; e.g., capesicitinib is administered on the first, second, third, and fourth days; and venetoclax is administered on the fourth, fifth, sixth, and seventh days of a seven-day dosing cycle. Other variations are possible.

[0070] In some embodiments, capesicitinib can be administered on two days of a seven-day dosing cycle, and venetoclax can be administered on four days of a seven-day dosing cycle. In some embodiments, the two agents are administered on overlapping days, e.g., on the first and second days of a seven-day dosing cycle. In some embodiments, the two agents are not administered on the same days, but on different days; e.g., capesicitinib is administered on the first and second days; and venetoclax is administered on the third, fourth, fifth, and sixth days of a seven-day dosing cycle. Other variations are possible.

[0071] In some embodiments, capesertinib may be administered on four days of a seven-day dosing cycle, and venetoclax may be administered on three days of a seven-day dosing cycle. In some embodiments, the two agents are administered on the same days; for example, capesertinib is administered on the first, second, third, and fourth days of a seven-day dosing cycle, and venetoclax is administered on the first, second, and third days. In some embodiments, the two agents are not administered on the same days but on different days; for example, capesertinib is administered on the first, second, third, and fourth days; and venetoclax is administered on the fifth, sixth, and seventh days of a seven-day dosing cycle. Other variations are possible.

[0072] In some embodiments, capesertinib may be administered on two days of a seven-day dosing cycle, and venetoclax may be administered on two days of a seven-day dosing cycle. In some embodiments, the two agents are administered on the same two days; for example, on the first and second days of a seven-day dosing cycle. In some embodiments, the two agents are not administered on the same days but on different days; for example, capesertinib is administered on the first and second days; and venetoclax is administered on the third and fourth days of a seven-day dosing cycle. Other variations are possible.

[0073] In some embodiments, capesertinib may be administered on four days of a seven-day dosing cycle, and venetoclax may be administered on two days of a seven-day dosing cycle. In some embodiments, the two agents are administered on the same days; for example, capesertinib is administered on the first, second, third, and fourth days of a seven-day dosing cycle, and venetoclax is administered on the first and second days. In some embodiments, venetoclax may be administered on non-consecutive days; for example, on the first and third days of a seven-day dosing cycle. Other variations are possible.

[0074] In some embodiments, capesertinib may be administered on two days of a seven-day dosing cycle, and venetoclax may be administered on two days of a seven-day dosing cycle. In some embodiments, the two agents are administered on overlapping days; for example, capesertinib is administered on the first and second days of a seven-day dosing cycle, and venetoclax is administered on the first and third days of a seven-day dosing cycle. Other variations are possible.

[0075] In some embodiments, capesertinib may be administered on four days of a seven-day dosing cycle, and venetoclax may be administered on one day of a seven-day dosing cycle. In some embodiments, the two agents are administered on the same day (e.g., capesertinib is administered on the first, second, third, and fourth days of a seven-day dosing cycle, and venetoclax is administered on the first day). In other embodiments, the agents are administered on separate days. Other variations are possible.

[0076] In some embodiments, capesicitinib can be administered on two days of a seven-day dosing cycle, and venetoclax can be administered on one day of a seven-day dosing cycle. In some embodiments, the two agents are administered on the same day (e.g., capesicitinib is administered on the first and second days of a seven-day dosing cycle, and venetoclax is administered on the first day). In other embodiments, the agents are administered on separate days. Other variations are possible.

[0077] In some embodiments, venetoclax can be administered at a recommended daily dose of less than 400 mg. This may be during an escalating dosing schedule according to the approved label, or may be during ongoing treatment after escalation has been completed. For example, the maintenance dose of venetoclax at less than the recommended daily dose can be 20 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, or 350 mg.

[0078] Thus, in some embodiments, 50 mg to 900 mg, or 300 mg to 800 mg of capesicitinib can be administered twice daily on the first, second, third, and fourth days of a seven-day dosing cycle; and a dose of venetoclax at less than the recommended daily dose of 400 mg can be administered once daily within the seven-day dosing cycle.

