HK40069821B - Therapeutic combinations of acalabrutinib and capivasertib to treat b-cell malignancies - Google Patents

Description

A combination of acalabrutinib and capabrutinib for the treatment of B-cell malignancies

Technical Field

This disclosure generally relates to treatment combinations of acalabrutinib and capapasetinib, methods of treatment with the combination of acalabrutinib and capapasetinib, pharmaceutical compositions comprising acalabrutinib and capapasetinib, and kits comprising acalabrutinib and capapasetinib.

Background Technology

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. Acalatinib (also known as ACP-196, chemical name 4-{8-amino-3-[(2S)-1-(but-2-ynyl)pyrrolidone-2-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(pyridin-2-yl)benzamide) is a selective, covalent BTK inhibitor and the active pharmaceutical ingredient in the drug product. 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 Waldenström macroglobulinemia.

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

Non-Hodgkin's lymphoma refers to a broad spectrum of diseases caused by lymphocytes "frozen" at various developmental stages. Despite increased understanding of the biology and genetics of non-Hodgkin's lymphoma in recent years, few effective or curative therapies exist for relapsed/refractory or aggressive non-Hodgkin's lymphoma. Due to the high morbidity and mortality associated with non-Hodgkin's lymphoma, and the limited number of effective treatment options, a significant unmet medical need remains.

This disclosure relates to the unexpected discovery that the combination of acalatinib and capascitinib provides an effective treatment option for B-cell malignancies such as non-Hodgkin's lymphoma, particularly in the treatment of diffuse large B-cell lymphoma (DLBCL), as described below.

Summary of the Invention

In one aspect, this disclosure relates to treatment combinations for simultaneous, separate, or sequential administration, wherein the combination comprises a compound having formula I:

Or a pharmaceutically acceptable salt thereof, and compounds having formula II:

Or its pharmaceutically acceptable salt.

On the other hand, this disclosure relates to a method for treating a subject with B-cell malignancy, the method comprising administering to the subject 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, wherein the first amount and the second amount together comprise a therapeutically effective amount.

On the other hand, this disclosure relates to a pharmaceutical composition comprising:

Compounds having formula I:

Or its pharmaceutically acceptable salt;

Compounds having formula II:

Or its pharmaceutically acceptable salt; and

Pharmaceutically acceptable carrier.

On the other hand, this disclosure relates to a reagent kit containing:

Compounds having formula I:

Or its pharmaceutically acceptable salt, and

Compounds having formula II:

Or its pharmaceutically acceptable salt.

Attached Figure Description

Figure 1 illustrates the combined signal heatmap (% growth signal inhibition) of TMD8 cells and OCI-LY10 cells 72 hours after treatment with a combination of acalatinib and capapasetinib.

Figures 2A and 2B illustrate the Western blots of TMD8 and OCI-LY10 cells 2 hours or 24 hours after treatment with acalabrutinib, capapasetinib, or a combination of acalabrutinib and capapasetinib, respectively.

Figure 3 illustrates the effect of acalatinib, cappacitinib, or a combination of acalatinib and cappacitinib on tumor volume in the TMD8 human ABC DLBCL xenograft mouse model.

Figure 4 illustrates the steady-state drug exposure levels of acalatinib and capapasetinib after treatment with acalatinib, capapasetinib, or a combination of acalatinib and capapasetinib in the TMD8 human ABC DLBCL xenograft mouse model.

Figure 5 illustrates the effect of treatment with acalabrutinib, cappacitinib, or a combination of acalabrutinib and cappacitinib on body weight in the TMD8 human ABC DLBCL xenograft mouse model.

Figure 6 illustrates the effect of acalatinib, cappacitinib, or a combination of acalatinib and cappacitinib on tumor volume in the OCI-ly10 human ABC DLBCL xenograft mouse model.

Figure 7 illustrates the effect of treatment with acalabrutinib, cappacitinib, or a combination of acalabrutinib and cappacitinib on body weight in the OCI-ly10 human ABC-DLBCL xenograft mouse model.

Figure 8 illustrates the effect of treatment with acalabrutinib, cappacitinib, or a combination of acalabrutinib and cappacitinib on survival duration in a disseminated TMD8-luc2 human ABC DLBCL xenograft mouse model.

Detailed Implementation

I. Definition

Unless otherwise defined, 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 subject pertains.

The term "combination" can refer to the simultaneous, separate, or sequential application of two or more agents. In one aspect, "combination" can mean simultaneous application (e.g., two agents applied in a single dosage form). In another aspect, "combination" means separate application (e.g., two agents applied in separate dosage forms, but substantially simultaneously). In another aspect of the invention, "combination" means sequential application (e.g., where a first agent is applied, followed by a delay, and then a second or additional agent is applied). In the case of sequential or separate application, the delay in applying the subsequent component should not be too long or too short to avoid losing the benefits of the combination.

As used herein, the terms “co-administered,” “in combination with,” “simultaneously,” and “at the same time” include administering two or more active pharmaceutical ingredients to a subject, and include simultaneous administration in separate compositions, administration in separate compositions at different times, or administration in a composition in which two or more active pharmaceutical ingredients are present.

The term "effective amount" or "therapeutic effective amount" refers to the amount of a compound or combination of compounds, as described herein, sufficient to affect the intended application (including, but not limited to, the treatment of a disease). Therapeutic effective amounts can vary depending on the intended application (in vitro or in vivo) or the subject being treated and the disease condition (e.g., the subject's weight, age, and sex), the severity of the disease condition, the method of administration, etc., which can be readily determined by one of ordinary skill in the art. This term also applies to doses that will induce a specific response in target cells (e.g., reduced platelet adhesion and/or cell migration). Specific doses will vary depending on the particular compound selected, the dosing 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 carrying the compound.

The term "therapeutic effect" as used herein includes therapeutic benefits and/or preventive benefits. Preventive effects include delaying or eliminating the onset of a disease or symptom, delaying or eliminating the onset of symptoms of a disease or symptom, slowing, stopping or reversing the progression of a disease or symptom, or any combination thereof.

The term "treatment" refers to at least partially alleviating, suppressing, preventing, and/or improving 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 efficacy of treatments for B-cell malignancies is assessed in a variety of ways, including but not limited to: inhibiting cancer cell proliferation (including reversing cancer growth); promoting cancer cell death (e.g., by promoting apoptosis or another cell death mechanism); improving symptoms; duration of treatment response; delaying disease progression; and prolonging survival. Treatment may also be assessed regarding the nature and extent of treatment-related side effects. Furthermore, efficacy can be assessed by biomarkers, such as the expression or phosphorylation levels of proteins known to be associated with a specific biological phenomenon. Other methods of assessing efficacy are known to those skilled in the art.

The term "QD" refers to once a day, once a day, or once daily.

The term "BID" refers to twice a day, twice a day, or twice daily.

The term "pharmaceutically acceptable salt" refers to a salt derived from a variety of organic and inorganic counterions known in the art. Pharmaceutically acceptable acid addition salts can be formed from 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 from 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.

The term "pharmaceutically acceptable carrier" or "pharmaceuticalally acceptable excipient" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption delay agents, as well as inert components. The use of such pharmaceutically acceptable carriers or excipients for the active pharmaceutical ingredient is well known in the art. Unless any conventional pharmaceutically acceptable carrier or 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.

When this document uses ranges to describe, for example, dosage amounts, it is intended to include all combinations and sub-combinations of ranges and specific embodiments thereof.

When referring to a number or range of values, the term "about" means that the number or range mentioned is an approximation within experimental variability (or statistical experimental error), and therefore the number or range of values can vary. Such variation is typically 0% to 15% of the number or range of values, preferably 0% to 10%, and more preferably 0% to 5%.

Unless the context otherwise requires, the terms “comprise”, “comprises”, and “comprising” are used on the basis of explicit understanding, and are interpreted inclusively rather than exclusively, and the applicant wishes that each of those words be interpreted in the interpretation of this patent (including the following claims).

As used in this application, the amount of a compound refers to the amount of the compound present as a free base.

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

Table 1

For clarity, Table 2 below summarizes the compound identifiers, chemical names, and structures that are interchangeable throughout this application for each compound discussed.

Table 2

II. Treatment Combinations, Treatment Methods, and Applications

This disclosure relates to treatment combinations and methods for treating B-cell malignancies, including non-Hodgkin's 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 combinations of capasacetinib or a pharmaceutically acceptable salt thereof, to subjects in need (particularly human subjects in need) to treat B-cell malignancies.

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

As reflected in the findings described in the examples below, the combination of capascalcitinib and acalotinib exhibits broader and greater activity in diffuse large B-cell lymphoma than either drug alone. Acalotinib has shown single-agent activity in several diffuse large B-cell lymphoma cell lines, particularly those classified as the activated B-cell (ABC) subtype. In contrast, capascalcitinib has shown single-agent activity in several diffuse large B-cell lymphoma cell lines, particularly those classified as the germinal center B-cell (GCB) subtype with PTEN deficiency. However, the combination of capascalcitinib and acalotinib shows broader and greater activity than either drug 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 capascalcitinib and acalotinib.

Although this specification primarily discusses the combination of acalatinib and capapasetinib, treatment combinations and methods including the administration of other therapeutic agents (such as triple therapy) to further enhance treatment are also within the scope of this disclosure.

