Therapeutic combination of acalabrutinib and capasitinib for the treatment of B-cell malignancies

Abstract

The present disclosure generally relates to therapeutic combinations of acalabrutinib and capasitinib, and to corresponding treatment methods, pharmaceutical compositions, and kits.

Description

Technical Field

[0001] The present disclosure generally relates to therapeutic combinations of acalabrutinib and capivasertib, methods of treatment with the combination of acalabrutinib and capivasertib, pharmaceutical compositions comprising acalabrutinib and capivasertib, and kits comprising acalabrutinib and capivasertib. Background Art

[0002] The B cell antigen receptor (BCR) is involved in the pathogenesis of several B cell malignancies, including diffuse large B cell lymphoma, follicular lymphoma, mantle cell lymphoma, and B cell chronic lymphocytic leukemia. Bruton's tyrosine kinase (BTK) is an essential kinase downstream of the BCR signaling complex. Acalabrutinib (also known as ACP-196, chemical name 4-{8-amino-3-[(2S)-1-(but-2-ynyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(pyridin-2-yl)benzamide) is a selective, covalent BTK inhibitor and a pharmaceutical product Active pharmaceutical ingredients. It is FDA-approved for the treatment of adults with relapsed or refractory mantle cell lymphoma, chronic lymphocytic leukemia, and small lymphocytic leukemia, and is currently being evaluated in clinical trials for other indications, including the treatment of Waldenstrom’s macroglobulinemia.

[0003] AKT is a serine / threonine-specific protein kinase that plays a key role in a variety of cellular processes, such as glucose metabolism, apoptosis, cell proliferation, transcription, and cell migration. Mammalian cells express three closely related AKT isoforms, which are encoded by different genes: AKT1 (protein kinase Bα), AKT2 (protein kinase Bβ), and AKT3 (protein kinase Bγ). Capasitinib (also known as AZD5363, 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. Capasitinib is currently being evaluated in clinical studies for use in the treatment of cancers including breast and prostate cancer.

[0004] Non-Hodgkin lymphoma represents a broad spectrum of diseases arising from lymphocytes that are "frozen" at various stages of development. Despite the increased understanding of the biology and genetics of non-Hodgkin lymphoma in recent years, there are few effective or curative therapies for the treatment of relapsed / refractory or aggressive non-Hodgkin lymphoma. Due to the morbidity and mortality associated with non-Hodgkin lymphoma and the few effective treatment options, there is still a large unmet medical need.

[0005] The present disclosure relates to the unexpected discovery that the therapeutic combination of acalabrutinib and capasitinib may provide an effective therapeutic option for the treatment of B-cell malignancies such as non-Hodgkin lymphoma, particularly in the treatment of diffuse large B-cell lymphoma (DLBCL) as described below. Summary of the invention

[0006] In one aspect, the disclosure relates to a therapeutic combination for simultaneous, separate or sequential administration, wherein the combination comprises a compound having Formula I:

[0007]

[0008] or a pharmaceutically acceptable salt thereof, and a compound having formula II:

[0009]

[0010] or a pharmaceutically acceptable salt thereof.

[0011] In another aspect, the disclosure relates to a method of treating a B-cell malignancy in a subject in need thereof, the method comprising administering to the subject a first amount of a compound having Formula I:

[0012]

[0013] or a pharmaceutically acceptable salt thereof, and a second amount of a compound having Formula II:

[0014]

[0015] or a pharmaceutically acceptable salt thereof, wherein the first amount and the second amount together comprise a therapeutically effective amount.

[0016] In another aspect, the disclosure relates to a pharmaceutical composition comprising:

[0017] Compounds having formula I:

[0018]

[0019] or a pharmaceutically acceptable salt thereof;

[0020] Compounds having formula II:

[0021]

[0022] or a pharmaceutically acceptable salt thereof; and

[0023] A pharmaceutically acceptable carrier.

[0024] In another aspect, the disclosure relates to a kit comprising:

[0025] Compounds having formula I:

[0026]

[0027] or a pharmaceutically acceptable salt thereof, and

[0028] Compounds having formula II:

[0029]

[0030] or a pharmaceutically acceptable salt thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 Illustrated is a combined signal heat map (% inhibition of growth signal) of TMD8 cells and OCI-LY10 cells after 72 hours of treatment with acalabrutinib and capasitinib combination.

[0032] Figure 2A and 2B Illustrated are western blots of TMD8 cells and OCI-LY10 cells after 2 or 24 h of treatment with acalabrutinib, capacitinib, or the combination of acalabrutinib and capacitinib, respectively.

[0033] Figure 3 The effects of treatment with acalabrutinib, capasitinib, or the combination of acalabrutinib and capasitinib on tumor volume in the TMD8 human ABC DLBCL xenograft mouse model are described.

[0034] Figure 4 Described are the steady-state drug exposure levels of acalabrutinib and capacitinib following treatment with acalabrutinib, capacitinib, or the combination of acalabrutinib and capacitinib in the TMD8 human ABC DLBCL xenograft mouse model.

[0035] Figure 5 The effects of treatment with acalabrutinib, capasitinib, or the combination of acalabrutinib and capasitinib on body weight in the TMD8 human ABC DLBCL xenograft mouse model are described.

[0036] Figure 6 The effects of treatment with acalabrutinib, capasitinib, or the combination of acalabrutinib and capasitinib on tumor volume in the OCI-ly10 human ABC DLBCL xenograft mouse model are illustrated.

[0037] Figure 7 The effects of treatment with acalabrutinib, capasitinib, or the combination of acalabrutinib and capasitinib on body weight in the OCI-ly10 human ABC-DLBCL xenograft mouse model are described.

[0038] Figure 8 The effect of treatment with acalabrutinib, capasitinib, or the combination of acalabrutinib and capasitinib on the duration of survival in a disseminated TMD8-luc2 human ABC DLBCL xenograft mouse model is described. DETAILED DESCRIPTION

[0039] I. definition

[0040] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0041] The term "combination" may refer to the simultaneous, separate or sequential administration of two or more agents. In one aspect, "combination" may refer to simultaneous administration (e.g., two agents are administered in a single dosage form). On the other hand, "combination" refers to separate administration (e.g., two agents are administered in separate dosage forms, but are administered substantially simultaneously). In another aspect of the invention, "combination" refers to sequential administration (e.g., wherein a first agent is administered, followed by a delay, followed by administration of a second or additional agent). In the case of sequential or separate administration, the delayed administration of the subsequent component should not be too long or too short, so as not to lose the benefit of the combination.

[0042] As used herein, the terms "co-administration," "in combination with," "simultaneously," and "concurrently" include administration of two or more active pharmaceutical ingredients to a subject, and include administration simultaneously in separate compositions, administration at different times in separate compositions, or administration in a composition in which two or more active pharmaceutical ingredients are present.

[0043] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound or combination of compounds as described herein that is sufficient to affect the intended application (including but not limited to disease treatment). The therapeutically effective amount can vary depending on the intended application (in vitro or in vivo) or the subject and disease condition being treated (e.g., the subject's weight, age and gender), the severity of the disease condition, the mode of administration, etc., which can be easily determined by one of ordinary skill in the art. The term also applies to doses that will induce a specific response in target cells (e.g., reducing platelet adhesion and / or cell migration). The specific dose will vary depending on the specific compound selected, the dosage regimen to be followed, whether the compound is administered in combination with other compounds, the time of administration, the tissue to which it is administered, and the physical delivery system that carries the compound.

[0044] The term "therapeutic effect" as used herein includes therapeutic benefit and / or prophylactic benefit. Prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, stopping or reversing the progression of a disease or condition, or any combination thereof.

[0045] The terms "treat, treating, treatment" refer to at least partially alleviating, inhibiting, preventing and / or ameliorating symptoms, disorders, or diseases (such as B cell malignancies). The term "treatment of B cell malignancies" includes both in vitro and in vivo treatments (including in warm-blooded animals (such as humans)). The effective performance of the treatment of B cell malignancies is evaluated in a variety of ways, including but not limited to: inhibiting cancer cell proliferation (including reversing cancer growth); promoting cancer cell death (for example, by promoting apoptosis or another cell death mechanism); improving symptoms; the duration of the therapeutic response; delaying the development of the disease; and prolonging survival. Treatment can also be evaluated with respect to the nature and extent of side effects associated with the treatment. In addition, effectiveness can be evaluated by biomarkers (such as expression levels or phosphorylation levels of proteins known to be associated with specific biological phenomena). Other ways of evaluating effectiveness are known to those skilled in the art.

[0046] The term "QD" means quaque die, once a day, or oncedaily.

[0047] The term "BID" means bis in die, twice a day, or twice daily.

[0048] The term "pharmaceutically acceptable salt" refers to salts derived from various organic and inorganic counterions known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines; substituted amines (including naturally occurring substituted amines); cyclic amines; and basic ion exchange resins. Examples include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine and ethanolamine.

[0049] "Pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and inert ingredients. The use of such pharmaceutically acceptable carriers or pharmaceutically acceptable excipients for active pharmaceutical ingredients is well known in the art. Unless any conventional pharmaceutically acceptable carrier or pharmaceutically acceptable excipient is incompatible with the active pharmaceutical ingredient, its use in the therapeutic compositions of the present invention is contemplated. Other active pharmaceutical ingredients, such as other drugs, may also be incorporated into the compositions and methods.

[0050] When ranges are used herein to describe, for example, dosage amounts, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included.

[0051] The term "about" when referring to a number or a numerical range means that the number or numerical range mentioned is an approximate value within the experimental variability (or within the statistical experimental error), so the number or numerical range can vary. The variation is usually 0% to 15% of the number or numerical range, preferably 0% to 10%, and more preferably 0% to 5%.

[0052] Unless the context requires otherwise, the terms "comprise," "comprises," and "comprising" are used with the clear understanding that they are to be interpreted inclusively and not exclusively, and Applicant intends that each of those words be interpreted accordingly in interpreting this patent, including the claims that follow.

[0053] As used herein, the amount of a compound refers to the amount of the compound present in the free base form.

[0054] The abbreviations listed in Table 1 below have the meanings indicated in the table.

[0055] Table 1

[0056]

[0057]

[0058] For clarity, Table 2 below summarizes the compound identifiers, chemical names, and structures used interchangeably throughout this application with respect to each compound discussed.

[0059] Table 2

[0060]

[0061] II. Therapeutic combinations, treatment methods and uses

[0062] This disclosure relates in part to therapeutic combinations and corresponding methods for treating B-cell malignancies, including non-Hodgkin lymphomas, such as diffuse large B-cell lymphoma. Specifically, this disclosure relates to treatment methods comprising administering acalabrutinib or a pharmaceutically acceptable salt thereof, and a therapeutic combination of capasitinib or a pharmaceutically acceptable salt thereof to a subject in need thereof, particularly a human subject in need thereof, to treat B-cell malignancies.

[0063] It has been found that the therapeutic combination of acalabrutinib or a pharmaceutically acceptable salt thereof, and capasitinib or a pharmaceutically acceptable salt thereof can be more effective than either agent alone in the treatment of B-cell malignancies. In some embodiments, the therapeutic combinations and methods discussed below exhibit synergistic effects that can result in greater efficacy, reduced side effects, the use of less active drug ingredients to achieve a given clinical outcome, or other synergistic effects. Such combinations can provide enhanced efficacy by, for example, promoting cancer cell death, inhibiting cancer growth (e.g., inhibiting tumor volume increase), and / or increasing the duration of response.

[0064] As reflected in the findings described in the examples below, the combination of capasitinib and acalabrutinib has broader and greater activity in diffuse large B-cell lymphoma than either agent alone. Acalabrutinib showed single-agent activity in several diffuse large B-cell lymphoma cell lines, particularly those classified as activated B cell (ABC) subtypes. In contrast, capasitinib showed single-agent activity in several diffuse large B-cell lymphoma cell lines, particularly those classified as germinal center B cell (GCB) subtypes and with PTEN loss. However, the combination of capasitinib and acalabrutinib showed broader and greater activity than either agent alone, for example, in a DLBCL xenograft model using the TMD8 cell line, an activated B cell (ABC) subtype that does not lack PTEN. This activity of the combination cannot be simply explained by the addition of the single-agent activity of capasitinib and acalabrutinib.

[0065] Although the present specification primarily discusses the combination of acalabrutinib and capasitinib, therapeutic combinations and methods of treatment that include administration of other therapeutic agents (triplet combinations, etc.) to further enhance treatment are also within the scope of the present disclosure.

[0066] Thus, in one embodiment, the disclosure relates to a therapeutic combination for simultaneous, separate or sequential administration, wherein the combination comprises a compound having Formula I:

[0067]

[0068] or a pharmaceutically acceptable salt thereof, and a compound having formula II:

[0069]

[0070] or a pharmaceutically acceptable salt thereof.

[0071] The compound of formula (I) is also known by the international nonproprietary name acalabrutinib. International application WO 2013 / 010868 discloses acalabrutinib (Example 6) and describes the synthesis of acalabrutinib. International application number PCT / EP 2019 / 072991 filed on August 28, 2019 further describes the synthesis of acalabrutinib. International application WO 2013 / 010868 and international application PCT / EP 2019 / 072991 are each incorporated by reference in their entirety.

[0072] The compound of formula (II) is also known by the international nonproprietary name Capasitinib. WO 2009 / 047563, incorporated by reference in its entirety, discloses Capasitinib (Example 9) and describes the synthesis of Capasitinib.