[0079] In some embodiments, 50 mg to 900 mg, or 300 mg to 800 mg of capesicitinib can be administered twice daily on the first, second, third, and fourth days of a seven-day dosing cycle; and a dose of venetoclax at less than the recommended daily dose of 400 mg can be administered on four days of the seven-day dosing cycle (e.g., on the first, second, third, and fourth days). Other variations are possible.

[0080] In some embodiments, 50 mg to 900 mg, or 300 mg to 800 mg of capesicitinib can be administered twice daily on the first and second days of a seven-day dosing cycle; and a dose of venetoclax at less than the recommended daily dose of 400 mg can be administered on four days of the seven-day dosing cycle (e.g., on the first, second, third, and fourth days). Other variations are possible.

[0081] In some embodiments, 50 mg to 900 mg, or 300 mg to 800 mg of capesicitinib can be administered twice daily on the first, second, third, and fourth days of a seven-day dosing cycle; and a dose of venetoclax at less than the recommended daily dose of 400 mg can be administered on two days of the seven-day dosing cycle (e.g., the first and second days; or the first and third days). Other variations are possible.

[0082] In some embodiments, 50 mg to 900 mg, or 300 mg to 800 mg of capesicitinib can be administered twice daily on the first and second days of a seven-day dosing cycle; and a dose of venetoclax below the recommended daily dose of 400 mg can be administered on two days (e.g., the first and second days; or the first and third days) of a seven-day dosing cycle. Other variations are possible.

[0083] In some embodiments, 50 mg to 900 mg, or 300 mg to 800 mg of capesicitinib can be administered twice daily on the first, second, third, and fourth days of a seven-day dosing cycle; and a dose of venetoclax below the recommended daily dose of 400 mg can be administered on one day (e.g., the first day) of a seven-day dosing cycle. Other variations are possible.

[0084] In some embodiments, 50 mg to 900 mg, or 300 mg to 800 mg of capesicitinib can be administered twice daily on the first and second days of a seven-day dosing cycle; and a dose of venetoclax below the recommended daily dose of 400 mg can be administered on one day (e.g., the first day) of a seven-day dosing cycle. Other variations are possible.

[0085] In some embodiments, treatment with venetoclax is started on an escalating schedule, whereby the patient takes a low dose within the first dosing cycle (e.g., a seven-day dosing cycle) and gradually takes larger doses in subsequent dosing cycles until the recommended daily dose (e.g., 400 mg) is reached. The escalating schedule can be 20 mg daily in week 1, 50 mg daily in week 2, 100 mg daily in week 3, 200 mg daily in week 4, and 400 mg daily in week 5 and above. Additional information can be found in the approved label for venetoclax. When administered in combination with capesicitinib, this escalating schedule can be started before the start of capesicitinib treatment; started together with the start of capesicitinib treatment; or started after the start of capesicitinib treatment.

[0086] In some embodiments, the initial target regimen includes a target dose and schedule for each of capesicitinib and venetoclax. The initial target regimen can be selected by a clinician and customized according to the needs of an individual patient. In some embodiments, the initial target regimen includes administering capesicitinib at 50 mg to 900 mg, or 300 mg to 800 mg, twice daily on the first, second, third, and fourth days of a seven-day dosing cycle; and administering venetoclax at 400 mg daily during the seven-day dosing cycle. In some embodiments, the initial target regimen includes administering capesicitinib at 480 mg twice daily on the first, second, third, and fourth days of a seven-day dosing cycle; and administering venetoclax at 400 mg daily during the seven-day dosing cycle. In some embodiments, the initial target regimen includes administering capesicitinib at 400 mg twice daily on the first, second, third, and fourth days of a seven-day dosing cycle; and administering venetoclax at 400 mg daily during the seven-day dosing cycle. In some embodiments, the initial target regimen includes administering capesicitinib at 640 mg twice daily on the first and second days of a seven-day dosing cycle; and administering venetoclax at 400 mg daily during the seven-day dosing cycle.