Therefore, in one embodiment, this disclosure relates to a treatment combination for simultaneous, separate, or sequential administration, wherein the combination comprises a compound having formula I:

Or a pharmaceutically acceptable salt thereof, and compounds having formula II:

Or its pharmaceutically acceptable salt.

Compounds having formula (I) are also known by the international non-proprietary name acalabrutinib. International application WO 2013/010868 discloses acalabrutinib (Example 6) and describes its synthesis. International application PCT/EP 2019/072991, filed on August 28, 2019, further describes the synthesis of acalabrutinib. International applications WO 2013/010868 and PCT/EP 2019/072991 are each incorporated herein by reference in their entirety.

Compounds having formula (II) are also known by the international nonproprietary name capapasetinib. Capapasetinib (Example 9) is disclosed by reference to WO 2009/047563, which is incorporated in its entirety, and its synthesis is described.

In another embodiment, this disclosure relates to a method of treating a subject with B-cell malignancy, the method comprising administering to the subject 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, wherein the first amount and the second amount together comprise a therapeutically effective amount. Alternatively, the first amount and the second amount together comprise a synergistic amount for the treatment of B-cell malignancies.

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.

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

In another embodiment, this disclosure relates to the use of a combination of compounds having formula I for the treatment of B-cell malignancies:

Or a pharmaceutically acceptable salt thereof, and compounds having formula II:

Or its pharmaceutically acceptable salt.

In another embodiment, this 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:

Or a pharmaceutically acceptable salt thereof, and compounds having formula II:

Or its pharmaceutically acceptable salt.

In some embodiments, B-cell malignancies are aggressive lymphomas.

In some embodiments, B-cell malignancies are non-Hodgkin lymphomas.

In some embodiments, B-cell malignancies are selected from the group consisting of: B-cell acute lymphoblastic leukemia, mature B-cell acute lymphoblastic leukemia, and diffuse large B-cell lymphoma.

In some embodiments, B-cell malignancies are selected from the group consisting of: mantle cell lymphoma; follicular lymphoma; newly diagnosed diffuse large B-cell lymphoma; transformed diffuse large B-cell lymphoma; T-cell/histocyte-rich large B-cell lymphoma; primary cutaneous diffuse large B-cell lymphoma; leg-type primary cutaneous diffuse large B-cell lymphoma; EBV-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 rearrangements or BCL6 and MYC rearrangements.

In some embodiments, the B-cell malignancy is selected from the group consisting of: newly diagnosed diffuse large B-cell lymphoma; transformed diffuse large B-cell lymphoma; T-cell/histocyte-rich large B-cell lymphoma; primary cutaneous diffuse large B-cell lymphoma; leg-type primary cutaneous diffuse large B-cell lymphoma; EBV-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 rearrangements or BCL6 and MYC rearrangements.

In some embodiments, the B-cell malignancy is diffuse large B-cell lymphoma. In one aspect, diffuse large B-cell lymphoma is selected from the group consisting of: newly diagnosed diffuse large B-cell lymphoma, relapsed/refractory diffuse large B-cell lymphoma, and transformed diffuse large B-cell lymphoma.

In some embodiments, diffuse large B-cell lymphoma is newly diagnosed diffuse large B-cell lymphoma.

In some embodiments, diffuse large B-cell lymphoma is relapsed/refractory diffuse large B-cell lymphoma.

In some embodiments, diffuse large B-cell lymphoma is transformed diffuse large B-cell lymphoma. In one aspect, transformed diffuse large B-cell lymphoma is Richter syndrome.

In some embodiments, 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.

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

The specific B-cell malignancy of the subject can be diagnosed based on recognized clinical practice. For example, see the 2016 guidelines for the classification of lymphomas developed by the World Health Organization (WHO) or the National Comprehensive Cancer Network (NCCN) guidelines for the classification of non-Hodgkin lymphomas.

In some embodiments, the human subject has previously received at least one prior chemoimmunotherapy targeting 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).

III. Combination Dosage and Administration Regimen

The amount of acalabrutinib and capapasetinib administered to a subject will depend on the subject being treated, the severity of the impairment or condition, the administration rate, the disposal of the compound, and the prescribing physician's judgment. In the various embodiments described below and throughout this specification, unless otherwise expressly stated, "acalabrutinib" refers to the free base of acalabrutinib or a pharmaceutically acceptable salt thereof; "capapasetinib" refers to the free base of capapasetinib or a pharmaceutically acceptable salt thereof; and the amount of each dose of acalabrutinib or capapasetinib stated therein is based on the amount of the free base of acalabrutinib or capapasetinib, respectively.

An effective amount of acalabrutinib and capapasetinib can be administered simultaneously, separately, or sequentially as a single or multiple dose via any acceptable administration modality for agents with similar efficacy. These administration modalities include rectal, buccal, intranasal, and transdermal routes, intra-arterial, intravenous, parenteral, intramuscular, subcutaneous, oral, topical, or inhalation. In a preferred embodiment, both acalabrutinib and capapasetinib are administered orally to human subjects.

In some embodiments, acalatinib and capacitinib are administered to the subject simultaneously.

In some embodiments, acalatinib and capacitinib are administered to the subject separately.

In some embodiments, acalatinib and capacitinib are administered to the subject sequentially.

In some embodiments, acalabrutinib is administered before capabrutinib administration 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 capabrutinib administration during the dosing cycle. In another aspect, 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 capabrutinib administration during the dosing cycle. In yet another aspect, 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 capabrutinib administration during the dosing cycle.

In some embodiments, capapasetinib is administered before acalabrutinib administration during the dosing cycle. In one aspect, capapasetinib 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 administration during the dosing cycle. In another aspect, capapasetinib 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 administration during the dosing cycle. In yet another aspect, capapasetinib 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 administration during the dosing cycle.

A. Acalatinib dosage and administration regimen

In combination with capapasetinib, acalotinib is typically administered at a daily dose of about 50 mg to about 400 mg. In some embodiments, acalotinib is administered at a daily dose of about 50 mg to about 350 mg. In one aspect, acalotinib is administered at a daily dose of about 50 mg to about 300 mg. In another aspect, acalotinib is administered at a daily dose of about 50 mg to about 250 mg. In another aspect, acalotinib is administered at a daily dose of about 75 mg to about 225 mg. In another aspect, acalotinib is administered at a daily dose of about 100 mg to about 200 mg. In another aspect, acalotinib is administered at a daily dose of about 75 mg to about 125 mg. In another aspect, acalotinib is administered at a daily dose of about 175 mg to about 225 mg. In another aspect, acalotinib is administered at a daily dose of about 100 mg. In another aspect, acalotinib is administered at a daily dose of about 200 mg. In another aspect, acalotinib is administered at a daily dose of about 400 mg.

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

In some embodiments, acalotinib is administered to the subject twice daily (BID). In one aspect, acalotinib is administered twice daily at a dose of about 25 mg to about 200 mg. In another aspect, acalotinib is administered twice daily at a dose of about 25 mg to about 150 mg. In another aspect, acalotinib is administered twice daily at a dose of about 50 mg to about 125 mg. In another aspect, acalotinib is administered twice daily at a dose of about 90 mg to about 110 mg. In another aspect, acalotinib is administered twice daily at a dose of about 95 mg to about 105 mg. In another aspect, acalotinib is administered twice daily at a dose of about 100 mg. In another aspect, acalotinib is initially administered twice daily at a dose of about 100 mg, and subsequently the dose is reduced to about 100 mg once daily during the dosing cycle. In another aspect, acalotinib is administered twice daily at a dose of about 200 mg.

In some embodiments, acalabrutinib is administered according to a continuous dosing schedule. The continuous dosing schedule does not include holidays within the dosing cycle. For example, in a seven-day dosing cycle, acalabrutinib will be administered continuously on days 1, 2, 3, 4, 5, 6, and 7. The dosing cycle is then repeated for the required 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 another aspect, the dosing cycle is 28 days. The administration of acalabrutinib and the repetition of the dosing cycle may continue as long as it is tolerable and beneficial to the subject.

In some embodiments, acalotinib is administered to the subject according to an intermittent dosing schedule. An intermittent dosing schedule may include dose holidays compared to a continuous dosing schedule. For example, intermittent dosing of acalotinib over a seven-day dosing cycle might be given on days 1 and 2, but not on days 3, 4, 5, 6, or 7. The dosing cycle is then repeated. This may be referred to as a 2-day dosing/5-day stop schedule, where acalotinib is given for two days followed by a five-day holiday. Similarly, intermittent dosing of acalotinib over a seven-day dosing cycle might be given on days 1, 2, 3, and 4, but not on days 5, 6, or 7. The dosing cycle is then repeated. This may be referred to as a 4-day dosing/3-day stop schedule, where acalotinib is given for four days, followed by a three-day holiday.

B. Carpacitinib Dosage and Administration Regimen

In combination with acalabrutinib, capapasetinib is typically administered to the subject at a daily dose of about 100 mg to about 1600 mg. In some embodiments, capapasetinib is administered at a daily dose of about 150 mg to about 1500 mg. In one aspect, capapasetinib is administered at a daily dose of about 200 mg to about 1400 mg. In another aspect, capapasetinib is administered at a daily dose of about 300 mg to about 1300 mg. In another aspect, capapasetinib is administered at a daily dose of about 400 mg to about 1200 mg. In another aspect, capapasetinib is administered at a daily dose of about 500 mg to about 1100 mg. In another aspect, capapasetinib is administered at a daily dose of about 600 mg to about 1000 mg.