[0073] In another embodiment, the disclosure relates to a method of treating a B-cell malignancy in a subject in need thereof, the method comprising administering to the subject a first amount of a compound having Formula I:

[0074]

[0075] or a pharmaceutically acceptable salt thereof, and a second amount of a compound having Formula II:

[0076]

[0077] or a pharmaceutically acceptable salt thereof, wherein the first amount and the second amount together comprise a therapeutically effective amount. In another aspect, the first amount and the second amount together comprise a synergistic amount for treating B cell malignancies.

[0078] In some embodiments, the subject is a mammal. In one aspect, the subject is a companion animal. In another aspect, the subject is a dog, cat, or horse. In a preferred aspect, the subject is a human.

[0079] In some embodiments, acalabrutinib and / or capasitinib are administered in their non-salt form (i.e., free base form). In other embodiments, acalabrutinib and / or capasitinib are administered in their pharmaceutically acceptable salt form. In still other embodiments, one of acalabrutinib and capasitinib is administered in a non-salt form, and the other of acalabrutinib and capasitinib is administered in a pharmaceutically acceptable salt form.

[0080] In another embodiment, the disclosure relates to the use of a combination comprising a compound having Formula I for treating a B-cell malignancy:

[0081]

[0082] or a pharmaceutically acceptable salt thereof, and a compound having formula II:

[0083]

[0084] or a pharmaceutically acceptable salt thereof.

[0085] In another embodiment, the disclosure relates to the use of the following combination in the preparation of a medicament for treating B-cell malignancies, the combination comprising a compound having Formula I:

[0086]

[0087] or a pharmaceutically acceptable salt thereof, and a compound having formula II:

[0088]

[0089] or a pharmaceutically acceptable salt thereof.

[0090] In some embodiments, the B cell malignancy is an aggressive lymphoma.

[0091] In some embodiments, the B cell malignancy is non-Hodgkin's lymphoma.

[0092] In some embodiments, the B cell malignancy is selected from the group consisting of: B cell acute lymphoblastic leukemia, mature B cell acute lymphoblastic leukemia, and diffuse large B cell lymphoma.

[0093] In some embodiments, the B-cell malignancy is selected from the group consisting of mantle cell lymphoma; follicular lymphoma; de novo diffuse large B-cell lymphoma; transformed diffuse large B-cell lymphoma; T-cell / histiocyte-rich large B-cell lymphoma; primary cutaneous diffuse large B-cell lymphoma; primary cutaneous diffuse large B-cell lymphoma of the leg type; Epstein-Barr virus-positive diffuse large B-cell lymphoma; diffuse large B-cell lymphoma associated with chronic inflammation; primary mediastinal large B-cell lymphoma; intravascular large B-cell lymphoma; anaplastic lymphoma kinase-positive (ALK+) large B-cell lymphoma; and high-grade B-cell lymphoma with MYC and BCL2 rearrangement or BCL6 and MYC rearrangement.

[0094] In some embodiments, the B-cell malignancy is selected from the group consisting of: de novo diffuse large B-cell lymphoma; transformed diffuse large B-cell lymphoma; T cell / histiocyte-rich large B-cell lymphoma; primary cutaneous diffuse large B-cell lymphoma; primary cutaneous diffuse large B-cell lymphoma of leg type; Epstein-Barr virus-positive diffuse large B-cell lymphoma; diffuse large B-cell lymphoma associated with chronic inflammation; primary mediastinal large B-cell lymphoma; intravascular large B-cell lymphoma; anaplastic lymphoma kinase-positive (ALK+) large B-cell lymphoma; and high-grade B-cell lymphoma with MYC and BCL2 rearrangement or BCL6 and MYC rearrangement.

[0095] In some embodiments, the B cell malignancy is diffuse large B cell lymphoma. In one aspect, the diffuse large B cell lymphoma is selected from the group consisting of: de novo diffuse large B cell lymphoma, relapsed / refractory diffuse large B cell lymphoma, and transformed diffuse large B cell lymphoma.

[0096] In some embodiments, the diffuse large B-cell lymphoma is de novo diffuse large B-cell lymphoma.

[0097] In some embodiments, the diffuse large B-cell lymphoma is relapsed / refractory diffuse large B-cell lymphoma.

[0098] In some embodiments, the diffuse large B-cell lymphoma is a transformed diffuse large B-cell lymphoma. In one aspect, the transformed diffuse large B-cell lymphoma is Richter syndrome.

[0099] In some embodiments, the diffuse large B-cell lymphoma is selected from the group consisting of: germinal center B-cell diffuse large B-cell lymphoma and activated B-cell diffuse large B-cell lymphoma subtypes. In one aspect, the diffuse large B-cell lymphoma is selected from the group consisting of: relapsed / refractory germinal center B-cell diffuse large B-cell lymphoma and relapsed / refractory activated B-cell diffuse large B-cell lymphoma.

[0100] In some embodiments, the diffuse large B-cell lymphoma is activated B-cell diffuse large B-cell lymphoma. In one aspect, the diffuse large B-cell lymphoma is relapsed / refractory activated B-cell diffuse large B-cell lymphoma.

[0101] The specific B-cell malignancy that the subject suffers from can be diagnosed according to generally accepted clinical practice, for example, see the 2016 guidelines for the classification of lymphoid neoplasms developed by the World Health Organization (WHO), or the National Comprehensive Cancer Network (NCCN) guidelines for the classification of non-Hodgkin lymphomas.

[0102] In some embodiments, the human subject has previously received at least one prior chemoimmunotherapy for a B-cell malignancy. In one aspect, the B-cell malignancy is diffuse large B-cell lymphoma. In another aspect, the prior chemoimmunotherapy includes treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (i.e., R-CHOP).

[0103] III. Combination dose and administration schedule

[0104] The amount of acalabrutinib and capasitinib administered to a subject will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound, and the judgment of the prescribing physician. In the various embodiments described below and throughout this specification, unless otherwise expressly stated, "acalabrutinib" refers to acalabrutinib free base or a pharmaceutically acceptable salt thereof; "capasitinib" refers to capasitinib free base or a pharmaceutically acceptable salt thereof; and the amount of acalabrutinib or capasitinib per dose described is based on the amount of acalabrutinib free base or capasitinib free base, respectively.

[0105] An effective amount of the combination of acalabrutinib and capasitinib can be administered in single or multiple doses simultaneously, separately or sequentially by any acceptable mode of administration for agents with similar efficacy, including rectal, buccal, intranasal and transdermal routes, intraarterial injection, intravenous, parenteral, intramuscular, subcutaneous, oral, topical or as an inhalant. In a preferred embodiment, both acalabrutinib and capasitinib are administered orally to a human subject.

[0106] In some embodiments, acalabrutinib and capasitinib are administered to the subject simultaneously.

[0107] In some embodiments, acalabrutinib and capasitinib are administered separately to the subject.

[0108] In some embodiments, acalabrutinib and capasitinib are administered sequentially to the subject.

[0109] In some embodiments, acalabrutinib is administered before capasitinib is administered during the dosing cycle. In one aspect, acalabrutinib is administered at least 2 hours, at least 4 hours, at least 6 hours, at least 8 hours, at least 12 hours, at least 16 hours, at least 24 hours, or at least 48 hours before capasitinib is administered during the dosing cycle. On the other hand, acalabrutinib is administered no more than 2 hours, no more than 4 hours, no more than 6 hours, no more than 8 hours, no more than 12 hours, no more than 16 hours, no more than 24 hours, or no more than 48 hours before capasitinib is administered during the dosing cycle. On the other hand, acalabrutinib is administered 2 to 4 hours; 4 to 6 hours; 6 to 8 hours; 8 to 12 hours; 12 to 16 hours; 16 to 24 hours; 20 to 28 hours; or 24 to 48 hours before capasitinib is administered during the dosing cycle.

[0110] In some embodiments, capasitinib is administered before acalabrutinib is administered during the dosing cycle. In one aspect, capasitinib is administered at least 2 hours, at least 4 hours, at least 6 hours, at least 8 hours, at least 12 hours, at least 16 hours, at least 24 hours, or at least 48 hours before acalabrutinib is administered during the dosing cycle. On the other hand, capasitinib is administered no more than 2 hours, no more than 4 hours, no more than 6 hours, no more than 8 hours, no more than 12 hours, no more than 16 hours, no more than 24 hours, or no more than 48 hours before acalabrutinib is administered during the dosing cycle. On the other hand, capasitinib is administered 2 to 4 hours; 4 to 6 hours; 6 to 8 hours; 8 to 12 hours; 12 to 16 hours; 16 to 24 hours; 20 to 28 hours; or 24 to 48 hours before acalabrutinib is administered during the dosing cycle.

[0111] A. Acalabrutinib Dosage and Administration

[0112] In combination with capasitinib, acalabrutinib is generally administered at a daily dose of about 50 mg to about 400 mg. In some embodiments, acalabrutinib is administered at a daily dose of about 50 mg to about 350 mg. In one aspect, acalabrutinib is administered at a daily dose of about 50 mg to about 300 mg. On the other hand, acalabrutinib is administered at a daily dose of about 50 mg to about 250 mg. On the other hand, acalabrutinib is administered at a daily dose of about 75 mg to about 225 mg. On the other hand, acalabrutinib is administered at a daily dose of about 100 mg to about 200 mg. On the other hand, acalabrutinib is administered at a daily dose of about 75 mg to about 125 mg. On the other hand, acalabrutinib is administered at a daily dose of about 175 mg to about 225 mg. On the other hand, acalabrutinib is administered at a daily dose of about 100 mg. On the other hand, acalabrutinib is administered at a daily dose of about 200 mg. On the other hand, acalabrutinib is administered at a daily dose of about 400 mg.

[0113] In some embodiments, acalabrutinib is administered to a subject once a day (QD). In one aspect, acalabrutinib is administered once a day at a dosage of about 50 mg to about 400 mg. On the other hand, acalabrutinib is administered once a day at a dosage of about 50 mg to about 350 mg. On the other hand, acalabrutinib is administered once a day at a dosage of about 50 mg to about 300 mg. On the other hand, acalabrutinib is administered once a day at a dosage of about 50 mg to about 250 mg. On the other hand, acalabrutinib is administered once a day at a dosage of about 75 mg to about 225 mg. On the other hand, acalabrutinib is administered once a day at a dosage of about 100 mg to about 200 mg. On the other hand, acalabrutinib is administered once a day at a dosage of about 75 mg to about 125 mg. On the other hand, acalabrutinib is administered once a day at a dosage of about 175 mg to about 225 mg. On the other hand, acalabrutinib is administered once a day at a dosage of about 100 mg. On the other hand, acalabrutinib is administered once a day at a dosage of about 200 mg. In another aspect, acalabrutinib is initially administered at a dose of about 200 mg once daily, and the dose of acalabrutinib is subsequently reduced to a dose of about 100 mg once daily during the dosing cycle.

[0114] In some embodiments, acalabrutinib is administered to a subject twice a day (BID). In one aspect, acalabrutinib is administered twice a day at a dosage of about 25 mg to about 200 mg. On the other hand, acalabrutinib is administered twice a day at a dosage of about 25 mg to about 150 mg. On the other hand, acalabrutinib is administered twice a day at a dosage of about 50 mg to about 125 mg. On the other hand, acalabrutinib is administered twice a day at a dosage of about 90 mg to about 110 mg. On the other hand, acalabrutinib is administered twice a day at a dosage of about 95 mg to about 105 mg. On the other hand, acalabrutinib is administered twice a day at a dosage of about 100 mg. On the other hand, acalabrutinib is initially administered twice a day at a dosage of about 100 mg, and then the acalabrutinib dosage is reduced to a dosage of about 100 mg once a day in the dosing cycle. On the other hand, acalabrutinib is administered twice a day at a dosage of about 200 mg.

[0115] In some embodiments, acalabrutinib is administered according to a continuous dosing schedule. The continuous dosing schedule does not include holidays during the dosing cycle. For example, in a seven-day dosing cycle, acalabrutinib will be administered continuously on the first, second, third, fourth, fifth, sixth, and seventh days. The dosing cycle is then repeated for the desired number of cycles. In one aspect, for example, acalabrutinib is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, 21, 28, 35, 42, 49, or 56 days. In one aspect, the dosing cycle is 28 days. The administration of acalabrutinib and the repetition of the dosing cycle can continue as long as the subject tolerates and benefits.

[0116] In some embodiments, acalabrutinib is administered to a subject on an intermittent dosing schedule. In contrast to a continuous dosing schedule, an intermittent dosing schedule may include dose holidays. For example, intermittent dosing of acalabrutinib over a seven-day dosing cycle may be administered on days one and two, but not on days three, four, five, six, or seven. The dosing cycle is then repeated. This description may be referred to as a 2-day on / 5-day off schedule, where acalabrutinib is administered for two days, followed by a five-day holiday. Similarly, intermittent dosing of acalabrutinib over a seven-day dosing cycle may be administered on days one, two, three, and four, but not on days five, six, or seven. The dosing cycle is then repeated. This description may be referred to as a 4-day on / 3-day off schedule, where acalabrutinib is administered for four days, followed by a three-day holiday.