[0087] In some cases, patients treated with the initial target regimen may experience adverse side effects, including, for example, weight loss or an undesired change in blood glucose levels. In such cases where adverse side effects are actually observed in the initial target regimen, the initial target regimen can be modified. The modified regimen can be selected to mitigate or eliminate the adverse side effects while maintaining a high level of efficacy. In some embodiments, the initial target regimen is changed with respect to the dose of capesicitinib, the dosing schedule of capesicitinib, or both, without changing the dose or dosing schedule of venetoclax. In some embodiments, the initial target regimen is changed with respect to the dose of venetoclax, the dosing schedule of venetoclax, or both, without changing the dose or dosing schedule of capesicitinib. In some embodiments, the initial target regimen is changed with respect to the dose and / or dosing schedule of venetoclax and the dose and / or dosing schedule of capesicitinib.

[0088] In some embodiments, a modified regimen involving reducing the dose of venetoclax, reducing the dosing frequency of venetoclax, or both, without changing the dose or dosing schedule of capesicitinib can mitigate or eliminate the adverse side effects experienced in the initial target regimen while maintaining a high level of efficacy.

[0089] In some embodiments, modifications to the initial target regimen may include changing the dosing schedule of venetoclax. For example, the dosing schedule may be changed from daily dosing of venetoclax to dosing on six days of a seven-day dosing cycle; dosing on five days of a seven-day dosing cycle; dosing on four days of a seven-day dosing cycle; dosing on three days of a seven-day dosing cycle; dosing on two days of a seven-day dosing cycle; or dosing on one day of a seven-day dosing cycle.

[0090] In some embodiments, the initial target regimen may involve daily dosing of venetoclax within a seven-day dosing cycle, and the modified regimen may involve dosing venetoclax on four days of a seven-day dosing cycle. The modified regimen may involve dosing capesertib on four or two days of a seven-day dosing cycle. The modified regimen may involve dosing capesertib on the first, second, third, and fourth days of a seven-day dosing cycle and dosing venetoclax on the first, second, third, and fourth days of a seven-day dosing cycle. The modified regimen may involve dosing capesertib on the first and second days of a seven-day dosing cycle and dosing venetoclax on the first, second, third, and fourth days of a seven-day dosing cycle.

[0091] In some embodiments, the initial target regimen may involve daily dosing of venetoclax within a seven-day dosing cycle, and the modified regimen may involve dosing venetoclax on two days of a seven-day dosing cycle. The modified regimen may involve dosing capesertib on four or two days of a seven-day dosing cycle. The modified regimen may involve dosing capesertib on the first, second, third, and fourth days of a seven-day dosing cycle and dosing venetoclax on the first and second days, or the first and third days of a seven-day dosing cycle. The modified regimen may involve dosing capesertib on the first and second days of a seven-day dosing cycle and dosing venetoclax on the first and second days, or the first and third days of a seven-day dosing cycle.

[0092] In some embodiments, the initial target regimen may involve daily dosing of venetoclax within a seven-day dosing cycle, and the modified regimen may involve dosing venetoclax on one day of a seven-day dosing cycle. The modified regimen may involve dosing capesertib on four or two days of a seven-day dosing cycle. The modified regimen may involve dosing capesertib on the first, second, third, and fourth days of a seven-day dosing cycle and dosing venetoclax on the first day of a seven-day dosing cycle. The modified regimen may involve dosing capesertib on the first and second days of a seven-day dosing cycle and dosing venetoclax on the first day of a seven-day dosing cycle.

[0093] In some embodiments, modifications to the initial target regimen may include changing the dose of venetoclax. For example, the dose may 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.

[0094] In some embodiments, the modification of the initial target regimen may include changing both the dosing schedule and the dose of venetoclax. For example, the dosing schedule may be changed from daily dosing of venetoclax to dosing on six days in a seven-day dosing cycle; dosing on five days in a seven-day dosing cycle; dosing on four days in a seven-day dosing cycle; dosing on three days in a seven-day dosing cycle; dosing on two days in a seven-day dosing cycle; or dosing on one day in a seven-day dosing cycle; and the dose may 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 within the scope of the combinations described herein.

