Combination therapy of PI3K inhibitor with PD-1 inhibitor

Abstract

Provided herein are methods of treating a proliferative disease or condition (e.g., cancer) in a patient in need thereof using combination therapy of Compound I, or a pharmaceutically acceptable salt thereof, with a PD-1 inhibitor (e.g., pembumab). # imgabs0 #

Description

[0001] Cross-references

[0002] This international patent application claims the benefit of U.S. Provisional Patent Application No. 63 / 315,380, filed on March 1, 2022, which is incorporated herein by reference in its entirety. Background Art

[0003] Phosphoinositide 3-kinase (PI3K) plays a variety of roles in normal tissue physiology (Foukas & Shepherd, Biochem. Soc. Trans. 2004, 32, 330; Shepherd, Acta Physiol. Scand. 2005, 183, 3), among which p110α has a specific role in cancer growth, and p110β plays a role in the regulation of integrin α Π β3-mediated thrombosis has a specific role (Jackson et al., Nat. Med. 2005, 11, 507), and p110γ has a specific role in inflammation, rheumatoid arthritis and other chronic inflammatory states (Barber et al., Nat. Med. 2005, 11, 933; Camps et al., Nat. Med. 2005, 11, 936; Rommel et al., Nat. Rev. 2007, 7, 191; and Ito, et al., J. Pharm. Exp. Therap. 2007, 321, 1). Inhibitors of PI3K have therapeutic potential in the treatment of various proliferative diseases, including cancer. Summary of the invention

[0004] Provided herein are methods for treating cancer in a patient in need thereof in one or more treatment cycles comprising:

[0005] (i) administering Compound 1 or a pharmaceutically acceptable salt thereof to the patient for a first period of time in each of one or more treatment cycles; and

[0006] (ii) administering a PD-1 inhibitor to the patient after administering Compound I or a pharmaceutically acceptable salt thereof;

[0007] Wherein compound I has the following structure:

[0008]

[0009] In some embodiments, each of the one or more treatment cycles is at least about 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks.

[0010] In some embodiments, each of the one or more treatment cycles is about 6 weeks.

[0011] In some embodiments, each of the one or more treatment cycles is about 3 weeks.

[0012] In some embodiments, the PD-1 inhibitor is administered about 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days after the first period of time.

[0013] In some embodiments, each of the one or more treatment cycles is about 6 weeks and the PD-1 inhibitor is administered about 16 days after the first period of time.

[0014] In some embodiments, each of the one or more treatment cycles is about 3 weeks and the PD-1 inhibitor is administered about 8 days after the first period of time.

[0015] In some embodiments, the first period of time is 3 days, 4 days, 5 days, 6 days, or 1 week.

[0016] In some embodiments, the first period of time is 5 days.

[0017] In some embodiments, after the first time period, administration of the PD-1 inhibitor begins on the day after the second time period, wherein the second time period immediately follows the first time period.

[0018] In some embodiments, the second period of time is about 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days.

[0019] In some embodiments, the second period of time is about 16 days.

[0020] In some embodiments, the second period of time is about 8 days.

[0021] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered daily during the first period of time.

[0022] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to a patient on an intermittent dosing schedule.

[0023] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered only during the first time period of each of one or more treatment cycles and not on days after the first time period, and the first time period is shorter than each of the one or more treatment cycles.

[0024] In some embodiments, the first period of time is 3 days, 4 days, 5 days, 6 days, or 1 week.

[0025] In some embodiments, the first period of time is 5 days.

[0026] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered at a dose of 60 mg / day.

[0027] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered orally.

[0028] In some embodiments, the PD-1 inhibitor is administered once, twice, or three times in each of one or more treatment cycles.

[0029] In some embodiments, the PD-1 inhibitor is administered once in each of one or more treatment cycles.

[0030] In some embodiments, when each of the one or more treatment cycles is about 6 weeks, the PD-1 inhibitor is administered on day 22 of each of the one or more treatment cycles.

[0031] In some embodiments, when each of the one or more treatment cycles is about 3 weeks, the PD-1 inhibitor is administered on day 14 of each of the one or more treatment cycles.

[0032] In some embodiments, the PD-1 inhibitor is administered twice in each of one or more treatment cycles.

[0033] In some embodiments, when each of the one or more treatment cycles is about 6 weeks, the PD-1 inhibitor is administered on Day 14 and Day 35 of each of the one or more treatment cycles.

[0034] In some embodiments, the PD-1 inhibitor is pembrolizumab, nivolumab, cemiplimab, or dostarlimab, or a variant or biosimilar thereof, or a combination thereof.

[0035] In some embodiments, the PD-1 inhibitor is pembrolizumab or a variant or biosimilar thereof.

[0036] In some embodiments, the PD-1 inhibitor is administered for at least 6 weeks.

[0037] In some embodiments, the PD-1 inhibitor is administered for 6, 9, 12, 15, 18, 21, 24, 27, or 30 weeks.

[0038] In some embodiments, the PD-1 inhibitor is administered once every 3 weeks or once every 6 weeks.

[0039] In some embodiments, the PD-1 inhibitor is administered at a dose of 200 mg or 400 mg.

[0040] In some embodiments, the PD-1 inhibitor is administered once every 6 weeks.

[0041] In some embodiments, the PD-1 inhibitor is administered at a dose of 400 mg.

[0042] In some embodiments, the PD-1 inhibitor is administered once every 3 weeks.

[0043] In some embodiments, the PD-1 inhibitor is administered at a dose of 200 mg.

[0044] In some embodiments, the PD-1 inhibitor is administered intravenously.

[0045] In some embodiments, the first time period begins on day 1, day 2, day 3, day 4, day 5, day 6, day 7, or day 8 of each of one or more treatment cycles.

[0046] In some embodiments, the first period begins on day 1 of each of the one or more treatment cycles.

[0047] In some embodiments, each of the one or more treatment cycles is 6 weeks, Compound I or a pharmaceutically acceptable salt thereof is administered on days 1 to 5, and then the PD-1 inhibitor is administered once on day 22.

[0048] In some embodiments, each of the one or more treatment cycles is 3 weeks, Compound I or a pharmaceutically acceptable salt thereof is administered on days 1 to 5, and then the PD-1 inhibitor is administered once on day 14.

[0049] In some embodiments, the cancer is lung cancer (e.g., non-small cell lung cancer), melanoma, renal cell carcinoma, head and neck cancer, breast cancer (e.g., triple-negative breast cancer), non-Hodgkin lymphoma, Hodgkin lymphoma, colorectal cancer, urothelial carcinoma, gastric cancer, cervical cancer, hepatocellular carcinoma, Merkel cell carcinoma, esophageal cancer, endometrial cancer, squamous cell carcinoma of the skin, or mesothelioma.

[0050] In some embodiments, the cancer is lung cancer.

[0051] In some embodiments, the lung cancer is non-small cell lung cancer.

[0052] In some embodiments, the cancer is melanoma.

[0053] In some embodiments, the cancer is renal cell carcinoma.

[0054] In some embodiments, the cancer is hepatocellular carcinoma.

[0055] In some embodiments, the cancer is colorectal cancer.

[0056] In some embodiments, the colorectal cancer is microsatellite instability-high or mismatch repair deficient colorectal cancer.

[0057] In some embodiments, the methods provided herein further include (iii) evaluating the efficacy of administering a combination of Compound I or a pharmaceutically acceptable salt thereof and a PD-1 inhibitor by measuring the levels of regulatory T cells (CD25hi FoxP3+ T cells) or effector T cells (e.g., CD8+ and CD4+ cells).

[0058] In some embodiments, a level of regulatory T cells (CD25hi FoxP3+ T cells) or effector T cells (e.g., CD8+ and CD4+ cells) that is less than or equal to about 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15% or 10% of a baseline level of regulatory T cells (CD25hi FoxP3+ T cells) or effector T cells (e.g., CD8+ and CD4+ cells) indicates that one or more treatment cycles of administration of a combination of Compound I, or a pharmaceutically acceptable salt thereof, and a PD-1 inhibitor are effective.

[0059] In some embodiments, a level of regulatory T cells (CD25hi FoxP3+ T cells) or effector T cells (e.g., CD8+ and CD4+ cells) that is less than or equal to about 65% of a baseline level of regulatory T cells (CD25hi FoxP3+ T cells) or effector T cells (e.g., CD8+ and CD4+ cells) indicates that one or more treatment cycles of administration of a combination of Compound I, or a pharmaceutically acceptable salt thereof, and a PD-1 inhibitor are effective.

[0060] In some embodiments, co-administration of Compound 1, or a pharmaceutically acceptable salt thereof, with a PD-1 inhibitor is effective in treating cancer.

[0061] In another aspect, provided herein is a method for treating cancer in a patient in need thereof in one or more treatment cycles, comprising: (i) administering Compound 1 or a pharmaceutically acceptable salt thereof to the patient on day 1 to day 5 of each of the one or more treatment cycles; and (ii) administering a PD-1 inhibitor to the patient on day 22 of each of the treatment cycles; wherein each of the one or more treatment cycles is 6 weeks; and wherein Compound 1 has the following structure:

[0062]

[0063] In another aspect, provided herein is a method for treating cancer in a patient in need thereof in one or more treatment cycles, comprising: (i) administering Compound 1 or a pharmaceutically acceptable salt thereof to the patient on day 1 to day 5 of each of the one or more treatment cycles; and (ii) administering a PD-1 inhibitor to the patient on day 14 of each of the treatment cycles; wherein each of the one or more treatment cycles is 3 weeks; and wherein Compound 1 has the following structure:

[0064]

[0065] In yet another aspect, provided herein is a method for treating cancer in a patient in need thereof in one or more treatment cycles, comprising: (i) administering Compound 1 or a pharmaceutically acceptable salt thereof to the patient in Week 1 of an odd-numbered cycle (e.g., Cycle 1) of the one or more treatment cycles; and (ii) administering a PD-1 inhibitor to the patient in Week 1 of an even-numbered cycle (e.g., Cycle 2) of each of the treatment cycles; wherein each of the one or more treatment cycles is 3, 6 or 9 weeks; and wherein Compound 1 has the following structure:

[0066]

[0067] In yet another aspect, provided herein is a method for treating cancer in a patient in need thereof in one or more treatment cycles, comprising: (i) administering Compound 1 or a pharmaceutically acceptable salt thereof to the patient in week 1 of each of the one or more treatment cycles; and (ii) administering a PD-1 inhibitor to the patient in week 2 of each of the treatment cycles; wherein each of the one or more treatment cycles is 3 weeks; and wherein Compound 1 has the following structure:

[0068]

[0069] In yet another aspect, provided herein is a method for treating cancer in a patient in need thereof, comprising: (i) administering Compound 1 or a pharmaceutically acceptable salt thereof to the patient once a day for 1, 2, 3, 4 or 5 days every 3, 6 or 9 weeks; and (ii) administering a PD-1 inhibitor to the patient once every 3 or 6 weeks; wherein Compound 1 has the following structure:

[0070]

[0071] Incorporation by reference

[0072] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS

[0073] The novel features of the present disclosure are particularly set forth in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by referring to the following detailed description and accompanying drawings which set forth illustrative embodiments in which the principles of the invention are utilized, in which:

[0074] Figure 1 Illustrated is a Kaplan-Meier survival curve obtained from Example 2a, in which a study evaluating the efficacy of the combination therapy of Compound I and a PD-1 inhibitor (RMP1-14) was conducted in the MC38 murine adenocarcinoma model. The figure depicts the efficacy of two treatment cycles of the combination therapy compared to a single cycle of the combination therapy or a single cycle of a PD-1 inhibitor.

[0075] Figure 2 Illustrated is a Kaplan-Meier survival curve obtained from Example 2a, in which a study evaluating the efficacy of the combination therapy of Compound I with a PD-1 inhibitor (RMP1-14) was conducted in the MC38 murine adenocarcinoma model. The figure depicts the efficacy of two treatment cycles of combination therapy compared to a single cycle of combination therapy or a single cycle of combination with additional cycles of Compound I.

[0076] Figure 3 Illustrated are Kaplan-Meier survival curves obtained from Example 2a, in which a study evaluating the efficacy of combination therapy of Compound I with a PD-1 inhibitor (RMP1-14) was conducted in the MC38 murine adenocarcinoma model. The figure depicts the efficacy of two treatment cycles of combination therapy compared to a single cycle of combination therapy or a single cycle of combination with an additional cycle of a PD-1 inhibitor.

[0077] Figure 4 Depicted is the study design for a clinical study of Compound I in combination with pembrolizumab for the treatment of patients with certain cancers.

[0078] Figure 5 Study design The dosing schedules for Level 1 (top) and Level 2 (bottom) of Compound I in combination with pembrolizumab are illustrated. DETAILED DESCRIPTION

[0079] Provided herein are methods of treating a proliferative disease or disorder (e.g., cancer) in a patient in need thereof in one or more treatment cycles, wherein in each treatment cycle, the method comprises administering i) a PI3K inhibitor which is Compound I or a pharmaceutically acceptable salt thereof; and ii) a PD-1 inhibitor (e.g., pembrolizumab).

[0080] definition

[0081] To facilitate understanding of the disclosure set forth herein, a number of terms are defined below.

[0082] In general, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry and pharmacology described herein are those well known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as those generally understood by those skilled in the art of the present disclosure. The term "object" refers to an animal, including but not limited to primates (e.g., humans), cattle, pigs, sheep, goats, horses, dogs, cats, rabbits, rats or mice. The terms "object" and "patient" are used interchangeably herein, referring to, for example, mammalian subjects, such as human subjects, and in one embodiment, refer to humans.

[0083] The terms "treat," "treating," and "treatment" are meant to include alleviating or eliminating a disorder, disease, or condition, or one or more symptoms associated with a disorder, disease, or condition; or alleviating or eradicating the cause of the disorder, disease, or condition itself.

[0084] The terms "prevent," "preventing," and "prevention" are meant to include methods of delaying and / or arresting the onset of a disorder, disease or condition, and / or its attendant symptoms; blocking a subject from acquiring a disorder, disease or condition; or reducing the risk of a subject acquiring a disorder, disease or condition.

[0085] The terms "therapeutically effective amount" and "effective amount" are meant to include an amount of a compound that, when administered, is sufficient to prevent the development of, or alleviate to some extent, one or more symptoms of, the disorder, disease, or condition being treated. The terms "therapeutically effective amount" and "effective amount" also refer to an amount of a compound that is sufficient to elicit a biological or medical response of a biomolecule (e.g., protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor, or clinician.

[0086] The terms "pharmaceutically acceptable carrier", "pharmaceutically acceptable excipient", "physiologically acceptable carrier" and "physiologically acceptable excipient" refer to pharmaceutically acceptable materials, compositions or vehicles, such as liquid or solid fillers, diluents, solvents or encapsulating materials. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation and suitable for use in contact with the tissues or organs of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications, commensurate with a reasonable benefit / risk ratio. See, Remington: The Science and Practice of Pharmacy, 21st ed., Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th ed., Rowe et al., eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd ed., Ash and Ash, eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed., Gibson, ed., CRC Press LLC: Boca Raton, FL, 2009.

[0087] The terms "about" and "approximately" mean an acceptable error for a particular value as determined by one of ordinary skill in the art, which may depend in part on how the value is measured or determined. In certain embodiments, the terms "about" and "approximately" mean within 1, 2, 3, or 4 standard deviations. In certain embodiments, the terms "about" and "approximately" mean within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0088] The terms "active ingredient" and "active substance" refer to a compound that is administered to a subject alone or in combination with one or more pharmaceutically acceptable excipients for the treatment, prevention, or amelioration of one or more symptoms of a disorder, disease, or condition. As used herein, "active ingredient" and "active substance" may be an optically active isomer of a compound described herein.

[0089] The terms "drug," "therapeutic agent," and "chemotherapeutic agent" refer to a compound or pharmaceutical composition thereof administered to a subject for the treatment, prevention, or amelioration of one or more symptoms of a disorder, disease, or condition.

[0090] The terms "naturally occurring" and "native" when used in relation to biological materials such as nucleic acid molecules, polypeptides, host cells, etc., refer to materials that are found in nature and are not manipulated by humans. Similarly, "non-naturally occurring" or "non-naturally occurring" refers to materials that are not found in nature or that have been structurally modified or synthesized by humans.