In some embodiments, cappacitinib is administered to the subject once daily (QD). In one aspect, cappacitinib is administered once daily at a dose of about 100 mg to about 1000 mg. In another aspect, cappacitinib is administered once daily at a dose of about 150 mg to about 900 mg. In another aspect, cappacitinib is administered once daily at a dose of about 200 mg to about 850 mg. In another aspect, cappacitinib is administered once daily at a dose of about 250 mg to about 800 mg. In another aspect, cappacitinib is administered once daily at a dose of about 300 mg to about 750 mg. In another aspect, cappacitinib is administered once daily at a dose of about 350 mg to about 700 mg. In another aspect, cappacitinib is administered once daily at a dose of about 400 mg to about 650 mg.

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

In some embodiments, cappacitinib is administered according to a continuous dosing schedule. In one aspect, for example, cappacitinib 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. The administration of cappacitinib and the repetition of dosing cycles can continue as long as it is tolerable and beneficial to the subject.

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

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

In some embodiments, cappacitinib is administered to subjects according to an intermittent dosing schedule. For example, intermittent dosing of cappacitinib has greater efficacy and/or tolerability compared to a continuous dosing schedule. In one aspect, cappacitinib is administered intermittently on a 1-day/6-day dosing schedule (i.e., cappacitinib is administered for one day, followed by a six-day break). In another aspect, cappacitinib is administered intermittently on a 2-day/5-day dosing schedule (i.e., cappacitinib is administered for two days, followed by a five-day break). In yet another aspect, cappacitinib is administered intermittently on a 3-day/4-day dosing schedule (i.e., cappacitinib is administered for three days, followed by a four-day break). In yet another aspect, cappacitinib is administered intermittently on a 4-day/3-day dosing schedule (i.e., cappacitinib is administered for four days, followed by a three-day break). In yet another aspect, cappacitinib is administered intermittently on a 5-day/2-day dosing schedule (i.e., cappacitinib is administered for five days, followed by a two-day break). On the other hand, cappacitinib is administered intermittently on a 6-day/1-day schedule (i.e., cappacitinib is administered for six days, followed by a one-day break).

Then, the dosing cycles of these embodiments are repeated as long as the subjects tolerate them and find them beneficial. 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.

In some embodiments, the dosing cycle is 28 days, but no co-administration of cappacitinib is given to the subjects during the fourth week of the dosing cycle (i.e., there is a cappacitinib drug holiday during the last week of the dosing cycle).

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

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

C. Illustrative Examples

In some embodiments, both acalabrutinib and capapasetinib are administered continuously during a dosing cycle. In one aspect, both acalabrutinib and capapasetinib are administered orally continuously during a dosing cycle. In another aspect, both acalabrutinib and capapasetinib are administered orally continuously during a dosing cycle, with the amount of acalabrutinib administered twice daily being approximately 75 mg to approximately 125 mg. In another aspect, both acalabrutinib and capapasetinib are administered orally continuously during a dosing cycle, with the initial amount of acalabrutinib administered twice daily being approximately 100 mg, and subsequently, during the dosing cycle, the amount of acalabrutinib administered once daily being reduced to approximately 100 mg.

In some embodiments, acalabrutinib is administered continuously during a dosing cycle, while capapasetinib is administered intermittently during a dosing cycle. In one aspect, acalabrutinib is administered orally continuously during a dosing cycle, while capapasetinib is administered orally intermittently during a dosing cycle. In another aspect, acalabrutinib is administered orally continuously during a dosing cycle, while capapasetinib is administered orally intermittently during a dosing cycle, and the amount of acalabrutinib administered twice daily is about 75 mg to about 125 mg. In another aspect, acalabrutinib is administered orally continuously during a dosing cycle, while capapasetinib is administered orally intermittently during a dosing cycle, and the amount of acalabrutinib administered twice daily is about 100 mg. In yet another aspect, acalabrutinib is administered orally continuously during a dosing cycle, while capapasetinib is administered orally intermittently during a dosing cycle, initially at the start of the dosing cycle the amount of acalabrutinib administered twice daily is about 100 mg, and subsequently, during the dosing cycle, the amount of acalabrutinib administered once daily is reduced to a dose of about 100 mg.

In some embodiments, acalabrutinib is administered continuously during a dosing cycle, while capabrutinib is administered intermittently during the dosing cycle on a 1-day/6-day dosing schedule. In one aspect, acalabrutinib is administered orally twice daily at a dose of about 75 mg to about 125 mg during a dosing cycle, while capabrutinib is administered orally intermittently during the dosing cycle on a 1-day/6-day dosing schedule. In another aspect, acalabrutinib is administered orally twice daily at a dose of about 100 mg during a dosing cycle, while capabrutinib is administered orally intermittently during the dosing cycle on a 1-day/6-day dosing schedule, wherein the initial dose of acalabrutinib administered twice daily at the start of the dosing cycle is about 100 mg, and subsequently, the dose of acalabrutinib administered once daily during the dosing cycle is reduced to about 100 mg.

In some embodiments, acalabrutinib is administered continuously during a dosing cycle, while capasacetinib is administered intermittently during the dosing cycle on a 2-day/5-day dosing schedule. In one aspect, acalabrutinib is administered orally twice daily at a dose of about 75 mg to about 125 mg during a dosing cycle, while capasacetinib is administered orally intermittently during the dosing cycle on a 2-day/5-day dosing schedule. In another aspect, acalabrutinib is administered orally twice daily at a dose of about 100 mg during a dosing cycle, while capasacetinib is administered orally intermittently during the dosing cycle on a 2-day/5-day dosing schedule, wherein the initial dose of acalabrutinib administered twice daily at the start of the dosing cycle is about 100 mg, and subsequently, the dose of acalabrutinib administered once daily during the dosing cycle is reduced to about 100 mg.

In some embodiments, acalabrutinib is administered continuously during a dosing cycle, while capasacitinib is administered intermittently during the dosing cycle on a 3-day/4-day dosing schedule. In one aspect, acalabrutinib is administered orally twice daily at a dose of about 75 mg to about 125 mg during a dosing cycle, while capasacitinib is administered orally intermittently during the dosing cycle on a 3-day/4-day dosing schedule. In another aspect, acalabrutinib is administered orally twice daily at a dose of 100 mg during a dosing cycle, while capasacitinib is administered orally intermittently during the dosing cycle on a 3-day/4-day dosing schedule, wherein the initial dose of acalabrutinib administered twice daily at the start of the dosing cycle is about 100 mg, and subsequently, the dose of acalabrutinib administered once daily during the dosing cycle is reduced to about 100 mg.

In some embodiments, acalabrutinib is administered continuously during a dosing cycle, while capasacitinib is administered intermittently during the dosing cycle on a 4-day/3-day dosing schedule. In one aspect, acalabrutinib is administered orally twice daily at a dose of about 75 mg to about 125 mg during a dosing cycle, while capasacitinib is administered orally intermittently during the dosing cycle on a 4-day/3-day dosing schedule. In another aspect, acalabrutinib is administered orally twice daily at a dose of 100 mg during a dosing cycle, while capasacitinib is administered orally intermittently during the dosing cycle on a 4-day/3-day dosing schedule, wherein the initial dose of acalabrutinib administered twice daily at the start of the dosing cycle is about 100 mg, and subsequently, the dose of acalabrutinib administered once daily during the dosing cycle is reduced to about 100 mg.

In some embodiments, acalabrutinib is administered continuously during a dosing cycle, while capasacetinib is administered intermittently during the dosing cycle on a 5-day/2-day dosing schedule. In one aspect, acalabrutinib is administered orally twice daily at a dose of about 75 mg to about 125 mg during a dosing cycle, while capasacetinib is administered orally intermittently during the dosing cycle on a 5-day/2-day dosing schedule. In another aspect, acalabrutinib is administered orally twice daily at a dose of 100 mg during a dosing cycle, while capasacetinib is administered orally intermittently during the dosing cycle on a 5-day/2-day dosing schedule, wherein the initial dose of acalabrutinib administered twice daily at the start of the dosing cycle is about 100 mg, and subsequently, the dose of acalabrutinib administered once daily during the dosing cycle is reduced to about 100 mg.

In some embodiments, acalabrutinib is administered continuously during a dosing cycle, while capabrutinib is administered intermittently during a dosing cycle on a 6-day/1-day schedule. In one aspect, acalabrutinib is administered orally twice daily at a dose of about 75 mg to about 125 mg during a dosing cycle, while capabrutinib is administered orally intermittently during a dosing cycle on a 6-day/1-day schedule. In another aspect, acalabrutinib is administered orally twice daily at a dose of about 100 mg during a dosing cycle, while capabrutinib is administered orally intermittently during a dosing cycle on a 6-day/1-day schedule. In yet another aspect, acalabrutinib is administered orally continuously during a dosing cycle, while capabrutinib is administered orally intermittently during a dosing cycle on a 6-day/1-day schedule, wherein the initial dose of acalabrutinib administered twice daily at the start of the dosing cycle is about 100 mg, and subsequently, the dose of acalabrutinib administered once daily during the dosing cycle is reduced to about 100 mg.

