Patent Description:
The B-cell antigen receptor (BCR) is implicated in the pathogenesis of several B-cell malignancies, including diffuse large B-cell diffuse lymphoma, follicular lymphoma, mantle cell lymphoma, and B-cell chronic lymphocytic leukemia. Bruton Tyrosine Kinase (BTK) is an essential kinase downstream of the BCR signalling complex. Acalabrutinib (also known as ACP-<NUM> and by the chemical name of <NUM>-{<NUM>-amino-<NUM>-[(<NUM>)-<NUM>-(but-<NUM>-ynoyl)pyrrolidin-<NUM>-yl]imidazo[<NUM>,<NUM>-a]pyrazin-<NUM>-yl}-N-(pyridin-<NUM>-yl)benzamide) is a selective, covalent BTK inhibitor that is the active pharmaceutical ingredient in the drug product CALQUENCE®. CALQUENCE® 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 the treatment of other indications, including Waldenström's macroglobulinemia.

AKT is a a serine/threonine-specific protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription, and cell migration. Mammalian cells express three closely related AKT isoforms that are encoded by different genes: AKT1 (protein kinase Bα), AKT2 (protein kinase Bβ), and AKT3 (protein kinase Bγ). Capivasertib (also known as AZD5363 and by the chemical name of (S)-<NUM>-amino-N-(<NUM>-(<NUM>-chlorophenyl)-<NUM>-hydroxypropyl)-<NUM>-(<NUM>-pyrrolo[<NUM>,<NUM>-d]pyrimidin-<NUM>-yl)piperidine-<NUM>-carboxamide) is a selective inhibitor of all three AKT isoforms. Capivasertib currently is being evaluated in clinical studies for use in treating cancers including breast cancer and prostate cancer. <NPL>, discloses a Phase <NUM> clinical trial evaluating the use of acalabrutinib to treat ABC diffuse large B-cell lymphoma (Table <NUM>). <NPL>, discloses a preclinical study evaluating the effect of AZD5363 on cellular and in vivo models of diffuse large B-cell lymphoma, including PTEN deficient models and models with MYC aberrations.

Non-Hodgkin lymphoma represents a broad spectrum of diseases arising from lymphocytes "frozen" at various stages of development. Although understanding of the biology and genetics of non-Hodgkin lymphoma has increased in recent years, few impactful or curative therapies have emerged for the treatment of relapsed/refractory or aggressive non-Hodgkin lymphoma. There currently remains a high unmet medical need due to the disease-associated morbidity and mortality of non-Hodgkin lymphoma and the few efficacious treatment options.

The present disclosure relates to the unexpected finding that a combination of acalabrutinib and capivasertib can provide an efficacious therapeutic option for treating B-cell malignancies such as non-Hodgkin lymphoma, particularly in the treatment of diffuse large B-cell lymphoma (DLBCL) as described below.

The references to methods of treatment in the summary and detailed description of the invention in this description are to be interpreted as references to the compounds, pharmaceutical compositions and medicaments of the present invention for use in a method for treatment of the human (or animal) body by therapy.

In one aspect, the disclosure relates to therapeutic combinations for simultaneous, separate, or sequential administration, wherein the combination comprises a compound of Formula I:
<CHM>
or a pharmaceutically acceptable salt thereof, and a compound of Formula II:
<CHM>
or a pharmaceutically acceptable salt thereof.

In another aspect, the present disclosure relates to the treatment of a B-cell malignancy
in a subject in need thereof, comprising administering to the subject a first amount of a compound of Formula I:
<CHM>
or a pharmaceutically acceptable salt thereof, and a second amount of a compound of Formula II:
<CHM>
or a pharmaceutically acceptable salt thereof, wherein the first amount and the second amount together comprise a therapeutically effective amount.

In another aspect, the present disclosure relates to pharmaceutical compositions comprising:.

In another aspect, the present disclosure relates to kits comprising:.

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

The term "combination" can refer to simultaneous, separate, or sequential administration of two or more agents. In one aspect, "combination" can refer to simultaneous administration (e.g., administration of both agents in a single dosage form). In another aspect, "combination" refers to separate administration (e.g., administration of both agents in separate dosage forms, but at substantially the same time). In a further aspect of the invention, "combination" refers to sequential administration (e.g., where a first agent is administered, followed by a delay, followed by administration of a second or further agent). Where the administration is sequential or separate, the delay in administering the later component should be neither too long nor too short, so as not to lose the benefit of the combination.

The terms "co-administration. '' "in combination with," "simultaneous," and "concurrent," as used herein, encompass administration of two or more active pharmaceutical ingredients to a subject and include simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which two or more active pharmaceutical ingredients are present.

The term "effective amount" or "therapeutically effective amount" refers to that amount of a compound or combination of compounds as described herein that is sufficient to effect the intended application including, but not limited to, disease treatment. A therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated (e.g., the weight, age and gender of the subject), the severity of the disease condition, the manner of administration, etc. which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells (e.g., the reduction of platelet adhesion and/or cell migration). The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether the compound is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which the compound is carried.

A "therapeutic effect" as that term is used herein, encompasses a therapeutic benefit and/or a prophylactic benefit. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

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

The term "QD" means quaque die, once a day, or once daily.

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

The term "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counter ions known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese and 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.

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

When ranges are used herein to describe, for example, dosage amounts, all combinations and sub-combinations of ranges and specific embodiments therein are intended to be included.

Use of the term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary. The variation is typically from <NUM>% to <NUM>%, preferably from <NUM>% to <NUM>%, more preferably from <NUM>% to <NUM>% of the stated number or numerical range.

Unless the context requires otherwise, the terms "comprise," "comprises," and "comprising" are used on the basis and clear understanding that they are to be interpreted inclusively, rather than exclusively, and that Applicant intends each of those words to be so interpreted in construing this patent, including the claims below.

As used in this application, the amount of a compound refers to the amount of that compound in its free base form.

The abbreviations listed in Table <NUM> below have the meanings indicated in that table.

For clarity, Table <NUM> below summarizes the compound identifier, chemical name, and structure used interchangeably throughout this application with respect to each compound discussed.

The present disclosure relates, in part, to therapeutic combinations and corresponding use in methods for the treatment of B-cell malignancies, including non-Hodgkin lymphomas such as diffuse large B-cell lymphoma. In particular, the present disclosure relates to use in methods of treatment comprising administration of a therapeutic combination of acalabrutinib, or a pharmaceutically acceptable salt thereof, and capivasertib, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, particularly a human subject in need thereof, to treat a B-cell malignancy.

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

As reflected in the study results described later in the Examples, the combination of capivasertib and acalabrutinib has broader and greater activity in diffuse large B-cell lymphoma than either agent alone. Acalabrutinib has shown single agent activity in several diffuse large B-cell lymphoma cell lines, particularly those classified as activated B-cell (ABC) subtype. In contrast, capivasertib has shown single agent activity in several diffuse large B-cell lymphoma cell lines, particularly those classified as germinal center B-cell (GCB) subtype and having PTEN loss. The combination of capivasertib and acalabrutinib, however, has shown broader and greater activity than either agent alone, for example, in a xenograft model of DLBCL using the TMD8 cell line, which is an activated B-cell (ABC) subtype that is not PTEN deficient. Such activity for the combination cannot be explained simply by addition of the single agent activities of capivasertib and acalabrutinib.

Although this specification primarily discusses acalabrutinib and capivasertib combinations, therapeutic combinations and use in methods of treatment comprising the administration of additional therapeutic agents (triple combinations, etc.) to further enhance the treatment are also within the scope of this disclosure.

Accordingly, in one embodiment, the present disclosure relates to therapeutic combinations for simultaneous, separate, or sequential administration, wherein the combination comprises a compound of Formula I:
<CHM>
or a pharmaceutically acceptable salt thereof, and a compound of Formula II:
<CHM>
or a pharmaceutically acceptable salt thereof.

The compound of Formula (I) is also known by the International Nonproprietary Name of acalabrutinib. International Application <CIT> discloses acalabrutinib (Example <NUM>) and describes the synthesis of acalabrutinib. The synthesis of acalabrutinib is further described in International Application No.<CIT>.

The compound of Formula (II) is also known by the International Nonproprietary Name of capivasertib. <CIT>, discloses capivasertib (Example <NUM>) and describes the synthesis of capivasertib.

In another embodiment, the present disclosure relates to use in methods of treating a B-cell malignancy in a subject in need thereof, comprising administering to the subject a first amount of a compound of Formula I:
<CHM>
or a pharmaceutically acceptable salt thereof, and a second amount of a compound of Formula II:
<CHM>
or a pharmaceutically acceptable salt thereof, wherein the first amount and the second amount together comprise a therapeutically effective amount. In another aspect, the first amount and the second amount together comprise a synergistic amount for treating the B-cell malignancy.

In some embodiments, the subject is a mammal. In one aspect, the subject is a companion animal. In another aspect, the subject is a canine, feline, or equine. In a preferred aspect, the subject is a human.

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

In another embodiment, the present disclosure relates to use of a combination comprising a compound of Formula I:
<CHM>
or a pharmaceutically acceptable salt thereof, and a compound of Formula II:
<CHM>
or a pharmaceutically acceptable salt thereof, for the treatment of a B-cell malignancy.

In another embodiment, the present disclosure relates to use of a combination comprising a compound of Formula I:
<CHM>
or a pharmaceutically acceptable salt thereof, and a compound of Formula II:
<CHM>
or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a B-cell malignancy.