[0117] B. Capasitinib Dosage and Administration

[0118] In combination with acalabrutinib, capasitinib is generally administered to a subject at a daily dose of about 100 mg to about 1600 mg. In some embodiments, capasitinib is administered at a daily dose of about 150 mg to about 1500 mg. In one aspect, capasitinib is administered at a daily dose of about 200 mg to about 1400 mg. On the other hand, capasitinib is administered at a daily dose of about 300 mg to about 1300 mg. On the other hand, capasitinib is administered at a daily dose of about 400 mg to about 1200 mg. On the other hand, capasitinib is administered at a daily dose of about 500 mg to about 1100 mg. On the other hand, capasitinib is administered at a daily dose of about 600 mg to about 1000 mg.

[0119] In some embodiments, capasitinib is administered to a subject once a day (QD). In one aspect, capasitinib is administered once a day at a dosage of about 100 mg to about 1000 mg. On the other hand, capasitinib is administered once a day at a dosage of about 150 mg to about 900 mg. On the other hand, capasitinib is administered once a day at a dosage of about 200 mg to about 850 mg. On the other hand, capasitinib is administered once a day at a dosage of about 250 mg to about 800 mg. On the other hand, capasitinib is administered once a day at a dosage of about 300 mg to about 750 mg. On the other hand, capasitinib is administered once a day at a dosage of about 350 mg to about 700 mg. On the other hand, capasitinib is administered once a day at a dosage of about 400 mg to about 650 mg.

[0120] In some embodiments, capasitinib is administered to a subject twice a day (BID). In one aspect, capasitinib is administered twice a day at a dosage of about 50 mg to about 900 mg. On the other hand, capasitinib is administered twice a day at a dosage of about 100 mg to about 875 mg. On the other hand, capasitinib is administered twice a day at a dosage of about 200 mg to about 850 mg. On the other hand, capasitinib is administered twice a day at a dosage of about 250 mg to about 825 mg. On the other hand, capasitinib is administered twice a day at a dosage of about 150 mg to about 250 mg. On the other hand, capasitinib is administered twice a day at a dosage of about 250 mg to about 350 mg. On the other hand, capasitinib is administered twice a day at a dosage of about 350 mg to about 450 mg. On the other hand, capasitinib is administered twice a day at a dosage of about 450 mg to about 550 mg. On the other hand, capasitinib is administered twice a day at a dosage of about 550 mg to about 650 mg. On the other hand, capasitinib is administered twice daily at a dose of about 650 mg to about 750 mg. On the other hand, capasitinib is administered twice daily at a dose of about 750 mg to about 850 mg. On the other hand, capasitinib is administered twice daily at a dose of about 160 mg. On the other hand, capasitinib is administered twice daily at a dose of about 200 mg. On the other hand, capasitinib is administered twice daily at a dose of about 240 mg. On the other hand, capasitinib is administered twice daily at a dose of about 280 mg. On the other hand, capasitinib is administered twice daily at a dose of about 320 mg. On the other hand, capasitinib is administered twice daily at a dose of about 360 mg. On the other hand, capasitinib is administered twice daily at a dose of about 400 mg. On the other hand, capasitinib is administered twice daily at a dose of about 440 mg. On the other hand, capasitinib is administered twice daily at a dose of about 480 mg. In another aspect, capasitinib is administered at a dose of about 520 mg twice daily. In another aspect, capasitinib is administered at a dose of about 560 mg twice daily. In another aspect, capasitinib is administered at a dose of about 600 mg twice daily. In another aspect, capasitinib is administered at a dose of about 640 mg twice daily. In another aspect, capasitinib is administered at a dose of about 680 mg twice daily. In another aspect, capasitinib is administered at a dose of about 720 mg twice daily. In another aspect, capasitinib is administered at a dose of about 760 mg twice daily. In another aspect, capasitinib is administered at a dose of about 800 mg twice daily.

[0121] In some embodiments, capasitinib is administered according to a continuous dosing schedule. In one aspect, for example, capasitinib is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, 21, 28, 35, 42, 49, or 56 days. In another aspect, the dosing cycle is 28 days. As long as the subject tolerates and benefits, the administration of capasitinib and the repetition of the dosing cycle can continue.

[0122] In some embodiments, capasitinib is administered once a day (QD) according to a continuous dosing schedule. In one aspect, capasitinib is administered once a day at a dosage of about 100 mg to about 900 mg according to a continuous dosing schedule. On the other hand, capasitinib is administered once a day at a dosage of about 150 mg to about 875 mg according to a continuous dosing schedule. On the other hand, capasitinib is administered once a day at a dosage of about 175 mg to about 850 mg according to a continuous dosing schedule. On the other hand, capasitinib is administered once a day at a dosage of about 200 mg to about 825 mg according to a continuous dosing schedule. On the other hand, capasitinib is administered once a day at a dosage of about 225 mg to about 800 mg according to a continuous dosing schedule. On the other hand, capasitinib is administered once a day at a dosage of about 250 mg to about 750 mg according to a continuous dosing schedule. On the other hand, capasitinib is administered once a day at a dosage of about 275 mg to about 700 mg according to a continuous dosing schedule. In another aspect, capasitinib is administered once daily at a dose of about 300 mg to about 650 mg according to a continuous dosing schedule.

[0123] In some embodiments, capasitinib is administered twice a day (BID) according to a continuous dosing schedule. In one aspect, capasitinib is administered twice a day at a dosage of about 100 mg to about 800 mg according to a continuous dosing schedule. On the other hand, capasitinib is administered twice a day at a dosage of about 150 mg to about 750 mg according to a continuous dosing schedule. On the other hand, capasitinib is administered twice a day at a dosage of about 200 mg to about 700 mg according to a continuous dosing schedule. On the other hand, capasitinib is administered twice a day at a dosage of about 225 mg to about 650 mg according to a continuous dosing schedule. On the other hand, capasitinib is administered twice a day at a dosage of about 250 mg to about 650 mg according to a continuous dosing schedule. On the other hand, capasitinib is administered twice a day at a dosage of about 300 mg to about 600 mg according to a continuous dosing schedule. On the other hand, capasitinib is administered twice a day at a dosage of about 200 mg to about 300 mg according to a continuous dosing schedule. On the other hand, capasitinib is administered twice daily at a dose of about 300 mg to about 400 mg according to a continuous dosing schedule. On the other hand, capasitinib is administered twice daily at a dose of about 400 mg to about 500 mg according to a continuous dosing schedule. On the other hand, capasitinib is administered twice daily at a dose of about 500 mg to about 600 mg according to a continuous dosing schedule. On the other hand, capasitinib is administered twice daily at a dose of about 600 mg to about 700 mg according to a continuous dosing schedule. On the other hand, capasitinib is administered twice daily at a dose of about 700 mg to about 800 mg according to a continuous dosing schedule. On the other hand, capasitinib is administered twice daily at a dose of about 160 mg according to a continuous dosing schedule. On the other hand, capasitinib is administered twice daily at a dose of about 200 mg according to a continuous dosing schedule. On the other hand, capasitinib is administered twice daily at a dose of about 240 mg according to a continuous dosing schedule. On the other hand, capasitinib is administered twice daily at a dose of about 280 mg according to a continuous dosing schedule. In another aspect, capasitinib is administered at a dose of about 320 mg twice daily according to a continuous dosing schedule. In another aspect, capasitinib is administered at a dose of about 360 mg twice daily according to a continuous dosing schedule. In another aspect, capasitinib is administered at a dose of about 400 mg twice daily according to a continuous dosing schedule. In another aspect, capasitinib is administered at a dose of about 440 mg twice daily according to a continuous dosing schedule. In another aspect, capasitinib is administered at a dose of about 480 mg twice daily according to a continuous dosing schedule. In another aspect, capasitinib is administered at a dose of about 520 mg twice daily according to a continuous dosing schedule. In another aspect, capasitinib is administered at a dose of about 580 mg twice daily according to a continuous dosing schedule.In another aspect, capasitinib is administered at a dose of about 600 mg twice daily according to a continuous dosing schedule. In another aspect, capasitinib is administered at a dose of about 640 mg twice daily according to a continuous dosing schedule. In another aspect, capasitinib is administered at a dose of about 680 mg twice daily according to a continuous dosing schedule. In another aspect, capasitinib is administered at a dose of about 720 mg twice daily according to a continuous dosing schedule. In another aspect, capasitinib is administered at a dose of about 760 mg twice daily according to a continuous dosing schedule. In another aspect, capasitinib is administered at a dose of about 800 mg twice daily according to a continuous dosing schedule.

[0124] In certain embodiments, capasitinib is administered to a subject according to an intermittent dosage schedule. For example, compared with a continuous dosing schedule, capasitinib is administered according to an intermittent dosing schedule with greater effectiveness and / or tolerance. In one aspect, capasitinib is administered intermittently with a schedule of giving 1 day / stopping 6 days (i.e., capasitinib is administered for one day, followed by a six-day holiday). On the other hand, capasitinib is administered intermittently with a schedule of giving 2 days / stopping 5 days (i.e., capasitinib is administered for two days, followed by a five-day holiday). On the other hand, capasitinib is administered intermittently with a schedule of giving 3 days / stopping 4 days (i.e., capasitinib is administered for three days, followed by a four-day holiday). On the other hand, capasitinib is administered intermittently with a schedule of giving 4 days / stopping 3 days (i.e., capasitinib is administered for four days, followed by a three-day holiday). On the other hand, capasitinib is administered intermittently with a schedule of giving 5 days / stopping 2 days (i.e., capasitinib is administered for five days, followed by a two-day holiday). In another aspect, capasitinib is administered intermittently on a 6-day on / 1-day off schedule (ie, capasitinib is administered for six days, followed by a day off).

[0125] Then, the dosing cycle of these embodiments is repeated as long as the subject tolerates and benefits. In some embodiments, the dosing cycle is 7 days. In one aspect, the dosing cycle is 14 days. In another aspect, the dosing cycle is 21 days. In another aspect, the dosing cycle is 28 days. In another aspect, the dosing cycle is two months. In another aspect, the dosing cycle is six months. In another aspect, the dosing cycle is one year.

[0126] In some embodiments, the dosing cycle is 28 days, but during the fourth week of the dosing cycle, capasitinib is not co-administered to the subject (ie, there is a capasitinib drug holiday in the last week of the dosing cycle).

[0127] In some embodiments, capasitinib is administered once a day (QD) according to an intermittent dosing schedule. In one aspect, capasitinib is administered once a day at a dosage of about 100 mg to about 900 mg according to an intermittent dosing schedule. On the other hand, capasitinib is administered once a day at a dosage of about 150 mg to about 850 mg according to an intermittent dosing schedule. On the other hand, capasitinib is administered once a day at a dosage of about 175 mg to about 800 mg according to an intermittent dosing schedule. On the other hand, capasitinib is administered once a day at a dosage of about 200 mg to about 750 mg according to an intermittent dosing schedule. On the other hand, capasitinib is administered once a day at a dosage of about 225 mg to about 725 mg according to an intermittent dosing schedule. On the other hand, capasitinib is administered once a day at a dosage of about 250 mg to about 700 mg according to an intermittent dosing schedule. On the other hand, capasitinib is administered once a day at a dosage of about 275 mg to about 675 mg according to an intermittent dosing schedule. In another aspect, capasitinib is administered once daily at a dose of about 300 mg to about 650 mg according to an intermittent dosing schedule.

[0128] In some embodiments, capasitinib is administered twice a day (BID) according to an intermittent dosing schedule. In one aspect, capasitinib is administered twice a day at a dosage of about 100 mg to about 800 mg according to an intermittent dosing schedule. On the other hand, capasitinib is administered twice a day at a dosage of about 150 mg to about 750 mg according to an intermittent dosing schedule. On the other hand, capasitinib is administered twice a day at a dosage of about 200 mg to about 700 mg according to an intermittent dosing schedule. On the other hand, capasitinib is administered twice a day at a dosage of about 225 mg to about 675 mg according to an intermittent dosing schedule. On the other hand, capasitinib is administered twice a day at a dosage of about 250 mg to about 650 mg according to an intermittent dosing schedule. On the other hand, capasitinib is administered twice a day at a dosage of about 300 mg to about 625 mg according to an intermittent dosing schedule. On the other hand, capasitinib is administered twice a day at a dosage of about 200 mg to about 300 mg according to an intermittent dosing schedule. On the other hand, capasitinib is administered twice daily at a dose of about 300 mg to about 400 mg according to an intermittent dosing schedule. On the other hand, capasitinib is administered twice daily at a dose of about 400 mg to about 500 mg according to an intermittent dosing schedule. On the other hand, capasitinib is administered twice daily at a dose of about 500 mg to about 600 mg according to an intermittent dosing schedule. On the other hand, capasitinib is administered twice daily at a dose of about 600 mg to about 700 mg according to an intermittent dosing schedule. On the other hand, capasitinib is administered twice daily at a dose of about 700 mg to about 800 mg according to an intermittent dosing schedule. On the other hand, capasitinib is administered twice daily at a dose of about 160 mg according to an intermittent dosing schedule. On the other hand, capasitinib is administered twice daily at a dose of about 200 mg according to an intermittent dosing schedule. On the other hand, capasitinib is administered twice daily at a dose of about 240 mg according to an intermittent dosing schedule. On the other hand, capasitinib is administered twice daily at a dose of about 280 mg according to an intermittent dosing schedule. In another aspect, capasitinib is administered at a dose of about 320 mg twice daily according to an intermittent dosing schedule. In another aspect, capasitinib is administered at a dose of about 360 mg twice daily according to an intermittent dosing schedule. In another aspect, capasitinib is administered at a dose of about 400 mg twice daily according to an intermittent dosing schedule. In another aspect, capasitinib is administered at a dose of about 440 mg twice daily according to an intermittent dosing schedule. In another aspect, capasitinib is administered at a dose of about 480 mg twice daily according to an intermittent dosing schedule. In another aspect, capasitinib is administered at a dose of about 520 mg twice daily according to an intermittent dosing schedule. In another aspect, capasitinib is administered at a dose of about 580 mg twice daily according to an intermittent dosing schedule.In another aspect, capasitinib is administered at a dose of about 600 mg twice daily according to an intermittent dosing schedule. In another aspect, capasitinib is administered at a dose of about 640 mg twice daily according to an intermittent dosing schedule. In another aspect, capasitinib is administered at a dose of about 680 mg twice daily according to an intermittent dosing schedule. In another aspect, capasitinib is administered at a dose of about 720 mg twice daily according to an intermittent dosing schedule. In another aspect, capasitinib is administered at a dose of about 760 mg twice daily according to an intermittent dosing schedule. In another aspect, capasitinib is administered at a dose of about 800 mg twice daily according to an intermittent dosing schedule.