In some embodiments, both acalabrutinib and capapasetinib are administered orally continuously during a dosing cycle, with acalabrutinib administered at a dose of about 75 mg to about 225 mg daily, and capapasetinib administered at a dose of about 100 mg to about 1600 mg daily. In one aspect, both acalabrutinib and capapasetinib are administered orally continuously during a dosing cycle, with acalabrutinib administered once daily at a dose of about 75 mg to about 225 mg, and capapasetinib administered once daily at a dose of about 100 mg to about 900 mg. In another aspect, both acalabrutinib and capapasetinib are administered orally continuously during a dosing cycle, with acalabrutinib administered twice daily at a dose of about 75 mg to about 125 mg, and capapasetinib administered twice daily at a dose of about 150 mg to about 850 mg. On the other hand, both acalabrutinib and capapasetinib are administered orally continuously during a dosing cycle. Acalabrutinib is administered twice daily at a dose of approximately 100 mg, while capapasetinib is administered twice daily at a dose of approximately 200 mg to approximately 800 mg. Alternatively, both acalabrutinib and capapasetinib are administered orally continuously during a dosing cycle. Initially, acalabrutinib is administered twice daily at a dose of approximately 100 mg, capapasetinib is administered twice daily at a dose of approximately 200 mg to approximately 800 mg, and subsequently, the dose of acalabrutinib administered once daily is reduced to approximately 100 mg throughout the dosing cycle.

In some embodiments, acalabrutinib is administered continuously during a dosing cycle, while capabrutinib is administered intermittently during the dosing cycle. The daily dose of acalabrutinib is approximately 75 mg to approximately 225 mg, while the daily dose of capabrutinib is approximately 100 mg to approximately 1600 mg. In one aspect, acalabrutinib is administered continuously during a dosing cycle, while capabrutinib is administered intermittently during the dosing cycle. On each day of administration, acalabrutinib is administered once daily at a dose of approximately 75 mg to approximately 225 mg, while capabrutinib is administered once daily at a dose of approximately 100 mg to approximately 900 mg. In another aspect, acalabrutinib is administered continuously during a dosing cycle, while capabrutinib is administered intermittently during the dosing cycle. On each day of administration, acalabrutinib is administered twice daily at a dose of approximately 75 mg to approximately 125 mg, while capabrutinib is administered twice daily at a dose of approximately 150 mg to approximately 850 mg. On the other hand, acalabrutinib is administered continuously within a dosing cycle, while capabrutinib is administered intermittently within a dosing cycle. On each day of administration, acalabrutinib is administered twice daily at a dose of approximately 100 mg, while capabrutinib is administered twice daily at a dose of approximately 200 mg to approximately 800 mg. Alternatively, acalabrutinib is administered continuously within a dosing cycle, while capabrutinib is administered intermittently within a dosing cycle. On each day of administration, at the beginning of the dosing cycle, acalabrutinib is initially administered twice daily at a dose of approximately 100 mg, then capabrutinib is administered twice daily at a dose of approximately 200 mg to approximately 800 mg, and subsequently, throughout the dosing cycle, the dose of acalabrutinib administered once daily is reduced to approximately 100 mg.

In some embodiments, acalabrutinib is administered continuously during a dosing cycle, while capabrutinib is administered intermittently during a dosing cycle on a 2-day/5-day dosing schedule, with the daily dose of acalabrutinib being about 75 mg to about 225 mg, and the daily dose of capabrutinib being about 100 mg to about 1600 mg. In one aspect, acalabrutinib is administered orally continuously during a dosing cycle, while capabrutinib is administered orally intermittently during a dosing cycle on a 2-day/5-day dosing schedule, with the daily dose of acalabrutinib being about 75 mg to about 225 mg once daily, and the daily dose of capabrutinib being about 100 mg to about 900 mg once daily. On the other hand, acalatinib is administered orally continuously during the dosing cycle, while capacitinib is administered orally intermittently on a 2-day dosing/5-day stop schedule. On each day of administration, acalatinib is administered twice daily at a dose of about 75 mg to about 125 mg, while capacitinib is administered twice daily at a dose of about 150 mg to about 850 mg.

In some embodiments, acalabrutinib is administered orally continuously during a dosing cycle, while capabrutinib is administered orally intermittently on a 2-day dosing/5-day stop schedule. On each day of administration, acalabrutinib is administered twice daily at a dose of approximately 100 mg, while capabrutinib is administered twice daily at a dose of approximately 200 mg to approximately 800 mg. In another aspect, acalabrutinib is administered orally continuously during a dosing cycle, while capabrutinib is administered orally intermittently on a 2-day dosing/5-day stop schedule. On each day of administration, at the start of the dosing cycle, acalabrutinib is initially administered twice daily at a dose of approximately 100 mg, then capabrutinib is administered twice daily at a dose of approximately 200 mg to approximately 800 mg, and subsequently, during the dosing cycle, the dose of acalabrutinib administered once daily is reduced to approximately 100 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capapasetinib is administered orally intermittently on a 2-day/5-day dosing schedule. On each day of administration, acalabrutinib is administered twice daily at a dose of approximately 100 mg, while capapasetinib is administered twice daily at a dose of approximately 250 mg to approximately 350 mg. (This text is repeated four times in the original.) On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capasacetinib is administered orally intermittently on a 2-day/5-day dosing schedule. On each day of administration, acalabrutinib is administered twice daily at a dose of approximately 100 mg, while capasacetinib is administered twice daily at a dose of approximately 550 mg to approximately 650 mg. (This text is repeated four times in the original.) On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capapasetinib is administered orally intermittently on a 2-day/5-day dosing schedule. Acalabrutinib is administered twice daily at a dose of approximately 100 mg, while capapasetinib is administered twice daily at a dose of approximately 320 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capapasetinib is administered orally intermittently on a 2-day/5-day dosing schedule. Acalabrutinib is administered twice daily at a dose of approximately 100 mg, while capapasetinib is administered twice daily at a dose of approximately 400 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capapasetinib is administered orally intermittently on a 2-day/5-day dosing schedule. Acalabrutinib is administered twice daily at a dose of approximately 100 mg, while capapasetinib is administered twice daily at a dose of approximately 480 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capapasetinib is administered orally intermittently on a 2-day/5-day dosing schedule. Acalabrutinib is administered twice daily at a dose of approximately 100 mg, while capapasetinib is administered twice daily at a dose of approximately 560 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capapasetinib is administered orally intermittently on a 2-day/5-day dosing schedule. Acalabrutinib is administered twice daily at a dose of approximately 100 mg, while capapasetinib is administered twice daily at a dose of approximately 640 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capapasetinib is administered orally intermittently on a 2-day/5-day dosing schedule. Acalabrutinib is administered twice daily at a dose of approximately 100 mg, while capapasetinib is administered twice daily at a dose of approximately 800 mg.

In some embodiments, acalabrutinib is administered continuously during a dosing cycle, while capabrutinib is administered intermittently during a dosing cycle on a 4-day dosing/3-day stop schedule, with the daily dose of acalabrutinib being about 75 mg to about 225 mg, and the daily dose of capabrutinib being about 100 mg to about 1600 mg. In one aspect, acalabrutinib is administered orally continuously during a dosing cycle, while capabrutinib is administered orally intermittently during a dosing cycle on a 4-day dosing/3-day stop schedule, with the daily dose of acalabrutinib being about 75 mg to about 225 mg once daily, and the daily dose of capabrutinib being about 100 mg to about 900 mg once daily. On the other hand, acalatinib is administered orally continuously during the dosing cycle, while capacitinib is administered orally intermittently on a 4-day dosing/3-day stop schedule. On each day of administration, acalatinib is administered twice daily at a dose of about 75 mg to about 125 mg, while capacitinib is administered twice daily at a dose of about 150 mg to about 850 mg.

In some embodiments, acalabrutinib is administered orally continuously during a dosing cycle, while capabrutinib is administered orally intermittently on a 4-day dosing/3-day stop schedule. On each day of administration, acalabrutinib is administered twice daily at a dose of approximately 100 mg, and capabrutinib is administered twice daily at a dose of approximately 200 mg to approximately 800 mg. In another aspect, acalabrutinib is administered orally continuously during a dosing cycle, while capabrutinib is administered orally intermittently on a 4-day dosing/3-day stop schedule. On each day of administration, acalabrutinib is administered twice daily at a dose of approximately 100 mg, and capabrutinib is administered twice daily at a dose of approximately 200 mg to approximately 750 mg, and subsequently, during the dosing cycle, the dose of acalabrutinib administered once daily is reduced to approximately 100 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capapasetinib is administered orally intermittently on a 4-day dosing/3-day stop-dosing schedule. On each day of administration, acalabrutinib is administered twice daily at a dose of approximately 100 mg, while capapasetinib is administered twice daily at a dose of approximately 200 mg to approximately 700 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capapasetinib is administered orally intermittently on a 4-day dosing/3-day stop-dosing schedule. On each day of administration, acalabrutinib is administered twice daily at a dose of approximately 100 mg, while capapasetinib is administered twice daily at a dose of approximately 250 mg to approximately 350 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capapasetinib is administered orally intermittently on a 4-day dosing/3-day stop-dosing schedule. On each day of administration, acalabrutinib is administered twice daily at a dose of approximately 100 mg, while capapasetinib is administered twice daily at a dose of approximately 350 mg to approximately 450 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capapasetinib is administered orally intermittently on a 4-day dosing/3-day stop-dosing schedule. On each day of administration, acalabrutinib is administered twice daily at a dose of approximately 100 mg, while capapasetinib is administered twice daily at a dose of approximately 450 mg to approximately 550 mg. (This text is repeated four times in the original.) On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capapasetinib is administered orally intermittently on a 4-day dosing/3-day stop-dosing schedule. Acalabrutinib is administered twice daily at a dose of approximately 100 mg, while capapasetinib is administered twice daily at a dose of approximately 200 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capapasetinib is administered orally intermittently on a 4-day dosing/3-day stop-dosing schedule. Acalabrutinib is administered twice daily at a dose of approximately 100 mg, while capapasetinib is administered twice daily at a dose of approximately 280 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capapasetinib is administered orally intermittently on a 4-day dosing/3-day stop-dosing schedule. Acalabrutinib is administered twice daily at a dose of approximately 100 mg, while capapasetinib is administered twice daily at a dose of approximately 320 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capapasetinib is administered orally intermittently on a 4-day dosing/3-day stop-dosing schedule. Acalabrutinib is administered twice daily at a dose of approximately 100 mg, while capapasetinib is administered twice daily at a dose of approximately 360 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capapasetinib is administered orally intermittently on a 4-day dosing/3-day stop-dosing schedule. Acalabrutinib is administered twice daily at a dose of approximately 100 mg, while capapasetinib is administered twice daily at a dose of approximately 400 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capapasetinib is administered orally intermittently on a 4-day dosing/3-day stop-dosing schedule. Acalabrutinib is administered twice daily at a dose of approximately 100 mg, while capapasetinib is administered twice daily at a dose of approximately 480 mg. On the other hand, acalabrutinib is administered orally continuously during the dosing cycle, while capabrutinib is administered orally intermittently on a 4-day dosing/3-day stop schedule. On each day of administration, acalabrutinib is administered twice daily at a dose of approximately 100 mg, while capabrutinib is administered twice daily at a dose of approximately 640 mg.