In some embodiments, the B-cell malignancy is aggressive lymphoma.

In some embodiments, the B-cell malignancy is non-Hodgkin lymphoma.

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

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

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

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

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

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

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

In some embodiments, the diffuse large B-cell lymphoma is selected from the group consisting of the 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, the diffuse large B-cell lymphoma is activated B-cell diffuse large B-cell lymphoma. In one aspect, the diffuse large B-cell lymphoma is relapsed/refractory activated B-cell diffuse large B-cell lymphoma.

Diagnosis of the specific B-cell malignancy from which a subject is suffering can be made in accordance with accepted clinical practice. See, for example, the <NUM> classification guidelines established by the World Health Organization (WHO) for lymphoid neoplasms, or the National Comprehensive Cancer Network (NCCN) classification guidelines for non-Hodgkin lymphoma.

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

The amount of acalabrutinib and capivasertib administered to the subject will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compounds, and the discretion of the prescribing physician. In the various embodiments described below and throughout this specification and unless otherwise specifically stated, "acalabrutinib" refers to acalabrutinib free base or a pharmaceutically acceptable salt thereof; "capivasertib" refers to capivasertib free base or a pharmaceutically acceptable salt thereof; and the amount of acalabrutinib or capivasertib per dose recited is based upon the amount of acalabrutinib free base or capivasertib free base, respectively.

An effective amount of the combination of acalabrutinib and capivasertib can be administered simultaneously, separately, or sequentially, and in either single or multiple doses, by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant. In preferred embodiments, both acalabrutinib and capivasertib are administered orally to a human subject.

In some embodiments, acalabrutinib and capivasertib are administered simultaneously to the subject.

In some embodiments, acalabrutinib and capivasertib are administered separately to the subject.

In some embodiments, acalabrutinib and capivasertib are administered sequentially to the subject.

In some embodiments, acalabrutinib is administered before capivasertib is administered within a dosing cycle. In one aspect, acalabrutinib is administered at least <NUM> hours, at least <NUM> hours, at least <NUM> hours, at least <NUM> hours, at least <NUM> hours, at least <NUM> hours, at least <NUM> hours, or at least <NUM> hours before capivasertib is administered within a dosing cycle. In another aspect, acalabrutinib is administered no more than <NUM> hours, no more than <NUM> hours, no more than <NUM> hours, no more than <NUM> hours, no more than <NUM> hours, no more than <NUM> hours, no more than <NUM> hours, or no more than <NUM> hours before capivasertib is administered within a dosing cycle. In another aspect, acalabrutinib is administered from <NUM> to <NUM> hours before; from <NUM> to <NUM> hours before; from <NUM> to <NUM> hours before; from <NUM> to <NUM> hours before; from <NUM> to <NUM> hours before; from <NUM> to <NUM> hours before; from <NUM> to <NUM> hours before; or from <NUM> to <NUM> hours before capivasertib is administered within a dosing cycle.

In some embodiments, capivasertib is administered before acalabrutinib is administered within a dosing cycle. In one aspect, capivasertib is administered at least <NUM> hours, at least <NUM> hours, at least <NUM> hours, at least <NUM> hours, at least <NUM> hours, at least <NUM> hours, at least <NUM> hours, or at least <NUM> hours before acalabrutinib is administered within a dosing cycle. In another aspect, capivasertib is administered no more than <NUM> hours, no more than <NUM> hours, no more than <NUM> hours, no more than <NUM> hours, no more than <NUM> hours, no more than <NUM> hours, no more than <NUM> hours, or no more than <NUM> hours before acalabrutinib is administered within a dosing cycle. In another aspect, capivasertib is administered from <NUM> to <NUM> hours before; from <NUM> to <NUM> hours before; from <NUM> to <NUM> hours before; from <NUM> to <NUM> hours before; from <NUM> to <NUM> hours before; from <NUM> to <NUM> hours before; from <NUM> to <NUM> hours before; or from <NUM> to <NUM> hours before acalabrutinib is administered within a dosing cycle.

In combinations with capivasertib, acalabrutinib generally is administered at a daily dosage from about <NUM> to about <NUM>. In some embodiments, acalabrutinib is administered at a daily dosage from about <NUM> to about <NUM>. In one aspect, acalabrutinib is administered at a daily dosage from about <NUM> to about <NUM>. In another aspect, acalabrutinib is administered at a daily dosage from about <NUM> to about <NUM>. In another aspect, acalabrutinib is administered at a daily dosage from about <NUM> to about <NUM>. In another aspect, acalabrutinib is administered at a daily dosage from about <NUM> to about <NUM>. In another aspect, acalabrutinib is administered at a daily dosage from about <NUM> to about <NUM>. In another aspect, acalabrutinib is administered at a daily dosage from about <NUM> to about <NUM>. In another aspect, acalabrutinib is administered at a daily dosage of about <NUM>. In another aspect, acalabrutinib is administered at a daily dosage of about <NUM>. In another aspect, acalabrutinib is administered at a daily dosage of about <NUM>.

In some embodiments, acalabrutinib is administered to the subject once daily (QD). In one aspect, acalabrutinib is administered at a dosage from about <NUM> to about <NUM> once daily. In another aspect, acalabrutinib is administered at a dosage from about <NUM> to about <NUM> once daily. In another aspect, acalabrutinib is administered at a dosage from about <NUM> to about <NUM> once daily. In another aspect, acalabrutinib is administered at a dosage from about <NUM> to about <NUM> once daily. In another aspect, acalabrutinib is administered at a dosage from about <NUM> to about <NUM> once daily. In another aspect, acalabrutinib is administered at a dosage from about <NUM> to about <NUM> once daily. In another aspect, acalabrutinib is administered at a dosage from about <NUM> to about <NUM> once daily. In another aspect, acalabrutinib is administered at a dosage from about <NUM> to about <NUM> once daily. In another aspect, acalabrutinib is administered at a dosage of about <NUM> once daily. In another aspect, acalabrutinib is administered at a dosage of about <NUM> once daily. In another aspect, acalabrutinib is initially administered at a dosage of about <NUM> once daily and the acalabrutinib dosage is subsequently reduced during the dosing cycle to a dosage of about <NUM> once daily.

In some embodiments, acalabrutinib is administered to the subject twice daily (BID). In one aspect, acalabrutinib is administered at a dosage from about <NUM> to about <NUM> twice daily. In another aspect, acalabrutinib is administered at a dosage from about <NUM> to about <NUM> twice daily. In another aspect, acalabrutinib is administered at a dosage from about <NUM> to about <NUM> twice daily. In another aspect, acalabrutinib is administered at a dosage from about <NUM> to about <NUM> twice daily. In another aspect, acalabrutinib is administered at a dosage from about <NUM> to about <NUM> twice daily. In another aspect, acalabrutinib is administered at a dosage of about <NUM> twice daily. In another aspect, acalabrutinib is initially administered at a dosage of about <NUM> twice daily and the acalabrutinib dosage is subsequently reduced during the dosing cycle to a dosage of about <NUM> once daily. In another aspect, acalabrutinib is administered at a dosage of about <NUM> twice daily.

In some embodiments, acalabrutinib is administered under a continuous dosing schedule. A continuous dosing schedule includes no holidays during a dosing cycle. For example, in a seven-day dosing cycle, continuously dosed acalabrutinib would be given on days one, two, three, four, five, six, and seven. The dosing cycle would then repeat for the desired number of cycles. In one aspect, for example, acalabrutinib is administered for more than <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or <NUM> days. In one aspect, the dosing cycle is <NUM> days. Administration of acalabrutinib and repeat of the dosing cycle can continue as long as tolerable and beneficial for the subject.

In some embodiments, acalabrutinib is administered to the subject under an intermittent dosing schedule. In contrast to a continuous dosing schedule, an intermittent dosage schedule can include dosage holidays. For example, intermittently dosed acalabrutinib in a seven-day dosing cycle might be given on days one and two, but not given on days three, four, five, six, or seven. The dosing cycle would then repeat. This illustration could be referred to as a <NUM> days on/<NUM> days off schedule, where acalabrutinib is given for two days followed by a five-day holiday. Similarly, intermittently dosed acalabrutinib in a seven-day dosing cycle might be given on days one, two, three, and four, but not given on days five, six, or seven. The dosing cycle would then repeat. This illustration could be referred to as a <NUM> days on/<NUM> days off schedule, where acalabrutinib is given for four days followed by a three-day holiday.

In combinations with acalabrutinib, capivasertib generally is administered to the subject at a daily dosage from about <NUM> to about <NUM>. In some embodiments, capivasertib is administered at a daily dosage from about <NUM> to about <NUM>. In one aspect, capivasertib is administered at a daily dosage from about <NUM> to about <NUM>. In another aspect, capivasertib is administered at a daily dosage from about <NUM> to about <NUM>. In another aspect, capivasertib is administered at a daily dosage from about <NUM> to about <NUM>. In another aspect, capivasertib is administered at a daily dosage from about <NUM> to about <NUM>. In another aspect, capivasertib is administered at a daily dosage from about <NUM> to about <NUM>.