[0095] The following regimens illustrate combination therapies using capmatinib and venetoclax.

[0096] Exemplary Scheme 1

[0097] Capmatinib is administered on the first, second, third, and fourth days of a seven-day dosing cycle, 480 mg, twice daily, with an optional drug holiday every four weeks; and venetoclax is administered daily at 400 mg. Optionally, on days when both are administered, there is a delay of two hours or more between the administrations of the two agents.

[0098] Exemplary Scheme 2

[0099] Capmatinib is administered on the first, second, third, and fourth days of a seven-day dosing cycle, 480 mg, twice daily, with an optional drug holiday every four weeks; and venetoclax is administered at 400 mg daily on the first, second, third, and fourth days of a seven-day dosing cycle. Optionally, on days when both are administered, there is a delay of two hours or more between the administrations of the two agents.

[0100] Exemplary Scheme 3

[0101] Capmatinib is administered on the first, second, third, and fourth days of a seven-day dosing cycle, 480 mg, twice daily, with an optional drug holiday every four weeks; and venetoclax is administered at 400 mg daily on the first and second days of a seven-day dosing cycle. Optionally, on days when both are administered, there is a delay of two hours or more between the administrations of the two agents.

[0102] Exemplary Scheme 4

[0103] Capacitnib is administered at 480 mg twice daily on the first, second, third, and fourth days of a seven-day dosing cycle, with an optional drug holiday every four weeks; and Venetoclax is administered at 400 mg daily on the first and third days of a seven-day dosing cycle. Optionally, on days when both are administered, there is a delay of two hours or more between the administrations of the two agents.

[0104] Exemplary Scheme 5

[0105] Capacitnib is administered at 480 mg twice daily on the first, second, third, and fourth days of a seven-day dosing cycle, with an optional drug holiday every four weeks; and Venetoclax is administered at 400 mg daily on the first day of a seven-day dosing cycle. Optionally, on days when both are administered, there is a delay of two hours or more between the administrations of the two agents.

[0106] Exemplary Scheme 6

[0107] Capacitnib is administered at 480 mg twice daily on the first, second, third, and fourth days of a seven-day dosing cycle, with an optional drug holiday every four weeks; and Venetoclax is administered at 300 mg daily. Optionally, on days when both are administered, there is a delay of two hours or more between the administrations of the two agents.

[0108] Exemplary Scheme 7

[0109] Capacitnib is administered at 480 mg twice daily on the first, second, third, and fourth days of a seven-day dosing cycle, with an optional drug holiday every four weeks; and Venetoclax is administered at 200 mg daily. Optionally, on days when both are administered, there is a delay of two hours or more between the administrations of the two agents.

[0110] Exemplary Scheme 8

[0111] Capacitnib is administered at 480 mg twice daily on the first, second, third, and fourth days of a seven-day dosing cycle, with an optional drug holiday every four weeks; and Venetoclax is administered at 100 mg daily. Optionally, on days when both are administered, there is a delay of two hours or more between the administrations of the two agents.

[0112] Exemplary Scheme 9

[0113] Capacitnib is administered on the first, second, third, and fourth days of a seven-day dosing cycle, 400 mg twice daily, with an optional drug holiday every four weeks; and Venetoclax is administered at 400 mg daily. Optionally, on days when both are administered, there is a delay of two hours or more between the administrations of the two agents.

[0114] Exemplary Scheme 10

[0115] Capacitnib is administered on the first, second, third, and fourth days of a seven-day dosing cycle, 400 mg twice daily, with an optional drug holiday every four weeks; and Venetoclax is administered at 400 mg daily on the first, second, third, and fourth days of a seven-day dosing cycle. Optionally, on days when both are administered, there is a delay of two hours or more between the administrations of the two agents.