IV. Pharmaceutical Compositions

This disclosure further relates in part to pharmaceutical compositions comprising acalatinib, capapasetinib, and a pharmaceutically acceptable carrier.

In some embodiments, the pharmaceutical composition comprises:

Compounds having formula I:

Or its pharmaceutically acceptable salt;

Compounds having formula II:

Or its pharmaceutically acceptable salt; and

Pharmaceutically acceptable carrier.

In one aspect, the composition comprises acalotinib and capapasetinib in their free base form. In another aspect, the composition comprises acalotinib and capapasetinib in their pharmaceutically acceptable salt form. In yet another aspect, the composition comprises one of acalotinib and capapasetinib in their free base form, and the other of acalotinib and capapasetinib in their pharmaceutically acceptable salt form.

The pharmaceutical composition is typically formulated to provide a therapeutically effective amount as described in this specification. The pharmaceutical composition may also contain one or more pharmaceutically acceptable excipients, carriers, diluents, and/or fillers. Acalatinib and capacratetinib, as active ingredients, can be combined with a drug carrier in a close mixture according to conventional pharmaceutical formulation techniques. The carrier can be in various forms depending on the desired formulation for administration.

In some embodiments, the pharmaceutical composition is suitable for oral administration. Pharmaceutical compositions suitable for oral administration may be presented in unit dosage forms, such as tablets, capsules, liquids, or aerosols, each containing a predetermined amount of the 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.

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; capapasetinib or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. In another embodiment, the pharmaceutical composition is an oral unit dosage form comprising acalabrutinib or a pharmaceutically acceptable salt thereof in an amount of about 100 mg; capapasetinib or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. In yet another embodiment, 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; capapasetinib 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; cappacitinib 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; cappacitinib 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; cappacitinib 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 about 100 mg of acalotinib or a pharmaceutically acceptable salt thereof; about 200 mg to about 800 mg of cappacitinib or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. In yet another aspect, the pharmaceutical composition is an oral unit dosage form comprising about 100 mg of acalotinib or a pharmaceutically acceptable salt thereof; about 300 mg to about 700 mg of cappacitinib or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

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

V. Reagent Kit

This disclosure further relates in part to kits containing acalabrutinib and capapasetinib. These kits contain acalabrutinib or a pharmaceutically acceptable salt thereof, and each of capapasetinib or a pharmaceutically acceptable salt thereof, alone or in combination in suitable packaging. These kits are intended for the simultaneous, separate, or sequential co-administration of acalabrutinib or a pharmaceutically acceptable salt thereof, and capapasetinib or a pharmaceutically acceptable salt thereof. These kits optionally include written materials that may include instructions for use, discussions of clinical studies, and a list of side effects. Such kits may also contain information indicating or determining the activity and/or benefits of the composition, such as scientific literature references, packaging inserts, clinical trial results and/or summaries of these, and/or information describing dosing, administration, side effects, drug interactions, or other information useful to healthcare providers. This information may be based on the results of various studies, such as studies using laboratory animals involving in vivo models and studies based on human clinical trials.

In some embodiments, the kit comprises:

A first pharmaceutical composition comprising a compound having formula I:

Or its pharmaceutically acceptable salts, and pharmaceutically acceptable carriers;

A second pharmaceutical composition comprising a compound having formula II:

Or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier thereof.

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

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

In some embodiments, the first and second pharmaceutical compositions are each oral unit dosage forms, the first pharmaceutical composition comprising acalabrutinib or a pharmaceutically acceptable salt thereof in an amount of about 75 mg to about 125 mg, and the second pharmaceutical composition comprising capapasetinib or a pharmaceutically acceptable salt thereof in an amount of about 100 mg to about 900 mg. In one aspect, the first and second pharmaceutical compositions are each oral unit dosage forms, the first pharmaceutical composition comprising acalabrutinib or a pharmaceutically acceptable salt thereof in an amount of about 75 mg to about 125 mg, and the second pharmaceutical composition comprising capapasetinib or a pharmaceutically acceptable salt thereof in an amount of about 200 mg to about 800 mg. In another aspect, the first and second pharmaceutical compositions are each oral unit dosage forms, the first pharmaceutical composition comprising acalabrutinib or a pharmaceutically acceptable salt thereof in an amount of about 75 mg to about 125 mg, and the second pharmaceutical composition comprising capapasetinib or a pharmaceutically acceptable salt thereof in an amount of about 300 mg to about 700 mg.

In some embodiments, the first pharmaceutical composition and the second pharmaceutical composition are each an oral unit dosage form, the first pharmaceutical composition comprising acalabrutinib or a pharmaceutically acceptable salt thereof in an amount of about 100 mg, and the second pharmaceutical composition comprising capapasetinib 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 comprising acalabrutinib or a pharmaceutically acceptable salt thereof in an amount of about 100 mg, and the second pharmaceutical composition comprising capapasetinib 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, the first pharmaceutical composition comprising acalabrutinib or a pharmaceutically acceptable salt thereof in an amount of about 100 mg, and the second pharmaceutical composition comprising capapasetinib or a pharmaceutically acceptable salt thereof in an amount of about 300 mg to about 700 mg.

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

Or a pharmaceutically acceptable salt thereof; compounds having formula II:

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 acalotinib 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 acalotinib or a pharmaceutically acceptable salt thereof in an amount of about 100 mg.

In some embodiments, the kit may further comprise another active pharmaceutical ingredient. In one aspect, acalabrutinib or a pharmaceutically acceptable salt thereof, and kappacitinib or a pharmaceutically acceptable salt thereof, along with another active pharmaceutical ingredient, are provided as separate pharmaceutical compositions in separate containers within the kit. In another aspect, acalabrutinib or a pharmaceutically acceptable salt thereof, and kappacitinib or a pharmaceutically acceptable salt thereof, along with the pharmaceutical preparation, are provided as a single composition in a container within the kit. Suitable packaging and other articles of use (e.g., measuring cups for liquid formulations, foil packaging to minimize air exposure, etc.) are known in the art and may be included in the kit. The kit may be provided, sold, and/or marketed to healthcare providers, including physicians, nurses, pharmacists, prescribing personnel, etc. In selected embodiments, the kit may also be sold directly to consumers.

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. This kit is for the simultaneous or separate co-administration of acalabrutinib, capapasetinib, cyclophosphamide, doxorubicin, vincristine, and/or prednisone.

The above-described kit is preferably used for treating B-cell malignancies described in this specification. For example, in one aspect, the B-cell malignancy is non-Hodgkin's lymphoma. In another aspect, the B-cell malignancy is diffuse large B-cell lymphoma. In yet another aspect, the B-cell malignancy is activated B-cell (ABC) diffuse large B-cell lymphoma.

VI. Examples

Example 1: In vitro pharmacological study in diffuse large B-cell lymphoma cell lines

A study was conducted in a group of diffuse large B-cell lymphoma cell lines to determine whether the combination of acalabrutinib and camapacetinib could provide benefits, as measured by enhanced proliferation inhibition and loss of cell viability, and indicated by the Loewe and HSA synergistic scores. Furthermore, the study explored the mechanism of action of the acalabrutinib and camapacetinib combination using Western blot analysis.

Cell viability assay

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

Treatment of cells with capapasetinib alone inhibited the growth of the GCB DLBCL cell line subset, but had the least effect on the growth of the ABC DLBCL cell line subset (see Table EX-1A below). Treatment of cells with acalatinib alone inhibited the growth of the ABC DLBCL cell line subset, but had the least effect on the growth of the tested GCB DLBCL cell line subset (see Table EX-1A below).