In some embodiments, capivasertib is administered to the subject once daily (QD). In one aspect, capivasertib is administered at a dosage from about <NUM> to about <NUM> once daily. In another aspect, capivasertib is administered at a dosage from about <NUM> to about <NUM> once daily. In another aspect, capivasertib is administered at a dosage from about <NUM> to about <NUM> once daily. In another aspect, capivasertib is administered at a dosage from about <NUM> to about <NUM> once daily. In another aspect, capivasertib is administered at a dosage from about <NUM> to about <NUM> once daily. In another aspect, capivasertib is administered at a dosage from about <NUM> to about <NUM> once daily. In another aspect, capivasertib is administered at a dosage from about <NUM> to about <NUM> once daily.

In some embodiments, capivasertib is administered to the subject twice daily (BID). In one aspect, capivasertib is administered at a dosage from about <NUM> to about <NUM> twice daily. In another aspect, capivasertib is administered at a dosage from about <NUM> to about <NUM> twice daily. In another aspect, capivasertib is administered at a dosage from about <NUM> to about <NUM> twice daily. In another aspect, capivasertib is administered at a dosage from about <NUM> to about <NUM> twice daily. In another aspect, capivasertib is administered at a dosage from about <NUM> to about <NUM> twice daily. In another aspect, capivasertib is administered at a dosage from about <NUM> to about <NUM> twice daily. In another aspect, capivasertib is administered at a dosage from about <NUM> to about <NUM> twice daily. In another aspect, capivasertib is administered at a dosage from about <NUM> to about <NUM> twice daily. In another aspect, capivasertib is administered at a dosage from about <NUM> to about <NUM> twice daily. In another aspect, capivasertib is administered at a dosage from about <NUM> to about <NUM> twice daily. In another aspect, capivasertib is administered at a dosage from about <NUM> to about <NUM> twice daily. In another aspect, capivasertib is administered at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered at a dosage of about <NUM> twice daily.

In some embodiments, capivasertib is administered under a continuous dosing schedule. In one aspect, for example, capivasertib is administered for more than <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or <NUM> days. In another aspect, the dosing cycle is <NUM> days. Administration of capivasertib and repeat of the dosing cycle can continue as long as tolerable and beneficial for the subject.

In some embodiments, capivasertib is administered once daily (QD) under a continuous dosing schedule. In one aspect, capivasertib is administered once daily under a continuous dosing schedule at a dosage from about <NUM> to about <NUM>. In another aspect, capivasertib is administered once daily under a continuous dosing schedule at a dosage from about <NUM> to about <NUM>. In another aspect, capivasertib is administered once daily under a continuous dosing schedule at a dosage from about <NUM> to about <NUM>. In another aspect, capivasertib is administered once daily under a continuous dosing schedule at a dosage from about <NUM> to about <NUM>. In another aspect, capivasertib is administered once daily under a continuous dosing schedule at a dosage from about <NUM> to about <NUM>. In another aspect, capivasertib is administered once daily under a continuous dosing schedule at a dosage from about <NUM> to about <NUM>. In another aspect, capivasertib is administered once daily under a continuous dosing schedule at a dosage from about <NUM> to about <NUM>. In another aspect, capivasertib is administered once daily under a continuous dosing schedule at a dosage from about <NUM> to about <NUM>.

In some embodiments, capivasertib is administered twice daily (BID) under a continuous dosing schedule. In one aspect, capivasertib is administered under a continuous dosing schedule at a dosage from about <NUM> to about <NUM> twice daily. In another aspect, capivasertib is administered under a continuous dosing schedule at a dosage from about <NUM> to about <NUM> twice daily. In another aspect, capivasertib is administered under a continuous dosing schedule at a dosage from about <NUM> to about <NUM> twice daily. In another aspect, capivasertib is administered under a continuous dosing schedule at a dosage from about <NUM> to about <NUM> twice daily. In another aspect, capivasertib is administered under a continuous dosing schedule at a dosage from about <NUM> to about <NUM> twice daily. In another aspect, capivasertib is administered under a continuous dosing schedule at a dosage from about <NUM> to about <NUM> twice daily. In another aspect, capivasertib is administered under a continuous dosing schedule at a dosage from about <NUM> to about <NUM> twice daily. In another aspect, capivasertib is administered under a continuous dosing schedule at a dosage from about <NUM> to about <NUM> twice daily. In another aspect, capivasertib is administered under a continuous dosing schedule at a dosage from about <NUM> to about <NUM> twice daily. In another aspect, capivasertib is administered under a continuous dosing schedule at a dosage from about <NUM> to about <NUM> twice daily. In another aspect, capivasertib is administered under a continuous dosing schedule at a dosage from about <NUM> to about <NUM> twice daily. In another aspect, capivasertib is administered under a continuous dosing schedule at a dosage from about <NUM> to about <NUM> twice daily. In another aspect, capivasertib is administered under a continuous dosing schedule at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered under a continuous dosing schedule at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered under a continuous dosing schedule at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered under a continuous dosing schedule at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered under a continuous dosing schedule at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered under a continuous dosing schedule at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered under a continuous dosing schedule at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered under a continuous dosing schedule at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered under a continuous dosing schedule at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered under a continuous dosing schedule at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered under a continuous dosing schedule at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered under a continuous dosing schedule at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered under a continuous dosing schedule at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered under a continuous dosing schedule at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered under a continuous dosing schedule at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered under a continuous dosing schedule at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered under a continuous dosing schedule at a dosage of about <NUM> twice daily.

In some embodiments, capivasertib is administered to the subject on an intermittent dosage schedule. Administering capivasertib on an intermittent dosage schedule can, for example, have greater effectiveness and/or tolerability than on a continuous dosing schedule. In one aspect, capivasertib is intermittently dosed on a <NUM> day on/<NUM> days off schedule (i.e., capivasertib is administered for one day followed by a six-day holiday). In another aspect, capivasertib is intermittently dosed on a <NUM> days on/<NUM> days off schedule (i.e., capivasertib is administered for two days followed by a five-day holiday). In another aspect, capivasertib is intermittently dosed on a <NUM> days on/<NUM> days off schedule (i.e., capivasertib is administered for three days followed by a four-day holiday). In another aspect, capivasertib is intermittently dosed on a <NUM> days on/<NUM> days off schedule (i.e., capivasertib is administered for four days followed by a three-day holiday). In another aspect, capivasertib is intermittently dosed on a <NUM> days on/<NUM> days off schedule (i.e., capivasertib is administered for five days followed by a two-day holiday). In another aspect, capivasertib is intermittently dosed on a <NUM> days on/<NUM> day off schedule (i.e., capivasertib is administered for six days followed by a one-day holiday).

The dosing cycle of such embodiments would then repeat as long as tolerable and beneficial for the subject. In some embodiments, the dosing cycle is <NUM> days. In one aspect, the dosing cycle is <NUM> days. In another aspect, the dosing cycle is <NUM> days. In another aspect, the dosing cycle is <NUM> 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 <NUM> days, but capivasertib is not co-administered to the subject during the fourth week of the dosing cycle (i.e., there is a capivasertib drug holiday during the final week of the dosing cycle).

In some embodiments, capivasertib is administered once daily (QD) under an intermittent dosing schedule. In one aspect, capivasertib is administered once daily under an intermittent dosing schedule at a dosage from about <NUM> to about <NUM>. In another aspect, capivasertib is administered once daily under an intermittent dosing schedule at a dosage from about <NUM> to about <NUM>. In another aspect, capivasertib is administered once daily under an intermittent dosing schedule at a dosage from about <NUM> to about <NUM>. In another aspect, capivasertib is administered once daily under an intermittent dosing schedule at a dosage from about <NUM> to about <NUM>. In another aspect, capivasertib is administered once daily under an intermittent dosing schedule at a dosage from about <NUM> to about <NUM>. In another aspect, capivasertib is administered once daily under an intermittent dosing schedule at a dosage from about <NUM> to about <NUM>. In another aspect, capivasertib is administered once daily under an intermittent dosing schedule at a dosage from about <NUM> to about <NUM>. In another aspect, capivasertib is administered once daily under an intermittent dosing schedule at a dosage from about <NUM> to about <NUM>.

In some embodiments, capivasertib is administered twice daily (BID) under an intermittent dosing schedule. In one aspect, capivasertib is administered under an intermittent dosing schedule at a dosage from about <NUM> to about <NUM> twice daily. In another aspect, capivasertib is administered under an intermittent dosing schedule at a dosage from about <NUM> to about <NUM> twice daily. In another aspect, capivasertib is administered under an intermittent dosing schedule at a dosage from about <NUM> to about <NUM> twice daily. In another aspect, capivasertib is administered under an intermittent dosing schedule at a dosage from about <NUM> to about <NUM> twice daily. In another aspect, capivasertib is administered under an intermittent dosing schedule at a dosage from about <NUM> to about <NUM> twice daily. In another aspect, capivasertib is administered under an intermittent dosing schedule at a dosage from about <NUM> to about <NUM> twice daily. In another aspect, capivasertib is administered under an intermittent dosing schedule at a dosage from about <NUM> to about <NUM> twice daily. In another aspect, capivasertib is administered under an intermittent dosing schedule at a dosage from about <NUM> to about <NUM> twice daily. In another aspect, capivasertib is administered under an intermittent dosing schedule at a dosage from about <NUM> to about <NUM> twice daily. In another aspect, capivasertib is administered under an intermittent dosing schedule at a dosage from about <NUM> to about <NUM> twice daily. In another aspect, capivasertib is administered under an intermittent dosing schedule at a dosage from about <NUM> to about <NUM> twice daily. In another aspect, capivasertib is administered under an intermittent dosing schedule at a dosage from about <NUM> to about <NUM> twice daily. In another aspect, capivasertib is administered under an intermittent dosing schedule at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered under an intermittent dosing schedule at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered under an intermittent dosing schedule at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered under an intermittent dosing schedule at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered under an intermittent dosing schedule at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered under an intermittent dosing schedule at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered under an intermittent dosing schedule at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered under an intermittent dosing schedule at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered under an intermittent dosing schedule at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered under an intermittent dosing schedule at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered under an intermittent dosing schedule at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered under an intermittent dosing schedule at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered under an intermittent dosing schedule at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered under an intermittent dosing schedule at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered under an intermittent dosing schedule at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered under an intermittent dosing schedule at a dosage of about <NUM> twice daily. In another aspect, capivasertib is administered under an intermittent dosing schedule at a dosage of about <NUM> twice daily.