[0116] Exemplary Scheme 11

[0117] Capacitnib is administered on the first, second, third, and fourth days of a seven-day dosing cycle, 400 mg twice daily, with an optional drug holiday every four weeks; and Venetoclax is administered at 400 mg daily on the first and second days of a seven-day dosing cycle. Optionally, on days when both are administered, there is a delay of two hours or more between the administrations of the two agents.

[0118] Exemplary Scheme 12

[0119] Capacitnib is administered on the first, second, third, and fourth days of a seven-day dosing cycle, 400 mg twice daily, with an optional drug holiday every four weeks; and Venetoclax is administered at 400 mg daily on the first and third days of a seven-day dosing cycle. Optionally, on days when both are administered, there is a delay of two hours or more between the administrations of the two agents.

[0120] Exemplary Scheme 13

[0121] Capacitnib is administered on the first, second, third, and fourth days of a seven-day dosing cycle, 400 mg twice daily, with an optional drug holiday every four weeks; and Venetoclax is administered at 400 mg daily on the first day of a seven-day dosing cycle. Optionally, on days when both are administered, there is a delay of two hours or more between the administrations of the two agents.

[0122] Exemplary Scheme 14

[0123] Capacitnib is administered at 400 mg twice daily on the first, second, third, and fourth days of a seven-day dosing cycle, with an optional drug holiday every four weeks; and Venetoclax is administered at 300 mg daily. Optionally, on days when both are administered, there is a delay of two hours or more between the administrations of the two agents.

[0124] Exemplary Scheme 15

[0125] Capacitnib is administered at 400 mg twice daily on the first, second, third, and fourth days of a seven-day dosing cycle, with an optional drug holiday every four weeks; and Venetoclax is administered at 200 mg daily. Optionally, on days when both are administered, there is a delay of two hours or more between the administrations of the two agents.

[0126] Exemplary Scheme 16

[0127] Capacitnib is administered at 400 mg twice daily on the first, second, third, and fourth days of a seven-day dosing cycle, with an optional drug holiday every four weeks; and Venetoclax is administered at 100 mg daily. Optionally, on days when both are administered, there is a delay of two hours or more between the administrations of the two agents.

[0128] Exemplary Scheme 17

[0129] Capacitnib is administered at 640 mg twice daily on the first and second days of a seven-day dosing cycle, with an optional drug holiday every four weeks; and Venetoclax is administered at 400 mg daily. Optionally, on days when both are administered, there is a delay of two hours or more between the administrations of the two agents.

[0130] Exemplary Scheme 18

[0131] Capacitnib is administered at 640 mg twice daily on the first and second days of a seven-day dosing cycle, with an optional drug holiday every four weeks; and Venetoclax is administered at 400 mg on the first, second, third, and fourth days of a seven-day dosing cycle. Optionally, on days when both are administered, there is a delay of two hours or more between the administrations of the two agents.

[0132] Exemplary Scheme 19

[0133] Capacitnib is administered at 640 mg twice daily on the first and second days of a seven-day dosing cycle, with an optional drug holiday every four weeks; and Venetoclax is administered at 400 mg on the first and second days of a seven-day dosing cycle. Optionally, on days when both are administered, there is a delay of two hours or more between the administrations of the two agents.

[0134] Exemplary Scheme 20

[0135] Capacitnib is administered on the first and second days of a seven-day dosing cycle at 640 mg twice daily, with an optional drug holiday every four weeks; and Venetoclax is administered at 400 mg on the first and third days of a seven-day dosing cycle. Optionally, on days when both are administered, there is a delay of two hours or more between the administrations of the two agents.

[0136] Exemplary Scheme 21

[0137] Capacitnib is administered on the first and second days of a seven-day dosing cycle at 640 mg twice daily, with an optional drug holiday every four weeks; and Venetoclax is administered at 400 mg on the first day of a seven-day dosing cycle. Optionally, on days when both are administered, there is a delay of two hours or more between the administrations of the two agents.