[0129] C. Illustrative Examples

[0130] In some embodiments, acalabrutinib and capasitinib are both administered continuously during the dosing cycle. In one aspect, acalabrutinib and capasitinib are both administered orally continuously during the dosing cycle. On the other hand, acalabrutinib and capasitinib are both administered orally continuously during the dosing cycle, and the amount of acalabrutinib administered twice a day is about 75 mg to about 125 mg. On the other hand, acalabrutinib and capasitinib are both administered orally continuously during the dosing cycle, and the amount of acalabrutinib administered twice a day is about 100 mg. On the other hand, acalabrutinib and capasitinib are both administered orally continuously during the dosing cycle, and the amount of acalabrutinib initially administered twice a day at the beginning of the dosing cycle is about 100 mg, and then during the dosing cycle, the amount of acalabrutinib administered once a day is reduced to a dosage of about 100 mg.

[0131] In some embodiments, acalabrutinib is administered continuously during the dosing cycle, while capasitinib is administered intermittently during the dosing cycle. In one aspect, acalabrutinib is administered orally continuously during the dosing cycle, while capasitinib is administered orally intermittently during the dosing cycle. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capasitinib is administered orally intermittently during the dosing cycle, and the amount of acalabrutinib administered twice a day is about 75 mg to about 125 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capasitinib is administered orally intermittently during the dosing cycle, and the amount of acalabrutinib administered twice a day is about 100 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capasitinib is administered orally intermittently during the dosing cycle, and the amount of acalabrutinib administered twice a day at the beginning of the dosing cycle is about 100 mg, and then during the dosing cycle, the amount of acalabrutinib administered once a day is reduced to a dose of about 100 mg.

[0132] In some embodiments, acalabrutinib is administered continuously during the dosing cycle, while capasitinib is administered intermittently during the dosing cycle with a schedule of giving 1 day / stopping 6 days. In one aspect, acalabrutinib is administered orally twice a day continuously in an amount of about 75 mg to about 125 mg during the dosing cycle, while capasitinib is administered orally intermittently in a schedule of giving 1 day / stopping 6 days during the dosing cycle. On the other hand, acalabrutinib is administered orally twice a day continuously in an amount of about 100 mg during the dosing cycle, while capasitinib is administered orally intermittently in a schedule of giving 1 day / stopping 6 days during the dosing cycle. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capasitinib is administered orally intermittently in a schedule of giving 1 day / stopping 6 days during the dosing cycle, and the amount of acalabrutinib initially administered twice a day at the beginning of the dosing cycle is about 100 mg, and then during the dosing cycle, the amount of acalabrutinib administered once a day is reduced to a dose of about 100 mg.

[0133] In some embodiments, acalabrutinib is administered continuously during the dosing cycle, while capasitinib is administered intermittently during the dosing cycle with a schedule of giving 2 days / stopping 5 days. In one aspect, acalabrutinib is administered orally twice a day continuously in an amount of about 75 mg to about 125 mg during the dosing cycle, while capasitinib is administered orally intermittently in a schedule of giving 2 days / stopping 5 days during the dosing cycle. On the other hand, acalabrutinib is administered orally twice a day continuously in an amount of about 100 mg during the dosing cycle, while capasitinib is administered orally intermittently in a schedule of giving 2 days / stopping 5 days during the dosing cycle. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capasitinib is administered orally intermittently in a schedule of giving 2 days / stopping 5 days during the dosing cycle, and the amount of acalabrutinib administered twice a day at the beginning of the dosing cycle is about 100 mg, and then during the dosing cycle, the amount of acalabrutinib administered once a day is reduced to a dose of about 100 mg.

[0134] In some embodiments, acalabrutinib is administered continuously during the dosing cycle, while capasitinib is administered intermittently during the dosing cycle with a schedule of 3 days / 4 days of administration. In one aspect, acalabrutinib is administered orally twice a day continuously in an amount of about 75 mg to about 125 mg during the dosing cycle, while capasitinib is administered orally intermittently in a schedule of 3 days / 4 days of administration during the dosing cycle. On the other hand, acalabrutinib is administered orally twice a day continuously in an amount of 100 mg during the dosing cycle, while capasitinib is administered orally intermittently in a schedule of 3 days / 4 days of administration during the dosing cycle. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capasitinib is administered orally intermittently in a schedule of 3 days / 4 days of administration during the dosing cycle, and the amount of acalabrutinib administered twice a day at the beginning of the dosing cycle is about 100 mg, and then during the dosing cycle, the amount of acalabrutinib administered once a day is reduced to a dose of about 100 mg.

[0135] In some embodiments, acalabrutinib is administered continuously during the dosing cycle, while capasitinib is administered intermittently during the dosing cycle with a schedule of 4 days / 3 days of administration. In one aspect, acalabrutinib is administered orally twice a day continuously in an amount of about 75 mg to about 125 mg during the dosing cycle, while capasitinib is administered orally intermittently in a schedule of 4 days / 3 days of administration during the dosing cycle. On the other hand, acalabrutinib is administered orally twice a day continuously in an amount of 100 mg during the dosing cycle, while capasitinib is administered orally intermittently in a schedule of 4 days / 3 days of administration during the dosing cycle. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capasitinib is administered orally intermittently in a schedule of 4 days / 3 days of administration during the dosing cycle, and the amount of acalabrutinib administered twice a day at the beginning of the dosing cycle is about 100 mg, and then during the dosing cycle, the amount of acalabrutinib administered once a day is reduced to a dose of about 100 mg.

[0136] In some embodiments, acalabrutinib is administered continuously during the dosing cycle, while capasitinib is administered intermittently during the dosing cycle with a schedule of giving 5 days / stopping 2 days. In one aspect, acalabrutinib is administered orally twice a day continuously in an amount of about 75 mg to about 125 mg during the dosing cycle, while capasitinib is administered orally intermittently in a schedule of giving 5 days / stopping 2 days during the dosing cycle. On the other hand, acalabrutinib is administered orally twice a day continuously in an amount of 100 mg during the dosing cycle, while capasitinib is administered orally intermittently in a schedule of giving 5 days / stopping 2 days during the dosing cycle. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capasitinib is administered orally intermittently in a schedule of giving 5 days / stopping 2 days during the dosing cycle, and the amount of acalabrutinib initially administered twice a day at the beginning of the dosing cycle is about 100 mg, and then during the dosing cycle, the amount of acalabrutinib administered once a day is reduced to a dose of about 100 mg.

[0137] In some embodiments, acalabrutinib is administered continuously during the dosing cycle, while capasitinib is administered intermittently during the dosing cycle on a schedule of 6 days / 1 day off. In one aspect, acalabrutinib is administered orally twice a day continuously in an amount of about 75 mg to about 125 mg during the dosing cycle, while capasitinib is administered orally intermittently in a schedule of 6 days / 1 day off during the dosing cycle. On the other hand, acalabrutinib is administered orally twice a day continuously in an amount of about 100 mg during the dosing cycle, while capasitinib is administered orally intermittently in a schedule of 6 days / 1 day off during the dosing cycle. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capasitinib is administered orally intermittently in a schedule of 6 days / 1 day off during the dosing cycle, and the amount of acalabrutinib initially administered twice a day at the beginning of the dosing cycle is about mg, and then during the dosing cycle, the amount of acalabrutinib administered once a day is reduced to a dose of about 100 mg.

[0138] In some embodiments, both acalabrutinib and capasitinib are administered orally continuously during a dosing cycle, and the amount of acalabrutinib administered daily is about 75 mg to about 225 mg, while the amount of capasitinib administered daily is about 100 mg to about 1600 mg. In one aspect, both acalabrutinib and capasitinib are administered orally continuously during a dosing cycle, and acalabrutinib is administered once a day in an amount of about 75 mg to about 225 mg, while capasitinib is administered once a day in an amount of about 100 mg to about 900 mg. On the other hand, both acalabrutinib and capasitinib are administered orally continuously during a dosing cycle, and acalabrutinib is administered twice a day in an amount of about 75 mg to about 125 mg, while capasitinib is administered twice a day in an amount of about 150 mg to about 850 mg. On the other hand, both acalabrutinib and capasitinib are administered orally continuously during a dosing cycle, with acalabrutinib administered twice daily in an amount of about 100 mg, and capasitinib administered twice daily in an amount of about 200 mg to about 800 mg. On the other hand, both acalabrutinib and capasitinib are administered orally continuously during a dosing cycle, with acalabrutinib initially administered twice daily in an amount of about 100 mg, capasitinib administered twice daily in an amount of about 200 mg to about 800 mg at the beginning of the dosing cycle, and then the amount of acalabrutinib administered once daily is reduced to an amount of about 100 mg during the dosing cycle.

[0139] In some embodiments, acalabrutinib is administered continuously during the dosing cycle, while capasitinib is administered intermittently during the dosing cycle, the amount of acalabrutinib administered daily is about 75 mg to about 225 mg, and the amount of capasitinib administered on each day of administration is about 100 mg to about 1600 mg. In one aspect, acalabrutinib is administered continuously during the dosing cycle, while capasitinib is administered intermittently during the dosing cycle, and on each day of administration, acalabrutinib is administered once a day in an amount of about 75 mg to about 225 mg, while capasitinib is administered once a day in an amount of about 100 mg to about 900 mg. On the other hand, acalabrutinib is administered continuously during the dosing cycle, while capasitinib is administered intermittently during the dosing cycle, and on each day of administration, acalabrutinib is administered twice a day in an amount of about 75 mg to about 125 mg, while capasitinib is administered twice a day in an amount of about 150 mg to about 850 mg. On the other hand, acalabrutinib is administered continuously during the dosing cycle, while capasitinib is administered intermittently during the dosing cycle, and on each day of administration, acalabrutinib is administered twice daily in an amount of about 100 mg, while capasitinib is administered twice daily in an amount of about 200 mg to about 800 mg. On the other hand, acalabrutinib is administered continuously during the dosing cycle, while capasitinib is administered intermittently during the dosing cycle, and on each day of administration, acalabrutinib is initially administered twice daily in an amount of about 100 mg at the beginning of the dosing cycle, capasitinib is administered twice daily in an amount of about 200 mg to about 800 mg, and then the amount of acalabrutinib administered once daily is reduced to an amount of about 100 mg during the dosing cycle.

[0140] In some embodiments, acalabrutinib is administered continuously during the dosing cycle, while capasitinib is administered intermittently during the dosing cycle on a 2-day / 5-day schedule, the amount of acalabrutinib administered daily is about 75 mg to about 225 mg, and the amount of capasitinib administered on each day of administration is about 100 mg to about 1600 mg. In one aspect, acalabrutinib is administered orally continuously during the dosing cycle, while capasitinib is administered orally intermittently during the dosing cycle on a 2-day / 5-day schedule, on each day of administration, acalabrutinib is administered once a day in an amount of about 75 mg to about 225 mg, and capasitinib is administered once a day in an amount of about 100 mg to about 900 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capasitinib is administered orally intermittently during the dosing cycle on a schedule of 2 days on / 5 days off, with acalabrutinib administered twice daily in an amount of about 75 mg to about 125 mg and capasitinib administered twice daily in an amount of about 150 mg to about 850 mg on each day of administration.