In some embodiments, both acalabrutinib and capivasertib are dosed continuously in a dosing cycle. In one aspect, both acalabrutinib and capivasertib are orally dosed continuously in a dosing cycle. In another aspect, both acalabrutinib and capivasertib are orally dosed continuously in a dosing cycle, and the amount of acalabrutinib administered is from about <NUM> to about <NUM> twice daily. In another aspect, both acalabrutinib and capivasertib are orally dosed continuously in a dosing cycle, and the amount of acalabrutinib administered is about <NUM> twice daily. In another aspect, both acalabrutinib and capivasertib are orally dosed continuously in a dosing cycle, the amount of acalabrutinib initially administered at the beginning of the dosing cycle is about <NUM> twice daily, and the amount of acalabrutinib administered is subsequently reduced during the dosing cycle to a dosage of about <NUM> once daily.

In some embodiments, acalabrutinib is dosed continuously and capivasertib is dosed intermittently in a dosing cycle. In one aspect, acalabrutinib is orally dosed continuously and capivasertib is orally dosed intermittently in a dosing cycle. In another aspect, acalabrutinib is orally dosed continuously and capivasertib is orally dosed intermittently in a dosing cycle, and the amount of acalabrutinib administered is from about <NUM> to about <NUM> twice daily. In another aspect, acalabrutinib is orally dosed continuously and capivasertib is orally dosed intermittently in a dosing cycle, and the amount of acalabrutinib administered is about <NUM> twice daily. In another aspect, acalabrutinib is orally dosed continuously and capivasertib is orally dosed intermittently in a dosing cycle, the amount of acalabrutinib initially administered at the beginning of the dosing cycle is about <NUM> twice daily, and the amount of acalabrutinib administered is subsequently reduced during the dosing cycle to a dosage of about <NUM> once daily.

In some embodiments, acalabrutinib is dosed continuously and capivasertib is dosed intermittently on a <NUM> day on/<NUM> days off schedule in a dosing cycle. In one aspect, acalabrutinib is orally dosed continuously in an amount of about <NUM> to about <NUM> twice daily and capivasertib is orally dosed intermittently on a <NUM> day on/<NUM> days off schedule in a dosing cycle. In another aspect, acalabrutinib is orally dosed continuously in an amount of about <NUM> twice daily and capivasertib is orally dosed intermittently on a <NUM> day on/<NUM> days off schedule in a dosing cycle. In another aspect, acalabrutinib is orally dosed continuously and capivasertib is orally dosed intermittently on a <NUM> day on/<NUM> days off schedule in a dosing cycle, the amount of acalabrutinib initially administered at the beginning of the dosing cycle is about <NUM> twice daily, and the amount of acalabrutinib administered is subsequently reduced during the dosing cycle to a dosage of about <NUM> once daily.

In some embodiments, acalabrutinib is dosed continuously and capivasertib is dosed intermittently on a <NUM> days on/<NUM> days off schedule in a dosing cycle. In one aspect, acalabrutinib is orally dosed continuously in an amount of about <NUM> to about <NUM> twice daily and capivasertib is orally dosed intermittently on a <NUM> days on/<NUM> days off schedule in a dosing cycle. In another aspect, acalabrutinib is orally dosed continuously in an amount of about <NUM> twice daily and capivasertib is orally dosed intermittently on a <NUM> days on/<NUM> days off schedule in a dosing cycle. In another aspect, acalabrutinib is orally dosed continuously and capivasertib is orally dosed intermittently on a <NUM> days on/<NUM> days off schedule in a dosing cycle, the amount of acalabrutinib initially administered at the beginning of the dosing cycle is about <NUM> twice daily, and the amount of acalabrutinib administered is subsequently reduced during the dosing cycle to a dosage of about <NUM> once daily.

In some embodiments, acalabrutinib is dosed continuously and capivasertib is dosed intermittently on a <NUM> days on/<NUM> days off schedule in a dosing cycle. In one aspect, acalabrutinib is orally dosed continuously in an amount of about <NUM> to about <NUM> twice daily and capivasertib is orally dosed intermittently on a <NUM> days on/<NUM> days off schedule in a dosing cycle. In another aspect, acalabrutinib is orally dosed continuously in an amount of <NUM> twice daily and capivasertib is orally dosed intermittently on a <NUM> days on/<NUM> days off schedule in a dosing cycle. In another aspect, acalabrutinib is orally dosed continuously and capivasertib is orally dosed intermittently on a <NUM> days on/<NUM> days off schedule in a dosing cycle, the amount of acalabrutinib initially administered at the beginning of the dosing cycle is about <NUM> twice daily, and the amount of acalabrutinib administered is subsequently reduced during the dosing cycle to a dosage of about <NUM> once daily.

In some embodiments, acalabrutinib is dosed continuously and capivasertib is dosed intermittently on a <NUM> days on/<NUM> day off schedule in a dosing cycle. In one aspect, acalabrutinib is orally dosed continuously in an amount of about <NUM> to about <NUM> twice daily and capivasertib is orally dosed intermittently on a <NUM> days on/<NUM> day off schedule in a dosing cycle. In another aspect, acalabrutinib is orally dosed continuously in an amount of about <NUM> twice daily and capivasertib is orally dosed intermittently on a <NUM> days on/<NUM> day off schedule in a dosing cycle. In another aspect, acalabrutinib is orally dosed continuously and capivasertib is orally dosed intermittently on a <NUM> days on/<NUM> day off schedule in a dosing cycle, the amount of acalabrutinib initially administered at the beginning of the dosing cycle is about mg twice daily, and the amount of acalabrutinib administered is subsequently reduced during the dosing cycle to a dosage of about <NUM> once daily.

In some embodiments, both acalabrutinib and capivasertib are orally dosed continuously in a dosing cycle, the amount of acalabrutinib administered daily is about <NUM> to about <NUM>, and the amount of capivasertib administered daily is about <NUM> to about <NUM>. In one aspect, both acalabrutinib and capivasertib are orally dosed continuously in a dosing cycle, acalabrutinib is administered once daily in an amount of about <NUM> to about <NUM>, and capivasertib is administered once daily in an amount about <NUM> to about <NUM>. In another aspect, both acalabrutinib and capivasertib are orally dosed continuously in a dosing cycle, acalabrutinib is administered in an amount of about <NUM> to about <NUM> twice daily, and capivasertib is administered in an amount of about <NUM> to about <NUM> twice daily. In another aspect, both acalabrutinib and capivasertib are orally dosed continuously in a dosing cycle, acalabrutinib is administered in an amount of about <NUM> twice daily, and capivasertib is administered in an amount of about <NUM> to about <NUM> twice daily. In another aspect, both acalabrutinib and capivasertib are orally dosed continuously in a dosing cycle, acalabrutinib is initially administered at the beginning of the dosing cycle in an amount of about <NUM> twice daily, capivasertib is administered in an amount of about <NUM> to about <NUM> twice daily, and the amount of acalabrutinib administered is subsequently reduced during the dosing cycle to an amount of about <NUM> once daily.

In some embodiments, acalabrutinib is dosed continuously and capivasertib is dosed intermittently in a dosing cycle, the amount of acalabrutinib administered daily is about <NUM> to about <NUM>, and the amount of capivasertib administered is about <NUM> to about <NUM> on each day of administration. In one aspect, acalabrutinib is dosed continuously and capivasertib is dosed intermittently in a dosing cycle, acalabrutinib is administered once daily in an amount of about <NUM> to about <NUM>, and capivasertib is administered once daily in an amount about <NUM> to about <NUM> on each day of administration. In another aspect, acalabrutinib is dosed continuously and capivasertib is dosed intermittently in a dosing cycle, acalabrutinib is administered in an amount of about <NUM> to about <NUM> twice daily, and capivasertib is administered in an amount of about <NUM> to about <NUM> twice daily on each day of administration. In another aspect, acalabrutinib is dosed continuously and capivasertib is dosed intermittently in a dosing cycle, acalabrutinib is administered in an amount of about <NUM> twice daily, and capivasertib is administered in an amount of about <NUM> to about <NUM> twice daily on each day of administration. In another aspect, acalabrutinib is dosed continuously and capivasertib is dosed intermittently in a dosing cycle, acalabrutinib is initially administered at the beginning of the dosing cycle in an amount of about <NUM> twice daily, capivasertib is administered in an amount of about <NUM> to about <NUM> twice daily on each day of administration, and the amount of acalabrutinib administered is subsequently reduced during the dosing cycle to an amount of about <NUM> once daily.