Table EX-1A

However, as shown by the Loewe and HSA synergistic scores reported in Tables EX-1B and EX-1C, respectively, treatment of cells with the combination of acalatinib and capacitinib enhanced cell growth inhibition and loss of cell viability in both ABC-DLBCL cell lines, TMD8 and OCI-LY10. A synergistic score greater than 3 (>3) indicates potential combined benefits in each synergistic model. See, for example, 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 therapy for networked systems”, Nat. Rev. Drug. Discov., 4, 71-78 (2005).

Table EX-1B

LOEWE Synergy Rating

cell lines Disease indications Disease subtypes Acaltinib + Capasetinib 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

Table EX-1C

HSA co-score of the combination

cell lines Disease indications Disease subtypes Acaltinib + Capasetinib 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

Figure 1 shows a combined signal heatmap (% growth signal inhibition) of TMD8 cells and OCI-LY10 cells 72 hours after treatment with a combination of acalatinib and capapasetinib.

This study showed that, in the human ABC-DLBCL cell line subpopulation, the combination of acalatinib and capapasetinib demonstrated combination benefits compared to single agents, and resulted in enhanced loss of cell viability.

Western blot analysis

For Western blot analysis, cells were seeded into 6-well plates and treated with 0.1% DMSO, 1 μM cappacitinib, 100 nM acalotinib, or a combination of 1 μM cappacitinib and 100 nM acalotinib for 2 h or 24 h. 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 phosphorylated proteins of interest were probed.

Figure 2 shows Western blots of TMD8 and OCI-LY10 cells 2 hours or 24 hours after treatment with the medium, acalanotetinib, camapacetinib, or a combination of acalanotetinib and camapacetinib. Treatment of TMD8 and OCI-LY10 cells with 1 μM camapacetinib resulted in increased phosphorylation of AKTS473 and decreased phosphorylation of downstream substrates PRAS40, GSK3β, FOXO, and S6. As indicated by the decreased phosphorylation of AKTS473, treatment with 100 nM acalanotetinib induced decreased phosphorylation of BTK and also inhibited AKT signaling. Treatment with the combination of camapacetinib and acalanotetinib resulted in reduced induction of AKTS473 phosphorylation and enhanced inhibition of S6 phosphorylation. Furthermore, this combination induced cleavage of caspase-3 at 24 hours, indicating enhanced apoptosis in these cell lines.

In this study on the mechanism of action in TMD8 and OCI-LY10 cells, the combination of acalatinib and capapasetinib resulted in the inhibition of AKT signaling and BTK, and further induced caspase activation.

Example 2: In vivo therapeutic effects in xenotransplantation models

A. In vivo efficacy in a TMD8-person ABC-DLBCL xenograft model

In a TMD8 human ABC-DLBCL xenograft mouse model, a study was conducted to evaluate the in vivo efficacy of acalabrutinib and capapasetinib monotherapy and combination therapy. Specifically, SCID mice bearing xenografts derived from the TMD8 human activated B-cell (ABC) diffuse large B-cell lymphoma (DLBCL) cell line were evaluated after treatment with acalabrutinib monotherapy, capapasetinib monotherapy, or combination therapy.

TMD8 human ABC-DLBCL tumor cells (5 x 10⁶ cells/mouse) were subcutaneously implanted into female CB.17 SCID mice. Mice were randomly assigned to five groups based on tumor volume and treated with the appropriate mediator (0.5% MC/0.1% Tween-80), 130 mg/kg cappacitinib, 20 mg/kg acalabrutinib, or a combination of cappacitinib and acalabrutinib. Cappacitinib was prepared in 10% DMSO/25% Kleptose pH=5, and acalabrutinib was prepared in 0.5% MC/0.1% Tween-80. Ten days post-implantation, all medications were administered orally according to the schedule listed in Table EX-2A below. Tumor length and width were measured with calipers, and tumor volume was calculated using the formula (length x ^width² ) * π/6. On day 20 of the efficacy study, a small sample (20 μl) was obtained from the tail vein to evaluate the plasma pharmacokinetics of acalabrutinib and capapasetinib.

After 24 days of treatment, capapasetinib monotherapy resulted in 0% tumor growth inhibition (TGI), acalabrutinib monotherapy resulted in 81% TGI, and the combination of the two agents resulted in 98% tumor regression. All treatments were well tolerated during the 24-day study period, with a maximum weight loss of 6%. Steady-state unbound plasma concentrations of acalabrutinib and capapasetinib were measured in three mice from the monotherapy and combination groups at time points of 1, 2, 4, and 8 hours during the study period. Drug exposure levels of acalabrutinib and capapasetinib were similar after oral administration of either monotherapy or combination. Overall results are summarized in Table EX-2A below.

Table EX-2A

*On day 34, the vector group had only n=4 mice.

**N/A = Not applicable**

Figure 3 shows the effect of treatment with the carcass, acalatinib, campacitinib, or a combination of acalatinib and campacitinib on tumor volume. Figure 4 shows steady-state drug exposure after treatment with acalatinib, campacitinib, or a combination of acalatinib and campacitinib. Figure 5 shows the effect of treatment with the carcass, acalatinib, campacitinib, or a combination of acalatinib and campacitinib on body weight.

Oral combination therapy with acalatinib and capapasetinib significantly enhanced antitumor efficacy, resulting in complete regression (98%) in the TMD8 human ABC-DLBCL xenograft model compared to single-agent therapy. In the combination therapy group, mice showed good tolerance to all treatments, with a maximum weight loss of 6%. Pharmacokinetic evaluation revealed comparable drug exposure levels between the acalatinib and capapasetinib single-agent groups and the combination group.

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

In a mouse subcutaneous xenograft model of OCI-Ly10 human ABC-DLBCL, a study was conducted to evaluate the in vivo efficacy of acalabrutinib and capapasetinib as monotherapy and in combination. Specifically, SCID mice bearing xenografts derived from the OCI-Ly10 human activated B-cell (ABC) diffuse large B-cell lymphoma (DLBCL) cell line were evaluated after treatment with acalabrutinib monotherapy, capapasetinib monotherapy, or in combination.

OCI-ly10 human ABC-DLBCL tumor cells (5 x 10⁶ cells/mouse) were subcutaneously implanted into female CB.17 SCID mice. Mice were randomly assigned to five groups based on tumor volume and treated with the appropriate mediator (0.5% MC/0.1% Tween-80), 130 mg/kg cappacitinib, 20 mg/kg acalabrutinib, or a combination of cappacitinib and acalabrutinib. Cappacitinib was prepared in 10% DMSO/25% Kleptose pH=5, and acalabrutinib was prepared in 0.5% MC/0.1% Tween-80. Nineteen days post-implantation, all medications were administered orally according to the schedule listed in Table EX-2B below. Tumor length and width were measured with calipers, and tumor volume was calculated using the formula (length x ^width² ) * π/6.

After 25 days of treatment, capapasetinib monotherapy resulted in 0% tumor growth inhibition (TGI), acalabrutinib monotherapy resulted in 74% TGI, and the combination of the two agents resulted in 78% tumor regression. All treatments were well tolerated during the 25-day study period, with a maximum weight loss of 7%. Overall results are summarized in Table EX-2B below.

Table EX-2B

*N/A = Not applicable

Figure 6 shows the effect of treatment with the carcass, acalatinib, campacitinib, or a combination of acalatinib and campacitinib on tumor volume. Figure 7 shows the effect of treatment with the carcass, acalatinib, campacitinib, or a combination of acalatinib and campacitinib on body weight over a 25-day dosing period.

Combination oral treatment with acalatinib and capapasetinib significantly enhanced antitumor efficacy, resulting in near-complete regression (78%) in the OCI-Ly10 human ABC-DLBCL xenograft model compared to single-agent therapy. Mice in the combination therapy group showed good tolerability to all treatments, with a maximum weight loss of 7%. Pharmacokinetic evaluation revealed comparable drug exposure levels between the acalatinib and capapasetinib single-agent groups and the combination group.

Example 3: In vivo efficacy in a disseminated TMD8-luc2 human ABC-DLBCL model

In a mouse subcutaneous xenograft mouse model of disseminated TMD8-luc2 human ABC-DLBCL, a study was conducted to evaluate the in vivo efficacy of acalabrutinib and camapacetinib as monotherapy and in combination. Specifically, SCID mice with the TMD8 human activated B-cell (ABC) diffuse large B-cell lymphoma (DLBCL) cell line were evaluated after intravenous injection of acalabrutinib monotherapy, camapacetinib monotherapy, or combination therapy.

TMD8 human ABC-DLBCL tumor cells containing luciferase reporter constructs (5 x 10⁶ cells/mouse) were intravenously injected into the tail vein of female CB.17 SCID mice. Tumor burden, body weight, and animal condition were recorded at least twice weekly using the XenogenIVIS imaging system. For Xenogen imaging, mice received an intraperitoneal administration of 150 mg/kg D-luciferin 10–15 minutes prior to imaging. Live mice were imaged under isoflurane anesthesia, and data were analyzed using real-time imaging software (Xenogen). Mice were randomly assigned to five groups based on dorsal and ventral bioluminescence intensity (BLI), receiving treatment with the mediator (0.5% MC/0.1% Tween-80), 130 mg/kg capapasetinib, 20 mg/kg acalabrutinib, or a combination of capapasetinib and capapasetinib, respectively. Carpacitinib was prepared in 10% DMSO/25% Kleptose pH=5, and acalabrutinib was prepared 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 dying mice being euthanized.

As shown in Figure 8, oral combination therapy with acalatinib and capapasetinib significantly enhanced survival benefits in a mouse model of disseminated TMD8-luc2 human ABC DLBCL compared to single-agent therapy. Mice tolerated all treatments well until the survival endpoint was reached.