[0141] In some embodiments, acalabrutinib is administered orally continuously during a dosing cycle, while capasitinib is administered orally intermittently during a dosing cycle on a 2-day on / 5-day off schedule, and on each day of administration, acalabrutinib is administered twice a day in an amount of about 100 mg, while capasitinib is administered twice a day in an amount of about 200 mg to about 800 mg. In one aspect, acalabrutinib is administered orally continuously during a dosing cycle, while capasitinib is administered orally intermittently during a dosing cycle on a 2-day on / 5-day off schedule, and on each day of administration, acalabrutinib is initially administered twice a day in an amount of about 100 mg at the beginning of the dosing cycle, capasitinib is administered twice a day in an amount of about 200 mg to about 800 mg, and then during the dosing cycle, the amount of acalabrutinib administered once a day is reduced to an amount of about 100 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capasitinib is administered orally intermittently during the dosing cycle on a 2-day on / 5-day off schedule, and on each day of administration, acalabrutinib is administered twice daily in an amount of about 100 mg, while capasitinib is administered twice daily in an amount of about 250 mg to about 350 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capasitinib is administered orally intermittently during the dosing cycle on a 2-day on / 5-day off schedule, and on each day of administration, acalabrutinib is administered twice daily in an amount of about 100 mg, while capasitinib is administered twice daily in an amount of about 350 mg to about 450 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capasitinib is administered orally intermittently during the dosing cycle on a 2-day on / 5-day off schedule, and on each day of administration, acalabrutinib is administered twice daily in an amount of about 100 mg, while capasitinib is administered twice daily in an amount of about 450 mg to about 550 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capasitinib is administered orally intermittently during the dosing cycle on a 2-day on / 5-day off schedule, and on each day of administration, acalabrutinib is administered twice daily in an amount of about 100 mg, while capasitinib is administered twice daily in an amount of about 550 mg to about 650 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capasitinib is administered orally intermittently during the dosing cycle on a 2-day on / 5-day off schedule, and on each day of administration, acalabrutinib is administered twice daily in an amount of about 100 mg, while capasitinib is administered twice daily in an amount of about 650 mg to about 750 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capasitinib is administered orally intermittently during the dosing cycle on a schedule of 2 days on / 5 days off, with acalabrutinib administered twice daily in an amount of about 100 mg and capasitinib administered twice daily in an amount of about 750 mg to about 850 mg on each day of administration.On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capasitinib is administered orally intermittently during the dosing cycle on a 2-day on / 5-day off schedule, and on each day of administration, acalabrutinib is administered twice daily in an amount of about 100 mg, while capasitinib is administered twice daily in an amount of about 320 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capasitinib is administered orally intermittently during the dosing cycle on a 2-day on / 5-day off schedule, and on each day of administration, acalabrutinib is administered twice daily in an amount of about 100 mg, while capasitinib is administered twice daily in an amount of about 400 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capasitinib is administered orally intermittently during the dosing cycle on a 2-day on / 5-day off schedule, and on each day of administration, acalabrutinib is administered twice daily in an amount of about 100 mg, while capasitinib is administered twice daily in an amount of about 480 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capasitinib is administered orally intermittently during the dosing cycle on a 2-day on / 5-day off schedule, and on each day of administration, acalabrutinib is administered twice daily in an amount of about 100 mg, while capasitinib is administered twice daily in an amount of about 560 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capasitinib is administered orally intermittently during the dosing cycle on a 2-day on / 5-day off schedule, and on each day of administration, acalabrutinib is administered twice daily in an amount of about 100 mg, while capasitinib is administered twice daily in an amount of about 640 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capasitinib is administered orally intermittently during the dosing cycle on a 2-day on / 5-day off schedule, and on each day of administration, acalabrutinib is administered twice daily in an amount of about 100 mg, while capasitinib is administered twice daily in an amount of about 800 mg.

[0142] In some embodiments, acalabrutinib is administered continuously during the dosing cycle, while capasitinib is administered intermittently during the dosing cycle on a 4-day / 3-day schedule, the amount of acalabrutinib administered daily is about 75 mg to about 225 mg, and the amount of capasitinib administered on each day of administration is about 100 mg to about 1600 mg. In one aspect, acalabrutinib is administered orally continuously during the dosing cycle, while capasitinib is administered orally intermittently during the dosing cycle on a 4-day / 3-day schedule, on each day of administration, acalabrutinib is administered once a day in an amount of about 75 mg to about 225 mg, and capasitinib is administered once a day in an amount of about 100 mg to about 900 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capasitinib is administered orally intermittently during the dosing cycle on a schedule of 4 days on / 3 days off, with acalabrutinib administered twice daily in an amount of about 75 mg to about 125 mg and capasitinib administered twice daily in an amount of about 150 mg to about 850 mg on each day of administration.

[0143] In some embodiments, acalabrutinib is administered orally continuously during the dosing cycle, while capasitinib is administered orally intermittently during the dosing cycle on a schedule of 4 days on / 3 days off, and on each day of administration, acalabrutinib is administered twice a day in an amount of about 100 mg, while capasitinib is administered twice a day in an amount of about 200 mg to about 800 mg. In one aspect, acalabrutinib is administered orally continuously during the dosing cycle, while capasitinib is administered orally intermittently during the dosing cycle on a schedule of 4 days on / 3 days off, and on each day of administration, acalabrutinib is administered twice a day in an amount of about 100 mg, capasitinib is administered twice a day in an amount of about 200 mg to about 750 mg, and then during the dosing cycle, the amount of acalabrutinib administered once a day is reduced to an amount of about 100 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capasitinib is administered orally intermittently during the dosing cycle on a 4-day on / 3-day off schedule, and on each day of administration, acalabrutinib is administered twice daily in an amount of about 100 mg, while capasitinib is administered twice daily in an amount of about 200 mg to about 700 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capasitinib is administered orally intermittently during the dosing cycle on a 4-day on / 3-day off schedule, and on each day of administration, acalabrutinib is administered twice daily in an amount of about 100 mg, while capasitinib is administered twice daily in an amount of about 250 mg to about 350 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capasitinib is administered orally intermittently during the dosing cycle on a 4-day on / 3-day off schedule, and on each day of administration, acalabrutinib is administered twice daily in an amount of about 100 mg, while capasitinib is administered twice daily in an amount of about 350 mg to about 450 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capasitinib is administered orally intermittently during the dosing cycle on a 4-day on / 3-day off schedule, and on each day of administration, acalabrutinib is administered twice daily in an amount of about 100 mg, while capasitinib is administered twice daily in an amount of about 450 mg to about 550 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capasitinib is administered orally intermittently during the dosing cycle on a 4-day on / 3-day off schedule, and on each day of administration, acalabrutinib is administered twice daily in an amount of about 100 mg, while capasitinib is administered twice daily in an amount of about 550 mg to about 650 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capasitinib is administered orally intermittently during the dosing cycle on a schedule of 4 days on / 3 days off, with acalabrutinib administered twice daily in an amount of about 100 mg and capasitinib administered twice daily in an amount of about 650 mg to about 750 mg on each day of administration.On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capasitinib is administered orally intermittently during the dosing cycle on a 4-day on / 3-day off schedule, and on each day of administration, acalabrutinib is administered twice daily in an amount of about 100 mg, while capasitinib is administered twice daily in an amount of about 200 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capasitinib is administered orally intermittently during the dosing cycle on a 4-day on / 3-day off schedule, and on each day of administration, acalabrutinib is administered twice daily in an amount of about 100 mg, while capasitinib is administered twice daily in an amount of about 280 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capasitinib is administered orally intermittently during the dosing cycle on a 4-day on / 3-day off schedule, and on each day of administration, acalabrutinib is administered twice daily in an amount of about 100 mg, while capasitinib is administered twice daily in an amount of about 320 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capasitinib is administered orally intermittently during the dosing cycle on a 4-day on / 3-day off schedule, and on each day of administration, acalabrutinib is administered twice daily in an amount of about 100 mg, while capasitinib is administered twice daily in an amount of about 360 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capasitinib is administered orally intermittently during the dosing cycle on a 4-day on / 3-day off schedule, and on each day of administration, acalabrutinib is administered twice daily in an amount of about 100 mg, while capasitinib is administered twice daily in an amount of about 400 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capasitinib is administered orally intermittently during the dosing cycle on a 4-day on / 3-day off schedule, and on each day of administration, acalabrutinib is administered twice daily in an amount of about 100 mg, while capasitinib is administered twice daily in an amount of about 480 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capasitinib is administered orally intermittently during the dosing cycle on a schedule of 4 days on / 3 days off, with acalabrutinib administered at about 100 mg twice a day and capasitinib administered at about 640 mg twice a day on each day of administration.

[0144] IV. Pharmaceutical composition

[0145] The present disclosure further relates in part to pharmaceutical compositions comprising acalabrutinib, capasitinib, and a pharmaceutically acceptable carrier.

[0146] In some embodiments, the pharmaceutical composition comprises:

[0147] Compounds having formula I:

[0148]

[0149] or a pharmaceutically acceptable salt thereof;

[0150] Compounds having formula II:

[0151]

[0152] or a pharmaceutically acceptable salt thereof; and

[0153] A pharmaceutically acceptable carrier.

[0154] In one aspect, the composition comprises acalabrutinib and capasitinib in their free base form. In another aspect, the composition comprises acalabrutinib and capasitinib in their pharmaceutically acceptable salt form. In another aspect, the combination comprises one of acalabrutinib and capasitinib in free base form and the other of acalabrutinib and capasitinib in pharmaceutically acceptable salt form.

[0155] The pharmaceutical composition is generally formulated to provide a therapeutically effective amount of the combination described in this specification. The pharmaceutical composition may also include one or more pharmaceutically acceptable excipients, carriers, diluents and / or fillers. According to conventional pharmaceutical formulation techniques, both acalabrutinib and capasitinib as active ingredients can be combined with a pharmaceutical carrier as a close mixture. Depending on the form of the formulation required for administration, the carrier can be in various forms.

[0156] In some embodiments, the pharmaceutical composition is suitable for oral administration. Pharmaceutical compositions suitable for oral administration can be presented as unit dosage forms, such as tablets, capsules, liquids or aerosols, each of which contains a predetermined amount of active ingredient. In one aspect, the pharmaceutical composition is an oral unit dosage form. In another aspect, the pharmaceutical composition is a tablet. In another aspect, the pharmaceutical composition is a capsule. In another aspect, the pharmaceutical composition is a liquid pharmaceutical composition suitable for oral consumption.

[0157] In some embodiments, the pharmaceutical composition is an oral unit dosage form comprising acalabrutinib or a pharmaceutically acceptable salt thereof in an amount of about 75 mg to about 125 mg; capasitinib or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. In another aspect, the pharmaceutical composition is an oral unit dosage form comprising acalabrutinib or a pharmaceutically acceptable salt thereof in an amount of about 100 mg; capasitinib or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. In another aspect, the pharmaceutical composition is an oral unit dosage form comprising acalabrutinib or a pharmaceutically acceptable salt thereof in an amount of about 75 mg to about 125 mg; capasitinib or a pharmaceutically acceptable salt thereof in an amount of about 100 mg to about 900 mg; and a pharmaceutically acceptable carrier. In another aspect, the pharmaceutical composition is an oral unit dosage form comprising acalabrutinib or a pharmaceutically acceptable salt thereof in an amount of about 75 mg to about 125 mg; capasitinib or a pharmaceutically acceptable salt thereof in an amount of about 200 mg to about 800 mg; and a pharmaceutically acceptable carrier. In another aspect, the pharmaceutical composition is an oral unit dosage form comprising acalabrutinib or a pharmaceutically acceptable salt thereof in an amount of about 75 mg to about 125 mg; capasitinib or a pharmaceutically acceptable salt thereof in an amount of about 300 mg to about 700 mg; and a pharmaceutically acceptable carrier. In another aspect, the pharmaceutical composition is an oral unit dosage form comprising acalabrutinib or a pharmaceutically acceptable salt thereof in an amount of about 100 mg; capasitinib or a pharmaceutically acceptable salt thereof in an amount of about 100 mg to about 900 mg; and a pharmaceutically acceptable carrier. In another aspect, the pharmaceutical composition is an oral unit dosage form comprising acalabrutinib or a pharmaceutically acceptable salt thereof in an amount of about 100 mg; capasitinib or a pharmaceutically acceptable salt thereof in an amount of about 200 mg to about 800 mg; and a pharmaceutically acceptable carrier. In another aspect, the pharmaceutical composition is an oral unit dosage form comprising acalabrutinib or a pharmaceutically acceptable salt thereof in an amount of about 100 mg; capasitinib or a pharmaceutically acceptable salt thereof in an amount of about 300 mg to about 700 mg; and a pharmaceutically acceptable carrier.

[0158] The above pharmaceutical composition is preferably used to treat the B cell malignancies described in this specification. For example, in one aspect, the B cell malignancy is non-Hodgkin's lymphoma. On the other hand, the B cell malignancy is diffuse large B cell lymphoma. On the other hand, the B cell malignancy is activated B cell (ABC) diffuse large B cell lymphoma.

[0159] V. Reagent test kit

[0160] The present disclosure further relates in part to kits comprising acalabrutinib and capasitinib. These kits contain acalabrutinib or a pharmaceutically acceptable salt thereof, and each of capasitinib or a pharmaceutically acceptable salt thereof, alone or in combination in suitable packaging. These kits are used to co-administer acalabrutinib or a pharmaceutically acceptable salt thereof, and capasitinib or a pharmaceutically acceptable salt thereof, simultaneously, separately or sequentially. These kits optionally contain written materials, which may include instructions for use, clinical study discussions, and lists of side effects. Such kits may also contain information indicating or determining the activity and / or advantages of the composition, such as scientific literature references, package insert materials, clinical trial results, and / or summaries of these, and / or information describing administration, application, side effects, drug interactions, or other information useful to health care providers. This information may be based on the results of various studies, for example, studies using experimental animals involving in vivo models and studies based on human clinical trials.