In some embodiments, acalabrutinib is dosed continuously and capivasertib is dosed intermittently on a <NUM> days on/<NUM> days off schedule in a dosing cycle, the amount of acalabrutinib administered daily is about <NUM> to about <NUM>, and the amount of capivasertib administered is about <NUM> to about <NUM> on each day of administration. In one aspect, acalabrutinib is orally dosed continuously and capivasertib is orally dosed intermittently on a <NUM> days on/<NUM> days off schedule in a dosing cycle, acalabrutinib is administered once daily in an amount of about <NUM> to about <NUM>, and capivasertib is administered once daily in an amount about <NUM> to about <NUM> on each day of administration. In another aspect, acalabrutinib is orally dosed continuously and capivasertib is orally dosed intermittently on a <NUM> days on/<NUM> days off schedule in a dosing cycle, acalabrutinib is administered in an amount of about <NUM> to about <NUM> twice daily, and capivasertib is administered in an amount of about <NUM> to about <NUM> twice daily on each day of administration.

In some embodiments, acalabrutinib is orally dosed continuously and capivasertib is orally dosed intermittently on a <NUM> days on/<NUM> days off schedule in a dosing cycle, acalabrutinib is administered in an amount of about <NUM> twice daily, and capivasertib is administered in an amount of about <NUM> to about <NUM> twice daily on each day of administration. In one aspect, acalabrutinib is orally dosed continuously and capivasertib is orally dosed intermittently on a <NUM> days on/<NUM> days off schedule in a dosing cycle, acalabrutinib is initially administered at the beginning of the dosing cycle in an amount of about <NUM> twice daily, capivasertib is administered in an amount of about <NUM> to about <NUM> twice daily on each day of administration, and the amount of acalabrutinib administered is subsequently reduced during the dosing cycle to an amount of about <NUM> once daily. In another aspect, acalabrutinib is orally dosed continuously and capivasertib is orally dosed intermittently on a <NUM> days on/<NUM> days off schedule in a dosing cycle, acalabrutinib is administered in an amount of about <NUM> twice daily, and capivasertib is administered in an amount of about <NUM> to about <NUM> twice daily on each day of administration. In another aspect, acalabrutinib is orally dosed continuously and capivasertib is orally dosed intermittently on a <NUM> days on/<NUM> days off schedule in a dosing cycle, acalabrutinib is administered in an amount of about <NUM> twice daily, and capivasertib is administered in an amount of about <NUM> to about <NUM> twice daily on each day of administration. In another aspect, acalabrutinib is orally dosed continuously and capivasertib is orally dosed intermittently on a <NUM> days on/<NUM> days off schedule in a dosing cycle, acalabrutinib is administered in an amount of about <NUM> twice daily, and capivasertib is administered in an amount of about <NUM> to about <NUM> twice daily on each day of administration. In another aspect, acalabrutinib is orally dosed continuously and capivasertib is orally dosed intermittently on a <NUM> days on/<NUM> days off schedule in a dosing cycle, acalabrutinib is administered in an amount of about <NUM> twice daily, and capivasertib is administered in an amount of about <NUM> to about <NUM> twice daily on each day of administration. In another aspect, acalabrutinib is orally dosed continuously and capivasertib is orally dosed intermittently on a <NUM> days on/<NUM> days off schedule in a dosing cycle, acalabrutinib is administered in an amount of about <NUM> twice daily, and capivasertib is administered in an amount of about <NUM> to about <NUM> twice daily on each day of administration. In another aspect, acalabrutinib is orally dosed continuously and capivasertib is orally dosed intermittently on a <NUM> days on/<NUM> days off schedule in a dosing cycle, acalabrutinib is administered in an amount of about <NUM> twice daily, and capivasertib is administered in an amount of about <NUM> to about <NUM> twice daily on each day of administration. In another aspect, acalabrutinib is orally dosed continuously and capivasertib is orally dosed intermittently on a <NUM> days on/<NUM> days off schedule in a dosing cycle, acalabrutinib is administered in an amount of about <NUM> twice daily, and capivasertib is administered in an amount of about <NUM> twice daily on each day of administration. In another aspect, acalabrutinib is orally dosed continuously and capivasertib is orally dosed intermittently on a <NUM> days on/<NUM> days off schedule in a dosing cycle, acalabrutinib is administered in an amount of about <NUM> twice daily, and capivasertib is administered in an amount of about <NUM> twice daily on each day of administration. In another aspect, acalabrutinib is orally dosed continuously and capivasertib is orally dosed intermittently on a <NUM> days on/<NUM> days off schedule in a dosing cycle, acalabrutinib is administered in an amount of about <NUM> twice daily, and capivasertib is administered in an amount of about <NUM> twice daily on each day of administration. In another aspect, acalabrutinib is orally dosed continuously and capivasertib is orally dosed intermittently on a <NUM> days on/<NUM> days off schedule in a dosing cycle, acalabrutinib is administered in an amount of about <NUM> twice daily, and capivasertib is administered in an amount of about <NUM> twice daily on each day of administration. In another aspect, acalabrutinib is orally dosed continuously and capivasertib is orally dosed intermittently on a <NUM> days on/<NUM> days off schedule in a dosing cycle, acalabrutinib is administered in an amount of about <NUM> twice daily, and capivasertib is administered in an amount of about <NUM> twice daily on each day of administration. In another aspect, acalabrutinib is orally dosed continuously and capivasertib is orally dosed intermittently on a <NUM> days on/<NUM> days off schedule in a dosing cycle, acalabrutinib is administered in an amount of about <NUM> twice daily, and capivasertib is administered in an amount of about <NUM> twice daily on each day of administration.

In some embodiments, acalabrutinib is orally dosed continuously and capivasertib is orally dosed intermittently on a <NUM> days on/<NUM> days off schedule in a dosing cycle, acalabrutinib is administered in an amount of about <NUM> twice daily, and capivasertib is administered in an amount of about of about <NUM> to about <NUM> twice daily on each day of administration. In one aspect, acalabrutinib is orally dosed continuously and capivasertib is orally dosed intermittently on a <NUM> days on/<NUM> days off schedule in a dosing cycle, acalabrutinib is administered in an amount of about <NUM> twice daily, capivasertib is administered in an amount of about of about <NUM> to about <NUM> twice daily on each day of administration, and the amount of acalabrutinib administered is subsequently reduced during the dosing cycle to an amount of about <NUM> once daily. In another aspect, acalabrutinib is orally dosed continuously and capivasertib is orally dosed intermittently on a <NUM> days on/<NUM> days off schedule in a dosing cycle, acalabrutinib is administered in an amount of about <NUM> twice daily, and capivasertib is administered in an amount of about <NUM> to about <NUM> twice daily on each day of administration. In another aspect, acalabrutinib is orally dosed continuously and capivasertib is orally dosed intermittently on a <NUM> days on/<NUM> days off schedule in a dosing cycle, acalabrutinib is administered in an amount of about <NUM> twice daily, and capivasertib is administered in an amount of about <NUM> to about <NUM> twice daily on each day of administration. In another aspect, acalabrutinib is orally dosed continuously and capivasertib is orally dosed intermittently on a <NUM> days on/<NUM> days off schedule in a dosing cycle, acalabrutinib is administered in an amount of about <NUM> twice daily, and capivasertib is administered in an amount of about <NUM> to about <NUM> twice daily on each day of administration. In another aspect, acalabrutinib is orally dosed continuously and capivasertib is orally dosed intermittently on a <NUM> days on/<NUM> days off schedule in a dosing cycle, acalabrutinib is administered in an amount of about <NUM> twice daily, and capivasertib is administered in an amount of about <NUM> to about <NUM> twice daily on each day of administration. In another aspect, acalabrutinib is orally dosed continuously and capivasertib is orally dosed intermittently on a <NUM> days on/<NUM> days off schedule in a dosing cycle, acalabrutinib is administered in an amount of about <NUM> twice daily, and capivasertib is administered in an amount of about <NUM> to about <NUM> twice daily on each day of administration. In another aspect, acalabrutinib is orally dosed continuously and capivasertib is orally dosed intermittently on a <NUM> days on/<NUM> days off schedule in a dosing cycle, acalabrutinib is administered in an amount of about <NUM> twice daily, and capivasertib is administered in an amount of about <NUM> to about <NUM> twice daily on each day of administration. In another aspect, acalabrutinib is orally dosed continuously and capivasertib is orally dosed intermittently on a <NUM> days on/<NUM> days off schedule in a dosing cycle, acalabrutinib is administered in an amount of about <NUM> twice daily, and capivasertib is administered in an amount of about <NUM> twice daily on each day of administration. In another aspect, acalabrutinib is orally dosed continuously and capivasertib is orally dosed intermittently on a <NUM> days on/<NUM> days off schedule in a dosing cycle, acalabrutinib is administered in an amount of about <NUM> twice daily, and capivasertib is administered in an amount of about <NUM> twice daily on each day of administration. In another aspect, acalabrutinib is orally dosed continuously and capivasertib is orally dosed intermittently on a <NUM> days on/<NUM> days off schedule in a dosing cycle, acalabrutinib is administered in an amount of about <NUM> twice daily, and capivasertib is administered in an amount of about <NUM> twice daily on each day of administration. In another aspect, acalabrutinib is orally dosed continuously and capivasertib is orally dosed intermittently on a <NUM> days on/<NUM> days off schedule in a dosing cycle, acalabrutinib is administered in an amount of about <NUM> twice daily, and capivasertib is administered in an amount of about <NUM> twice daily on each day of administration. In another aspect, acalabrutinib is orally dosed continuously and capivasertib is orally dosed intermittently on a <NUM> days on/<NUM> days off schedule in a dosing cycle, acalabrutinib is administered in an amount of about <NUM> twice daily, and capivasertib is administered in an amount of about <NUM> twice daily on each day of administration. In another aspect, acalabrutinib is orally dosed continuously and capivasertib is orally dosed intermittently on a <NUM> days on/<NUM> days off schedule in a dosing cycle, acalabrutinib is administered in an amount of about <NUM> twice daily, and capivasertib is administered in an amount of about <NUM> twice daily on each day of administration. In another aspect, acalabrutinib is orally dosed continuously and capivasertib is orally dosed intermittently on a <NUM> days on/<NUM> days off schedule in a dosing cycle, acalabrutinib is administered in an amount of about <NUM> twice daily, and capivasertib is administered in an amount of about <NUM> twice daily on each day of administration.