[0091] The term "PI3K" refers to phosphoinositide 3-kinase or a variant thereof, which is capable of phosphorylating the inositol ring of PI at the D-3 position. The term "PI3K variant" is intended to include proteins substantially homologous to natural PI3K, i.e., proteins (e.g., PI3K derivatives, homologs, and fragments) having one or more naturally or non-naturally occurring amino acid deletions, insertions, or substitutions compared to the amino acid sequence of natural PI3K. The amino acid sequence of a PI3K variant has at least about 80% identity, at least about 90% identity, or at least about 95% identity with natural PI3K. Examples of PI3K include, but are not limited to, p110α, p110β, p110δ, p110γ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, mTOR, ATM, ATR, and DNA-PK. See, Fry, Biochem. Biophys. Acta 1994, 1226, 237-268; Vanhaesebroeck and Waterfield, Exp. Cell. Res. 1999, 253, 239-254; and Fry, Breast Cancer Res. 2001, 3, 304-312. PI3K is classified into at least four classes. Class I includes p110α, p110β, p110δ, and p110γ. Class II includes PI3K-C2α, PI3K-C2β, and PI3K-C2γ. Class III includes Vps34. Class IV includes mTOR, ATM, ATR, and DNA-PK. In certain embodiments, PI3K is a class I kinase. In certain embodiments, PI3K is p110α, p110β, p110δ, or p110γ. In certain embodiments, PI3K is a variant of a class I kinase. In certain embodiments, PI3K is a p110α mutant. Examples of p110α mutants include, but are not limited to, R38H, G106V, K111N, K227E, N345K, C420R, P539R, E542K, E545A, E545G, E545K, Q546K, Q546P, E453Q, H710P, I800L, T1025S, M10431, M1043V, H1047L, H1047R, and H1047Y (Ikenoue et al., Cancer Res. 2005, 65, 4562-4567; Gymnopoulos et al., Proc. Natl. Acad Sci., 2007, 104, 5569-5574). In certain embodiments, PI3K is a class II kinase. In certain embodiments, the PI3K is PI3K-C2α, PI3K-C2β, or PI3K-C2γ. In certain embodiments, the PI3K is a class III kinase. In certain embodiments, the PI3K is Vps34.In certain embodiments, the PI3K is a class IV kinase.In certain embodiments, the PI3K is mTOR, ATM, ATR or DNA-PK.

[0092] The term "PD-1" refers to programmed cell death-1 receptor or programmed cell death protein 1, also known as cluster of differentiation 279 (CD279). The human PD-1 protein is encoded by the PDCD1 gene. PD-1 is a cell surface receptor that plays an important role in downregulating the immune system and promoting self-tolerance by inhibiting T-cell inflammatory activity. PD-1 is expressed on the surface of activated T cells and defends against autoimmunity by a dual mechanism of promoting apoptosis (programmed cell death) of antigen-specific T cells in the lymph nodes while simultaneously reducing apoptosis of regulatory T cells (anti-inflammatory, suppressive T cells). PD-1 inhibitors activate the immune system to attack tumors and are therefore used to treat some types of cancer.

[0093] The term "PD-L1" refers to programmed death-ligand 1, also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1). PD-L1 is a protein encoded by the CD274 gene. PD-L1 is a transmembrane protein that plays a major role in suppressing the immune system. PD-L1 binds to its receptor PD-1 (found in activated T cells, B cells, and myeloid cells) to regulate the activation or inhibition of T cell responses. PD-L1 (a ligand of PD-1) is highly expressed in several cancers. Inhibition of the interaction between PD-1 and PD-L1 can enhance T cell responses against cancer cells or tumors, and is therefore useful for treating cancer.

[0094] As used herein, the terms "synergy", "synergism" and "synergistic" refer to a combination of therapies (e.g., Compound I using a PI3K inhibitor and a PD-1 inhibitor (e.g., pembrolizumab)) that is more effective than the expected additive effect of any two or more monotherapies. For example, the synergistic effect of the combination of therapies allows the use of lower doses of one or more therapies and / or less frequent administration of the therapy to the subject. The ability to utilize lower doses of the therapy and / or less frequent administration of the therapy reduces the toxicity associated with administering the therapy to the subject without reducing the efficacy of the therapy in preventing, managing, treating, or ameliorating a given disease (such as an autoimmune disease, an inflammatory disease, or a cancer including, but not limited to, chronic lymphocytic leukemia or non-Hodgkin's lymphoma). In addition, the synergistic effect can result in improved efficacy of the therapy in preventing, managing, treating, or ameliorating a given disease (such as an autoimmune disease, an inflammatory disease, or a cancer including, but not limited to, chronic lymphocytic leukemia or non-Hodgkin's lymphoma). Finally, the synergistic effect of the combination of therapies can avoid or reduce adverse or undesirable side effects associated with the use of any single therapy. The "synergy", "synergy" or "synergistic" effect of a combination can be determined herein by the methods of Chou et al. and / or Clarke et al. See Ting-Chao Chou, Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies, Pharmacol. Rev. 58: 621-681 (2006) and Clarke et al., Issues in experimental design and endpoint analysis in the study of experimental cytotoxic agents in vivo in breast cancer and other models, Breast Cancer Research and Treatment 46: 255-278 (1997), both of which are incorporated by reference into methods for determining the "synergy", "synergy" or "synergistic" effect of a combination.

[0095] Compound I of PI3K inhibitor

[0096] One therapeutic agent administered in the combination therapy provided herein is a PI3K inhibitor. In some embodiments, the PI3K inhibitor is Compound 1 or a pharmaceutically acceptable salt or hydrate thereof, wherein Compound 1 has the following structure:

[0097]

[0098] PD-1 inhibitors

[0099] Another therapeutic agent administered in the combination therapies provided herein is a PD-1 inhibitor.

[0100] The PD-1 (programmed cell death–1) receptor (also known as CD279) is expressed on the surface of activated T cells. Its ligand, PD-L1, is typically expressed on the surface of dendritic cells or macrophages. In some cases, the PD-1 and PD-L1 interaction stops or limits the development of T cell responses. When PD-L1 binds to PD-1, an inhibitory signal is transmitted to the T cell, which reduces cytokine production and inhibits T cell proliferation. In some cases, cancer or tumor cells exploit this signaling pathway as a mechanism to evade detection and suppress immune responses. In some cases, PD-L1 is overexpressed on cancer or tumor cells or on non-transformed cells in the tumor microenvironment. In some cases, PD-L1 expressed on tumor cells binds to the PD-1 receptor on activated T cells, which results in the inhibition of cytotoxic T cells. These inactivated T cells remain suppressed in the tumor microenvironment. The PD1 / PD-L1 pathway represents an adaptive immune resistance mechanism exerted by cancer or tumor cells in response to endogenous anti-tumor activity.

[0101] PD-1 inhibitors (or anti-PD-1 agents) and PD-L1 inhibitors (or anti-PD-L1 agents) block the interaction between PD-1 and PD-L1 and enhance the immune response to cancer cells. In some cases, the blockade of receptor engagement leads to an amplification of the antigen-specific T cell response to cancer cells. In some cases, antibodies that block the PD-1 / PD-L1 interaction target lymphocyte receptors or their ligands to enhance endogenous anti-tumor activity. In some cases, PD-1 inhibitors and PD-L1 inhibitors overcome different immunosuppressive pathways within the tumor microenvironment. In some cases, PD-1 inhibitors and / or PD-L1 inhibitors are useful for treating cancer.

[0102] Any suitable PD-1 inhibitor can be used in combination with the PI3K inhibitors described herein. In some embodiments, the PD-1 inhibitor is an antagonist of PD-1. In some embodiments, the PD-1 inhibitor is an antibody, a variant thereof, or a biosimilar. In some embodiments, the PD-1 inhibitor is a monoclonal antibody. In some embodiments, the method of treating cancer with the PI3K inhibitors described herein in combination with the PD-1 inhibitors provided herein results in a transient reduction in systemic immunosuppression levels.

[0103] Some embodiments provided herein describe pharmaceutical compositions or methods for using pharmaceutical compositions, the pharmaceutical compositions comprising a combination of a PI3K inhibitor and a PD-1 inhibitor as described herein. The PD-1 inhibitors used in the pharmaceutical compositions and methods provided herein include, but are not limited to, nivolumab. Pembrolizumab MEDI0680 (AMP-514), AMP-224, AMP-514 (Amplimmune), BGB-A317, PDR001, REGN2810, JS001, AGEN2034, and variants and biosimilars thereof. In some embodiments, the PD-1 inhibitor is nivolumab Pembrolizumab MEDI0680 (AMP-514), AMP-224, AMP-514 (Amplimmune), or variants or biosimilars thereof. In some embodiments, the PD-1 inhibitor is pidilzumab (CT-011), or variants or biosimilars thereof. In some embodiments, the PD-1 inhibitor is nivolumab Pembrolizumab or a variant or biosimilar thereof. In some embodiments, the PD-1 inhibitor is BGB-A317, a BGB-A317 variant, or a BGB-A317 biosimilar. In some embodiments, the PD-1 inhibitor is PDR001, a PDR001 variant, or a PDR001 biosimilar. In some embodiments, the PD-1 inhibitor is REGN2810, a REGN2810 variant, or a REGN2810 biosimilar.

[0104] In a preferred embodiment, the PD-1 inhibitor is pembrolizumab Pembrolizumab variants or pembrolizumab biosimilars.

[0105] In another embodiment, the PD-1 inhibitor is nivolumab Nivolumab variants or nivolumab biosimilars.

[0106] How to use

[0107] Provided herein are methods for treating cancer in a patient in need thereof in one or more treatment cycles, comprising: (i) administering Compound 1, or a pharmaceutically acceptable salt thereof, to the patient for a first time period within each of the one or more treatment cycles; and (ii) administering a PD-1 inhibitor (e.g., pembrolizumab) to the patient after administering Compound 1, or a pharmaceutically acceptable salt thereof.

[0108] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof and a PD-1 inhibitor (e.g., pembrolizumab) are administered sequentially in each of one or more treatment cycles. In some embodiments of sequential administration, Compound 1 or a pharmaceutically acceptable salt thereof is administered intermittently (e.g., there is an interval of at least 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days between the days of administration of Compound 1 or a pharmaceutically acceptable salt thereof). The sequential administration of Compound 1 or a pharmaceutically acceptable salt thereof and a PD-1 inhibitor (e.g., pembrolizumab) is more effective than the concomitant administration of Compound 1 or a pharmaceutically acceptable salt thereof and a PD-1 inhibitor (e.g., pembrolizumab), for example, Compound 1 or a pharmaceutically acceptable salt thereof is administered continuously, and the PD-1 inhibitor (e.g., pembrolizumab) is also administered on one or more days of administration of Compound 1 or a pharmaceutically acceptable salt thereof.

[0109] As used herein, the term "intermittent" or "intermittently" is intended to mean stopping and starting at regular or irregular intervals. For example, intermittent administration of a compound is administration for five days in each three-week treatment cycle, administration during the treatment cycle (e.g., daily administration for five days in each 3-week treatment cycle, followed by a rest period of 12 days without administration).

[0110] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof exhibits higher affinity and biological activity for PI3K (e.g., PI3Kδ) compared to other PI3K inhibitors (including but not limited to idelalisib). In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof exhibits improved or superior drug distribution to blood cells compared to other PI3K inhibitors (including but not limited to idelalisib).

[0111] In some embodiments, the combination therapy of a PD-1 inhibitor (e.g., pembrolizumab) and Compound 1 or a pharmaceutically acceptable salt thereof shows low toxicity to normal cells. In various embodiments, the combination of a PD-1 inhibitor (e.g., pembrolizumab) and Compound 1 or a pharmaceutically acceptable salt thereof is selectively toxic to rapidly proliferating cells (e.g., cancerous tumors) or is more toxic to normal cells.

[0112] In some embodiments, the combination therapy described herein avoids or reduces adverse or undesirable, serious or fatal side effects associated with the use of PI3K inhibitors (e.g., idelalisib) and / or PD-1. In some embodiments, the combination therapy described herein avoids, reduces or minimizes (serious) infection, neutropenia, (serious) diarrhea, colon inflammation, colitis, lung tissue inflammation (pneumonitis), intestinal perforation, pneumonia, anemia, thrombocytopenia, nausea, fever, fatigue, cough, abdominal pain, chills, rash, vomiting, hypertriglyceridemia, hyperglycemia, elevated liver enzymes (e.g., ALT and ALST) levels, hepatotoxicity, swelling of the limbs, or a combination thereof in patients receiving the combination therapy. In certain embodiments, the combination therapy described herein avoids, reduces or minimizes the incidence of infection (including severe infection). In certain embodiments, the combination therapy described herein avoids, reduces or minimizes the incidence of neutropenia. In certain embodiments, the combination therapy described herein avoids, reduces or minimizes the incidence of diarrhea (including severe diarrhea). In certain embodiments, the combination therapy described herein avoids, reduces or minimizes the incidence of colon inflammation. In certain embodiments, the combination therapy described herein avoids, reduces or minimizes the incidence of colitis. In certain embodiments, the combination therapy described herein avoids, reduces or minimizes the incidence of lung tissue inflammation (lung inflammation). In certain embodiments, the combination therapy described herein avoids, reduces or minimizes the incidence of intestinal perforation. In certain embodiments, the combination therapy described herein avoids, reduces or minimizes the incidence of pneumonia. In certain embodiments, the combination therapy described herein avoids, reduces or minimizes the incidence of anemia. In certain embodiments, the combination therapy described herein avoids, reduces or minimizes the incidence of thrombocytopenia. In certain embodiments, the combination therapy described herein avoids, reduces or minimizes the incidence of nausea. In certain embodiments, the combination therapy described herein avoids, reduces or minimizes the incidence of fever. In certain embodiments, the combination therapy described herein avoids, reduces or minimizes the incidence of fatigue. In certain embodiments, the combination therapy described herein avoids, reduces or minimizes the incidence of cough. In certain embodiments, the combination therapies described herein avoid, reduce, or minimize the incidence of abdominal pain. In certain embodiments, the combination therapies described herein avoid, reduce, or minimize the incidence of chills. In certain embodiments, the combination therapies described herein avoid, reduce, or minimize the incidence of rash. In certain embodiments, the combination therapies described herein avoid, reduce, or minimize the incidence of vomiting.In certain embodiments, the combination therapies described herein avoid, reduce, or minimize the incidence of hypertriglyceridemia.

[0113] In certain embodiments, the combination therapies described herein avoid, reduce or minimize the incidence of hyperglycemia. In certain embodiments, the combination therapies described herein avoid, reduce or minimize the incidence of elevated liver enzyme (e.g., ALT and ALST) levels. In certain embodiments, the combination therapies described herein avoid, reduce or minimize the incidence of hepatotoxicity. In certain embodiments, the combination therapies described herein avoid, reduce or minimize the incidence of swelling of the limbs.

[0114] In some embodiments, the combination therapy described herein avoids or reduces adverse or undesirable side effects associated with chemotherapy, radiotherapy or cancer therapy. In some cases, the combination therapy described herein and / or composition provide chemoprotection and / or radioprotection properties for non-cancerous cells. In other or additional embodiments, the lower amount / dose of PI3K inhibitors reduces or minimizes any undesirable side effects associated with chemotherapy. Non-limiting examples of side effects associated with chemotherapy, radiotherapy or cancer therapy include fatigue, anemia, changes in appetite, bleeding problems, diarrhea, constipation, hair loss, nausea, vomiting, pain, peripheral neuropathy, swelling, skin and nail changes, urine and bladder changes, and dysphagia.

[0115] Some embodiments provided herein describe methods for treating or preventing proliferative diseases or disorders (e.g., cancer), including administering a PI3K inhibitor in combination with a PD-1 inhibitor (e.g., pembrolizumab). In certain embodiments, provided herein are methods for treating or preventing a disease, including administering a therapeutically effective amount of Compound I or administering a pharmaceutically acceptable salt thereof with a therapeutically effective amount of a PD-1 inhibitor (e.g., pembrolizumab). In some embodiments, Compound I or its pharmaceutically acceptable salt is administered at a dose less than the therapeutically effective amount of Compound I or its pharmaceutically acceptable salt administered alone. In some embodiments, PD-1 inhibitors (e.g., pembrolizumab) are administered at a dose less than the therapeutically effective amount of PD-1 inhibitors (e.g., pembrolizumab) administered alone. In some embodiments, the co-administration of Compound I or its pharmaceutically acceptable salt with a PD-1 inhibitor (e.g., pembrolizumab) is effective in treating cancer. In some embodiments, the PD-1 inhibitor is pembrolizumab or nivolumab. In a preferred embodiment, the PD-1 inhibitor is pembrolizumab.