Example 4: In vivo efficacy in a patient-derived xenotransplantation model

A study was conducted to evaluate the in vivo efficacy of acalabrutinib and camapacetinib in two patient-derived xenograft (PDX) models: the subcutaneous ABC-DLBCL PDX model (LY0257) and the subcutaneous GCB-DLBCL PDX model (LY2214). Primary human tumor fragments (2–3 mm in diameter) from patients in LY2214 and LY0257 were subcutaneously implanted into female NOD/SCID and B/C nude mice, respectively. Mice were randomly assigned to five groups based on tumor volume, receiving either the mediator, acalabrutinib, camapacetinib, or a combination of acalabrutinib and camapacetinib. Acalabrutinib was prepared in 0.5% MC + 0.1% Tween-80, and camapacetinib was prepared in 10% DMSO/25% Kleptose pH 5. When the tumor size is between 150 and 300 ^mm³ , the mediator, acalabrutinib, capabrutinib, and combinations of acalabrutinib and capabrutinib will be administered orally according to the schedule listed in Table EX-2A of Example 2. Two-dimensional tumor volume will be measured twice weekly using calipers, expressed in ^mm³ , using the following formula: “V = (L x W x W)/2, where V is the tumor volume, L is the tumor length (longest tumor size), and W is the tumor width (longest tumor size perpendicular to L).”

Example 5: RNA-seq research

RNA-seq studies were performed on TMD8 cells treated with acalabrutinib, capapasetinib, or a combination of acalabrutinib and capapasetinib. Specifically, TMD8 cells were seeded into six-well plates and treated with 0.1% DMSO, 1 μM capapasetinib, 100 nM acalabrutinib, or a combination of 1 μM capapasetinib and 100 nM acalabrutinib for six hours or 24 hours. Cell pellets were then created and RNA was isolated. RNA samples were sent to Novogene for cDNA library generation and mRNA sequencing (RNA-seq). RNA-seq 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).

Example 6: In vivo pharmacodynamics study

A pharmacodynamic study was conducted to evaluate the response to acalabrutinib and capapasetinib as monotherapy and in combination. TMD8 human ABC-DLBCL tumor cells (5 x 10⁶ cells/mouse) were subcutaneously implanted into female CB.17 SCID mice. Mice were randomized to three groups for evaluation based on tumor volume reaching approximately 300 to 600 ^mm³ , and then treated at 2, 8, 14, and 24 hours with a single acute dose or multiple doses of any of the mediators (0.5% MC/0.1% Tween-80), 20 mg/kg acalabrutinib, 130 mg/kg capapasetinib, or a combination thereof. Pharmacodynamic evaluation of acalabrutinib and capapasetinib will include pS6, pBTK, pAKT, p4EBP1, and pPLCγ2.

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

A phase 1/2, single-arm, open-label, proof-of-concept study was conducted to evaluate the combination of acalabrutinib and camapacitinib in the treatment of patients with relapsed/refractory DLBCL. This study will assess the safety, pharmacokinetics, pharmacodynamics, and efficacy of the acalabrutinib and camapacitinib combination therapy for relapsed/refractory DLBCL, evaluating the clinical potential of the dual BTK and AKT inhibition approach.

Research Objective

The objectives of Part 1 of the clinical trial included determining the dosage and schedule for the combination of carpacitinib and acalacitinib 100 mg BID for evaluation in Part 2 of the clinical trial. The primary objective of Part 2 was to evaluate the safety of the co-administration of acalacitinib and carpacitinib. Secondary objectives of Part 2 included evaluating the pharmacokinetics, pharmacodynamics, and clinical activity of the co-administration of acalacitinib and carpacitinib.

The safety parameters to be evaluated include, but are not limited to, the type, frequency, severity, and relationship to the investigational drug of any treatment-emergent adverse events (TEAEs) or laboratory trial abnormalities, serious adverse events (SAEs), dose-limiting toxicities (DLTs), and adverse events (AEs) that lead to the discontinuation of one or more investigational drugs.

The plasma pharmacokinetics of acalatinib and capapasetinib will be characterized using non-compartmental analysis, and the following pharmacokinetic parameters will be calculated from the plasma concentrations of the analytes as far as possible: (1) AUC _(0-last) : the area under the plasma concentration-time curve calculated using the linear trapezoidal sum from time 0 to time 1, where “last” is the time at which the last measurable concentration was reached; AUC _(0-infinity) : the area under the plasma concentration-time curve calculated using the following formula: AUC _(0-infinity) = AUC _(0-last) + C _(last/λz) , where _λz is the apparent terminal elimination rate constant; _Cmax : the maximum observed plasma concentration; _Tmax : the time at which the maximum plasma concentration was reached (obtained without interpolation); t1 _/2 : the terminal elimination half-life (as far as possible); _λz : the terminal elimination rate constant (as far as possible); CL/F: oral clearance; _Vz /F: oral volume of distribution.

The pharmacodynamic evaluation of acalatinib and capapasetinib will include (1) measuring the BTK occupancy of acalatinib in peripheral blood mononuclear cells (PBMCs) using an acalatinib analog probe, (2) assessing the effects of acalatinib and capapasetinib on biomarkers of B cell function and/or AKT inhibition in PBMCs and/or tumor tissues, and (3) assessing the effects of acalatinib and capapasetinib on circulating tumor DNA (ctDNA). Cell populations and immune markers will be monitored for therapeutic 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 status. Other markers may include Ki67, pS6, pBTK, pAKT, pPRAS40, pGSK3β, p4EBP1, FOXO3, and pPLCγ2.

The clinical activity of acalatinib and capapasetinib was evaluated by measuring overall response rate (ORR = CR + PR), complete response (CR) rate, duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

Table EX-7A below summarizes the research objectives and endpoints.

Table EX-7A

Research Design

This study is an exploratory, multicenter, open-label, non-randomized phase I platform study that will be conducted at approximately 25 sites.

Number of subjects

The study will recruit up to 21 evaluable participants.

Dosage form and strength

Acalatinib is a pharmaceutical product provided as a hard gelatin capsule containing 100 mg of acalatinib for oral administration.

The carpacitinib pharmaceutical product is provided as film-coated tablets containing 160 mg or 200 mg of carpacitinib for oral administration.

Dosage regimen and route of administration

Acalatinib and capapasetinib are administered orally twice daily with 8 ounces (approximately 240 mL) of water (avoid grapefruit juice or Seville orange juice as they may inhibit CYP3A). Dosage is administered approximately 12 hours apart daily (±1 hour windows are permitted). For all doses, subjects must fast (water only) for at least two hours before and at least one hour after administration. Acalatinib capsules and capapasetinib tablets are taken simultaneously and swallowed whole. Acalatinib is taken daily, while capapasetinib is taken on a 4-day dosing, 3-day stop-dosing schedule.

Selection criteria

To be eligible to participate in this study, participants must meet the following inclusion criteria:

1. A diagnosis of relapsed/refractory DLBCL or aggressive lymphoma (i.e., B-cell NHL) with histological evidence according to the criteria established by the World Health Organization (WHO). Eligible histological findings include:

(a) DLBCL (new-onset and transformation, including Likert syndrome)

(b) Large B-cell lymphoma rich in T-cells/histone cells

(c) Primary cutaneous DLBCL

(d) Leg-type primary skin DLBCL

(e) EBV positive (EBV ⁺ ) DLBCL

(f) DLBCL associated with chronic inflammation

(g) Primary mediastinal (thymic) large B-cell lymphoma

(h) Intravascular large B-cell lymphoma

(i) Anaplastic lymphoma kinase positive (ALK ⁺ ) large B-cell lymphoma

(j) High-grade B-cell lymphoma with MYC and BCL2 rearrangements or BCL6 and MYC rearrangements

2. Applicants must have previously received rituximab, cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), vincristine sulfate, and prednisone (R-CHOP) or equivalent regimens, as well as high-dose therapy with stem-cell rescue, or be ineligible for high-dose therapy with stem-cell rescue and/or chimeric antigen receptor (CAR) T-cell therapy. Researchers will determine eligibility for high-dose therapy with stem-cell rescue and/or CAR T-cell therapy (including subjects who refuse transplantation).

3. Sufficient hematological function is defined as:

(a) ANC ≥ 1000 cells/ ^mm³ (1.0 x ^10⁹ cells/L).

(b) Platelet count ≥100,000 cells/ ^mm³ (100 x ^10⁹ /L) or ≥50,000 cells/ ^mm³ (50 x ^10⁹ /L), with bone marrow or spleen involvement. Platelet count must be met for inclusion in the absence of transfusion support.

(c) Hemoglobin ≥ 9 g/dL.

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

5. Women should use highly effective contraception, should not breastfeed, and if they are of fertility 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 fertility potential:

(a) Postmenopausal women are defined as women aged >50 years who have had amenorrhea for ≥12 months after stopping all exogenous hormone therapy, or women under 50 years of age who have had amenorrhea for ≥12 months after stopping exogenous hormone therapy, and whose serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels are within the postmenopausal range of the institution.

(b) A history of irreversible surgical infertility resulting from hysterectomy, bilateral oophorectomy, or bilateral salpingectomy without tubal ligation.

(c) Medically confirmed irreversible premature ovarian failure.