[0161] In some embodiments, the kit comprises:

[0162] A first pharmaceutical composition comprising a compound having Formula I:

[0163]

[0164] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier;

[0165] A second pharmaceutical composition comprising a compound having Formula II:

[0166]

[0167] or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

[0168] In some embodiments, the first pharmaceutical composition and the second pharmaceutical composition are each a unit dosage form. In one aspect, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form. In another aspect, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, and the first pharmaceutical composition comprises acalabrutinib or a pharmaceutically acceptable salt thereof in an amount of about 75 mg to about 125 mg. In another aspect, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, and the first pharmaceutical composition comprises acalabrutinib or a pharmaceutically acceptable salt thereof in an amount of about 100 mg.

[0169] In some embodiments, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, and the second pharmaceutical composition comprises capasitinib or a pharmaceutically acceptable salt thereof in an amount of about 100 mg to about 900 mg. In one aspect, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, and the second pharmaceutical composition comprises capasitinib or a pharmaceutically acceptable salt thereof in an amount of about 200 mg to about 800 mg. In another aspect, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, and the second pharmaceutical composition comprises capasitinib or a pharmaceutically acceptable salt thereof in an amount of about 300 mg to about 700 mg.

[0170] In some embodiments, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, the first pharmaceutical composition comprises acalabrutinib or a pharmaceutically acceptable salt thereof in an amount of about 75 mg to about 125 mg, and the second pharmaceutical composition comprises capasitinib or a pharmaceutically acceptable salt thereof in an amount of about 100 mg to about 900 mg. In one aspect, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, the first pharmaceutical composition comprises acalabrutinib or a pharmaceutically acceptable salt thereof in an amount of about 75 mg to about 125 mg, and the second pharmaceutical composition comprises capasitinib or a pharmaceutically acceptable salt thereof in an amount of about 200 mg to about 800 mg. On the other hand, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, the first pharmaceutical composition comprises acalabrutinib or a pharmaceutically acceptable salt thereof in an amount of about 75 mg to about 125 mg, and the second pharmaceutical composition comprises capasitinib or a pharmaceutically acceptable salt thereof in an amount of about 300 mg to about 700 mg.

[0171] In some embodiments, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, the first pharmaceutical composition comprises acalabrutinib or a pharmaceutically acceptable salt thereof in an amount of about 100 mg, and the second pharmaceutical composition comprises capasitinib or a pharmaceutically acceptable salt thereof in an amount of about 100 mg to about 900 mg. In one aspect, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, the first pharmaceutical composition comprises acalabrutinib or a pharmaceutically acceptable salt thereof in an amount of about 100 mg, and the second pharmaceutical composition comprises capasitinib or a pharmaceutically acceptable salt thereof in an amount of about 200 mg to about 800 mg. On the other hand, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, the first pharmaceutical composition comprises acalabrutinib or a pharmaceutically acceptable salt thereof in an amount of about 100 mg, and the second pharmaceutical composition comprises capasitinib or a pharmaceutically acceptable salt thereof in an amount of about 300 mg to about 700 mg.

[0172] In some embodiments, acalabrutinib or a pharmaceutically acceptable salt thereof, and capasitinib or a pharmaceutically acceptable salt thereof, are provided as a single composition in a container in a kit. Thus, in one aspect, the kit comprises a pharmaceutical composition comprising a compound having Formula I:

[0173]

[0174] or a pharmaceutically acceptable salt thereof; a compound of formula II:

[0175]

[0176] or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. In one aspect, the pharmaceutical composition is a unit dosage form. In another aspect, the pharmaceutical composition is an oral unit dosage form. In another aspect, the pharmaceutical composition is an oral unit dosage form comprising acalabrutinib, or a pharmaceutically acceptable salt thereof, in an amount of about 75 mg to about 125 mg. In another aspect, the pharmaceutical composition is an oral unit dosage form comprising acalabrutinib, or a pharmaceutically acceptable salt thereof, in an amount of about 100 mg.

[0177] In some embodiments, the kit may further include another active pharmaceutical ingredient. In one aspect, acalabrutinib or a pharmaceutically acceptable salt thereof, and capasitinib or a pharmaceutically acceptable salt thereof, and another active pharmaceutical ingredient are provided as separate pharmaceutical compositions in separate containers in the kit. On the other hand, acalabrutinib or a pharmaceutically acceptable salt thereof, and capasitinib or a pharmaceutically acceptable salt thereof, and the medicament are provided as a single composition in a container in the kit. Suitable packaging and other use articles (e.g., measuring cups for liquid preparations, foil packaging to minimize exposure to air, etc.) are known in the art and may be included in the kit. The kit can be provided, sold and / or promoted to health care providers, including physicians, nurses, pharmacists, prescribers, etc. In selected embodiments, the kit can also be sold directly to consumers.

[0178] In some embodiments, the kit may further comprise a pharmaceutical composition containing a therapeutically effective amount of cyclophosphamide, doxorubicin, vincristine, prednisone, or a combination thereof. The kit is used to co-administer acalabrutinib, capasitinib, cyclophosphamide, doxorubicin, vincristine, and / or prednisone simultaneously or separately.

[0179] The above kit is preferably used to treat the B cell malignancies described in this specification. For example, in one aspect, the B cell malignancy is non-Hodgkin's lymphoma. On the other hand, the B cell malignancy is diffuse large B cell lymphoma. On the other hand, the B cell malignancy is activated B cell (ABC) diffuse large B cell lymphoma.

[0180] VI. Examples

[0181] Example 1: In vitro pharmacology studies in diffuse large B-cell lymphoma cell lines

[0182] A study was conducted in a panel of diffuse large B-cell lymphoma cell lines to determine whether the combination of acalabrutinib and capacitinib could provide benefit as measured by enhanced inhibition of proliferation and loss of cell viability and indicated by Loewe and HSA synergy scores. In addition, the study further explored the mechanism of action of the combination of acalabrutinib and capacitinib using Western blot analysis.

[0183] Cell viability assay

[0184] For cell viability assays, cells were seeded in 384-well plates and treated with 0.1% DMSO control or increasing concentrations of acalabrutinib, capasitinib, or acalabrutinib and capasitinib combination for 72 hours. Cell viability was measured using Cell Titer Glo reagent and read using a Tecan plate reader with an integration time of 100 ms. Data analysis was performed using GeneData software version 15. Growth inhibition values ​​were less than 1 μM (GI 50 <1 μM) indicates sensitivity.

[0185] Treatment of cells with capasitinib alone inhibited the growth of a subset of GCB DLBCL cell lines, but had minimal effects on the growth of a subset of ABC DLBCL cell lines (see Table EX-1A below). Treatment of cells with acalabrutinib alone inhibited the growth of a subset of ABC DLBCL cell lines, but had minimal effects on the growth of the GCB DLBCL cell lines tested (see Table EX-1A below).

[0186] Table EX-1A

[0187]

[0188] However, as shown by the Loewe and HSA synergy scores reported in Tables EX-1B and EX-1C, respectively, treatment of cells with the combination of acalabrutinib and capasitinib enhanced cell growth inhibition and loss of cell viability in two ABC-DLBCL cell lines, TMD8 and OCI-LY10. Synergy scores exceeding 3 (>3) indicated potential combination benefit in each synergy model. See, e.g., J. Foucquier et al., “Analysis of drug combinations: current methodological landscape,” Pharmacol. Res. Perspect., 3(3) (June 2015); C. J. Lehár et al., “Chemical combination effects predict connectivity in biological systems,” Mol. Syst. Biol., 3:80 (2007); and Keith et al., “Multicomponent therapeutics for networked systems,” Nat. Rev. Drug. Discov., 4, 71-78 (2005).

[0189] Table EX-1B

[0190] LOEWE Synergy Rating for the combination

[0191] Cell lines Disease indications Disease subtype Acalabrutinib + Capasitinib TMD8 DLBCL ABC 4.5 OCI-LY10 DLBCL ABC 3.28 U2932 DLBCL ABC 1.04 HLY1 DLBCL ABC 0 OCI-LY3 DLBCL ABC -0.0453 WILL1 DLBCL Int 0.10 WSU-DLCL2 DLBCL GCB -3.41 SuDHL4 DLBCL GCB -1.10 Karpas-422 DLBCL GCB 0.15 OCI-LY19 DLBCL GCB 0.26 SuDHL6 DLBCL GCB 0.20

[0192] Table EX-1C

[0193] Combined HSA Synergy Score

[0194] Cell lines Disease indications Disease subtype Acalabrutinib + Capasitinib TMD8 DLBCL ABC 9.344 OCI-LY10 DLBCL ABC 3.28 U2932 DLBCL ABC 1.42 HLY1 DLBCL ABC -0.17 OCI-LY3 DLBCL ABC N / A WILL1 DLBCL Int 0.10 SuDHL4 DLBCL GCB 0.26 Karpas-422 DLBCL GCB 0.15 OCI-LY19 DLBCL GCB 0.26 SuDHL6 DLBCL GCB 0.51

[0195] Figure 1 Shown is a heat map of combined signals (% inhibition of growth signal) for TMD8 cells and OCI-LY10 cells after 72 hours of treatment with acalabrutinib and capasitinib combination.

[0196] The study showed that in a subset of human ABC-DLBCL cell lines, the combination of acalabrutinib and capasitinib showed a combination benefit and resulted in enhanced loss of cell viability compared with single agents.

[0197] Western blot analysis

[0198] For Western blot analysis, cells were seeded into 6-well plates and treated with 0.1% DMSO, 1 μM capasitinib, 100 nM acalabrutinib, or a combination of 1 μM capasitinib and 100 nM acalabrutinib for two hours or 24 hours. Cells were then lysed in SDS lysis buffer, centrifuged, and protein concentrations were estimated. Samples were loaded onto Bis-Tris-Novex gels, transferred to nitrocellulose membranes, and probed for phosphorylated proteins of interest.

[0199] Figure 2 shows the Western blot of TMD8 cells and OCI-LY10 cells after 2 hours or 24 hours of treatment with vehicle, acalabrutinib, capasitinib, or acalabrutinib and capasitinib combination. Treatment of TMD8 and OCI-LY10 cells with 1 μM capasitinib results in an increase in the phosphorylation of AKTS473 and reduces the phosphorylation of downstream substrates PRAS40, GSK3β, FOXO and S6. As shown in the phosphorylation reduction of AKTS473, treatment of cells with 100 nM acalabrutinib induces a decrease in the phosphorylation of BTK, and also inhibits AKT signaling. Treatment of cells with a combination of capasitinib and acalabrutinib results in a decrease in the phosphorylation induction of AKTS473, while the phosphorylation inhibition of S6 is enhanced. In addition, the combination results in the induction of cleaved caspase 3 at 24 hours, indicating that apoptosis in these cell lines is enhanced.

[0200] In this mechanism-of-action study in TMD8 and OCI-LY10 cells, the combination of acalabrutinib and capasitinib resulted in inhibition of AKT signaling and BTK, and further induced caspase activation.

[0201] Example 2: In vivo efficacy in a xenograft model

[0202] A. In vivo efficacy in the TMD8 human ABC-DLBCL xenograft model

[0203] A study was conducted to evaluate the in vivo efficacy of acalabrutinib and capasitinib monotherapy and combination responses in the TMD8 human ABC-DLBCL xenograft mouse subcutaneous model. Specifically, SCID mice bearing xenograft tumors derived from the TMD8 human activated B cell (ABC) diffuse large B-cell lymphoma (DLBCL) cell line were evaluated following treatment with acalabrutinib monotherapy, capasitinib monotherapy, or combination therapy.

[0204] TMD8 human ABC-DLBCL tumor cells (5x106 / mouse) were subcutaneously implanted into female CB.17 SCID mice. Mice were randomly divided into five groups according to tumor volume and treated with vehicle (0.5% MC / 0.1% Tween-80), 130mg / kg capasitinib, 20mg / kg acalabrutinib, or a combination of acalabrutinib and capasitinib. Capasitinib was formulated in 10% DMSO / 25% Kleptose pH=5, and acalabrutinib was formulated in 0.5% MC / 0.1% Tween-80. Ten days after tumor cell implantation, all agents were administered orally according to the schedule listed in the following Table EX-2A. Tumor length and width were measured with calipers, and the formula (length x width 2 )*π / 6 to calculate the tumor volume. On day 20 of the efficacy study, microsamples (20 μl) were obtained from tail vein live blood to evaluate the plasma pharmacokinetics of acalabrutinib and capasitinib.

[0205] After twenty-four days of treatment, capasitinib monotherapy resulted in 0% tumor growth inhibition (TGI), acalabrutinib monotherapy resulted in 81% tumor growth inhibition (TGI), and the combination of the two agents resulted in 98% tumor regression. During the 24-day study, all treatments were tolerated during dosing, with a maximum weight loss of 6%. During the study, steady-state unbound plasma concentrations of acalabrutinib and capasitinib were measured from three mice in the single agent and combination groups at 1, 2, 4, and 8 hours. After oral administration of acalabrutinib and capasitinib single agents or combinations, the drug exposure levels of acalabrutinib and capasitinib were similar. The overall results are summarized in Table EX-2A below.

[0206] Table EX-2A

[0207]

[0208]

[0209] * Day 34, vehicle group only n=4 mice

[0210] **N / A = Not Applicable

[0211] Figure 3 The effect of treatment with vehicle, acalabrutinib, capasitinib, or the combination of acalabrutinib and capasitinib on tumor volume is shown. Figure 4 Steady-state drug exposures following treatment with acalabrutinib, capasitinib, or the combination of acalabrutinib and capasitinib are shown. Figure 5 The effects of treatment with vehicle, acalabrutinib, capasitinib, or the combination of acalabrutinib and capasitinib on body weight are shown.