[0116] In some embodiments, the proliferative disease or condition is cancer. In certain embodiments, the proliferative disease or condition is a blood cancer. In certain embodiments, the proliferative disease or condition is a solid tumor. In certain embodiments, the proliferative disease or condition is breast cancer, skin cancer, prostate cancer, cervical cancer, uterine cancer, ovarian cancer, testicular cancer, bladder cancer, lung cancer, liver cancer, laryngeal cancer, oral cancer, colon cancer and gastrointestinal cancer (e.g., esophageal cancer, gastric cancer, pancreatic cancer), brain cancer, thyroid cancer, blood cancer and lymphatic system cancer.

[0117] In certain embodiments, cancers treatable by the methods provided herein include, but are not limited to (1) leukemia, including, but not limited to, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia such as myeloid leukemia, promyelocytic leukemia, myelomonocytic leukemia, monocytic leukemia, erythroleukemia, and myelodysplastic syndrome or symptoms thereof (such as anemia, thrombocytopenia, neutropenia, bicytopenia or pancytopenia), refractory anemia (RA), refractory anemia with ringed sideroblasts ... myelodysplastic syndrome or symptoms thereof (such as anemia, thrombocytopenia, neutropenia, bicytopenia or pancytopenia), refractory anemia (RA), refractory anemia with ringed sideroblasts, and myelodysplastic syndrome or myelodysplastic syndrome or symptoms thereof (such as anemia, thrombocytopenia, neutropenia, bicytopenia or pancytopenia), refractory anemia (RA), (RARS), refractory anemia with excess blasts (RAEB), RAEB-transformed (RAEB-T), preleukemia and chronic myelomonocytic leukemia (CMML); (2) chronic leukemia, including but not limited to chronic myeloid (granulocytic) leukemia, chronic lymphocytic leukemia and hairy cell leukemia; (3) polycythemia vera; (4) lymphoma, including but not limited to Hodgkin's disease and non-Hodgkin's disease; (5) multiple myeloma, including but not limited to smoldering multiple myeloma, non-secretory myeloma, osteosclerotic myeloma, plasma cell leukemia, (6) Waldenstrom's macroglobulinemia; (7) monoclonal gammopathy of undetermined significance; (8) benign monoclonal gammopathy; (9) heavy chain disease; (10) bone and connective tissue sarcomas, including but not limited to osteosarcoma, osteosarcoma (osteosarcoma), chondrosarcoma, Ewing's sarcoma, malignant giant cell tumor, fibrosarcoma of bone, chordoma, periosteal sarcoma, soft tissue sarcoma, angiosarcoma (angiosarcoma), fibrosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, metastatic cancer, schwannoma, rhabdomyosarcoma and synovial sarcoma; (11) brain tumors, including but not limited to glioma, astrocytoma, brain stem glioma, ependymoma, oligodendrogliorna, non-glioma, acoustic neuroma, craniopharyngioma, medulloblastoma, meningioma, pineal cell tumor, pineoblastoma and primary brain lymphoma; (12) breast cancer, including but not limited to adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma, medullary breast cancer, mutinous breast cancer, breast cancer), tubular breast cancer, papillary breast cancer, primary carcinoma, Paget's disease and inflammatory breast cancer; (13) adrenal cancer, including but not limited to pheochromocytoma and adrenocortical carcinoma; (14) thyroid cancer, including but not limited to papillary or follicular thyroid cancer, medullary thyroid cancer and anaplastic thyroid cancer; (15) pancreatic cancer, including but not limited to insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin-secreting tumor and carcinoid or islet cell tumor; (16) pituitary cancer, including but not limited to Cushing's disease, prolactin-secreting tumor, acromegaly and diabetes insipius;(17) Eye cancer, including but not limited to ocular melanomas such as iris melanoma, choroidal melanoma and ciliary body melanoma, and retinoblastoma; (18) Vaginal cancer, including but not limited to squamous cell carcinoma, adenocarcinoma and melanoma; (19) Vulvar cancer, including but not limited to squamous cell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma and Paget's disease; (20) Cervical cancer, including but not limited to squamous cell carcinoma and adenocarcinoma; (21) Uterine cancer, including but not limited to endometrial carcinoma and uterine sarcoma; (22) Ovarian cancer, including but not limited to ovarian epithelial carcinoma, borderline tumors, germ cell tumors and stromal tumors; (23) Esophageal cancer, including but not limited to squamous cell carcinoma, adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma and oat cell (small cell) carcinoma; (24) Gastric cancer, including but not limited to adenocarcinoma, mycosis fungoides (polypoid) (25) Colon cancer; (26) Rectal cancer; (27) Liver cancer, including but not limited to hepatoma and hepatoblastoma; (28) Gallbladder cancer, including but not limited to adenocarcinoma; (29) Cholangiocarcinoma, including but not limited to papillary, nodular and diffuse; (30) Lung cancer, including but not limited to non-small cell lung cancer, squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma, large cell carcinoma and small cell lung cancer; (31) Testicular cancer, including but not limited to germinal tumors, seminoma, undifferentiated type, classic type (typical), spermatoblastoma, nonserninoma, embryonal carcinoma, teratoma carcinoma and choriocarcinoma (yolk sac tumor); (32) Prostate cancer, including but not limited to adenocarcinoma, leiomyosarcoma and rhabdomyosarcoma; (33) Penile cancer (penal) cancer); (34) oral cancer, including but not limited to squamous cell carcinoma; (35) basal carcinoma; (36) salivary gland cancer, including but not limited to adenocarcinoma, mucoepidermoid carcinoma and adenoid cystic carcinoma; (37) pharyngeal cancer, including but not limited to squamous cell carcinoma and verrucous; (38) skin cancer, including but not limited to basal cell carcinoma, squamous cell carcinoma and melanoma, superficial spreading melanoma, nodular melanoma, lentigo malignant melanoma and acral lentigo melanoma; (39 ) renal cancer, including but not limited to renal cell carcinoma, adenocarcinoma, adrenal tumor, fibrosarcoma and transitional cell carcinoma (renal pelvis and / or uterus); (40) Wilms' tumor; (41) bladder cancer, including but not limited to transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma and carcinosarcoma; (42) reproductive system cancer, such as cervical cancer, uterine cancer, ovarian cancer or testicular cancer; (43) esophageal cancer; (44) laryngeal cancer; (45) head and neck cancer (such as cancer of the mouth, nose, pharynx, larynx, paranasal sinuses or salivary glands);and other cancers, including but not limited to myxosarcoma, osteogenic sarcoma, endotheliosarcoma, lymphangioendotheliosarcoma, mesothelioma, synovioma, hemangioblastoma, epithelial cancer, cystadenocarcinoma, bronchial carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, and papillary adenocarcinoma (see Fishman et al., 1985, Medicine, 2nd Edition, JB Lippincott Co., Philadelphia and Murphy et al., 1997, Informed Decisions: The Complete Book of Cancer Diagnosis, Treatment, and Recovery, Viking Penguin, Penguin Books USA, Inc., United States of America). In some embodiments, the cancer is non-small cell lung cancer, melanoma, renal cell carcinoma, head and neck cancer, colon cancer, or mesothelioma. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is melanoma. ;

[0118] In certain embodiments, provided herein is a method for treating a hematological malignancy in a patient with an effective amount of Compound I or a pharmaceutically acceptable salt thereof and an effective amount of a PD-1 inhibitor in combination. In certain embodiments, the hematological malignancy is a leukemia, a lymphoma, a myeloma, a non-Hodgkin's lymphoma, a Hodgkin's lymphoma, a T-cell malignancy, or a B-cell malignancy. In some embodiments, the hematological malignancy is Hodgkin's lymphoma. In some embodiments, the hematological malignancy is chronic lymphocytic leukemia, follicular lymphoma, diffuse large B-cell lymphoma, or non-Hodgkin's lymphoma. In some embodiments, the hematological malignancy is chronic lymphocytic leukemia or non-Hodgkin's lymphoma. In some embodiments, the hematological malignancy is chronic lymphocytic leukemia. In other embodiments, the hematological malignancy is non-Hodgkin's lymphoma. In some embodiments, the hematological malignancy is follicular lymphoma. In other embodiments, the hematological malignancy is diffuse large B-cell lymphoma.

[0119] In certain embodiments, the hematological malignancy is a T-cell malignancy. In certain embodiments, the T-cell malignancy includes peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma, angioimmunoblastic lymphoma, cutaneous T-cell lymphoma, adult T-cell leukemia / lymphoma (ATLL), blastic NK-cell lymphoma, enteropathy-type T-cell lymphoma, hematosplenic gamma-delta T-cell lymphoma, lymphoblastic lymphoma, nasal NK / T-cell lymphoma, or treatment-related T-cell lymphoma.

[0120] In certain embodiments, the hematological malignancy is a B-cell malignancy. In certain embodiments, the B-cell malignancies include acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute monocytic leukemia (AMoL), chronic lymphocytic leukemia (CLL), high-risk chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk small lymphocytic lymphoma (SLL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's giant In some embodiments, the B cell malignancy is diffuse large B cell lymphoma (DLBCL). In some embodiments, the hematological malignancy is diffuse large B cell lymphoma (DLBCL). In some embodiments, the hematological malignancy is diffuse large B cell lymphoma (DLBCL). In certain embodiments, the DLBCL is activated B-cell DLBCL (ABC-DLBCL), germinal center B-cell-like DLBCL (GBC-DLBCL), double-hit DLBCL (DH-DLBCL) or triple-hit DLBCL (TH-DLBCL). In certain embodiments, the hematological malignancy is relapsed refractory diffuse large B-cell lymphoma (r / r DLBCL).

[0121] In certain embodiments, the hematological malignancy is a relapsed or refractory hematological malignancy. In certain embodiments, the relapsed or refractory hematological malignancy is a relapsed or refractory T-cell malignancy. In certain embodiments, the relapsed or refractory hematological malignancy is a relapsed or refractory B-cell malignancy.

[0122] In other embodiments, the disease or disorder is a solid tumor cancer. In some embodiments, the solid tumor cancer is selected from carcinoma, adenocarcinoma, adrenocortical carcinoma, colon adenocarcinoma, colorectal adenocarcinoma, colorectal cancer, ductal cell carcinoma, lung cancer, thyroid cancer, nasopharyngeal carcinoma, melanoma, non-melanoma skin cancer, and lung cancer.

[0123] In certain embodiments, the cancer is lung cancer (e.g., non-small cell lung cancer), melanoma, renal cell carcinoma, head and neck cancer, breast cancer (e.g., triple-negative breast cancer), non-Hodgkin lymphoma, Hodgkin lymphoma, colorectal cancer, urothelial carcinoma, gastric cancer, cervical cancer (e.g., advanced cervical cancer), hepatocellular carcinoma, Merkel cell carcinoma (e.g., advanced Merkel cell carcinoma), esophageal cancer, endometrial cancer, squamous cell carcinoma of the skin, or mesothelioma.

[0124] In one embodiment, the cancer is melanoma. In another embodiment, the cancer is lung cancer. In a specific embodiment, the lung cancer is non-small cell lung cancer. In another embodiment, the cancer is renal cell carcinoma. In yet another embodiment, the cancer is hepatocellular carcinoma. In yet another embodiment, the cancer is colorectal cancer. In another specific embodiment, the colorectal cancer is microsatellite high instability or mismatch repair deficient colorectal cancer. In yet another embodiment, the cancer is urothelial carcinoma (e.g., advanced urothelial carcinoma). In yet another embodiment, the cancer is advanced endometrial carcinoma. In yet another embodiment, the cancer is a cancer with a high tumor mutation burden.

[0125] In some embodiments of the methods provided herein, the method further comprises (iii) evaluating the efficacy of administering a combination of Compound I or a pharmaceutically acceptable salt thereof and a PD-1 inhibitor by measuring the level of regulatory T cells (CD25hi FoxP3+T cells) or effector T cells (e.g., CD8+ and CD4+ cells). In some embodiments, when regulatory T cells (CD25hi FoxP3+T cells) or effector T cells (e.g., CD8+ and CD4+ cells) are suppressed below a certain threshold (e.g., at least 35%) compared to baseline levels, it indicates an effective treatment (e.g., combination therapy). In some embodiments, a level of regulatory T cells (CD25hi FoxP3+ T cells) or effector T cells (e.g., CD8+ and CD4+ cells) that is less than or equal to about 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15% or 10% of a baseline level of regulatory T cells (CD25hi FoxP3+ T cells) or effector T cells (e.g., CD8+ and CD4+ cells) indicates that one or more treatment cycles of administration of a combination of Compound I, or a pharmaceutically acceptable salt thereof, and a PD-1 inhibitor are effective. In some embodiments, a level of regulatory T cells (CD25hi FoxP3+ T cells) or effector T cells (e.g., CD8+ and CD4+ cells) that is less than or equal to about 65% of a baseline level of regulatory T cells (CD25hi FoxP3+ T cells) or effector T cells (e.g., CD8+ and CD4+ cells) indicates that one or more treatment cycles of administration of a combination of Compound I, or a pharmaceutically acceptable salt thereof, and a PD-1 inhibitor are effective.

[0126] Depending on the disorder, disease or condition to be treated and the condition of the patient, Compound I or a pharmaceutically acceptable salt or a PD-1 inhibitor (e.g., pembrolizumab) can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracistemal injection or infusion, subcutaneous injection or implant), inhalation, nasal, vaginal, rectal, sublingual or topical (e.g., transdermal or topical) administration routes and can be formulated in suitable dosage units alone or with pharmaceutically acceptable excipients, carriers, adjuvants and vehicles suitable for each route of administration as described elsewhere herein.

[0127] Dosage and administration schedule

[0128] In certain embodiments, the methods provided herein include administering Compound 1 or a pharmaceutically acceptable salt thereof and a PD-1 inhibitor (e.g., pembrolizumab) to a patient simultaneously or sequentially. In a preferred embodiment, Compound 1 or a pharmaceutically acceptable salt thereof and a PD-1 inhibitor (e.g., pembrolizumab) are administered sequentially.

[0129] The suitability of a particular route of administration for a particular active agent will depend on the active agent itself (e.g., whether it can be administered orally without decomposing before entering the bloodstream) and the disease being treated. Recommended routes of administration for second active agents are known to those of ordinary skill in the art. See, e.g., Physicians' Desk Reference, 1755-1760 (56th Edition, 2002).

[0130] In certain embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered simultaneously, substantially at the same time, or sequentially with a PD-1 inhibitor (e.g., pembrolizumab). If administration occurs sequentially, the PD-1 inhibitor may be administered before or after administration of Compound 1 or a pharmaceutically acceptable salt thereof. In some preferred embodiments, the PD-1 inhibitor is administered after administration of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the PD-1 inhibitor is administered simultaneously with the administration of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the PD-1 inhibitor is administered before administration of Compound 1 or a pharmaceutically acceptable salt thereof.

[0131] In certain embodiments, Compound I or a pharmaceutically acceptable salt thereof and a PD-1 inhibitor (e.g., pembrolizumab) do not need to be administered with the aid of the same vehicle. In some embodiments, Compound I or a pharmaceutically acceptable salt thereof and a PD-1 inhibitor (e.g., pembrolizumab) are administered with different vehicles. The PD-1 inhibitor (e.g., pembrolizumab) can be administered once or multiple times, and the number of administrations of each component in the combination can be the same or different. In addition, Compound I or a pharmaceutically acceptable salt thereof and a PD-1 inhibitor (e.g., pembrolizumab) do not need to be administered at the same site.