Sexually active women of reproductive potential must be willing to use two forms of contraception from the time of screening and continue for two days after the last dose of acalabrutinib and four weeks after the last dose of capacitinib. During this period, women must also avoid egg donation and breastfeeding.

6. During the study period and for 16 weeks after the last dose of capapasetinib, men must use condoms (containing spermicide) with all sexual partners. Men must not donate sperm during this time. If this has not been done previously, male subjects wishing to conceive are advised to store sperm before receiving capapasetinib.

Exclusion criteria

If a participant meets any of the following exclusion criteria, they are not eligible for this study:

1. Any one of the following cardiac criteria at the time of screening:

(a) The mean resting corrected QT interval (QTc) obtained from three consecutive electrocardiograms (ECGs) is >470 ms.

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

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

(d) Having undergone 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) classification ≥2.

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

(f) Cardiac ejection fraction exceeding the normal range or <50% as measured by echocardiography (whichever is higher) (or, if echocardiography is not feasible or uncertain, perform a multiple gated acquisition [MUGA] scan).

2. Clinically significant abnormalities in glucose metabolism as defined by any of the following criteria at the time of screening:

(a) Subjects with type 1 or type 2 diabetes who require insulin therapy.

(b) HbA1c≥8.0% (63.9mmol/mol).

3. Renal insufficiency demonstrated by creatinine > 1.5 × ULN and creatinine clearance < 50 mL/min (measured or calculated using the Cockcroft and Gault formula); creatinine clearance only needs to be confirmed when creatinine > 1.5 × ULN.

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

5. Currently 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 septum surgery and bariatric surgery (such as gastric bypass).

6. It is known that the patient has tested positive for human immunodeficiency virus (HIV) and requires restrictive drug treatment.

7. Effective inhibitors or inducers of CYP3A4 within 2 weeks before the first dose of capapasetinib (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 capapasetinib (narrow treatment window).

8. Treatment with a proton pump inhibitor (e.g., omeprazole, esomeprazole, lansoprazole, dextrorotatory lansoprazole, rabeprazole, or pantoprazole) is required. Subjects receiving a proton pump inhibitor who have switched to an H2 receptor antagonist or antacid are eligible to participate in this study.

9. Major surgery performed within 28 days prior to the first dose of study treatment. Note: If a subject has undergone major surgery, they must have fully recovered from any toxicities and/or complications of the intervention prior to receiving the first dose of study treatment. For local surgeries (e.g., placement of a systemic port and biopsy), it is necessary to discuss with the medical caregiver to assess the subject's risk of serious bleeding.

Clinical data will confirm that co-administration of acalatinib and camapasetinib provides unexpected improvements in the treatment of DLBCL (e.g., new-onset DLBCL, relapsed/refractory DLBCL, and/or transformed DLBCL) compared to monotherapy with either acalatinib or camapasetinib.

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This written description uses examples to disclose the invention and enable those skilled in the art to practice it, including the manufacture and use of any salt, substance, or composition disclosed herein, and the carrying out of any method or process disclosed herein. The patentable scope of the invention is defined by the claims and may include other examples that would occur to those skilled in the art. Such other examples are intended to be covered within the scope of the claims if they have elements that are indistinguishable from the literal language of the claims, or if they include equivalent elements that are not substantially different from the literal language of the claims. While preferred embodiments of the invention have been 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 described embodiments of the invention may be employed in practicing the invention. Section headings used in this section and throughout the disclosure are not intended to be limiting.

All the foregoing references (patented and non-patented) are incorporated herein by reference. The discussion of these references is intended only to outline the assertions made by their authors. No reference (or any portion thereof) is acknowledged as applicable prior art. The applicant reserves the right to question the accuracy and relevance of any cited references.

Claims (22)

1. The first quantity of compounds having formula I: Or a pharmaceutically acceptable salt thereof, and a second amount of a compound having formula II: The use of a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating B-cell malignancies in human subjects in need, 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: newly diagnosed diffuse large B-cell lymphoma; transformed diffuse large B-cell lymphoma; T-cell/histocyte-rich large B-cell lymphoma; primary cutaneous diffuse large B-cell lymphoma; leg-type primary cutaneous diffuse large B-cell lymphoma; EBV-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 rearrangements or BCL6 and MYC rearrangements. 2. The use as described in claim 1, wherein the B-cell malignancy is diffuse large B-cell lymphoma. 3. The use as described in claim 2, wherein the diffuse large B-cell lymphoma is selected from the group consisting of: newly diagnosed diffuse large B-cell lymphoma, relapsed/refractory diffuse large B-cell lymphoma, and transformed diffuse large B-cell lymphoma. 4. The use as described in 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 as described in claim 2, wherein the diffuse large B-cell lymphoma is an activated B-cell diffuse large B-cell lymphoma. 6. The use as described in claim 2, wherein the human subject has previously received at least one prior chemoimmunotherapy for the diffuse large B-cell lymphoma. 7. The use as claimed in claim 1, wherein the compound having formula I or a pharmaceutically acceptable salt thereof and the compound having formula II or a pharmaceutically acceptable salt thereof are administered orally to the human subject. 8. The use as claimed in claim 7, wherein the compound having formula I or a pharmaceutically acceptable salt thereof is orally co-administered to the human subject with the compound having formula II or a pharmaceutically acceptable salt thereof. 9. The use as claimed in claim 7, wherein the compound having formula I or a pharmaceutically acceptable salt thereof is administered orally to the human subject before or after the compound having formula II or a pharmaceutically acceptable salt thereof. 10. The use as claimed in any one of claims 1 to 9, wherein the first amount of the compound having formula I or a pharmaceutically acceptable salt thereof administered to the human subject is 75 mg to 225 mg per day. 11. The use as claimed in any one of claims 1 to 9, wherein the first amount of the compound having formula I or a pharmaceutically acceptable salt thereof administered to the human subject is 100 mg once daily. 12. The use as claimed in any one of claims 1 to 9, wherein the first amount of the compound having formula I or a pharmaceutically acceptable salt thereof administered to the human subject is 100 mg twice daily. 13. The use as described in any one of claims 1 to 9, wherein the compound having formula I or a pharmaceutically acceptable salt thereof is administered orally to the human subject in accordance with a continuous dosing schedule. 14. The use as claimed in any one of claims 1 to 9, wherein the compound having formula II or a pharmaceutically acceptable salt thereof is administered orally to the human subject according to an intermittent dosing schedule. 15. The use as described in any one of claims 1 to 9, wherein: The compound having Formula I or a pharmaceutically acceptable salt thereof was administered orally to the human subject according to a continuous dosing schedule; and The compound having formula II or its pharmaceutically acceptable salt was administered orally to the human subject according to an intermittent dosing schedule. 16. The use as claimed in any one of claims 1 to 9, wherein the second amount of the compound having formula II or a pharmaceutically acceptable salt thereof administered to the human subject is from 50 mg twice daily to 900 mg twice daily. 17. The use as claimed in any one of claims 1 to 9, wherein the compound having formula I or a pharmaceutically acceptable salt thereof is administered orally continuously during the dosing cycle and the compound having formula II or a pharmaceutically acceptable salt thereof is administered orally intermittently during the dosing cycle on a 4-day/3-day schedule; on each day of administration, the compound having formula I or a pharmaceutically acceptable salt thereof is administered twice daily in an amount of 100 mg, and the compound having formula II or a pharmaceutically acceptable salt thereof is administered twice daily in an amount of 320 mg. 18. The use as claimed in any one of claims 1 to 9, wherein the compound having formula I or a pharmaceutically acceptable salt thereof is administered orally continuously during the dosing cycle and the compound having formula II or a pharmaceutically acceptable salt thereof is administered orally intermittently during the dosing cycle on a 4-day/3-day schedule; on each day of administration, the compound having formula I or a pharmaceutically acceptable salt thereof is administered twice daily in an amount of 100 mg, and the compound having formula II or a pharmaceutically acceptable salt thereof is administered twice daily in an amount of 400 mg. 19. A combination for simultaneous, separate, or sequential administration, wherein the combination comprises 75 mg to 125 mg of a compound having formula I: Or a pharmaceutically acceptable salt thereof, and in amounts of 100 mg to 900 mg of compounds having formula II: Or its pharmaceutically acceptable salt. 20. Use of compounds having the following combination in the preparation of a medicament for treating B-cell malignancies: Or a pharmaceutically acceptable salt thereof, and compounds having formula II: Or its pharmaceutically acceptable salt. The B-cell malignancies were selected from the following groups: newly diagnosed diffuse large B-cell lymphoma; transformed diffuse large B-cell lymphoma; T-cell/histocyte-rich large B-cell lymphoma; primary cutaneous diffuse large B-cell lymphoma; leg-type primary cutaneous diffuse large B-cell lymphoma; EBV-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 rearrangements or BCL6 and MYC rearrangements. 21. A pharmaceutical composition comprising: Compounds of formula I in amounts ranging from 75 mg to 125 mg: Or its pharmaceutically acceptable salt; Compounds of formula II in amounts ranging from 100 mg to 900 mg: Or its pharmaceutically acceptable salt; and Pharmaceutically acceptable carrier. 22. A kit comprising: A first pharmaceutical composition comprising 75 mg to 125 mg of a compound having formula I: Or its pharmaceutically acceptable salts, and pharmaceutically acceptable carriers; A second pharmaceutical composition comprising 100 mg to 900 mg of a compound having formula II: Or its pharmaceutically acceptable salt, and Pharmaceutically acceptable carrier.