The present disclosure further relates, in part, to pharmaceutical compositions comprising acalabrutinib, capivasertib, and a pharmaceutically acceptable carrier.

In some embodiments, the pharmaceutical composition comprises:.

In one aspect, the combination comprises acalabrutinib and capivasertib in their free base forms. In another aspect, the combination comprises acalabrutinib and capivasertib in their pharmaceutically acceptable salt forms. In another aspect, the combination comprises one of acalabrutinib and capivasertib in free base form and the other of acalabrutinib and capivasertib in pharmaceutically acceptable salt form.

The pharmaceutical compositions typically are formulated to provide a therapeutically effective amount of the combinations described in this specification. The pharmaceutical compositions also may comprise one or more pharmaceutically acceptable excipients, carriers, diluents, and/or fillers. Each of acalabrutinib and capivasertib as active ingredients can be combined in an intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration.

In some embodiments, the pharmaceutical compositions are suitable for oral administration. Pharmaceutical compositions suitable for oral administration can be presented as unit dosage forms, such as tablets, capsules, liquids, or aerosol sprays each containing a predetermined amount of the active ingredients. 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 from about <NUM> to about <NUM>; capivasertib, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. In another aspect, the pharmaceutical composition is an oral unit dosage form comprising acalabrutinib, or a pharmaceutically acceptable salt thereof, in an amount of about <NUM>; capivasertib, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. In another aspect, the pharmaceutical composition is an oral unit dosage form comprising acalabrutinib, or a pharmaceutically acceptable salt thereof, in an amount from about <NUM> to about <NUM>; capivasertib, or a pharmaceutically acceptable salt thereof, in an amount from about <NUM> to about <NUM>; 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 from about <NUM> to about <NUM>; capivasertib, or a pharmaceutically acceptable salt thereof, in an amount from about <NUM> to about <NUM>; 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 from about <NUM> to about <NUM>; capivasertib, or a pharmaceutically acceptable salt thereof, in an amount from about <NUM> to about <NUM>; 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 <NUM>; capivasertib, or a pharmaceutically acceptable salt thereof, in an amount from about <NUM> to about <NUM>; 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 <NUM>; capivasertib, or a pharmaceutically acceptable salt thereof, in an amount from about <NUM> to about <NUM>; 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 <NUM>; capivasertib, or a pharmaceutically acceptable salt thereof, in an amount from about <NUM> to about <NUM>; and a pharmaceutically acceptable carrier.

The pharmaceutical compositions described above are preferably for use in the treatment of the B-cell malignancies described in this specification. For example, in one aspect, the B-cell malignancy is non-Hodgkin lymphoma. In another aspect, the B-cell malignancy is diffuse large B-cell lymphoma. In another aspect, the B-cell malignancy is activated B-cell (ABC) diffuse large B-cell lymphoma.

The present disclosure further relates, in part, to kits comprising acalabrutinib and capivasertib. The kits include each of acalabrutinib, or a pharmaceutically acceptable salt thereof, and capivasertib, or a pharmaceutically acceptable salt thereof, either alone or in combination in suitable packaging. The kits are for co-administration of acalabrutinib, or a pharmaceutically acceptable salt thereof, and capivasertib, or a pharmaceutically acceptable salt thereof, simultaneously, separately, or sequentially. The kits optionally comprise written material that can include instructions for use, discussion of clinical studies and listing of side effects. Such kits may also include information, such as scientific literature references, package insert materials, clinical trial results, and/or summaries of these and the like, which indicate or establish the activities and/or advantages of the composition, and/or which describe dosing, administration, side effects, drug interactions, or other information useful to the health care provider. Such information may be based on the results of various studies, for example, studies using experimental animals involving in vivo models and studies based on human clinical trials.

In some embodiments, the first pharmaceutical composition and the second pharmaceutical composition are each unit dosage forms. In one aspect, the first pharmaceutical composition and the second pharmaceutical composition are each oral unit dosage forms. In another aspect, the first pharmaceutical composition and the second pharmaceutical composition are each oral unit dosage forms, and the first pharmaceutical composition comprises acalabrutinib, or a pharmaceutically acceptable salt thereof, in an amount from about <NUM> to about <NUM>. In another aspect, the first pharmaceutical composition and the second pharmaceutical composition are each oral unit dosage forms, and the first pharmaceutical composition comprises acalabrutinib, or a pharmaceutically acceptable salt thereof, in an amount of about <NUM>.

In some embodiments, the first pharmaceutical composition and the second pharmaceutical composition are each oral unit dosage forms, and the second pharmaceutical composition comprises capivasertib, or a pharmaceutically acceptable salt thereof, in an amount from about <NUM> to about <NUM>. In one aspect, the first pharmaceutical composition and the second pharmaceutical composition are each oral unit dosage forms, and the second pharmaceutical composition comprises capivasertib, or a pharmaceutically acceptable salt thereof, in an amount from about <NUM> to about <NUM>. In another aspect, the first pharmaceutical composition and the second pharmaceutical composition are each oral unit dosage forms, and the second pharmaceutical composition comprises capivasertib, or a pharmaceutically acceptable salt thereof, in an amount from about <NUM> to about <NUM>.

In some embodiments, the first pharmaceutical composition and the second pharmaceutical composition are each oral unit dosage forms, the first pharmaceutical composition comprises acalabrutinib, or a pharmaceutically acceptable salt thereof, in an amount from about <NUM> to about <NUM>, and the second pharmaceutical composition comprises capivasertib, or a pharmaceutically acceptable salt thereof, in an amount from about <NUM> to about <NUM>. In one aspect, the first pharmaceutical composition and the second pharmaceutical composition are each oral unit dosage forms, the first pharmaceutical composition comprises acalabrutinib, or a pharmaceutically acceptable salt thereof, in an amount from about <NUM> to about <NUM>, and the second pharmaceutical composition comprises capivasertib, or a pharmaceutically acceptable salt thereof, in an amount from about <NUM> to about <NUM>. In another aspect, the first pharmaceutical composition and the second pharmaceutical composition are each oral unit dosage forms, the first pharmaceutical composition comprises acalabrutinib, or a pharmaceutically acceptable salt thereof, in an amount from about <NUM> to about <NUM>, and the second pharmaceutical composition comprises capivasertib, or a pharmaceutically acceptable salt thereof, in an amount from about <NUM> to about <NUM>.

In some embodiments, the first pharmaceutical composition and the second pharmaceutical composition are each oral unit dosage forms, the first pharmaceutical composition comprises acalabrutinib, or a pharmaceutically acceptable salt thereof, in an amount of about <NUM>, and the second pharmaceutical composition comprises capivasertib, or a pharmaceutically acceptable salt thereof, in an amount from about <NUM> to about <NUM>. In one aspect, the first pharmaceutical composition and the second pharmaceutical composition are each oral unit dosage forms, the first pharmaceutical composition comprises acalabrutinib, or a pharmaceutically acceptable salt thereof, in an amount of about <NUM>, and the second pharmaceutical composition comprises capivasertib, or a pharmaceutically acceptable salt thereof, in an amount from about <NUM> to about <NUM>. In another aspect, the first pharmaceutical composition and the second pharmaceutical composition are each oral unit dosage forms, the first pharmaceutical composition comprises acalabrutinib, or a pharmaceutically acceptable salt thereof, in an amount of about <NUM>, and the scecond pharmaceutical composition comprises capivasertib, or a pharmaceutically acceptable salt thereof, in an amount from about <NUM> to about <NUM>.

In some embodiments, acalabrutinib, or a pharmaceutically acceptable salt thereof, and capivasertib, or a pharmaceutically acceptable salt thereof, are provided as a single composition within a container in the kit. In one aspect, therefore, the kit comprises a pharmaceutical composition comprising a compound of Formula I:
<CHM>
or a pharmaceutically acceptable salt thereof; a compound of Formula II:
<CHM>
or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. In one aspect, the pharmaceutical composition is a unit dosage form. In another aspect, the pharmaceutical composition is an oral unit dosage form. In another aspect, the pharmaceutical composition is an oral unit dosage form comprising acalabrutinib, or a pharmaceutically acceptable salt thereof, in an amount from about <NUM> to about <NUM>. 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 <NUM>.