[0132] In another aspect, provided herein is a method for treating cancer in a patient in need thereof in one or more treatment cycles, comprising: (i) administering Compound 1 or a pharmaceutically acceptable salt thereof to the patient on day 1 to day 5 of each of the one or more treatment cycles; and (ii) administering a PD-1 inhibitor to the patient on day 22 of each of the treatment cycles; wherein each of the one or more treatment cycles is 6 weeks; and wherein Compound 1 has the following structure:

[0133] In another aspect, provided herein is a method for treating cancer in a patient in need thereof in one or more treatment cycles, comprising: (i) administering Compound 1 or a pharmaceutically acceptable salt thereof to the patient on day 1 to day 5 of each of the one or more treatment cycles; and (ii) administering a PD-1 inhibitor to the patient on day 14 of each of the treatment cycles; wherein each of the one or more treatment cycles is 3 weeks; and wherein Compound 1 has the following structure: Treatment cycle

[0134] In some preferred embodiments, the methods described herein further include administering Compound I or a pharmaceutically acceptable salt thereof and a PD-1 inhibitor (e.g., pembrolizumab) to a patient in need in one or more treatment cycles, the treatment cycles being repeated on a regular schedule, optionally with a rest period between two treatment cycles. For example, in some cases, the combination therapy provided herein is administered for 3 weeks, followed by no rest period before the next treatment cycle. In some cases, the combination therapy provided herein is administered for 6 weeks, followed by no rest period before the next treatment cycle. In other embodiments, the combination therapy provided herein is administered for 3 weeks, followed by a 1 week rest before the next treatment cycle. In other embodiments, the combination therapy provided herein is administered for 6 weeks, followed by a 3 week rest before the next treatment cycle.

[0135] In some cases, the cycle includes administering Compound 1 or a pharmaceutically acceptable salt thereof while administering a PD-1 inhibitor (e.g., pembrolizumab). In some cases, the treatment cycle includes administering Compound 1 or a pharmaceutically acceptable salt thereof on a day different from the day on which the PD-1 inhibitor (e.g., pembrolizumab) is administered. In some cases, Compound 1 or a pharmaceutically acceptable salt thereof is administered about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, or about 28 days apart from the administration of the PD-1 inhibitor (e.g., pembrolizumab).

[0136] In some cases, the treatment cycle includes administering Compound I or a pharmaceutically acceptable salt thereof for a first period of time, followed by a second period of time. In some embodiments, wherein the administration of the PD-1 inhibitor occurs on the second day of the second period of time. In some cases, the first period of time is about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days. In some embodiments, the first period of time is 3 days, 4 days, 5 days, 6 days, or 1 week. In a preferred embodiment, the first period of time is 5 days.

[0137] In some embodiments, the first time period begins on day 1, day 2, day 3, day 4, day 5, day 6, day 7, or day 8 of each of one or more treatment cycles.

[0138] In some embodiments, the second time period is 0 days, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks or about 8 weeks. In a preferred embodiment, the second time period is 16 days. In another embodiment, the second time period is about 3 weeks.

[0139] In some embodiments, administration of the PD-1 inhibitor begins on the day after the second time period, wherein the second time period immediately follows the first time period.

[0140] In some embodiments, the PD-1 inhibitor is administered about 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 days after the first time period. In a preferred embodiment, the PD-1 inhibitor is administered about 8 days after the first time period. In another preferred embodiment, the PD-1 inhibitor is administered about 16 days after the first time period.

[0141] In some embodiments, the PD-1 inhibitor is administered for at least 6 weeks. In some embodiments, the PD-1 inhibitor is administered for 6, 9, 12, 15, 18, 21, 24, 27, or 30 weeks. In some embodiments, the PD-1 inhibitor is administered once every 3 weeks or once every 6 weeks. In some embodiments, the PD-1 inhibitor is administered at a dose of about 200 mg or about 400 mg. In one embodiment, the PD-1 inhibitor is administered at a dose of about 200 mg. In one embodiment, the PD-1 inhibitor is administered at a dose of about 400 mg.

[0142] In some embodiments, the PD-1 inhibitor is administered intravenously (eg, by infusion).

[0143] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered at about 60 mg / day for 5 days in combination with pembrolizumab at a dose of about 400 mg once in each 6-week treatment cycle. In some specific embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered at about 60 mg / day on days 1-5 in combination with pembrolizumab at a dose of about 400 mg on day 22 of each 6-week treatment cycle. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered with pembrolizumab for 1 to 10 treatment cycles. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered with pembrolizumab for 1 treatment cycle. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered with pembrolizumab for 2 treatment cycles. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered with pembrolizumab for 3 treatment cycles. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered with pembrolizumab for 4 treatment cycles. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered with pembrolizumab for 5 treatment cycles. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered with pembrolizumab for 6 treatment cycles. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered with pembrolizumab for 7 treatment cycles. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered with pembrolizumab for 8 treatment cycles. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered with pembrolizumab for 9 treatment cycles. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered with pembrolizumab for 10 treatment cycles. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered with pembrolizumab for more than 10 treatment cycles.

[0144] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered at about 60 mg / day for 5 days in combination with pembrolizumab at a dose of about 200 mg once in each 3-week treatment cycle. In some specific embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered at about 60 mg / day on days 1-5 in combination with pembrolizumab at a dose of about 200 mg on day 14 of each 3-week treatment cycle. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered with pembrolizumab for 1 to 10 treatment cycles. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered with pembrolizumab for 1 treatment cycle. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered with pembrolizumab for 2 treatment cycles. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered with pembrolizumab for 3 treatment cycles. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered with pembrolizumab for 4 treatment cycles. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered with pembrolizumab for 5 treatment cycles. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered with pembrolizumab for 6 treatment cycles. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered with pembrolizumab for 7 treatment cycles. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered with pembrolizumab for 8 treatment cycles. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered with pembrolizumab for 9 treatment cycles. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered with pembrolizumab for 10 treatment cycles. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered with pembrolizumab for more than 10 treatment cycles.

[0145] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered at about 60 mg / day for 10 days in combination with pembrolizumab at a dose of about 200 mg twice in each 6-week treatment cycle. In some specific embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered at about 60 mg / day on days 1-5 and 22-26 in combination with pembrolizumab at a dose of about 200 mg on days 14 and 35 of each 6-week treatment cycle. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered with pembrolizumab for 1 to 10 treatment cycles. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered with pembrolizumab for 1 treatment cycle. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered with pembrolizumab for 2 treatment cycles. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered with pembrolizumab for 3 treatment cycles. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered with pembrolizumab for 4 treatment cycles. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered with pembrolizumab for 5 treatment cycles. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered with pembrolizumab for 6 treatment cycles. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered with pembrolizumab for 7 treatment cycles. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered with pembrolizumab for 8 treatment cycles. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered with pembrolizumab for 9 treatment cycles. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered with pembrolizumab for 10 treatment cycles. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered with pembrolizumab for more than 10 treatment cycles.

[0146] In some cases, the cycle includes administration of only Compound I or a pharmaceutically acceptable salt thereof. In some cases, Compound I or a pharmaceutically acceptable salt thereof is administered for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, or about 28 days. In a preferred embodiment, Compound I or a pharmaceutically acceptable salt thereof is administered for about 5 days. In another preferred embodiment, Compound I or a pharmaceutically acceptable salt thereof is administered for about 5 consecutive days.

[0147] In some embodiments, each of the one or more treatment cycles is 6 weeks, Compound I or a pharmaceutically acceptable salt thereof is administered on days 1 to 5, and then the PD-1 inhibitor is administered once on day 22.

[0148] In some embodiments, each of the one or more treatment cycles is 3 weeks, Compound I or a pharmaceutically acceptable salt thereof is administered on days 1 to 5, and then the PD-1 inhibitor is administered once on day 14.

[0149] In some cases, the treatment cycle includes administering only a PD-1 inhibitor. In some cases, the PD-1 inhibitor is administered 1, 2, 3, or 4 times in a treatment cycle. In a preferred embodiment, the PD-1 inhibitor is administered once in a treatment cycle.

[0150] In some cases, the method for multiple treatment cycles includes administering a second treatment cycle within about 60 days or about 3 months. In some cases, the method for multiple treatment cycles includes administering a second treatment cycle within 50 days of a previous treatment cycle. In another case, the second treatment cycle is administered within 45, 40, 35, 30, 25, 21, 20, 15, 14, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 days of the first treatment cycle. In some embodiments, the administration of any additional treatment cycle is within 10 days of the previous treatment cycle. In some embodiments, the administration of any additional treatment cycle is within 9 days of the previous treatment cycle. In some embodiments, the administration of any additional treatment cycle is about 3 weeks of the previous treatment cycle. In some embodiments, the administration of any additional treatment cycle is within 7 days of the previous treatment cycle. In some embodiments, the administration of any additional treatment cycle is within 6 days of the previous treatment cycle. In some embodiments, the administration of any additional treatment cycle is within 5 days of the previous treatment cycle. In some embodiments, the administration of any additional treatment cycle is within 4 days of the previous treatment cycle. In some embodiments, the administration of any additional treatment cycle is within 3 days of the previous treatment cycle. In some embodiments, the administration of any additional treatment cycle is within 2 days of the previous treatment cycle. In some embodiments, the administration of any additional treatment cycle is within 1 day of the previous treatment cycle.

[0151] The length of the treatment cycle depends on the treatment being administered. In some embodiments, the length of the treatment cycle ranges from two to six weeks. In some embodiments, the length of the treatment cycle ranges from four to six weeks. In some embodiments, the length of the treatment cycle is 3 weeks. In some embodiments, the length of the treatment cycle is 6 weeks. In some embodiments, the treatment cycle lasts for one, two, three, or four weeks. In some embodiments, the treatment cycle lasts for four weeks. The number of treatment doses planned in each cycle also varies depending on the drug being administered.

[0152] In some cases, the method of multiple treatment cycle compounds comprises administering Compound 1 or a pharmaceutically acceptable salt thereof with a PD-1 inhibitor in an alternate treatment cycle. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in treatment cycles 1, 3, 5, 7, 9, and 11, and the PD-1 inhibitor is administered in treatment cycles 2, 4, 6, 8, 10, and 12.

[0153] In some cases, the method for administering multiple compounds occurs in a sequential order, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered prior to a PD-1 inhibitor (e.g., pembrolizumab). In another case, a PD-1 inhibitor (e.g., pembrolizumab) is administered prior to Compound 1 or a pharmaceutically acceptable salt thereof.

[0154] In some cases, the method for administering Compound 1 or a pharmaceutically acceptable salt thereof is oral and the method for administering a PD-1 inhibitor (e.g., pembrolizumab) is by injection. In some cases, the method for administering Compound 1 or a pharmaceutically acceptable salt thereof is by inhalation and the method for administering a PD-1 inhibitor (e.g., pembrolizumab) is by injection. In some cases, the method for administering Compound 1 or a pharmaceutically acceptable salt thereof is by injection and the method for administering a PD-1 inhibitor (e.g., pembrolizumab) is by injection.

[0155] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered every day, every other day, every other day 3 times a week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 3 days, every 4 days, every 5 days, every 6 days, every week, twice a week, 3 times a week, 4 times a week, 5 times a week, 6 times a week, once a month, twice a month, 3 times a month, once every 2 months, once every 3 months, once every 4 months, once every 5 months, or once every 6 months. In some preferred embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered every day.

[0156] In some embodiments, the PD-1 inhibitor is administered every day, every other day, every 3 days, every 4 days, every 5 days, every 6 days, every week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, twice a week, 3 times a week, 4 times a week, 5 times a week, 6 times a week, once a month, twice a month, 3 times a month, once every 2 months, once every 3 months, once every 4 months, once every 5 months, or once every 6 months. In some preferred embodiments, the PD-1 inhibitor is administered once every 3 weeks (Q3W) or once every 6 weeks (Q6W).

[0157] In some embodiments, Compound I or its pharmaceutically acceptable salt or PD-1 inhibitor is optionally administered continuously; alternatively, the dose of the administered therapeutic agent (Compound I or its pharmaceutically acceptable salt or PD-1 inhibitor) is temporarily reduced or suspended for a certain length of time (i.e., a "drug holiday"). In some embodiments, the length of the drug holiday varies between 2 days and 1 year, including (by way of example only) 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 12 days, 14 days, 15 days, 20 days, 21 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. Dose reductions during a drug holiday include 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%.

[0158] In certain embodiments, in the treatment, prevention, or amelioration of one or more symptoms of a disorder, disease, or condition described herein, the range of appropriate dosage levels of Compound 1 or a pharmaceutically acceptable salt thereof is generally about 1 mg to about 1000 mg, about 1 mg to about 500 mg, about 5 mg to about 500 mg, about 5 mg to about 200 mg, about 5 mg to about 250 mg, or about 10 mg to about 150 mg, which can be administered in a single or multiple doses. In certain embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in a dosage of about 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 , 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 450 mg or 500 mg. In certain embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered at about 1 mg / day, about 5 mg / day, about 10 mg / day, about 15 mg / day, about 20 mg / day, about 25 mg / day, about 30 mg / day, about 35 mg / day, about 40 mg / day, about 45 mg / day, about 50 mg / day, about 55 mg / day, about 60 mg / day, about 65 mg / day, about 70 mg / day, about 75 mg / day, about 80 mg / day, about 85 mg / day, about 90 mg / day, about 95 mg / day, about 100 mg / day, about 105 mg / day, about 110 mg / day, about 115 mg / day, about 120 mg / day, about 125 In some embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered in an amount of about 30 mg / day.In certain embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered in an amount of about 45 mg / day. In certain embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered in an amount of about 60 mg / day. In certain embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered in an amount of about 90 mg / day. In certain embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered in an amount of about 120 mg / day. In certain embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered in an amount of about 150 mg / day. In certain embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered in an amount of about 180 mg / day. In some preferred embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered in an amount of about 60 mg / day.

[0159] For oral administration, the pharmaceutical compositions provided herein can be formulated into tablets or capsules containing about 1.0 to about 1,000 mg of Compound I or its pharmaceutically acceptable salt, in one embodiment, about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 750 mg, about 800 mg, about 900 mg and about 1,000 mg of Compound I or its pharmaceutically acceptable salt for symptomatic adjustment of the dose to the patient to be treated. In some preferred embodiments, the pharmaceutical compositions provided herein can be formulated into tablets containing about 60 mg of Compound I or its pharmaceutically acceptable salt. The pharmaceutical compositions comprising Compound I or its pharmaceutically acceptable salt are administered in a regimen of 1 to 4 times per day (including once, twice, three times and four times per day). In some preferred embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered once a day. In some embodiments, about 30 mg, about 45 mg, or about 60 mg of Compound I or a pharmaceutically acceptable salt thereof is administered once a day. In some embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered to patients in need in an amount of about 60 mg for 1, 2, 3, 4, 5, 6, 7 consecutive days per day. In some embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered to patients in need in an amount of about 60 mg for 5 consecutive days per day. In some embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered to patients in need in an amount of about 60 mg for 2 consecutive days per day in a treatment cycle. In some embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered to patients in need in an amount of about 60 mg for 3 consecutive days per day in a treatment cycle. In some embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered to patients in need in an amount of about 60 mg for 4 consecutive days per day in a treatment cycle. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof in an amount of about 60 mg per day for 6 consecutive days in a treatment cycle. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof in an amount of about 60 mg per day for 7 consecutive days in a treatment cycle.

[0160] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in week 1 of the treatment cycle. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in week 2 of the treatment cycle. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in week 3 of the treatment cycle. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in week 4 of the treatment cycle. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in week 5 of the treatment cycle. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in week 6 of the treatment cycle. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in week 7 of the treatment cycle. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in week 8 of the treatment cycle. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in week 9 of the treatment cycle. In some embodiments, the treatment cycle is 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, or 9 weeks.

[0161] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in week 1 of a 3-week treatment cycle. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in week 2 of a 3-week treatment cycle. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in week 3 of a 3-week treatment cycle.

[0162] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in week 1 of a 6-week treatment cycle. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in week 2 of a 6-week treatment cycle. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in week 3 of a 6-week treatment cycle. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in week 4 of a 6-week treatment cycle. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in week 5 of a 6-week treatment cycle. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in week 6 of a 6-week treatment cycle.

[0163] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in week 1 of a 9-week treatment cycle. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in week 2 of a 9-week treatment cycle. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in week 3 of a 9-week treatment cycle. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in week 3 of a 9-week treatment cycle. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in week 4 of a 9-week treatment cycle. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in week 5 of a 9-week treatment cycle. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in week 6 of a 9-week treatment cycle. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in week 7 of a 9-week treatment cycle. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in week 8 of a 9-week treatment cycle. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in week 9 of a 9-week treatment cycle.