[0212] Oral treatment with acalabrutinib and capasitinib combination significantly enhanced antitumor efficacy, resulting in complete regression (98%) of the TMD8 human ABC-DLBCL xenograft model relative to single-agent therapy. Mice were observed to be well tolerated to all treatments in the combination treatment group, with a maximum weight loss of 6%. Pharmacokinetic assessment revealed comparable drug exposure levels in the acalabrutinib and capasitinib single-agent and combination groups.

[0213] B. In vivo efficacy in the OCI-Ly10 human ABC-DLBCL xenograft model

[0214] A study was conducted to evaluate the in vivo efficacy of acalabrutinib and capacitinib monotherapy and combination responses in the OCI-Ly10 human ABC-DLBCL xenograft mouse subcutaneous model. Specifically, SCID mice bearing xenograft tumors derived from the OCI-Ly10 human activated B-cell (ABC) diffuse large B-cell lymphoma (DLBCL) cell line were evaluated following treatment with acalabrutinib monotherapy, capacitinib monotherapy, or combination therapy.

[0215] OCI-ly10 human ABC-DLBCL tumor cells (5x106 / mouse) were subcutaneously implanted into female CB.17 SCID mice. According to the tumor volume, the mice were randomly divided into five groups and treated with vehicle (0.5% MC / 0.1% Tween-80), 130mg / kg capasitinib, 20mg / kg acalabrutinib, or a combination of acalabrutinib and capasitinib. Capasitinib was prepared in 10% DMSO / 25% Kleptose pH=5, and acalabrutinib was prepared in 0.5% MC / 0.1% Tween-80. Nineteen days after tumor cell implantation, all agents were administered orally according to the schedule listed in the following Table EX-2B. Tumor length and width were measured by caliper, and the formula (length x width 2 )*π / 6 to calculate the tumor volume.

[0216] After twenty-five days of treatment, capasitinib monotherapy resulted in 0% tumor growth inhibition (TGI), acalabrutinib monotherapy resulted in 74% tumor growth inhibition (TGI), and the combination of the two agents resulted in 78% tumor regression. During the 25-day study, all treatments were well tolerated during dosing, with a maximum weight loss of 7%. The overall results are summarized in Table EX-2B below.

[0217] Table EX-2B

[0218]

[0219] *N / A = Not Applicable

[0220] Figure 6 The effect of treatment with vehicle, acalabrutinib, capasitinib, or the combination of acalabrutinib and capasitinib on tumor volume is shown. Figure 7 Shown are the effects of treatment with vehicle, acalabrutinib, capasitinib, or the combination of acalabrutinib and capasitinib on body weight over a 25-day dosing period.

[0221] Oral treatment with acalabrutinib and capasitinib combined significantly enhanced antitumor efficacy, resulting in almost complete regression (78%) in the OCI-Ly10 human ABC-DLBCL xenograft model relative to single-agent therapy. Good tolerability of all treatments was observed in mice in the combination treatment group, with a maximum weight loss of 7%. Pharmacokinetic assessments revealed comparable drug exposure levels in the acalabrutinib and capasitinib single-agent and combination groups.

[0222] Example 3: In vivo efficacy in the disseminated TMD8-luc2 human ABC-DLBCL model

[0223] A study was conducted to evaluate the in vivo efficacy of acalabrutinib and capasitinib monotherapy and combination responses in a disseminated TMD8-luc2 human ABC-DLBCL xenograft mouse subcutaneous model. Specifically, SCID mice injected intravenously with luciferase-labeled TMD8 human activated B cell (ABC) diffuse large B-cell lymphoma (DLBCL) cell line were evaluated following acalabrutinib monotherapy, capasitinib monotherapy, or combination therapy.

[0224] TMD8 human ABC-DLBCL tumor cells containing luciferase reporter constructs (5x106 / mouse) were injected intravenously into the tail vein of female CB.17 SCID mice. During the study, tumor burden, body weight and animal condition measured using the Xenogen IVIS imaging system were recorded at least twice a week. For Xenogen imaging, mice received intraperitoneal administration of 150mg / kg D-luciferin 10-15 minutes before imaging. Live mice were imaged under isoflurane anesthesia, and real-time image software (Xenogen) was used to analyze the data. According to the dorsal and ventral bioluminescence intensity (BLI), mice were randomly divided into five groups and treated with vehicle (0.5% MC / 0.1% Tween-80), 130mg / kg capasitinib, 20mg / kg acalabrutinib, or a combination of acalabrutinib and capasitinib. Capasitinib was formulated in 10% DMSO / 25% Kleptose pH=5, and acalabrutinib was formulated in 0.5% MC / 0.1% Tween-80. Fourteen days after tumor cell injection, all agents were administered orally according to the schedule listed in Table EX-2A of Example 2. Disseminated tumor burden was measured by Xenogen, and study endpoints were determined based on the condition of individual animals, with moribund mice sacrificed artificially.

[0225] like Figure 8 As shown, oral treatment with acalabrutinib and capasitinib combination significantly enhanced survival benefit compared with single-agent therapy in the disseminated TMD8-luc2 human ABC DLBCL xenograft mouse model. All treatments were well tolerated by the mice until the animals reached the survival study endpoint.

[0226] Example 4: In vivo efficacy in patient-derived xenograft models

[0227] A study was conducted to evaluate the in vivo efficacy of acalabrutinib and capasitinib as monotherapy and combination responses in two patient-derived xenograft (PDX) models, the subcutaneous ABC-DLBCL PDX model (LY0257) and the subcutaneous GCB-DLBCL PDX model (LY2214). LY2214 and LY0257 human patient-derived DLBCL primary human tumor fragments (2-3 mm in diameter) were subcutaneously implanted into female NOD / SCID and B / C nude mice, respectively. Mice were randomly divided into five groups based on tumor volume and treated with vehicle, acalabrutinib, capasitinib, or a combination of acalabrutinib and capasitinib. Acalabrutinib was formulated in 0.5% MC+0.1% Tween-80, and capasitinib was formulated in 10% DMSO / 25% Kleptose pH=5. When the tumor size was between 150 and 300 mm 3Vehicle, acalabrutinib, capasitinib, and the combination of acalabrutinib and capasitinib were orally administered between 1 and 2 weeks according to the schedule listed in Table EX-2A of Example 2. Two-dimensional tumor volumes were measured twice weekly using calipers, with volumes expressed in mm. 3 The formula is as follows: “V = (L x W x W) / 2, where V is the tumor volume, L is the tumor length (the longest tumor dimension), and W is the tumor width (the longest tumor dimension perpendicular to L).

[0228] Example 5: RNAseq study

[0229] RNAseq studies were performed on TMD8 cells treated with acalabrutinib, capasitinib, or a combination of acalabrutinib and capasitinib. Specifically, TMD8 cells were seeded into six-well plates and treated with 0.1% DMSO, 1 μM capasitinib, 100 nM acalabrutinib, or a combination of 1 μM capasitinib and 100 nM acalabrutinib for six hours or 24 hours. Cell pellets were then made and RNA was isolated. RNA samples were sent to Novogene for cDNA library generation and mRNA sequencing (RNA-seq). RNAseq data were analyzed using an in-house R&D production system, and gene expression was quantified using the Salmon method (Patro R, 2017). Differential expression analysis was performed using DESeq2 (Love MI, 2014). Enrichment analysis was performed using GSVA ( S, 2013).

[0230] Example 6: In vivo pharmacodynamic study

[0231] A pharmacodynamic study was conducted to evaluate the monotherapy and combination responses of acalabrutinib and capasitinib. Female CB.17 SCID mice were implanted subcutaneously with TMD8 human ABC-DLBCL tumor cells (5x106 cells / mouse). The tumor volume reached approximately 300 to 600 mm 3 Mice will be randomized into three groups for evaluation and then treated with a single acute dose or multiple doses of either vehicle (0.5% MC / 0.1% Tween-80), 20 mg / kg acalabrutinib, 130 mg / kg capasitinib, or a combination thereof at 2, 8, 14, and 24 hours. The pharmacodynamic evaluation of acalabrutinib and capasitinib will include pS6, pBTK, pAKT, p4EBP1, and pPLCγ2.

[0232] Example 7: Clinical study of combination therapy for relapsed / refractory DLBCL lymphoma

[0233] A Phase 1 / 2, single-arm, open-label, proof-of-concept study was conducted to evaluate the combination of acalabrutinib and capasitinib for the treatment of patients with relapsed / refractory DLBCL. The study will evaluate the clinical potential of the dual inhibition approach of BTK and AKT by evaluating the safety, pharmacokinetics, pharmacodynamics, and efficacy of the combination of acalabrutinib and capasitinib in the treatment of relapsed / refractory DLBCL.

[0234] Purpose

[0235] The objectives of clinical study part 1 include determining the dose and schedule of capasitinib in combination with acalabrutinib 100 mg BID to be evaluated in clinical study part 2. The primary objective of clinical study part 2 is to evaluate the safety of acalabrutinib when co-administered with capasitinib. Secondary objectives of clinical study part 2 include evaluating the pharmacokinetics, pharmacodynamics, and clinical activity of acalabrutinib when co-administered with capasitinib.

[0236] Safety parameters that will be evaluated include, but are not limited to, the type, frequency, severity, and relationship to study drug of any treatment-emergent adverse event (TEAE) or laboratory test abnormality, serious adverse events (SAE), dose-limiting toxicities (DLTs), and adverse events (AEs) leading to discontinuation of one or more study drugs.

[0237] The plasma pharmacokinetics of acalabrutinib and capasitinib will be characterized using noncompartmental analysis, and the following pharmacokinetic parameters will be calculated from the plasma concentrations of the analytes whenever possible: (1) AUC (0-最后) : Area under the plasma concentration-time curve calculated using the linear trapezoidal summation from time 0 to time last, where “last” is the time of the last measurable concentration; AUC (0-无穷大) : The area under the plasma concentration-time curve from 0 to infinity calculated using the following formula: AUC (0-无穷大) =AUC (0-最后) +C (最后 / λz) , where λ z is the apparent terminal elimination rate constant; C 最大 : maximum observed plasma concentration; T 最大 : time of maximum plasma concentration (obtained without interpolation); t 1 / 2 : terminal elimination half-life (as far as possible); λ z : terminal elimination rate constant (as far as possible); CL / F: oral clearance; V z / F: oral distribution volume.

[0238] Pharmacodynamic evaluation of acalabrutinib and capasitinib will include (1) measurement of BTK occupancy by acalabrutinib in peripheral blood mononuclear cells (PBMCs) using an acalabrutinib analog probe, (2) evaluation of the effects of acalabrutinib and capasitinib on biomarkers of B cell function and / or AKT inhibition in PBMCs and / or tumor tissue, and (3) evaluation of the effects of acalabrutinib and capasitinib on circulating tumor DNA (ctDNA). Cell populations and immune markers will be monitored for treatment efficacy, which may include, but are not limited to, leukocyte or lymphocyte subsets (e.g., T, B, and natural killer [NK] cells) and their activation state. Other markers may include Ki67, pS6, pBTK, pAKT, pPRAS40, pGSK3β, p4EBP1, FOXO3, and pPLCγ2.

[0239] The clinical activity of acalabrutinib and capasitinib was evaluated by measuring the overall response rate (ORR=CR+PR), complete response (CR) rate, duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

[0240] Table EX-7A below summarizes the study objectives and endpoints.

[0241] Table EX-7A

[0242]

[0243]

[0244] Study Design

[0245] The study is an exploratory, multicenter, open-label, non-randomized Phase I platform study that will be conducted at approximately 25 sites.

[0246] Number of subjects

[0247] The study will enroll up to 21 evaluable subjects.

[0248] Dosage forms and strengths

[0249] The acalabrutinib drug product is supplied as hard gelatin capsules containing 100 mg of acalabrutinib for oral administration.

[0250] The capasitinib drug product is supplied as film-coated tablets containing 160 mg or 200 mg of capasitinib for oral administration.

[0251] Dosage Regimen and Route of Administration

[0252] Acalabrutinib and capasitinib are administered orally twice daily with 8 ounces (approximately 240 mL) of water (avoid grapefruit juice or Seville orange juice due to possible inhibition of CYP3A). Doses are administered daily at approximately the same interval of 12 hours (allowing for a ±1 hour window). For all doses, subjects will fast (with drinking water only) from at least two hours before and at least one hour after dosing. Take acalabrutinib capsules and capasitinib tablets at the same time and swallow them whole. Acalabrutinib is taken daily, while capasitinib is taken on a schedule of 4 days on and 3 days off.