[0138] Exemplary Scheme 22

[0139] Capacitnib is administered on the first and second days of a seven-day dosing cycle at 640 mg twice daily, with an optional drug holiday every four weeks; and Venetoclax is administered at 300 mg daily. Optionally, on days when both are administered, there is a delay of two hours or more between the administrations of the two agents.

[0140] Exemplary Scheme 23

[0141] Capacitnib is administered on the first and second days of a seven-day dosing cycle at 640 mg twice daily, with an optional drug holiday every four weeks; and Venetoclax is administered at 200 mg daily. Optionally, on days when both are administered, there is a delay of two hours or more between the administrations of the two agents.

[0142] Exemplary Scheme 24

[0143] Capacitnib is administered on the first and second days of a seven-day dosing cycle at 640 mg twice daily, with an optional drug holiday every four weeks; and Venetoclax is administered at 100 mg daily. Optionally, on days when both are administered, there is a delay of two hours or more between the administrations of the two agents.

[0144] Example

[0145] Abbreviation Explanation BID Twice a day BID 10 / 14 Twice a day, with a 10-hour interval from morning to afternoon and a 14-hour interval from afternoon to morning CR Complete response DLBCL Diffuse large B-cell lymphoma DMSO Dimethyl sulfoxide GCB Germinal center B cell mg / kg Milligram per kilogram mL / kg Milliliter per kilogram PEG Polyethylene glycol PO By mouth (oral administration) QD Once a day SCID Severe combined immunodeficiency SEM Standard error of the mean TGI Tumor growth inhibition

[0146] Example 1: SUDHL4 human GCB-DLBCL tumor cells

[0147] For the following experiment, SUDHL4 human GCB-DLBCL tumor cells (10×10 6 / mouse) were implanted subcutaneously into female CB.17 SCID mice. The mice were randomly grouped, 5 mice per group, and efficacy and tolerance were evaluated based on tumor volume. They were treated with 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 capesicitinib, 100 mg / kg venetoclax, or a combination of capesicitinib and venetoclax. Capesicitinib was formulated in 10% DMSO / 25% Kleptose pH = 5, and venetoclax was formulated in 10% ethanol / 30% PEG 400 / 60% Phosal PG-50. After tumor cell implantation, all agents were administered by oral gavage at a dose volume of 5 ml / kg according to the described schedule. Tumor length and width were measured with calipers, and tumor volume was calculated using the formula (length × width 2 )*π / 6.

[0148] The co-administration of capesicitinib and venetoclax at their respective clinically relevant doses and schedules (capesicitinib 130 mg / kg BID 10 / 14, 4 days on / 3 days off; venetoclax 100 mg / kg QD, in the morning (15 minutes after capesicitinib)) resulted in weight loss ( Figure 1 ) and drug interaction ( Figure 2 and Figure 3 ). The dosing schedule is shown in the table below:

[0149]

[0150] A 4-hour dosing interval between capesicitinib and venetoclax (capesicitinib 130 mg / kg BID 10 / 14, 4 days on / 3 days off; venetoclax 100 mg / kg QD, in the morning (4 hours after capesicitinib)) reduced weight loss ( Figure 4 ) and improved the exposure profile ( Figure 5 and Figure 6 ). However, weight loss ( Figure 7 ) and drug interaction were observed after extended dosing. The dosing schedule is shown in the table below:

[0151]

[0152] Figure 8Shows the venetoclax plasma concentration after the following administrations: venetoclax 100 mg / kg QD monotherapy, and capmatinib 130 mg / kg BID 10 / 14, 4 days on / 3 days off; venetoclax 100 mg / kg QD, in the morning (4 hours after capmatinib).

[0153] The following table describes further dosing schedules and the resulting TGI and maximum mean weight loss.