[0164] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered for 1, 2, 3, 4, 5, 6 or 7 consecutive days of the week in which Compound 1 or a pharmaceutically acceptable salt thereof is administered. In one embodiment, Compound 1 or a pharmaceutically acceptable salt thereof is administered on days 1-2 of the week in which Compound 1 or a pharmaceutically acceptable salt thereof is administered. In another embodiment, Compound 1 or a pharmaceutically acceptable salt thereof is administered on days 1-3 of the week in which Compound 1 or a pharmaceutically acceptable salt thereof is administered. In yet another embodiment, Compound 1 or a pharmaceutically acceptable salt thereof is administered on days 1-4 of the week in which Compound 1 or a pharmaceutically acceptable salt thereof is administered. In yet another embodiment, Compound 1 or a pharmaceutically acceptable salt thereof is administered on days 1-5 of the week in which Compound 1 or a pharmaceutically acceptable salt thereof is administered. In yet another embodiment, Compound 1 or a pharmaceutically acceptable salt thereof is administered on days 1-6 of the week in which Compound 1 or a pharmaceutically acceptable salt thereof is administered. In yet another embodiment, Compound 1 or a pharmaceutically acceptable salt thereof is administered on days 1-7 of the week in which Compound 1 or a pharmaceutically acceptable salt thereof is administered.

[0165] In the methods of treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition described herein, the range of appropriate dosage levels of PD-1 inhibitors (e.g., pembrolizumab) is generally about 0.1 mg to 2000 mg per day. In some embodiments, 1-500 mg once or more per day is effective for achieving the desired result.

[0166] In certain embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered once a day, twice a day, or three times a day. In certain embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered once a day. In certain embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is co-administered once a day (e.g., in a single dosage form).

[0167] In certain embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered once a week. In certain embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered once every two weeks, three weeks, four weeks, or five weeks. In certain embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered intravenously or by direct injection. In a preferred embodiment, the PD-1 inhibitor is administered every three weeks.

[0168] In some embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered in week 1 of the treatment cycle. In some embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered in week 2 of the treatment cycle. In some embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered in week 3 of the treatment cycle. In some embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered in week 4 of the treatment cycle. In some embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered in week 5 of the treatment cycle. In some embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered in week 6 of the treatment cycle. In some embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered in week 7 of the treatment cycle. In some embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered in week 8 of the treatment cycle. In some embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered in week 9 of the treatment cycle. In some embodiments, the treatment cycle is 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, or 9 weeks.

[0169] In some embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered in week 1 of a 3-week treatment cycle. In some embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered in week 2 of a 3-week treatment cycle. In some embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered in week 3 of a 3-week treatment cycle.

[0170] In some embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered in week 1 of a 6-week treatment cycle. In some embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered in week 2 of a 6-week treatment cycle. In some embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered in week 3 of a 6-week treatment cycle. In some embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered in week 4 of a 6-week treatment cycle. In some embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered in week 5 of a 6-week treatment cycle. In some embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered in week 6 of a 6-week treatment cycle.

[0171] In some embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered in week 1 of a 9-week treatment cycle. In some embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered in week 2 of a 9-week treatment cycle. In some embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered in week 3 of a 9-week treatment cycle. In some embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered in week 4 of a 9-week treatment cycle. In some embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered in week 5 of a 9-week treatment cycle. In some embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered in week 6 of a 9-week treatment cycle. In some embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered in week 7 of a 9-week treatment cycle. In some embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered in week 8 of a 9-week treatment cycle. In some embodiments, the PD-1 inhibitor (eg, pembrolizumab) is administered in week 9 of a 9-week treatment cycle.

[0172] In some embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered on day 1, day 2, day 3, day 4, day 5, day 6, or day 7 of the week in which the PD-1 inhibitor (e.g., pembrolizumab) is administered. In one embodiment, the PD-1 inhibitor (e.g., pembrolizumab) is administered on day 1 of the week in which the PD-1 inhibitor (e.g., pembrolizumab) is administered.

[0173] In certain embodiments, the PD-1 inhibitor is pembrolizumab and the amount of pembrolizumab administered is from about 10 mg / day up to and including 1000 mg / day. In certain embodiments, the amount of pembrolizumab administered is about 10 mg / day to 600 mg / day. In certain embodiments, the amount of pembrolizumab administered is about 100 mg / day to 600 mg / day. In certain embodiments, the amount of pembrolizumab administered per day is about 200 mg or about 400 mg. In some embodiments, pembrolizumab is administered once every 3 weeks (Q3W) at a dose of 200 mg. In some embodiments, pembrolizumab is administered once every 6 weeks (Q6W) at a dose of 400 mg.

[0174] In certain embodiments, the methods described herein further comprise administering pembrolizumab intravenously at a dose of 1-10 mg / kg every three weeks. In certain embodiments, pembrolizumab is administered intravenously at a dose of 2 mg / kg every three weeks. In certain embodiments, 2 mg / kg of pembrolizumab is administered as 200 mg every 3 weeks or 400 mg every 6 weeks as an intravenous infusion over 30 minutes.

[0175] In some embodiments, Compound I or its pharmaceutically acceptable salt is not administered at the same time as a PD-1 inhibitor (e.g., Pembrolizumab), but the two compounds are administered at different times. In some embodiments, Compound I or its pharmaceutically acceptable salt is administered at least once with a PD-1 inhibitor (e.g., Pembrolizumab) during a treatment cycle. A treatment cycle as used herein means a certain period of time during which each therapeutic agent has been administered at least once. The treatment cycle can be about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 days. In some embodiments, the treatment cycle is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 weeks. In certain embodiments, the treatment cycle is at least 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 weeks.

[0176] However, it will be understood that for any particular patient, the specific dosage level and dosage frequency may vary and will depend on various factors, including the activity of the specific compound employed, the metabolic stability and length of action of the compound, age, body weight, general health, sex, diet, mode and time of administration, excretion rate, drug combination, severity of the particular condition, and the host receiving therapy. The dosage can be determined by standard clinical techniques. The precise dosage to be employed in the formulation will also depend on the route of administration and the severity of the disease or condition, and in some embodiments, should be determined according to the judgment of the practitioner and the circumstances of each patient.

[0177] In the context of the present disclosure, the dose administered to the subject should be sufficient to affect the therapeutic response. Those skilled in the art will recognize that the dose will depend on a variety of factors, including the efficacy of the specific compound, the age, condition and weight of the patient, and the stage / severity of the disease. The dose will also be determined by the route (administration form), timing and frequency of administration.

[0178] Add-on combination therapy

[0179] In certain embodiments, the methods of combination therapy comprising Compound 1, or a pharmaceutically acceptable salt thereof, and a PD-1 inhibitor (e.g., pembrolizumab) may also be combined or used in combination with a third agent or therapy useful in treating, preventing, or ameliorating one or more symptoms of a proliferative disorder, disease, or condition.

[0180] Suitable third therapeutic agents include, but are not limited to (1) α-adrenergic agents; (2) antiarrhythmic agents; (3) antiatherosclerotic agents, such as ACAT inhibitors; (4) antibiotics, such as anthracyclines, bleomycin, mitomycin, actinomycin D, and plicamycin; (5) anticancer agents and cytotoxic agents, for example, alkylating agents such as nitrogen mustards, alkyl sulfonates, nitrosoureas, ethyleneimines, and triazenes; (6) anticoagulants, such as acenocoumarol, argatroban, bivalirudin, lepirudin, fondaparinux, heparin, phenindione, warfarin, and xirnelagatran; (7) antidiabetic agents. (8) antifungal agents, such as amorolfine, amphotericin B, anidulafungin, bifonazole, butenafine, butoconazole, caspofungin, ciclopirox, clotrimazole, econazole, fenticonazole, filipin, fluconazole, isoconazole, itraconazole, ketoconazole, micafungin, miconazole, naftifine, Natamycin, nystatin, oxyconazole, ravuconazole, posaconazole, chelamycin, sertaconazole, sulconazole, terbinafine, terconazole, tioconazole and voriconazole; (9) anti-inflammatory agents, for example, nonsteroidal anti-inflammatory agents such as aceclofenac, acemetacin, amoxicillin, aspirin, azapropazone, benolate, bromfenac, carprofen, celecoxib, choline magnesium salicylate, diclofenac, diflunisal, etodolac, etoricoxib, faislamine , fenbufen, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, lumiracoxib, meclofenamic acid, mefenamic acid, meloxicam, metamizole, methyl salicylate, magnesium salicylate, nabumetone, naproxen, nimesulide, oxyphenbutazone, parecoxib, phenylbutazone, piroxicam, salicylate, sulindac, sulfinpyrazone, suprofen, tenoxicam, tiaprofenic acid and tolmetin; (10) antimetabolites such as folic acid antagonists, purine analogs and pyrimidine analogs;(11) antiplatelet agents, such as GPIIb / IlIa blockers (e.g., abciximab, eptifibatide, and tirofiban), P2Y(AC) antagonists (e.g., clopidogrel, ticlopidine, and CS-747), cilostazol, dipyridamole, and aspirin; (12) antiproliferative agents, such as methotrexate, FK506 (tacrolimus), and mycophenolate mofetil; (13) anti-TNF antibodies or soluble TNF receptors, such as etanercept, rapamycin, and leflunomide; (14) a P2 inhibitors; (15) β-adrenergic agents, such as carvedilol and metoprolol; (16) bile acid sequestrants, such as questran; (17) calcium channel inhibitors, such as amlodipine besylate; (18) chemotherapeutic agents; (19) cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib and rofecoxib; (20) cyclosporine; (21) cytotoxic agents. Toxic drugs such as azathioprine and cyclophosphamide; (22) diuretics such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichlorothiazide, polythiazide, benzothiazide, ethacrynic acid, ticrynafen, chlorthalidone, furosemide, muzolomide, bumetanide, ammonia phenylteridine, amiloride and spironolactone; (23) endothelin converting enzyme (ECE) inhibitors, such as phosphoramidon; (24) enzymes, such as L-asparaginase; (25) factor VIIa inhibitors and factor Xa inhibitors; (26) famesyl protein transferase inhibitors; (27) fibrates; (28) growth factor inhibitors, such as PDGF activity modulators; (29) growth hormone secretagogues; (30) HMG CoA reductase inhibitors, such as pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (also known as itavastatin, nivastatin or nisbastatin) and ZD-4522 (also known as rosuvastatin, atavastatin or visastatin); neutral endopeptidase (NEP) inhibitors; (31) hormonal agents, such as glucocorticoids (e.g., cortisone), estrogens / antiestrogens, androgens / antiandrogens, progestins and luteinizing hormone-releasing hormone antagonists, and octreotide acetate; (32) immunosuppressants; (33) mineralocorticoid receptor antagonists, such as spironolactone and eplerenone; (34) microtubule disrupting agents, such as ecteinascidins;(35) microtubule stabilizers, such as paclitaxel, docetaxel, and epothilone AF; (36) MTP inhibitors; (37) niacin; (38) phosphodiesterase inhibitors, such as PDE III inhibitors (e.g., cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil, and vardenafil); (39) plant-derived products such as vinca alkaloids, epipodophyllotoxins, and taxanes; (40) platelet activating factor (PAF) antagonists; (41) platinum coordination complexes such as cisplatin, satraplatin, and carboplatin; (42) potassium channel openers; (43) prenyl protein transferase inhibitors; (44) protein tyrosine kinase inhibitors; (45) renin inhibitors; (46) squalene synthetase inhibitors; (47) steroids such as aldosterone, beclomethasone, betamethasone, deoxycorticosterone acetate, fludrocortisone, hydrocortisone (Cortisol), prednisolone, prednisone, methylprednisolone, dexamethasone, and triamcinolone; (48) TNF-α inhibitors, such as Such as tenidap; (49) thrombin inhibitors, such as hirudin; (50) thrombolytics, such as anistreplase, reteplase, tenecteplase, tissue-type plasminogen activator (tPA), recombinant tPA, streptokinase, urokinase, prourokinase and anisoylated plasminogen streptokinase activator complex (APSAC); (51) thromboxane receptor antagonists, such as ifetroban; (52) topoisomerase inhibitors; (53) vasopeptidase inhibitors (dual NEP-ACE inhibitors), such as omapatrilat and gemopatrilat, and (54) various other agents, such as hydroxyurea, procarbazine, mitotane, hexamethylmelamine and gold compounds.

[0181] In certain embodiments, third therapies that can be used in combination with the methods provided herein include, but are not limited to, surgery, endocrine therapy, biological response modifiers (e.g., interferons, interleukins, and tumor necrosis factor (TNF)), hyperthermia and cryotherapy, and agents that attenuate any adverse effects (e.g., antiemetics).

[0182] In certain embodiments, third therapeutic agents that can be used in combination with the compounds provided herein include, but are not limited to, alkylating drugs (mechlorethamine, chlorambucil, cyclophosphamide, melphalan, and ifosfamide), antimetabolites (cytarabine (also known as cytosine arabinoside or Ara-C) and methotrexate), purine antagonists and pyrimidine antagonists (6-mercaptopurine, 5-fluorouracil, cytarabine, and gemcitabine), spindle poisons (vinblastine, vincristine, and vinorelbine), podophyllotoxins (etoposide, irinotecan, and topotecan), antibiotics (daunorubicin, doxorubicin, bleomycin, and mitomycin), nitrosoureas (carmustine and lomustine), enzymes (asparaginase), and hormones (tamoxifen, leuprolide, flutamide, and megestrol acetate), imatinib, doxorubicin, dexamethasone, and cyclophosphamide. For a more comprehensive discussion of newer cancer therapies; see http: / / www.nci.nih.gov / , a list of FDA-approved oncology drugs at http: / / www.fda.gov / cder / cancer / dnigli stframe.htm, and The Merck Manual, Seventeenth Edition 1999, the entire contents of which are hereby incorporated by reference.

[0183] In another embodiment, the methods provided herein include administering Compound I or a pharmaceutically acceptable salt thereof with a PD-1 inhibitor (e.g., pembrolizumab) together with one or more chemotherapeutic agents and / or therapies selected from the following: alkylating agents (e.g., cisplatin, carboplatin); antimetabolites (e.g., methotrexate and 5-FU); antitumor antibiotics (e.g., doxorubicin and bleomycin); antitumor plant alkaloids (e.g., paclitaxel and etoposide); antitumor hormones (e.g., dexamethasone and tamoxifen); antitumor immune agents (e.g., interferon α, β and γ); radiation therapy; and surgery. In certain embodiments, one or more chemotherapeutic agents and / or therapies are administered to the patient before, during, or after the administration of Compound I or a pharmaceutically acceptable salt thereof with a PD-1 inhibitor (e.g., pembrolizumab).

[0184] Such other agents or drugs can be administered simultaneously or sequentially with Compound 1 or its pharmaceutically acceptable salt and PD-1 inhibitor (e.g., pembrolizumab) by routes and amounts commonly used therefor. When Compound 1 or its pharmaceutically acceptable salt and PD-1 inhibitor (e.g., pembrolizumab) are used simultaneously with one or more other drugs, pharmaceutical compositions containing such other drugs in addition to Compound 1 or its pharmaceutically acceptable salt and PD-1 inhibitor (e.g., pembrolizumab) can be utilized, but are not required. Accordingly, the pharmaceutical compositions provided herein include those containing one or more other active ingredients or therapeutic agents in addition to Compound 1 or its pharmaceutically acceptable salt.

[0185] Pharmaceutical compositions and routes of administration

[0186] Provided herein are pharmaceutical compositions comprising Compound 1 or a pharmaceutically acceptable salt thereof, a PD-1 inhibitor (e.g., pembrolizumab), and a pharmaceutically acceptable excipient, adjuvant, carrier, buffer, or stabilizer. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof and a PD-1 inhibitor (e.g., pembrolizumab) are present in the same pharmaceutical composition. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof and a PD-1 inhibitor (e.g., pembrolizumab) are in different pharmaceutical compositions.

[0187] In some embodiments, the first pharmaceutical composition comprises Compound 1 or a pharmaceutically acceptable salt thereof and a first pharmaceutically acceptable excipient or carrier. In some embodiments, the second pharmaceutical composition comprises a PD-1 inhibitor (e.g., pembrolizumab) and a second pharmaceutically acceptable excipient or carrier.

[0188] In one embodiment, the pharmaceutical composition is provided in a dosage form for oral administration, comprising a compound provided herein and one or more pharmaceutically acceptable excipients or carriers. The pharmaceutical composition provided herein that is formulated for oral administration can be in tablet, capsule, powder or liquid form. In some embodiments, the tablet comprises a solid carrier or adjuvant. The liquid pharmaceutical composition generally comprises a liquid carrier such as water, petroleum, animal or vegetable oil, mineral oil or synthetic oil. Physiological saline solution, dextrose or other sugar solutions, or glycols such as ethylene glycol, propylene glycol or polyethylene glycol can be included. In some embodiments, the capsule comprises a solid carrier, such as gelatin.