[0253] Inclusion Criteria

[0254] Subjects must meet the following inclusion criteria to be eligible for this study:

[0255] 1. Have a diagnosis of relapsed / refractory DLBCL or aggressive lymphoma (i.e., B-cell NHL) with a histology based on criteria established by the World Health Organization (WHO). Eligible histologies are:

[0256] (a) DLBCL (de novo and transformed, including Richter syndrome)

[0257] (b) T cell / histiocyte-rich large B cell lymphoma

[0258] (c) Primary cutaneous DLBCL

[0259] (d) Leg-type primary cutaneous DLBCL

[0260] (e) EBV positive + )DLBCL

[0261] (f) DLBCL associated with chronic inflammation

[0262] (g) Primary mediastinal (thymic) large B-cell lymphoma

[0263] (h) Intravascular large B-cell lymphoma

[0264] (i) Anaplastic lymphoma kinase positive (ALK + Large B-cell lymphoma

[0265] (j) High-grade B-cell lymphoma with MYC and BCL2 rearrangement or BCL6 and MYC rearrangement

[0266] 2. Subjects who have previously received rituximab, cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), vincristine sulfate and prednisone (ie, R-CHOP) or equivalent regimens, and high-dose therapy with stem-cell rescue, or are not eligible for high-dose therapy with stem-cell rescue and / or chimeric antigen receptor (CAR) T-cell therapy. The researchers will determine whether they are eligible for high-dose therapy with stem-cell rescue and / or CAR T-cell therapy (including subjects who refuse transplantation).

[0267] 3. Adequate hematologic function is defined as:

[0268] (a) ANC ≥ 1000 cells / mm 3 (1.0x10 9 / L).

[0269] (b) Platelet count ≥ 100,000 cells / mm 3 (100x10 9 cells / L) or ≥50,000 cells / mm 3 (50x10 9 / L), bone marrow or spleen involvement. Platelet count inclusion requirements must be met without transfusion support.

[0270] (c) Hemoglobin ≥9 g / dL.

[0271] 4. Willing and able to participate in all required assessments and procedures in this study protocol, including swallowing capsules / tablets without difficulty.

[0272] 5. Females should use highly effective contraceptive measures, should not breastfeed, and if of childbearing potential, must have a negative pregnancy test (urine or serum) before starting medication, or must meet one of the following criteria at screening to demonstrate no childbearing potential:

[0273] (a) Postmenopausal women, defined as women aged >50 years with amenorrhea for ≥12 months after cessation of all exogenous hormone therapy, or women aged <50 years with amenorrhea for ≥12 months after cessation of exogenous hormone therapy and serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels within the postmenopausal range of the institution.

[0274] (b) Have a record of irreversible surgical infertility by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy but not tubal ligation.

[0275] (c) Medically confirmed irreversible premature ovarian failure.

[0276] Sexually active women of reproductive potential must be willing to use 2 forms of contraception starting at screening and continuing until 2 days after the last dose of acalabrutinib and 4 weeks after the last dose of capasitinib. Women must also refrain from donating eggs and breastfeeding during this same time period.

[0277] 6. During the study and for 16 weeks after the last dose of capasitinib, men must use condoms (containing spermicide) with all sexual partners. During this same time, men are not allowed to donate sperm. If this has not been done before, male subjects who wish to have children are advised to store sperm before receiving capasitinib.

[0278] Exclusion criteria

[0279] Subjects were not eligible for this study if they met any of the following exclusion criteria:

[0280] 1. Any of the following cardiac criteria at screening:

[0281] (a) The average resting corrected QT interval (QTc) obtained from three consecutive electrocardiograms (ECGs) was >470 ms.

[0282] (b) Any clinically significant abnormality in rhythm, conduction, or morphology of the resting ECG (e.g., complete left bundle branch block or third degree heart block).

[0283] (c) Any factor that increases the risk of QTc prolongation or arrhythmic events, such as heart failure, hypokalemia, potential for torsades de pointes, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under the age of 40, or any concomitant medication known to prolong the QT interval.

[0284] (d) Any of the following procedures or conditions within the past 6 months: coronary artery bypass grafting, angioplasty, vascular stenting, myocardial infarction, angina pectoris, congestive heart failure New York Heart Association (NYHA) class ≥2.

[0285] (e) Uncontrolled hypotension - systolic blood pressure <90 mmHg and / or diastolic blood pressure <50 mmHg.

[0286] (f) Cardiac ejection fraction outside the institutional normal range or <50%, whichever is higher, as measured by echocardiography (or a multiple gated acquisition [MUGA] scan if echocardiography is not possible or inconclusive).

[0287] 2. Clinically significant abnormalities in glucose metabolism at screening as defined by any of the following:

[0288] (a) Subjects with type 1 diabetes or type 2 diabetes requiring insulin treatment.

[0289] (b) HbA1c≥8.0% (63.9mmol / mol).

[0290] 3. Renal insufficiency as evidenced by creatinine >1.5×ULN and creatinine clearance <50 mL / min (measured or calculated by Cockcroft and Gault formula); confirmation of creatinine clearance is required only when creatinine is >1.5×ULN.

[0291] 4. Presence of central nervous system (CNS) lymphoma or leptomeningeal disease.

[0292] 5. Current refractory nausea and vomiting, malabsorption syndrome, diseases that significantly affect gastrointestinal (G1) function, gastrectomy, extensive small bowel resection that may affect absorption, symptomatic inflammatory bowel disease, partial or complete intestinal obstruction, or gastric interposition and bariatric surgery (such as gastric bypass).

[0293] 6. Known to have tested positive for human immunodeficiency virus (HIV) and require restrictive drug treatment.

[0294] 7. Effective inhibitors or inducers of CYP3A4 within 2 weeks before the first dose of capasitinib (3 weeks for St. John's wort) and within 7 days before the first dose of acalabrutinib; or sensitive substrates of CYP3A4, CYP2C9 and / or CYP2D6 within 1 week before the first dose of capasitinib (narrow therapeutic window).

[0295] 8. Requires treatment with a proton pump inhibitor (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving proton pump inhibitors who switch to H2 receptor antagonists or antacids are eligible to participate in this study.

[0296] 9. Major surgical procedure within 28 days prior to the first dose of study treatment. Note: If the subject has undergone major surgery, they must have fully recovered from any toxicity and / or complications of the intervention before receiving the first dose of study treatment. For local surgery (e.g., placement of systemic ports and biopsies), a discussion with the medical monitor is required to assess the subject's risk of major bleeding.

[0297] Clinical data will demonstrate that co-administration of acalabrutinib and capasitinib provides unexpected improvements in the treatment of DLBCL (e.g., de novo DLBCL, relapsed / refractory DLBCL, and / or transformed DLBCL) compared to monotherapy administration of acalabrutinib and capasitinib alone.

[0298] ***********

[0299] This written description uses examples to disclose the invention and enable those skilled in the art to practice the invention, including making and using any salt, substance or composition disclosed herein, and performing any method or process disclosed herein. The patentable scope of the invention is defined by the claims and may include other examples that occur to those skilled in the art. If such other examples have elements that are indistinguishable from the literal language of the claims, or if they include equivalent elements that are insubstantially different from the literal language of the claims, these examples are intended to be included within the scope of the claims. Although preferred embodiments of the invention are shown and described in this specification, such embodiments are provided by way of example only and are not intended to otherwise limit the scope of the invention. Various alternatives to the embodiments of the invention may be employed when implementing the invention. The section headings used in this section and throughout the disclosure are not intended to be limiting.

[0300] All of the above references (patent and non-patent) are incorporated into this patent application by reference. The discussion of these references is intended only to summarize the assertions made by their authors. No admission is made that any reference (or part of any reference) is relevant prior art (or is prior art). Applicants reserve the right to question the accuracy and relevance of the cited references.

Claims

1. A first amount of a compound having formula I: or a pharmaceutically acceptable salt thereof, and a second amount of a compound having Formula II: or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a B-cell malignancy in a human subject in need thereof, wherein the first amount and the second amount together comprise a therapeutically effective amount; and wherein the B-cell malignancy is selected from the group consisting of: de novo diffuse large B-cell lymphoma; transformed diffuse large B-cell lymphoma; T cell / histiocyte-rich large B-cell lymphoma; primary cutaneous diffuse large B-cell lymphoma; primary cutaneous diffuse large B-cell lymphoma of the leg type; Epstein-Barr virus-positive diffuse large B-cell lymphoma; diffuse large B-cell lymphoma associated with chronic inflammation; primary mediastinal large B-cell lymphoma; intravascular large B-cell lymphoma; anaplastic lymphoma kinase-positive (ALK+) large B-cell lymphoma; and high-grade B-cell lymphoma with MYC and BCL2 rearrangement or BCL6 and MYC rearrangement.

2. The method of claim 1, wherein the B-cell malignancy is diffuse large B-cell lymphoma.

3. The use according to claim 2, wherein the diffuse large B-cell lymphoma is selected from the group consisting of: de novo diffuse large B-cell lymphoma, relapsed / refractory diffuse large B-cell lymphoma and transformed diffuse large B-cell lymphoma.

4. The use according to claim 2, wherein the diffuse large B-cell lymphoma is selected from the group consisting of germinal center B-cell diffuse large B-cell lymphoma and activated B-cell diffuse large B-cell lymphoma.

5. The use according to claim 2, wherein the diffuse large B-cell lymphoma is activated B-cell diffuse large B-cell lymphoma.

6. The use of claim 2, wherein the human subject has previously received at least one prior chemoimmunotherapy for the diffuse large B-cell lymphoma.

7. The use of claim 1, wherein the compound of formula I or a pharmaceutically acceptable salt thereof and the compound of formula II or a pharmaceutically acceptable salt thereof are orally administered to the human subject.

8. The use of claim 7, wherein the compound of formula I or a pharmaceutically acceptable salt thereof and the compound of formula II or a pharmaceutically acceptable salt thereof are co-administered orally to the human subject.

9. The use of claim 7, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is orally administered to the human subject before or after the compound of formula II or a pharmaceutically acceptable salt thereof.

10. The use of any one of claims 1 to 9, wherein the first amount of the compound of formula I or a pharmaceutically acceptable salt thereof administered to the human subject is 75 mg to 225 mg per day.

11. The use of any one of claims 1 to 9, wherein the first amount of the compound of formula I or a pharmaceutically acceptable salt thereof administered to the human subject is 100 mg once a day.

12. The use of any one of claims 1 to 9, wherein the first amount of the compound of formula I or a pharmaceutically acceptable salt thereof administered to the human subject is 100 mg twice a day.

13. The use of any one of claims 1 to 9, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is orally administered to the human subject according to a continuous dosing schedule.

14. The use of any one of claims 1 to 9, wherein the compound of formula II or a pharmaceutically acceptable salt thereof is orally administered to the human subject according to an intermittent dosing schedule.

15. The use according to any one of claims 1 to 9, wherein: orally administering the compound of Formula I or a pharmaceutically acceptable salt thereof to the human subject according to a continuous dosing schedule; and The compound of Formula II or a pharmaceutically acceptable salt thereof is orally administered to the human subject according to an intermittent dosing schedule.

16. The use of any one of claims 1 to 9, wherein the second amount of the compound of Formula II or a pharmaceutically acceptable salt thereof administered to the human subject is 50 mg twice daily to 900 mg twice daily.

17. The use according to any one of claims 1 to 9, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is orally administered continuously during the administration cycle and the compound of formula II or a pharmaceutically acceptable salt thereof is orally administered intermittently during the administration cycle with a schedule of 4 days on / 3 days off; on each day of administration, the compound of formula I or a pharmaceutically acceptable salt thereof is administered twice a day in an amount of 100 mg, and the compound of formula II or a pharmaceutically acceptable salt thereof is administered twice a day in an amount of 320 mg.

18. The use according to any one of claims 1 to 9, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is orally administered continuously during the administration cycle and the compound of formula II or a pharmaceutically acceptable salt thereof is orally administered intermittently during the administration cycle with a schedule of 4 days on / 3 days off; on each day of administration, the compound of formula I or a pharmaceutically acceptable salt thereof is administered twice a day in an amount of 100 mg, and the compound of formula II or a pharmaceutically acceptable salt thereof is administered twice a day in an amount of 400 mg.

19. A combination for simultaneous, separate or sequential administration, wherein the combination comprises a compound of formula I in an amount of 75 mg to 125 mg: or a pharmaceutically acceptable salt thereof, and a compound having formula II in an amount of 100 mg to 900 mg: or a pharmaceutically acceptable salt thereof.

20. Use of a combination comprising: a compound of formula I: or a pharmaceutically acceptable salt thereof, and a compound having formula II: or a pharmaceutically acceptable salt thereof, wherein the B-cell malignancy is selected from the group consisting of: de novo diffuse large B-cell lymphoma; transformed diffuse large B-cell lymphoma; T-cell / histiocyte-rich large B-cell lymphoma; primary cutaneous diffuse large B-cell lymphoma; primary cutaneous diffuse large B-cell lymphoma of the leg type; Epstein-Barr virus-positive diffuse large B-cell lymphoma; diffuse large B-cell lymphoma associated with chronic inflammation; primary mediastinal large B-cell lymphoma; intravascular large B-cell lymphoma; anaplastic lymphoma kinase-positive (ALK+) large B-cell lymphoma; and high-grade B-cell lymphoma with MYC and BCL2 rearrangement or BCL6 and MYC rearrangement.

21. A pharmaceutical composition comprising: An amount of 75 mg to 125 mg of a compound having formula I: or a pharmaceutically acceptable salt thereof; An amount of 100 mg to 900 mg of a compound having formula II: or a pharmaceutically acceptable salt thereof; and A pharmaceutically acceptable carrier.

22. A kit comprising: A first pharmaceutical composition comprising a compound having Formula I in an amount of 75 mg to 125 mg: or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; A second pharmaceutical composition comprising a compound having Formula II in an amount of 100 mg to 900 mg: or a pharmaceutically acceptable salt thereof, and A pharmaceutically acceptable carrier.

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