[0154]

[0155] In Study 1, treatment with capmatinib monotherapy for twenty-two days resulted in 82% TGI, and venetoclax monotherapy resulted in 42% TGI. When the two agents were administered in a simultaneous 4 days on 3 days off schedule, 100% tumor regression (5 / 5 CR) was achieved, but with a significant 13% weight loss. The dosing schedule is shown in the table below:

[0156]

[0157] Figure 9 Shows the resulting weight changes over time. Figure 10 Shows the tumor volume over time for the following administrations: two agents (capmatinib BID 10 / 14, 4 days on / 3 days off × 22 days; venetoclax QD, in the morning (4 hours after capmatinib), 4 days on / 3 days off × 22 days), compared to vehicle and single drugs administered on the same schedule. Weight loss can be controlled by introducing a dosing holiday.

[0158] To minimize weight loss, alternative dosing regimens were investigated. Administering capmatinib and venetoclax sequentially on separate days resulted in 95% TGI, with a maximum mean weight loss of 5%. The dosing schedule is shown in the table below:

[0159]

[0160] Figure 11 Shows the resulting weight changes over time. Figure 12 Shows the tumor volume over time for the following administrations: two agents administered in a sequential dosing schedule (capmatinib BID 10 / 14, 4 days on / 3 days off; venetoclax QD, 4 days off / 3 days on), compared to vehicle and single drugs.

[0161] Reducing the frequency of venetoclax to once or twice weekly, in combination with clinically relevant doses and schedules of capmatinib, resulted in 100% tumor regression, with a minimum weight loss ≤ 5% for either regimen. The dosing schedule is shown in the table below:

[0162]

[0163]

[0164] Figure 13 Shows the weight change caused over time. Figure 14 Shows the tumor volume over time for the following administrations: two agents (capmatinib BID 10 / 14, 4 days on / 3 days off; venetoclax QW or 2QW), comparator vehicle, and single agents.

[0165] In Study 2, capmatinib was administered at 45 mg / kg BID for 28 days, in combination with a clinically relevant dose of venetoclax, which reduced the efficacy in the SUDHL4 xenograft model, resulting in 36% TGI. The dosing schedule is shown in the table below:

[0166]

[0167] Figure 15 Shows the tumor volume of the comparator vehicle over time. Figure 16 Shows the weight change caused over time. The 28-day dosing period is as shown.

[0168] Venetoclax was administered at 30 mg / kg QD, in combination with a clinically relevant dose and schedule of capmatinib, and was well tolerated and achieved 100% tumor regression in the SUDHL4 xenograft model. The dosing schedule is shown in the table below:

[0169]

[0170] Figure 17 Shows the tumor volume of the comparator vehicle over time. Figure 18 Shows the weight change caused over time. The 28-day dosing period is as shown.

[0171] Other embodiments fall within the scope of the appended claims.

Claims

1. A method for treating a B-cell malignancy in a patient in need thereof, the method comprising: Administer to the patient a first amount of capesicitinib 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.

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

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

5. The method according to any one of claims 1 to 3, wherein on days when both capesicitinib and venetoclax are administered, venetoclax is administered at least two hours after capesicitinib.

6. The method according to any one of claims 1 to 5, wherein capesicitinib is administered on four days within a seven-day dosing cycle.

7. The method according to any one of claims 1 to 5, wherein on the first, second, third, and fourth days of a seven-day dosing cycle, capesicitinib is administered twice daily at a dose of 300 mg to 800 mg, optionally twice daily at a dose of about 320 mg, about 400 mg, or about 480 mg.

8. The method according to any one of claims 1 to 5, wherein capesicitinib is administered on two days within a seven-day dosing cycle.

9. The method according to any one of claims 1 to 5, wherein on the first and second days of a seven-day dosing cycle, capesicitinib is administered twice daily at a dose of 300 mg to 800 mg, optionally twice daily at a dose of about 480 mg, about 560 mg, or about 640 mg.

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

11. The method according to any one of claims 1 to 10, wherein venetoclax is administered on seven days within a seven-day dosing cycle.

12. The method according to any one of claims 1 to 10, wherein venetoclax is administered for one, two, three, four, five, or six days within a seven-day dosing cycle.

13. The method according to any one of claims 1 to 10, wherein venetoclax is administered for four days within a seven-day dosing cycle.

14. The method according to any one of claims 1 to 10, wherein venetoclax is administered for three days within a seven-day dosing cycle.