[0189] In another embodiment, the pharmaceutical composition is provided in a dosage form for parenteral administration, comprising a compound provided herein and one or more pharmaceutically acceptable excipients or carriers. When the pharmaceutical composition can be formulated for intravenous injection, skin injection or subcutaneous injection, the active ingredient will be in the form of an aqueous solution acceptable to parenteral administration, which is pyrogen-free and has a suitable pH, isotonicity and stability. Those skilled in the art will be fully able to use, for example, isotonic vehicles (such as sodium chloride injection, Ringer's injection or lactated Ringer's injection) to prepare suitable solutions. In some embodiments, preservatives, stabilizers, buffers, antioxidants and / or other additives are included as needed.

[0190] In yet another embodiment, a pharmaceutical composition is provided in a dosage form for topical administration, the pharmaceutical composition comprising a compound provided herein and one or more pharmaceutically acceptable excipients or carriers.

[0191] Pharmaceutical compositions can also be formulated as modified release dosage forms, including delayed release, extended release, sustained release, delayed release, pulsed release, controlled release, accelerated release, fast release, targeted release and programmed release dosage forms, and gastric retention dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (see, Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, 2nd edition, Rathbone et al., ed., Marcel Dekker, Inc.: New York, NY, 2008).

[0192] The pharmaceutical composition provided herein can be provided in unit dosage form or multiple dosage form. As used herein, unit dosage form refers to physically discrete units, suitable for use to human and animal subjects, and individually packaged as known in the art. Each unit dose contains a predetermined amount of active ingredient sufficient to produce the desired therapeutic effect and required pharmaceutical carrier or excipient. The example of unit dosage form includes ampoules, injections, and individually packaged tablets and capsules. The unit dosage form can be used in part or multiple thereof. Multiple dosage form is a plurality of identical unit dosage forms to be used in a single container in an isolated unit dosage form. The example of multiple dosage form includes a bottle of a vial, tablet or capsule, or a pint or gallon bottle.

[0193] The pharmaceutical composition provided herein can be administered once or multiple times at intervals. It is understood that the precise dosage and duration of treatment can vary due to the age, weight and condition of the treated patient, and can be determined empirically using known test procedures or by extrapolation from in vivo or in vitro tests or diagnostic data. It is further understood that for any particular individual, a specific dosage regimen should be adjusted over time according to the professional judgment of the personnel who need to administer or supervise the administration of the preparation.

[0194] In certain embodiments, the pharmaceutical compositions provided herein further comprise one or more chemotherapeutic agents as defined herein.

[0195] A. Oral administration

[0196] The pharmaceutical composition for oral administration provided herein can be provided with solid, semisolid or liquid dosage forms for oral administration. As used herein, oral administration also includes oral cavity, tongue and sublingual administration. Suitable oral dosage forms include but are not limited to tablets, fast dissolving agents, chewable tablets, capsules, pills, medicine strips, lozenges, pastilles, pastilles, cachets, pellets, medicinal chewing gum, bulk powders, effervescent or non-effervescent powders or granules, oral mists, solutions, emulsions, suspensions, wafers, sprays, elixirs and syrups. In addition to active ingredients, pharmaceutical compositions can contain one or more pharmaceutically acceptable carriers or excipients, including but not limited to adhesives, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, colorants, dye migration inhibitors, sweeteners, flavoring agents, emulsifiers, suspending agents and dispersants, preservatives, solvents, non-aqueous liquids, organic acids and carbon dioxide sources.

[0197] Binders or granulating agents impart cohesive properties to the tablet, ensuring that the tablet remains intact after compression. Suitable binders or granulating agents include, but are not limited to, starches such as corn starch, potato starch, and pregelatinized starch (e.g., STARCH 1500); gelatin; sugars such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums such as acacia, alginic acid, alginates, Irish moss extract, panwar gum, ghatti gum, isabgol husks gum, carboxymethyl cellulose, methyl cellulose, polyvinyl pyrrolidone (PVP), Veegum, larch arabinogalactan, powdered tragacanth gum, and guar gum; cellulosics such as ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC); microcrystalline cellulose such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, PA); and mixtures thereof. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. The amount of binder or filler in the pharmaceutical compositions provided herein varies depending on the type of formulation and is readily discernible to one of ordinary skill in the art. The binder or filler may be present in the pharmaceutical compositions provided herein in an amount of from about 50% to about 99% by weight.

[0198] Suitable diluents include but are not limited to dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, anhydrous starch and powdered sugar. Some diluents, such as mannitol, lactose, sorbitol, sucrose and inositol, when present in sufficient amounts, can give some compressed tablets the properties of allowing disintegration in the mouth by chewing. Such compressed tablets can be used as chewable tablets. The amount of the diluent in the pharmaceutical composition provided herein changes according to the type of preparation, and is easily distinguishable for those of ordinary skill in the art.

[0199] Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses such as methylcellulose and carboxymethylcellulose; wood products; natural sponges; cation exchange resins; alginic acid; gums such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses such as cross-linked carboxymethylcellulose; cross-linked polymers such as crospovidone; cross-linked starch; calcium carbonate; microcrystalline cellulose such as sodium starch glycolate; potassium polacrilin; starches such as corn starch, potato starch, tapioca starch, and pregelatinized starch; clay; lignin (aligns); and mixtures thereof. The amount of disintegrant in the pharmaceutical compositions provided herein varies depending on the type of formulation and is readily discernible to one of ordinary skill in the art. The amount of disintegrant in the pharmaceutical compositions provided herein varies depending on the type of formulation and is readily discernible to one of ordinary skill in the art. The pharmaceutical compositions provided herein may contain about 0.5% to about 15% or about 1% to about 5% disintegrant by weight.

[0200] Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols such as glyceryl behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oils, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laurate; agar; starch; lycopodium; silicon dioxide or silica gel, such as 200 (WR Grace Co., Baltimore, MD) and (Cabot Co. of Boston, MA); and mixtures thereof. The pharmaceutical compositions provided herein may contain from about 0.1% to about 5% by weight of a lubricant.

[0201] Suitable glidants include, but are not limited to, colloidal silicon dioxide, (Cabot Co. of Boston, MA) and asbestos-free talc. Suitable colorants include, but are not limited to, any approved certified water-soluble FD&C dyes and water-insoluble FD&C dyes suspended on alumina hydrates, as well as lakes and mixtures thereof. Lakes are combinations of insoluble forms of dyes obtained by adsorption of water-soluble dyes to hydrated oxides of heavy metals. Suitable flavoring agents include, but are not limited to, natural flavors extracted from plants (such as fruits), and synthetic blends of compounds that produce pleasant tastes, such as peppermint oil and methyl salicylate. Suitable sweeteners include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame. Suitable emulsifiers include, but are not limited to, gelatin, gum arabic, gum tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate ( 20), polyoxyethylene sorbitan monooleate 80 ( 80) and triethanolamine oleate. Suitable suspending agents and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth gum, Veegum, gum arabic, sodium carboxymethylcellulose, hydroxypropyl methylcellulose and polyvinyl pyrrolidone. Suitable preservatives include, but are not limited to, glycerol, methyl and propyl parabens, benzoic acid, sodium benzoate and alcohol. Suitable wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Suitable solvents include, but are not limited to, glycerol, sorbitol, ethanol and syrup. Suitable non-aqueous liquids used in emulsions include, but are not limited to, mineral oil and cottonseed oil. Suitable organic acids include, but are not limited to, citric acid and tartaric acid. Suitable sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate.

[0202] It will be appreciated that many carriers and excipients may serve multiple functions, even within the same formulation.

[0203] The pharmaceutical compositions for oral administration provided herein can be provided as compressed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets or enteric-coated tablets, sugar-coated tablets or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that resists gastric acid but dissolves or disintegrates in the intestine, thereby protecting the active ingredients from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which can be beneficial in masking unpleasant tastes or odors and protecting tablets from oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate. Film coatings impart the same general characteristics as sugar coatings. Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets and compressed or dry-coated tablets.

[0204] Tablet dosage forms can be prepared from active ingredients in powder, crystalline or granular form alone or in combination with one or more carriers or excipients described herein (including binders, disintegrants, controlled release polymers, lubricants, diluents and / or coloring agents). Flavoring agents and sweeteners are particularly useful in forming chewable tablets and lozenges.

[0205] The pharmaceutical composition for oral administration provided herein can be provided as a soft capsule or a hard capsule, and the capsule can be made of gelatin, methylcellulose, starch or calcium alginate. Hard gelatin capsules, also known as dry fill capsules (DFCs), consist of two parts, one part sliding over the other part, thereby completely enclosing the active ingredient. Soft elastic capsules (SECs) are soft spherical shells, such as gelatin shells, which are plasticized by adding glycerol, sorbitol or similar polyols. Soft gelatin shells can contain preservatives to prevent microbial growth. Suitable preservatives are those described herein, including methylparaben and propylparaben, and sorbic acid. Liquid, semisolid and solid dosage forms provided herein can be encapsulated in capsules. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Patent Nos. 4,328,245; 4,409,239 and 4,410,545. As known to those skilled in the art, capsules may also be coated to modify or sustain dissolution of the active ingredient.

[0206] The pharmaceutical compositions for oral administration provided herein can be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. Emulsions are two-phase systems in which one liquid is dispersed in another liquid in the form of globules, and the other liquid can be oil-in-water or water-in-oil. Emulsions can include pharmaceutically acceptable non-aqueous liquids or solvents, emulsifiers, and preservatives. Suspensions can include pharmaceutically acceptable suspending agents and preservatives. Aqueous alcoholic solutions can include pharmaceutically acceptable acetals, such as di(lower alkyl) acetals of lower alkyl aldehydes, such as acetaldehyde diethyl acetal; and water-miscible solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened aqueous alcoholic solutions. Syrups are concentrated aqueous solutions of sugars (e.g., sucrose) and can also contain preservatives. For liquid dosage forms, for example, solutions in polyethylene glycol can be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier (e.g., water) to facilitate measurement for administration.

[0207] Other useful liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredients provided herein and dialkylated monoalkylene glycols or polyalkylene glycols, including 1,2-dimethoxymethane, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550 and 750 refer to the approximate average molecular weight of polyethylene glycol. These formulations may further comprise one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters and dithiocarbamates.

[0208] The pharmaceutical compositions provided herein for oral administration can also be provided in the form of liposomes, micelles, microspheres or nanosystems. Micellar dosage forms can be prepared as described in US Pat. No. 6,350,458.

[0209] The pharmaceutical composition for oral administration provided herein can be provided as non-effervescent or effervescent granules and powders to be reconstructed into liquid dosage forms. Pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders can include diluents, sweeteners and wetting agents. Pharmaceutically acceptable carriers and excipients used in effervescent granules or powders can include organic acids and carbon dioxide sources.

[0210] Coloring and flavoring agents can be used in all of the above dosage forms.

[0211] The pharmaceutical compositions provided herein for oral administration can be formulated as immediate release or modified release dosage forms, including delayed release, extended release, pulsed release, controlled release, targeted release, and programmed release forms.

[0212] B. Parenteral Administration

[0213] The pharmaceutical compositions provided herein can be administered parenterally by injection, infusion or implantation for local or systemic administration. As used herein, parenteral administration includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrasynovial, intravesical and subcutaneous administration.

[0214] The pharmaceutical composition for parenteral administration provided herein can be formulated into any dosage form suitable for parenteral administration, including solution, suspension, emulsion, micelle, liposome, microsphere, nanosystem and the solid form of solution or suspension in liquid before being suitable for injection. Such dosage form can be prepared according to conventional methods known to those of ordinary skill in the field of pharmaceutical science (see, Remington:The Science and Practice of Pharmacy, the same).

[0215] Pharmaceutical compositions intended for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against microbial growth, stabilizers, solution enhancers, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering agents or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusters, and inert gases.

[0216] Suitable aqueous vehicles include but are not limited to water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringer's injection. Suitable non-aqueous vehicles include but are not limited to fixed oils of plant origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil and coconut oil medium chain triglycerides and palm seed oil. Suitable water miscible vehicles include but are not limited to ethanol, 1,3-butylene glycol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerol, N-methyl-2-pyrrolidone, N, N-dimethylacetamide and dimethyl sulfoxide.

[0217] Suitable antimicrobial agents or preservatives include, but are not limited to, phenol, cresol, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl parabens, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl and propyl parabens, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerol, and dextrose. Suitable buffers include, but are not limited to, phosphates and citrates. Suitable antioxidants are those described herein, including bisulfites and sodium pyrosulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending agents and dispersants are those described herein, including sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable emulsifiers are those described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable sequestrants or chelating agents include, but are not limited to, EDTA. Suitable pH regulators include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin and sulfobutyl ether 7-β-cyclodextrin ( CyDex, Lenexa, KS).

[0218] When the pharmaceutical compositions provided herein are formulated for multiple dose administration, the multiple dose parenteral formulations must contain bacteriostatic or fungistatic concentrations of antimicrobial agents.All parenteral formulations must be sterile, as is known and practiced in the art.

[0219] In one embodiment, the pharmaceutical composition for parenteral administration is provided as a ready-to-use sterile solution. In another embodiment, the pharmaceutical composition is provided as a sterile dry soluble product (including lyophilized powder and subcutaneous injection tablets) to be reconstituted with a vehicle before use. In another embodiment, the pharmaceutical composition is provided as a ready-to-use sterile suspension. In another embodiment, the pharmaceutical composition is provided as a sterile dry insoluble product to be reconstituted with a vehicle before use. In another embodiment, the pharmaceutical composition is provided as a ready-to-use sterile emulsion.

[0220] The pharmaceutical compositions provided herein for parenteral administration may be formulated as immediate release or modified release dosage forms, including delayed release, extended release, pulsed release, controlled release, targeted release, and programmed release forms.

[0221] The pharmaceutical compositions for parenteral administration provided herein can be formulated as suspensions, solids, semisolids or thixotropic liquids for administration as implanted depots. In one embodiment, the pharmaceutical compositions provided herein are dispersed in a solid inner matrix surrounded by an outer polymer membrane that is insoluble in body fluids but allows the active ingredients in the pharmaceutical composition to diffuse through.

[0222] Suitable inner matrices include, but are not limited to, polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic acid and methacrylic acid, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate.

[0223] Suitable outer polymer films include, but are not limited to, polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, chloroprene rubber, chlorinated polyethylene, polyvinyl chloride, copolymers of vinyl chloride and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, and ethylene / vinyloxyethanol copolymers.

[0224] C. Topical application

[0225] The pharmaceutical compositions provided herein can be topically applied to the skin, orifices or mucous membranes. As used herein, topical administration includes dermal (intra), conjunctival, intracorneal, intraocular, ocular, ear, transdermal, nasal, vaginal, urethral, ​​respiratory system and rectal administration.

[0226] The pharmaceutical compositions provided herein can be formulated into any dosage form suitable for topical administration for local or systemic effects, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, lavages, sprays, suppositories, bandages, and skin patches. Topical formulations of the pharmaceutical compositions provided herein can also include liposomes, micelles, microspheres, nanosystems, and mixtures thereof.

[0227] Pharmaceutically acceptable carriers and excipients suitable for use in the topical formulations provided herein include, but are not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives to prevent microbial growth, stabilizers, solution enhancers, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestrants or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickening agents, and inert gases.

[0228] The pharmaceutical composition can also be delivered by electroporation, iontophoresis, sonophoresis, or microneedle, or needle-free injection such as POWDERJECT TM(Chiron Corp., Emeryville, CA) and BIOJECT TM (Bioject Medical Technologies Inc., Tualatin, OR) for topical administration.

[0229] The pharmaceutical compositions provided herein can be provided in the form of ointments, creams and gels. Suitable ointment vehicles include oily or hydrocarbon vehicles, including lard, benzoinized lard, olive oil, cottonseed oil and other oils, white vaseline; emulsifiable or absorbable vehicles, such as hydrophilic vaseline, hydroxy stearyl sulfate and anhydrous lanolin; dewaterable vehicles, such as hydrophilic ointments; water-soluble ointment vehicles, including polyethylene glycols with different molecular weights; emulsion vehicles, water-in-oil (W / O) emulsions or oil-in-water (O / W) emulsions, including cetyl alcohol, glyceryl monostearate, lanolin and stearic acid (see, Remington: The Science and Practice of Pharmacy, supra). These vehicles are emollient, but usually require the addition of antioxidants and preservatives.