In some embodiments, the kits may further contain another active pharmaceutical ingredient. In one aspect, acalabrutinib, or a pharmaceutically acceptable salt thereof, and capivasertib, or a pharmaceutically acceptable salt thereof, and 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 capivasertib, or a pharmaceutically acceptable salt thereof, and the agent are provided as a single composition within a container in the kit. Suitable packaging and additional articles for use (e.g., measuring cup for liquid preparations, foil wrapping to minimize exposure to air, and the like) are known in the art and may be included in the kit. The kits can be provided, marketed and/or promoted to health providers, including physicians, nurses, pharmacists, formulary officials, and the like. The kits may also, in selected embodiments, be marketed directly to the consumer.

In some embodiments, the kits may further comprise a pharmaceutical composition comprising a therapeutically effective amount of cyclophosphamide, doxorubicin, vincristine, prednisone, or combinations thereof. The kit is for co-administration of acalabrutinib, capivasertib, cyclophosphamide, doxorubicin, vincristine, and/or prednisone, either simultaneously or separately.

The kits described above are preferably for use in the treatment of the B-cell malignancies described in this specification. For example, in one aspect, the B-cell malignancy is non-Hodgkin lymphoma. In another aspect, the B-cell malignancy is diffuse large B-cell lymphoma. In another aspect, the B-cell malignancy is activated B-cell (ABC) diffuse large B-cell lymphoma.

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

For the cell viability assays, cells were seeded in <NUM>-well plates and treated with <NUM>% DMSO control or increasing concentrations of acalabrutinib, capivasertib, or the combination of acalabrutinib and capivasertib for <NUM> hours. Cell viability was measured using Cell Titer Glo reagent and readouts were taken using a Tecan plate reader with a <NUM> integration time. Data analysis was carried out using GeneData software version <NUM>. A growth inhibition value less than <NUM> (GI<NUM> <<NUM>) indicates sensitivity.

Treatment of the cells with capivasertib alone inhibited growth of a subset of GCB DLBCL cell lines but had minimal effect on growth in a subset of ABC DLBCL cell lines (see Table EX-1A below). Treatment of the cells with acalabrutinib alone inhibited growth of a subset of ABC DLBCL cell lines but had minimal effect on growth in the subset of GCB DLBCL cell lines tested (see Table EX-1A below).

Treatment of the cells with a combination of acalabrutinib and capivasertib, however, resulted in enhanced inhibition of cell growth and loss of cell viability in two ABC DLBCL cell lines, TMD8 and OCI-LY10, as indicated by Loewe's and HSA synergy scores which are reported in Tables EX-1B and EX-1C, respectively. A synergy score more than <NUM> (> <NUM>) indicates potential combination benefit in each synergy model. See, e.g., <NPL>); <NPL>); and <NPL>).

<FIG> depicts Combination Signal Heatmaps (% inhibition of growth signal) for TMD8 cells and OCI-LY10 cells after treatment with a combination of acalabrutinib and capivasertib for <NUM> hours.

The study indicated that acalabrutinib in combination with capivasertib showed combination benefit and resulted in enhanced loss of cell viability compared to single agents in a subset of human ABC DLBCL cell lines.

For the western blot analysis, cells were seeded into <NUM> well plates and treated with <NUM>% DMSO, <NUM> capivasertib, <NUM> acalabrutinib, or a combination of <NUM> capivasertib and <NUM> acalabrutinib for two or <NUM> hours. Cells were then lysed in SDS lysis buffer, centrifuged and protein concentrations estimated. Samples were loaded onto Bis-Tris Novex gels, transferred onto nitrocellulose membranes and probed for phospho-proteins of interest.

<FIG> depicts western blots for TMD8 cells and OCI-LY10 cells after treatment with vehicle, acalabrutinib, capivasertib, or a combination of acalabrutinib and capivasertib for <NUM> hours or <NUM> hours. Treatment of TMD8 and OCI-LY10 cells with <NUM> capivasertib resulted in increased phosphorylation of AKTS473 and decreased phosphorylation of the downstream substrates PRAS40, GSK3β, FOXO and S6. Treatment of the cells with <NUM> acalabrutinib induced a decrease in phosphorylation of BTK and also inhibited AKT signalling, as indicated by decreased phosphorylation of AKTS473. Treatment of the cells with a combination of capivasertib and acalabrutinib resulted in reduced induction of phosphorylation of AKTS473 and enhanced inhibition of phosphorylation of S6. In addition, the combination lead to induction of cleaved caspase <NUM> at <NUM> hours, suggesting enhanced apoptosis in these cell lines.

In this mechanism of action study in TMD8 and OCI-LY10 cells, the combination of acalabrutinib and capivasertib resulted in inhibition of AKT signalling and BTK, and further induced caspase activation.

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

TMD8 human ABC-DLBCL tumor cells (<NUM> x <NUM>/mouse) were implanted subcutaneously in female CB. <NUM> SCID mice. The mice were randomized into groups of five for efficacy based on tumor volume and treated with either vehicle (<NUM>% MC/<NUM>% Tween-<NUM>), <NUM>/kg capivasertib, <NUM>/kg acalabrutinib, or a combination of acalabrutinib and capivasertib. Capivasertib was formulated in <NUM>% DMSO/<NUM>% Kleptose pH = <NUM> and acalabrutinib was formulated in <NUM>% MC/<NUM>% Tween-<NUM>. Ten days following tumor cell implantation, all agents were dosed orally according to the schedules listed in Table EX-2A below. Tumor length and width was measured by caliper and tumor volume was calculated using the formula (length x width<NUM>) * π/<NUM>. Plasma pharmacokinetics of acalabrutinib and capivasertib were assessed on day <NUM> of the efficacy study from micro samples (<NUM>µl) obtained from tail vein live bleeds.

After twenty-four days of treatment, capivasertib monotherapy resulted in <NUM>% tumor growth inhibition (TGI), acalabrutinib monotherapy resulted in <NUM>% tumor growth inhibition (TGI), and the combination of both agents resulted in <NUM>% tumor regression. All treatments were tolerated during the dosing period with maximal body weight loss of <NUM>% over the course of the <NUM>-day study. During the study, steady-state unbound plasma concentrations of acalabrutinib and capivasertib were measured from three mice in the single agent and combination groups at <NUM>, <NUM>, <NUM>, and <NUM>-hour time points. Drug exposure levels of acalabrutinib and capivasertib were similar following oral administration of acalabrutinib and capivasertib single agents or in combination. The overall results are summarized in Table EX-2A below.

<FIG> depicts the effect of treatment with vehicle, acalabrutinib, capivasertib, or a combination of acalabrutinib and capivasertib on tumor volume. <FIG> depicts the steady state drug exposure after treatment with acalabrutinib, capivasertib, or a combination of acalabrutinib and capivasertib. <FIG> depicts the effect of treatment with vehicle, acalabrutinib, capivasertib, or a combination of acalabrutinib and capivasertib on body weight.

Oral treatment with a combination of acalabrutinib and capivasertib resulted in markedly enhanced anti-tumor efficacy leading to complete regression (<NUM>%) in a TMD8 human ABC DLBCL xenograft model relative to single agent therapies. All treatments were well tolerated in mice with a maximum body weight loss of <NUM>% observed in the combination treatment group. Pharmacokinetic assessments revealed comparable drug exposure levels for the acalabrutinib and capivasertib single agent and combination groups.

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

OCI-ly10 human ABC-DLBCL tumor cells (<NUM> x <NUM>/mouse) were implanted subcutaneously in female CB. <NUM> SCID mice. The mice were randomized into groups of five for efficacy based on tumor volume and treated with either vehicle (<NUM>% MC/<NUM>% Tween-<NUM>), <NUM>/kg capivasertib, <NUM>/kg acalabrutinib, or a combination of acalabrutinib and capivasertib. Capivasertib was formulated in <NUM>% DMSO/<NUM>% Kleptose pH = <NUM> and acalabrutinib was formulated in <NUM>% MC/<NUM>% Tween-<NUM>. Nineteen days following tumor cell implantation, all agents were dosed orally according to the schedules listed in Table EX-2B below. Tumor length and width was measured by caliper and tumor volume was calculated using the formula (length x width<NUM>) * π/<NUM>.

After twenty-five days of treatment, capivasertib monotherapy resulted in <NUM>% tumor growth inhibition (TGI), acalabrutinib monotherapy resulted in <NUM>% tumor growth inhibition (TGI), and the combination of both agents resulted in <NUM>% tumor regression. All treatments were tolerated during the dosing period with maximal body weight loss of <NUM>% over the course of the <NUM>-day study. The overall results are summarized in Table EX-2B below.

<FIG> depicts the effect of treatment with vehicle, acalabrutinib, capivasertib, or a combination of acalabrutinib and capivasertib on tumor volume. <FIG> depicts the effect of treatment with vehicle, acalabrutinib, capivasertib, or a combination of acalabrutinib and capivasertib on body weight during the <NUM>-day dosing period.

Oral treatment with a combination of acalabrutinib and capivasertib resulted in markedly enhanced anti-tumor efficacy leading to near complete regression (<NUM>%) in a OCI-Ly10 human ABC DLBCL xenograft model relative to single agent therapies. All treatments were well tolerated in mice with a maximum body weight loss of <NUM>% observed in the combination treatment group. Pharmacokinetic assessments revealed comparable drug exposure levels for the acalabrutinib and capivasertib single agent and combination groups.