15. The method according to any one of claims 1 to 10, wherein venetoclax is administered for two days within a seven-day dosing cycle.

16. The method according to any one of claims 1 to 10, wherein venetoclax is administered for one day within a seven-day dosing cycle.

17. The method according to any one of claims 1 to 10, wherein venetoclax is administered only on the day when capesicitinib is administered.

18. The method according to any one of claims 1 to 5 and 10, wherein capesertinib is administered on two or four days of a seven-day dosing cycle, and venetoclax is administered on one, two, three, four, five, six, or seven days of a seven-day dosing cycle.

19. The method according to claim 18, wherein venetoclax is administered on one, two, four, or seven days of a seven-day dosing cycle.

20. A method of treating B-cell malignancies in a patient in need thereof, the method comprising: administering to the patient, within a seven-day dosing cycle: a first amount of capesertinib or a pharmaceutically acceptable salt thereof, for two or four days; and a second amount of venetoclax or a pharmaceutically acceptable salt thereof, for seven days; and administering to the patient, within a subsequent seven-day dosing cycle: a first amount of capesertinib or a pharmaceutically acceptable salt thereof, for two or four days; and a second amount of venetoclax or a pharmaceutically acceptable salt thereof, for one, two, three, four, five, or six days; wherein the first amount and the second amount together constitute a therapeutically effective amount.

21. The method according to claim 20, wherein capesertinib is administered on the first, second, third, and fourth days of a seven-day dosing cycle, and venetoclax is administered on the first day and one additional day, two additional days, or three additional days of the seven-day dosing cycle.

22. The method according to claim 20, wherein capesertinib is administered on the first and second days of a seven-day dosing cycle, and venetoclax is administered on the first day and one additional day, two additional days, or three additional days of the seven-day dosing cycle.

23. The method according to any one of claims 20 to 22, wherein venetoclax is administered on the first day and the second or third day of the seven-day dosing cycle.

24. A method of treating B-cell malignancies in a patient in need thereof, the method comprising: administering to the patient, within a seven-day dosing cycle: a first amount of capesertinib or a pharmaceutically acceptable salt thereof, for two or four days; and a second amount of venetoclax or a pharmaceutically acceptable salt thereof, for seven days; and administering to the patient, within a subsequent seven-day dosing cycle: a first amount of capesertinib or a pharmaceutically acceptable salt thereof, for two or four days; and a third amount of venetoclax or a pharmaceutically acceptable salt thereof, for seven days, wherein the third amount is less than the second amount; wherein the first amount and the second amount together constitute a therapeutically effective amount, and wherein the first amount and the third amount together constitute a therapeutically effective amount.

25. A method of treating B-cell malignancies in a patient in need thereof, the method comprising: administering to the patient, within a seven-day dosing cycle: 300 mg to 800 mg of capesertinib, twice daily on the first, second, and optionally on the third and fourth days; and 20 mg to 400 mg of venetoclax, once daily for seven days; administering to the patient, within a subsequent seven-day dosing cycle: 300 mg to 800 mg of capesertinib, twice daily on the first and second days and optionally on the third and fourth days of the subsequent seven-day dosing cycle; and Venetoclax from 20 mg to 400 mg, once daily on the first day of the subsequent seven-day dosing cycle and on one additional day, two additional days, or three additional days.

26. Capmatinib, for use in the method according to any one of the preceding claims.

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

28. A kit, the kit comprising: (i) Capmatinib; and (ii) Instructions for use of capmatinib in the method according to any one of claims 1 to 25.

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

30. Use of the combination of capesertib and venetoclax in the method according to any one of claims 1 to 25, said combination comprising: A first amount of capmatinib or a pharmaceutically acceptable salt thereof, and a second amount of venetoclax or a pharmaceutically acceptable salt thereof; wherein said first amount and said second amount together constitute a therapeutically effective amount; wherein said combination is for simultaneous, separate, or sequential administration of capmatinib and venetoclax.

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

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