[0230] Suitable cream bases can be oil-in-water or water-in-oil. Suitable cream vehicles can be washable and contain an oil phase (emulsifier) ​​and an aqueous phase. The oil phase is also referred to as the "internal" phase, which is generally composed of vaseline and fatty alcohols (such as cetyl alcohol or stearyl alcohol). The aqueous phase generally (but not necessarily) exceeds the oil phase in volume and generally contains a wetting agent. In some embodiments, the emulsifier in the cream formulation is a nonionic, anionic, cationic or amphoteric surfactant.

[0231] Gels are semisolid suspension-type systems. Single-phase gels contain organic macromolecules substantially uniformly distributed in a liquid carrier. Suitable gelling agents include, but are not limited to, cross-linked acrylic acid polymers such as carbomers, carboxypolyolefins and Hydrophilic polymers such as polyethylene oxide, polyoxyethylene-polyoxypropylene copolymers, and polyvinyl alcohol; cellulose polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose; gums such as tragacanth and xanthan gum; sodium alginate and gelatin. To prepare a uniform gel, a dispersant such as alcohol or glycerol may be added, or the gelling agent may be dispersed by grinding, mechanical mixing, and / or stirring.

[0232] The pharmaceutical compositions provided herein can be administered rectally, urethrally, vaginally or around the vagina in the form of suppositories, vaginal suppositories, bougies, poultices or poultices, pastes, powders, dressings, creams, plasters, contraceptives, ointments, solutions, emulsions, suspensions, sanitary napkins, gels, foams, sprays or enemas. These dosage forms can be manufactured using conventional methods as described in Remington: The Science and Practice of Pharmacy, supra.

[0233] Rectal suppositories, urethral suppositories and vaginal suppositories are solids for insertion into body orifices, which are solid at room temperature but melt or soften at body temperature to release active ingredients in the orifices. When formulated with the pharmaceutical compositions provided herein, the pharmaceutically acceptable carriers used in rectal and vaginal suppositories include a matrix or vehicle (such as a hardener) that produces a melting point close to body temperature; and antioxidants as described herein, including bisulfites and sodium pyrosulfite. Suitable vehicles include, but are not limited to, cocoa butter (cocoa butter), glycerol-gelatin, polyethylene glycol (polyoxyethylene glycol), spermaceti, paraffin, white wax and yellow wax, and suitable mixtures of monoglycerides, diglycerides and triglycerides of fatty acids and hydrogels, such as polyvinyl alcohol, hydroxyethyl methacrylate and polyacrylic acid. Combinations of various vehicles can also be used. Rectal and vaginal suppositories can be prepared by compression or molding. The typical weight of rectal and vaginal suppositories is from about 2g to about 3g.

[0234] The pharmaceutical compositions provided herein can be administered to the eye in the form of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solutions, gels, ophthalmic inserts, and implants.

[0235] The pharmaceutical composition provided herein can be administered intranasally or by suction to the respiratory tract. The pharmaceutical composition can be provided in the form of an aerosol or solution, for use of a pressurized container, pump, ejector, atomizer (such as an atomizer using electrohydrodynamics to produce a fine mist) or a sprayer alone or in combination with a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane for delivery. The pharmaceutical composition can also be provided as a dry powder for insufflation alone or in combination with an inert carrier (such as lactose or phospholipid) and nasal drops. For intranasal use, powders can include bioadhesives, including chitosan or cyclodextrin.

[0236] Solutions or suspensions for use in a pressurized container, pump, spray, atomizer or nebulizer can be formulated to contain ethanol, aqueous ethanol or a suitable alternative for dispersing, solubilizing or prolonging the release of the active ingredients provided herein; a propellant as a solvent; and / or a surfactant, such as sorbitan trioleate, oleic acid or oligolactic acid.

[0237] The pharmaceutical compositions provided herein can be micronized to a size suitable for delivery by inhalation, such as about 50 microns or less, or about 10 microns or less. Such sized particles can be prepared using pulverization methods known to those skilled in the art (such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing) to form nanoparticles, high pressure homogenization or spray drying.

[0238] Capsules, blisters and cartridges for inhalers or insufflators can be formulated into powder mixtures containing the pharmaceutical compositions provided herein; suitable powder bases, such as lactose or starch; and performance modifiers, such as l-leucine, mannitol or magnesium stearate. Lactose can be in the form of anhydrous or monohydrate. Other suitable excipients or carriers include, but are not limited to, dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose. The pharmaceutical compositions provided herein for inhalation / intranasal administration can further include suitable flavoring agents, such as menthol and levomenthol; and / or sweeteners, such as saccharin and saccharin sodium.

[0239] The pharmaceutical compositions provided herein for topical administration can be formulated to be immediate release or modified release, including delayed release, extended release, pulsed release, controlled release, targeted release, and programmed release.

[0240] D. Modified Release

[0241] The pharmaceutical composition provided herein can be formulated as a modified release dosage form. As used herein, the term "modified release" refers to a dosage form in which the release rate or position of the active ingredient is different from the release rate or position of the immediate dosage form when administered by the same route. Modified release dosage forms include, but are not limited to, delayed release dosage forms, extended release dosage forms, sustained release dosage forms, delayed release dosage forms, pulse release dosage forms, controlled release dosage forms, accelerated release dosage forms and rapid release dosage forms, targeted release dosage forms, programmed release dosage forms and gastric retention dosage forms. The pharmaceutical composition in a modified release dosage form can be prepared using a variety of modified release devices and methods known to those skilled in the art, including but not limited to matrix controlled release devices, osmotic controlled release devices, multi-particle controlled release devices, ion exchange resins, enteric coatings, multi-layer coatings, microspheres, liposomes and combinations thereof. The release rate of the active ingredient can also be changed by changing the particle size and polymorphism of the active ingredient.

[0242] Examples of modified release include, but are not limited to, those described in U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,8 Those described in 91,474; 5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358 and 6,699,500.

[0243] 1. Matrix controlled release device

[0244] The pharmaceutical compositions provided herein in modified release dosage forms can be manufactured using matrix controlled release devices known to those skilled in the art (see Takada et al., "Encyclopedia of Controlled Drug Delivery," Vol. 2, Mathiowitz, ed., Wiley, 1999).

[0245] In certain embodiments, the pharmaceutical compositions provided herein in modified release dosage forms are formulated using an erodible matrix device that is a water-swellable, erodible, or soluble polymer, including but not limited to synthetic polymers and naturally occurring polymers and derivatives, such as polysaccharides and proteins.

[0246] Materials that can be used to form the erodible matrix include, but are not limited to, chitin, chitosan, dextran, and pullulan; agar, gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenan, gum ghatti, guar gum, xanthan gum, and scleroglucan; starches such as dextrin and maltodextrin; hydrophilic colloids such as pectin; phospholipids such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; celluloses such as ethylcellulose (EC), methylethylcellulose (MEC), carboxymethylcellulose (CMC), CMEC, hydroxyethylcellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methylcellulose acetate trimellitate (HPMCAT) and ethyl hydroxyethyl cellulose (EHEC); polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid esters; polyacrylamide; polyacrylic acid; copolymers of ethyl acrylic acid or methacrylic acid ( Rohm America, Inc., Piscataway, NJ); poly(2-hydroxyethyl-methacrylate), polylactic acid; copolymers of L-glutamic acid and ethyl-L-glutamate; degradable lactic acid-glycolic acid copolymers; poly-D-(-)-3-hydroxybutyric acid; and other acrylic acid derivatives, such as homopolymers and copolymers of butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl) methacrylate, and (trimethylaminoethyl) methacrylate chloride.

[0247] In certain embodiments, the pharmaceutical compositions provided herein are formulated using a non-erodible matrix device. The active ingredient is dissolved or dispersed in the inert matrix and, upon administration, is released primarily by diffusion through the inert matrix. Materials suitable for use as the non-erodible matrix device include, but are not limited to, insoluble plastics such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethyl methacrylate, polybutyl methacrylate, chlorinated polyethylene, polyvinyl chloride, methyl acrylate-methyl methacrylate copolymers, ethylene-vinyl acetate copolymers, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, copolymers of vinyl chloride and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, ethylene / ethyleneoxyethanol copolymers, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubber, polydimethylsiloxane and silicone carbonate copolymers; hydrophilic polymers such as ethylcellulose, cellulose acetate, crospovidone and cross-linked partially hydrolyzed polyvinyl acetate; and fatty compounds such as carnauba wax, microcrystalline wax and triglycerides.

[0248] In a matrix controlled release system, the desired release kinetics can be controlled, for example, via the type of polymer employed, polymer viscosity, particle size of the polymer and / or active ingredient, ratio of active ingredient to polymer, and other excipients or carriers in the composition.

[0249] The pharmaceutical compositions provided herein in modified release dosage forms can be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, and melt granulation followed by compression.

[0250] Manufactured products

[0251] The compounds provided herein can also be provided as articles of manufacture using packaging materials well known to those skilled in the art. See, for example, U.S. Patent Nos. 5,323,907; 5,052,558; and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, and any packaging material suitable for the selected formulation and the planned mode of administration and treatment.

[0252] Also provided herein are kits that, when used by a physician, can simplify administering an appropriate amount of active ingredient to a subject. In certain embodiments, the kits provided herein include one or more containers and a dosage form of Compound I or a pharmaceutically acceptable salt thereof and a PD-1 inhibitor (e.g., pembrolizumab).

[0253] In certain embodiments, the kits provided herein include one or more containers and a dosage form of Compound I or a pharmaceutically acceptable salt thereof and a PD-1 inhibitor (e.g., pembrolizumab). The kits provided herein may further include a device for administering the active ingredient. Examples of such devices include, but are not limited to, syringes, needleless syringe drip bags, patches, and inhalers.

[0254] The kit provided herein may further include a pharmaceutically acceptable vehicle that can be used to administer one or more active ingredients. For example, if the active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit may include a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particle-free sterile solution suitable for parenteral administration. Examples of pharmaceutically acceptable vehicles include, but are not limited to, aqueous vehicles, including, but not limited to, water for injection USP, sodium chloride injection, Ringer's injection, dextrose injection, dextrose and sodium chloride injection, and lactated Ringer's injection; water-miscible vehicles, including, but not limited to, ethanol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles, including, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0255] Example

[0256] As used herein, the symbols and conventions used in these processes, schemes and examples, whether or not a particular abbreviation is explicitly defined, are consistent with those used in contemporary scientific literature such as the Journal of the American Chemical Society or the Journal of Biological Chemistry. The following abbreviations may be used explicitly but not limitedly in the examples and throughout this specification: g (gram); mg (milligram); mL (milliliter); μL (microliter); M (mole); mM (millimole), μM (micromole); eq. (equivalent); mmol (millimole), Hz (hertz), MHz (megahertz); hr or hrs (hour or hour); min (minute); and MS (mass spectrometry).

[0257] For all the following examples, standard work-ups and purification methods known to those skilled in the art can be utilized. Unless otherwise indicated, all temperatures are expressed in ° C (degrees Celsius). Unless otherwise indicated, all reactions are carried out at room temperature. The synthetic methods described herein are intended to illustrate applicable chemistry by using specific examples and do not indicate the scope of the present disclosure.

[0258] Example 1: Synthesis of 4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(2-methyl-1-(2-(1-methylpiperidin-4-yl)phenyl)propan-2-yl)-6-morpholino-1,3,5-triazine-2-amine (Compound I)

[0259] The synthesis of Compound I is described in US Pat. No. 9,056,852 B2, which is incorporated by reference into the present disclosure.

[0260] A mixture of 4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(2-methyl-1-(2-(piperidin-4-yl)phenyl)propan-2-yl)-6-morpholino-1,3,5-triazin-2-amine (80 mg, 0.14 mmol), aqueous formaldehyde (37%, 23 mg) and sodium cyanoborohydride (11 mg, 0.17 mmol) in methanol (2 mL) was stirred at room temperature for 1 hour. The crude product was purified by preparative HPLC to provide Compound I (11 mg, 13% yield) as a white solid: 99% purity (HPLC); MS m / z: 577.3 (M+1); 1 H NMR(CDCl3,500MHz)δ8.37(d,1H),7.90(d,1H),7.64(t,1H),7.42(m,2H),7.32(d,1H),7.24(1,1H),7.13(t,1H),7.07(d,1 H),5.15(s,1H),4.00-3.70(m,8H),3.28(s,2H),2.94(m,2H),2.78(m,2H),2.28(s,3H),1.891.60(m,6H),1.53(s,6H)ppm.

[0261] Example 2: MC38 mouse colon cancer model for the combination of PI3K inhibitors and PD-1 inhibitors

[0262] The MC38 murine colon cancer syngeneic model was used to evaluate the combination of a PI3K inhibitor (Compound I) and a PD-1 inhibitor (RMP1-14) in female immunocompetent C57BL / 6 mice. The study was designed to plot the survival time of murine samples when treated with a combination of Compound I and a PD-1 inhibitor.

[0263] Compound I dosing solutions were prepared weekly. Compound I formulations were prepared by adding an appropriate amount of 20% VE-TPGS, 80% 100 mM citrate buffer, pH 3.5 solution (vehicle) to Compound I. The resulting suspension was stirred overnight to produce a 5 mg / mL dosing solution. This solution provided a dose of 50 mg / kg at a dosing volume of 10 mL / kg. When not in use, Compound I dosing solutions were stored at 4°C.

[0264] PD-1 inhibitor (anti-PD-1 antibody clone RMP1-14, lot number 5792-599016J1) was purchased from Bio X Cell through CR Discovery Services and stored at 4° C. upon receipt. Anti-PD-1 antibody dosing solution was prepared by diluting an aliquot of the stock solution (6.37 mg / mL) to 0.5 mg / mL in sterile PBS, yielding a dose of 100 μg / animal at a fixed dosing volume of 0.2 mL / animal.

[0265] Tumor measurements were made twice weekly. Treatment response was assessed from tumor growth delay (TGD), increase in median time to endpoint (TTE) in treated mice compared to control mice, and comparison of survival curves using log-rank analysis. 3 At the volume endpoint, it was marked as tumor progression, and any animal that did not reach the endpoint was euthanized at the end of the study and assigned a TTE value equal to the last day of the study (Day 45).

[0266] The median TTE for Control Group 1 was 19.0 days, establishing a maximum TGD of 137% for this study.All treatments evaluated in the study were acceptably tolerated, with acceptable mean BW losses and no treatment-related (TR) deaths.

[0267] Tumor growth delay (TGD) analysis

[0268] Animals were monitored individually for tumor growth until day 45. The study protocol specified that tumor growth delay determination be based on the median time to endpoint (TTE) of the treated group compared to the control group. 3 When the volume endpoint was reached, it was labeled as tumor progression (TP). The TTE of each mouse was calculated using the following equation:

[0269]

[0270] Wherein b is the intercept, and m is the slope of the line obtained by the linear regression of the tumor growth data set transformed by logarithm. The data set consists of the first observation exceeding the research endpoint volume and the three consecutive observations immediately before reaching the endpoint volume. At the end of the study, any animal that did not reach the endpoint was euthanized and the TTE value was specified to be equal to the last day of the study (the 45th day). In the case where the TTE calculated by logarithmic conversion is earlier than the day before reaching the endpoint or exceeds the day when reaching the tumor volume endpoint, linear interpolation is performed to approximate TTE.

[0271] At day 45, MTV(n) was defined as the median tumor volume of the number of animals n that survived to the last day and whose tumors had not reached the volume endpoint. Any animal determined to have died from a TR cause was assigned a TTE value equal to the day of death. Any animal that died from an NTR cause was excluded from the analysis. Treatment outcome was assessed from TGD, which was defined as the increase in median TTE in the treatment group compared to the control group:

[0272] TGD=TC

[0273] Expressed as days or as a percentage of the median TTE of the control group:

[0274]

[0275] in

[0276] T = median TTE of the treatment group,

[0277] C = median TTE of the control group.

[0278] Survival was analyzed by the Kaplan-Meier method. Log-rank (Mantel-Cox) and Gehan-Breslow-Wilcoxon tests determined the significance of the difference between the total survival experience (survival curve) of the two groups based on the TTE value. Scatter plots were constructed to display the TTE values ​​of individual mice by group. The median tumor volume of the group was plotted as a function of time. When an animal withdrew from the study due to tumor size, the final tumor volume recorded for the animal was included together with the data for calculating the median volume at subsequent time points. Kaplan-Meier curves were constructed to display the percentage of animals in the remaining study in each group over time.