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

TMD8 human ABC-DLBCL tumor cells harboring a luciferase reporter construct (<NUM> x <NUM>/mouse) were injected intravenously into the tail vein of female CB. <NUM> SCID mice. Tumor burden as measured using the Xenogen IVIS imaging system, body weight, and animal condition were recorded minimally twice weekly for the duration of the study. For Xenogen imaging, mice received an intraperitoneal administration of <NUM>/kg D-Luciferin <NUM>-<NUM> minutes prior to imaging. Imaging of live mice was performed under isoflurane anesthesia and data analyzed using Living Image software (Xenogen). Mice were randomized into groups of five for efficacy based on dorsal and ventral bioluminescence intensity (BLI) and treated with either vehicle (<NUM>% MC/<NUM>% Tween-<NUM>), <NUM>/kg capivasertib, <NUM>/kg acalabrutinib, or a combination of acalabrutinib and capivasertib. Capivasertib was formulated in <NUM>% DMSO/<NUM>% Kleptose pH = <NUM> and acalabrutinib was formulated in <NUM>% MC/<NUM>% Tween-<NUM>. Fourteen days following tumor cell injection, all agents were dosed orally according to the schedules listed in Table EX-2A of Example <NUM>. Disseminated tumor burden was measured by Xenogen and study endpoints were determined by the condition of individual animals in which moribound mice were humanely sacrificed.

As depicted in <FIG>, oral treatment with a combination of acalabrutinib and capivasertib resulted in markedly enhanced survival benefit in a disseminated TMD8-luc2 human ABC DLBCL xenograft mouse model relative to single agent therapies. All treatments were well tolerated in mice until animals reached survival study endpoints.

A study is conducted to evaluate the in vivo efficacy of monotherapy and combination responses of acalabrutinib and capivasertib in two patient-derived xenograft (PDX) models, a subcutaneous ABC-DLBCL PDX model (LY0257) and a subcutaneous GCB-DLBCL PDX model (LY2214). LY2214 and LY0257 human patient-derived DLBCL primary human tumor fragments (<NUM>-<NUM> in diameter) will be implanted subcutaneously into female NOD/SCID and B/C nude mice, respectively. The mice will be randomized into groups of five based on tumor volume and treated with either vehicle, acalabrutinib, capivasertib, or a combination of acalabrutinib and capivasertib. Acalabrutinib will be formulated in <NUM>%MC + <NUM>% Tween-<NUM> and capivasertib will formulated in <NUM>% DMSO/<NUM>% Kleptose pH = <NUM>. When tumors reach sizes between <NUM> to <NUM><NUM>, vehicle, acalabrutinib, capivasertib, and the combination of acalabrutinib and capivasertib will be dosed orally at the schedules listed in Table EX-2A of Example <NUM>. Tumor volumes will be measured twice per week in two dimensions using a caliper, and the volume will be expressed in mm<NUM> using the formula: "V = (L x W x W)/<NUM>, where V is tumor volume, L is tumor length (the longest tumor dimension), and W is tumor width (the longest tumor dimension perpendicular to L).

An RNAseq study is conducted on TMD8 cells treated with acalabrutinib, capivasertib, or a combination of acalabrutinib and capivasertib. Specifically, TMD8 cells are seeded into six well plates and treated with <NUM>% DMSO, <NUM> capivasertib, <NUM> acalabrutinib, or a combination of <NUM> capivasertib and <NUM> acalabrutinib for six or <NUM> hours. Cells pellets are then made and RNA isolated. RNA samples are sent to Novogene for cDNA library generation, and mRNA sequencing (RNA-seq). RNAseq data is analyzed using inhouse pipeline, quantifying gene expression using Salmon method (Patro R, <NUM>). Differential expression analysis is carried out using DESeq2 (Love MI, <NUM>). Enrichment analysis is carried using GSVA (Hänzelmann S, <NUM>).

A pharmacodynamic study is conducted to evaluate monotherapy and combination responses of acalabrutinib and capivasertib. TMD8 human ABC-DLBCL tumor cells (<NUM> x <NUM>/mouse) will be implanted subcutaneously in female CB. <NUM> SCID mice. The mice will be randomized into groups of three for evaluation based on when tumor volumes reach approximately <NUM> to <NUM><NUM> and then will be treated with either a single acute dose or multiple doses of either vehicle (<NUM>% MC/<NUM>% Tween-<NUM>), <NUM>/kg acalabrutinib, <NUM>/kg capivasertib, or the combination at <NUM>, <NUM>, <NUM>, <NUM>-hour time points. The pharmacodynamic assessment of acalabrutinib and capivasertib will include pS6, pBTK, pAKT, p4EBP1, and pPLCγ2.

A Phase <NUM>/<NUM>, single-arm, open-label, proof-of-concept study is conducted to evaluate the combination of acalabrutinib with capivasertib for treating patients with relapsed/refractory DLBCL. The study will assess the clinical potential of a dual BTK and AKT inhibition approach by evaluating the safety, pharmacokinetics, pharmacodynamics, and efficacy of acalabrutinib and capivasertib combination therapy in treating relapsed/refractory DLBCL.

The objectives of Part <NUM> of the clinical study include determining a dose and schedule for capivasertib in combination with acalabrutinib <NUM> BID for evaluation in Part <NUM> of the clinical study. The primary objective of Part <NUM> of the clinical study is to evaluate the safety of acalabrutinib and capivasertib when co-administered. Secondary objectives of Part <NUM> of the clinical study include evaluating the pharmacokinetics, pharmacodynamics, and clinical activity of acalabrutinib and capivasertib when co-administered.

Safety parameters that will be evaluated include, but are not limited to, type, frequency, severity, and relationship to study drug of any treatment-emergent adverse events (TEAEs) or abnormalities of laboratory tests, serious adverse events (SAEs), dose limiting toxicities (DLTs), and adverse events (AEs) leading to discontinuation of study drug(s).

The plasma pharmacokinetics of acalabrutinib and capivasertib will be characterized using noncompartmental analysis and the following pharmacokinetic parameters will be calculated, whenever possible, from plasma concentrations of analytes: (<NUM>) AUC(<NUM>-last): area under the plasma concentration-time curve calculated using linear trapezoidal summation from time <NUM> to time last, where "last" is the time of the last measurable concentration; AUC(<NUM>-inf): area under the plasma concentration-time curve from <NUM> to infinity, calculated using the formula: AUC(<NUM>-inf) = AUC(<NUM>-last) + C(last / λz), where λz is the apparent terminal elimination rate constant; Cmax: maximum observed plasma concentration; Tmax: time of the maximum plasma concentration (obtained without interpolation); t½: terminal elimination half-life (whenever possible); λz: terminal elimination rate constant (whenever possible); CL/F: oral clearance; Vz/F: oral volume of distribution.

The pharmacodynamic assessment of acalabrutinib and capivasertib will include (<NUM>) measuring the occupancy of BTK by acalabrutinib in peripheral blood mononuclear cells (PBMCs) with the aid of an acalabrutinib analogue probe, (<NUM>) evaluating the effect of acalabrutinib and capivasertib on biologic markers of B-cell function and/or AKT inhibition in PBMCs and/or tumor tissue, and (<NUM>) assessing the effect of acalabrutinib and capivasertib on circulating tumor DNA (ctDNA). Cell populations and immunological markers will be monitored for effect of treatment, which may include, but are not limited to, leukocyte or lymphocyte subsets (e.g., T, B and natural killer [NK] cells) and their activation states. Additional markers may include Ki67, pS6, pBTK, pAKT, pPRAS40, pGSK3β, p4EBP1, FOXO3, and pPLCγ2.

Clinical activity of acalabrutinib and capivasertib will be 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).

The study objectives and endpoints are summarized in Table EX-7A below.

The study is an exploratory, multicenter, open-label, non-randomized Phase I platform study to be conducted at approximately <NUM> sites.

The study will enroll up to <NUM> evaluable subjects.

Acalabrutinib drug product is provided as hard gelatin capsules containing <NUM> of acalabrutinib for oral administration.

Capivasertib drug product is provided as film-coated tablets containing either <NUM> or <NUM> of capivasertib for oral administration.

Acalabrutinib and capivasertib are administered orally twice daily with <NUM> ounces (approximately <NUM>) of water (avoid grapefruit juice or Seville orange juice due to potential inhibition of CYP3A). Doses are administered <NUM> hours apart (a window of ±<NUM> hour is allowed) at approximately the same times each day. Subjects will fast (water to drink only) from at least two hours before taking a dose to at least one hour post-dose for all doses. The acalabrutinib capsules and capivasertib tablets are taken concomitantly and are swallowed intact. Acalabrutinib is taken every day while capivasertib is taken on a schedule of <NUM> days on, <NUM> days off.

To be eligible for the study, subjects must meet the following inclusion criteria:.

Subjects are not eligible for the study if the meet any of the following exclusion criteria:.

Claim 1:
A combination of a compound of Formula I:
<CHM>
or a pharmaceutically acceptable salt thereof, and a compound of Formula II:
<CHM>
or a pharmaceutically acceptable salt thereof, for use in a method of treating a B-cell malignancy in a human subject in need thereof, comprising administering to the human subject a first amount of the compound of Formula I or a pharmaceutically acceptable salt thereof, and a second amount of the compound of Formula II or a pharmaceutically acceptable salt thereof, wherein the first amount and the second amount together comprise a therapeutically effective amount.