[0279] Example 2a

[0280] On day 1 of the study, four groups of C57BL / 6 mice (n=10 for control group and PD-1 monotherapy; n=20 for combination therapy) were dosed. Compound I was administered by oral gavage (po) at a dose of 50 mg / kg with a dosing volume of 10 mL / kg, adjusted based on the most recent body weight measurement. The PD-1 inhibitor was administered intraperitoneally (ip) at a dose of 100 μg / animal with a fixed dosing volume of 0.2 mL / animal.

[0281] Group 1 remained untreated and served as the control group for %TGD.

[0282] Group 2 was treated with PD-1 inhibitor ip at a dose of 100 μg / animal twice a week for two weeks.

[0283] Group 3 received Compound I po at 50 mg / kg qd x 7 starting on day 1. Then starting on day 8, this group was treated with the PD-1 inhibitor ip at 100 μg / animal biwk x 2.

[0284] Group 4 received Compound I po at 50 mg / kg qd x 7 starting on day 1. Starting on day 8, this group was treated with the PD-1 inhibitor ip at 100 μg / animal biwk x 2, with the final dose occurring on day 18. On day 22, treatment with Compound I was resumed at 50 mg / kg once daily for five days (qd x 5, starting on day 22).

[0285] Group 5 received Compound I po at 50 mg / kg qd x 7 starting on day 1. On day 8, these animals received the PD-1 inhibitor ip at 100 μg / animal biwk x 2, with the final dose occurring on day 18. The second course of PD-1 inhibitor was administered starting on day 27 biwk x 2.

[0286] Group 6 received Compound I po at 50 mg / kg qd x 7 starting on day 1. On day 8, these animals received the PD-1 inhibitor ip at 100 μg / animal biwk x 2, with the final dose occurring on day 18. Treatment with Compound I was resumed on day 22 at 50 mg / kg qd x5. A second course of PD-1 inhibitor was administered starting on day 27 biwk x 2.

[0287] Group 7 received Compound I po at 50 mg / kg qd x 7 starting on D1 and then again for 7 days starting on day 22 (qd x 7, starting on day 22), in combination with a PD-1 inhibitor ip at 100 μg / animal biwk x 2 starting on day 8.

[0288] Treatment with Compound I and PD-1 inhibitors was well tolerated. All Compound I / PD-1 inhibitor combinations provided a statistically significant survival benefit. The combination regimen of Compound I and PD-1 inhibitors administered in two treatment cycles was more effective than one treatment cycle (Group 6 vs. Group 3) and more effective than a single cycle of PD-1 inhibitors (Group 6 vs. Group 2). The results are depicted in Figure 1 middle.

[0289] The combination regimen of Compound I and a PD-1 inhibitor administered in two treatment cycles was more effective than administering one cycle of combination treatment and one cycle of Compound I treatment (Group 6 vs. Group 4), and was more effective than administering a single cycle of Compound I and a PD-1 inhibitor combination treatment (Group 6 vs. Group 3). The results are depicted in Figure 2 middle.

[0290] The combination regimen of Compound I and a PD-1 inhibitor administered in two treatment cycles was more effective than administering one cycle of the combination and one cycle of PD-1 inhibitor treatment (Group 6 vs. Group 5), and was more effective than administering a single cycle of Compound I and a PD-1 inhibitor combination treatment (Group 6 vs. Group 3). The results are depicted in Figure 3 middle.

[0291] Example 3: Clinical study of combination therapy of Compound I and pembrolizumab

[0292] This example relates to a 3-cohort clinical study of Compound I in combination with anti-PD-1 therapy with pembrolizumab in subjects with advanced renal cell carcinoma, advanced melanoma, or advanced hepatocellular carcinoma. The study included a 42-day (6-week) DLT window. The study design was Figure 4 Described in.

[0293] Study Design & Dosing Schedule

[0294] The study included administration of the combination of Compound I and pembrolizumab to three cohorts of patients (N=20 to 30): Cohort 1: patients with advanced renal cell carcinoma (RCC), specifically advanced RCC clear cell subtype; Cohort 2: patients with melanoma; and Cohort 3: patients with advanced hepatocellular carcinoma (HCC).

[0295] The dosing schedule of the study was designed in Figure 5 In the description.

[0296] In level 1 of the study, Compound I was administered for 5 days from day 1 to day 5 in the first three weeks (cycle 1), and administration was stopped for 16 days, and was not administered in cycle 2. Compound I was administered once a day (qd) at a dose of 60 mg / day. Pembrolizumab was administered starting on day 1 of week 4 (day 1 of cycle 2; C2D1), and was not administered in cycle 3 (where Compound I was administered). Pembrolizumab was administered via infusion at a dose of 400 mg. Then, administration of Compound I was repeated on cycles 3, 5, 7... and administration of Pembrolizumab was repeated on cycles 4, 6, 8... Each cycle was 3 weeks (21 days).

[0297] In level 2 of the study, Compound I was administered once a day (qd) for 5 days on days 1 to 5 in each of the 3-week treatment cycles at a dose of 60 mg / day, and administration was stopped for 16 days. Pembrolizumab was administered once via infusion at a dose of 400 mg on day 14 in each of the 3-week treatment cycles. Then, administration of Compound I with Pembrolizumab was repeated on cycles 2, 3, 4, 5, 7, 8, ... Each cycle was 3 weeks (21 days).

[0298] Response was assessed by iRECIST. CT scans were repeated every 12 weeks to confirm CR or PD. For example, CT scan images can be reviewed by blinded independent central review.

[0299] Study End Points

[0300] The primary endpoint of the study included overall response rate (ORR; CT scan imaging was submitted for collection for blinded independent central review).

[0301] Secondary endpoints of the study included ORR (investigator review), duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

[0302] From the foregoing it will be appreciated that, although specific embodiments have been described herein for purposes of illustration, various modifications may be made without departing from the spirit and scope provided herein.All references mentioned above are incorporated herein by reference in their entirety.

Claims

1. A method for treating cancer in a patient in need thereof in one or more treatment cycles, the method comprising: (i) administering Compound 1 or a pharmaceutically acceptable salt thereof to the patient during a first period of time in each of the one or more treatment cycles; as well as (ii) administering a PD-1 inhibitor to the patient after administering Compound I or a pharmaceutically acceptable salt thereof; Wherein compound I has the following structure:

2. The method of claim 1, wherein each of the one or more treatment cycles is at least about 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 weeks.

3. The method of claim 1 or 2, wherein each of the one or more treatment cycles is about 6 weeks.

4. The method of claim 1 or 2, wherein each of the one or more treatment cycles is about 3 weeks.

5. The method of claim 1, wherein the PD-1 inhibitor is administered about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days after the first period of time.

6. The method of any one of claims 1-3 and 5, wherein each of the one or more treatment cycles is about 6 weeks and the PD-1 inhibitor is administered about 16 days after the first period of time.

7. The method of any one of claims 1, 2, 4, and 5, wherein each of the one or more treatment cycles is about 3 weeks and the PD-1 inhibitor is administered about 8 days after the first period of time.

8. The method of any one of claims 1 to 7, wherein the first period of time is 3 days, 4 days, 5 days, 6 days or 1 week.

9. The method of claim 8, wherein the first period of time is 5 days.

10. The method of claim 1, wherein after the first time period, the PD-1 inhibitor is administered beginning on the day after a second time period, wherein the second time period is immediately after the first time period.

11. The method of claim 10, wherein the second period of time is about 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 days.

12. The method of claim 11, wherein the second period of time is about 16 days.

13. The method of claim 11, wherein the second period of time is about 8 days.

14. The method of any one of claims 1-13, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered daily during the first period of time.

15. The method of claim 1, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered to the patient on an intermittent dosing schedule.

16. The method of claim 15, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered only during the first time period of each of the one or more treatment cycles and not on days after the first time period, and the first time period is shorter than each of the one or more treatment cycles.

17. The method of claim 15 or 16, wherein the first period of time is 3 days, 4 days, 5 days, 6 days or 1 week.

18. The method of any one of claims 15 to 17, wherein the first period of time is 5 days.

19. The method of any one of claims 1 to 18, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered once daily at a dose of 60 mg.

20. The method of any one of claims 1 to 19, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered orally.

21. The method of any one of claims 1 to 20, wherein the PD-1 inhibitor is administered once, twice or three times in each of the one or more treatment cycles.

22. The method of claim 21, wherein the PD-1 inhibitor is administered once in each of the one or more treatment cycles.

23. The method of claim 22, wherein when each of the one or more treatment cycles is about 6 weeks, the PD-1 inhibitor is administered on day 22 of each of the one or more treatment cycles.

24. The method of claim 22, wherein when each of the one or more treatment cycles is about 3 weeks, the PD-1 inhibitor is administered on day 14 of each of the one or more treatment cycles.

25. The method of claim 21, wherein the PD-1 inhibitor is administered twice in each of the one or more treatment cycles.

26. The method of claim 25, wherein when each of the one or more treatment cycles is about 6 weeks, the PD-1 inhibitor is administered on Day 14 and Day 35 of each of the one or more treatment cycles.

27. The method of any one of claims 1 to 26, wherein the PD-1 inhibitor is pembrolizumab, nivolumab, cemiplimab, or dotalimumab, or a variant or biosimilar thereof, or a combination thereof.

28. The method of claim 27, wherein the PD-1 inhibitor is pembrolizumab or a variant or biosimilar thereof.

29. The method of any one of claims 1 to 28, wherein the PD-1 inhibitor is administered for at least 6 weeks.

30. The method of any one of claims 1 to 29, wherein the PD-1 inhibitor is administered for 6, 9, 12, 15, 18, 21, 24, 27, or 30 weeks.

31. The method of any one of claims 1 to 30, wherein the PD-1 inhibitor is administered once every 3 weeks or once every 6 weeks.

32. The method of any one of claims 1 to 31, wherein the PD-1 inhibitor is administered at a dose of 200 mg or 400 mg.

33. The method of claim 31, wherein the PD-1 inhibitor is administered once every 6 weeks.

34. The method of claim 32, wherein the PD-1 inhibitor is administered at a dose of 400 mg.

35. The method of claim 31, wherein the PD-1 inhibitor is administered once every 3 weeks.

36. The method of claim 34, wherein the PD-1 inhibitor is administered at a dose of 200 mg.

37. The method of any one of claims 1-36, wherein the PD-1 inhibitor is administered intravenously.

38. The method of any one of claims 1 to 37, wherein the first time period begins on day 1, day 2, day 3, day 4, day 5, day 6, day 7, or day 8 of each of the one or more treatment cycles.

39. The method of any one of claims 1 to 38, wherein the first time period begins on day 1 of each of the one or more treatment cycles.

40. The method of claim 1, wherein each of the one or more treatment cycles is 6 weeks, Compound 1 or a pharmaceutically acceptable salt thereof is administered on day 1 to day 5, and then the PD-1 inhibitor is administered once on day 22.

41. The method of claim 1, wherein each of the one or more treatment cycles is 3 weeks, Compound 1 or a pharmaceutically acceptable salt thereof is administered on days 1 to 5, and then the PD-1 inhibitor is administered once on day 14.

42. The method of any one of claims 1 to 41, wherein the cancer is lung cancer (e.g., non-small cell lung cancer), melanoma, renal cell carcinoma, head and neck cancer, breast cancer (e.g., triple-negative breast cancer), non-Hodgkin lymphoma, Hodgkin lymphoma, colorectal cancer, urothelial carcinoma, gastric cancer, cervical cancer, hepatocellular carcinoma, Merkel cell carcinoma, esophageal cancer, endometrial cancer, squamous cell carcinoma of the skin, or mesothelioma.

43. The method of claim 42, wherein the cancer is lung cancer.

44. The method of claim 43, wherein the lung cancer is non-small cell lung cancer.

45. The method of claim 42, wherein the cancer is melanoma.

46. ​​The method of claim 42, wherein the cancer is renal cell carcinoma.

47. The method of claim 42, wherein the cancer is hepatocellular carcinoma.

48. The method of claim 42, wherein the cancer is colorectal cancer.

49. The method of claim 48, wherein the colorectal cancer is microsatellite instability-high or mismatch repair-deficient colorectal cancer.

50. The method of any one of claims 1 to 49, further comprising (iii) evaluating the efficacy of administering the combination of Compound I or a pharmaceutically acceptable salt thereof and the PD-1 inhibitor by measuring the levels of regulatory T cells (CD25hi FoxP3+ T cells) or effector T cells (e.g., CD8+ and CD4+ cells).

51. The method of claim 50, wherein a level of regulatory T cells (CD25hiFoxP3+ T cells) or effector T cells (e.g., CD8+ and CD4+ cells) that is less than or equal to about 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15% or 10% of the baseline level of regulatory T cells (CD25hiFoxP3+ T cells) or effector T cells (e.g., CD8+ and CD4+ cells) indicates that the one or more treatment cycles of administering the combination of Compound I, or a pharmaceutically acceptable salt thereof, and the PD-1 inhibitor are effective.

52. The method of claim 50 or 51, wherein a level of regulatory T cells (CD25hiFoxP3+T cells) or effector T cells (e.g., CD8+ and CD4+ cells) that is less than or equal to about 65% of the baseline level of regulatory T cells (CD25hiFoxP3+T cells) or effector T cells (e.g., CD8+ and CD4+ cells) indicates that the one or more treatment cycles of administering the combination of Compound I, or a pharmaceutically acceptable salt thereof, and the PD-1 inhibitor are effective.

53. The method of any one of claims 1 to 52, wherein co-administration of Compound 1, or a pharmaceutically acceptable salt thereof, with the PD-1 inhibitor is effective in treating the cancer.

54. A method for treating cancer in a patient in need thereof in one or more treatment cycles, the method comprising: (i) administering Compound 1 or a pharmaceutically acceptable salt thereof to the patient on day 1 to day 5 of each of the one or more treatment cycles; as well as (ii) administering a PD-1 inhibitor to the patient on day 22 of each of the treatment cycles; wherein each of the one or more treatment cycles is 6 weeks; and Wherein compound I has the following structure:

55. A method for treating cancer in a patient in need thereof in one or more treatment cycles, the method comprising: (i) administering Compound 1 or a pharmaceutically acceptable salt thereof to the patient on day 1 to day 5 of each of the one or more treatment cycles; as well as (ii) administering a PD-1 inhibitor to the patient on day 14 of each of the treatment cycles; wherein each of the one or more treatment cycles is 3 weeks; and Wherein compound I has the following structure:

56. A method for treating cancer in a patient in need thereof in one or more treatment cycles, the method comprising: (i) administering Compound 1 or a pharmaceutically acceptable salt thereof to the patient in Week 1 of an odd-numbered cycle (e.g., Cycle 1) in the one or more treatment cycles; as well as (ii) administering a PD-1 inhibitor to the patient in Week 1 of an even-numbered cycle (e.g., Cycle 2) of each of the treatment cycles; wherein each of the one or more treatment cycles is 3, 6 or 9 weeks; and Wherein compound I has the following structure:

57. A method for treating cancer in a patient in need thereof in one or more treatment cycles, the method comprising: (i) administering Compound 1 or a pharmaceutically acceptable salt thereof to the patient in week 1 of each of the one or more treatment cycles; as well as (ii) administering a PD-1 inhibitor to the patient in week 2 of each of the treatment cycles; wherein each of the one or more treatment cycles is 3 weeks; and Wherein compound I has the following structure:

58. A method for treating cancer in a patient in need thereof, the method comprising: (i) administering Compound 1 or a pharmaceutically acceptable salt thereof to the patient once a day for 1, 2, 3, 4 or 5 days every 3, 6 or 9 weeks; and (ii) administering a PD-1 inhibitor to the patient once every 3 or 6 weeks; Wherein compound I has the following structure:

59. A pharmaceutical composition comprising Compound I having the following structure: or a pharmaceutically acceptable salt thereof, for use in combination with a PD-1 inhibitor for treating cancer in a patient, wherein (i) administering Compound 1 or a pharmaceutically acceptable salt thereof to the patient for a first period of time in each of the one or more treatment cycles; and (ii) administering the PD-1 inhibitor to the patient after administering Compound 1 or a pharmaceutically acceptable salt thereof.

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