Combination therapy of PI3K inhibitor and PD-1 inhibitor

Abstract

Provided herein are methods of treating a proliferative disease or disorder (e.g., cancer) in a patient in need of such treatment using combination therapy of Compound (I) or a pharma- ceutical acceptable salt thereof and a PD-1 inhibitor (e.g., pembrolizumab).

Description

[Technical field]

[0001] cross reference This international patent application claims the benefit of U.S. Provisional Patent Application No. 63 / 315,380, filed March 1, 2022, which is incorporated by reference in its entirety. [Background technology]

[0002] Phosphoinositide-3-kinases (PI3Ks) play a variety of roles in normal tissue physiology (Foukas & Shepherd, Biochem. Soc. Trans. 2004, 32, 330; Shepherd, Acta Physiol. Scand. 2005, 183, 3), with p110α acting in cancer proliferation and p110β acting on integrin α Π β3-mediated thrombus formation (Jackson et al., Nat. Med. 2005, 11, 507), and p110γ plays a specific role in inflammation, rheumatoid arthritis, and other chronic inflammatory conditions (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

[0003] Provided herein is a method for treating cancer in a patient in need thereof, with one or more treatment cycles, comprising: (i) administering to the patient Compound I, or a pharma- ceutically acceptable salt thereof, for a first period of each of one or more treatment cycles; (ii) administering to the patient a PD-1 inhibitor following administration of Compound I or a pharma- ceutical acceptable salt thereof; Including, Compound I is:

[0004] [ka] A method is provided having the structure:

[0005] In some embodiments, each of the one or more treatment cycles is at least 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks long.

[0006] In some embodiments, each of the one or more treatment cycles is about 6 weeks.

[0007] In some embodiments, each of the one or more treatment cycles is about three weeks.

[0008] 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.

[0009] 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.

[0010] In some embodiments, each of the one or more treatment cycles is about three weeks, and the PD-1 inhibitor is administered about 8 days after the first period.

[0011] In some embodiments, the first period of time is 3 days, 4 days, 5 days, 6 days, or 1 week.

[0012] In some embodiments, the first period of time is five days.

[0013] In some embodiments, after the first period of time, the PD-1 inhibitor is administered beginning the day after the second period of time, which second period of time immediately follows the first period of time.

[0014] In some embodiments, the second period of time is about 0 days, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, or 20 days.

[0015] In some embodiments, the second period of time is about 16 days.

[0016] In some embodiments, the second period of time is about 8 days.

[0017] In some embodiments, Compound I or a pharma- ceutically acceptable salt thereof is administered daily during the first period of time.

[0018] In some embodiments, Compound I, or a pharma- ceutically acceptable salt thereof, is administered to the patient on an intermittent dosing schedule.

[0019] In some embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered only during a first period of each of the one or more treatment cycles and is not administered on a day after the first period, and the first period is shorter than each of the one or more treatment cycles.

[0020] In some embodiments, the first period of time is 3 days, 4 days, 5 days, 6 days, or 1 week.

[0021] In some embodiments, the first period of time is five days.

[0022] In some embodiments, Compound I or a pharma- ceutically acceptable salt thereof is administered at a dose of 60 mg / day.

[0023] In some embodiments, Compound I or a pharma- ceutically acceptable salt thereof is administered orally.

[0024] In some embodiments, the PD-1 inhibitor is administered once, twice, or three times in each of one or more treatment cycles.

[0025] In some embodiments, the PD-1 inhibitor is administered once in each of one or more treatment cycles.

[0026] 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.

[0027] 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.

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

[0029] In some embodiments, when each of the one or more treatment cycles is about 6 weeks, the PD-1 inhibitor is administered on days 14 and 35 of each of the one or more treatment cycles.

[0030] In some embodiments, the PD-1 inhibitor is pembrolizumab, nivolumab, cemiplimab, or dostallimab, or a variant or biosimilar thereof, or a combination thereof.

[0031] In some embodiments, the PD-1 inhibitor is pembrolizumab, or a variant or biosimilar thereof.

[0032] In some embodiments, the PD-1 inhibitor is administered for at least 6 weeks.

[0033] In some embodiments, the PD-1 inhibitor is administered for 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 27 weeks, or 30 weeks.

[0034] In some embodiments, the PD-1 inhibitor is administered once every three weeks or once every six weeks.

[0035] In some embodiments, the PD-1 inhibitor is administered at a dose of 200 mg or 400 mg.

[0036] In some embodiments, the PD-1 inhibitor is administered once every six weeks.

[0037] In some embodiments, the PD-1 inhibitor is administered at a dose of 400 mg.

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

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

[0040] In some embodiments, the PD-1 inhibitor is administered intravenously.

[0041] In some embodiments, the first period begins on day 1, 2, 3, 4, 5, 6, 7, or 8 of each of one or more treatment cycles.

[0042] In some embodiments, the first period begins on day 1 of each of one or more treatment cycles.

[0043] In some embodiments, each of the one or more treatment cycles is 6 weeks, with compound I or a pharma- ceutically acceptable salt thereof being administered on days 1-5, and then the PD-1 inhibitor being administered once on day 22.

[0044] In some embodiments, each of the one or more treatment cycles is three weeks, with compound I or a pharma- ceutically acceptable salt thereof being administered on days 1-5, and then the PD-1 inhibitor being administered once on day 14.

[0045] 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's lymphoma, Hodgkin's lymphoma, colorectal cancer, urothelial carcinoma, gastric cancer, cervical cancer, hepatocellular carcinoma, Merkel cell carcinoma, esophageal cancer, endometrial cancer, squamous cell carcinoma, or mesothelioma.

[0046] In some embodiments, the cancer is lung cancer.

[0047] In some embodiments, the lung cancer is non-small cell lung cancer.

[0048] In some embodiments, the cancer is melanoma.

[0049] In some embodiments, the cancer is renal cell carcinoma.

[0050] In some embodiments, the cancer is hepatocellular carcinoma.

[0051] In some embodiments, the cancer is colorectal cancer.

[0052] In some embodiments, the colorectal cancer is microsatellite instability high or mismatch repair deficient colorectal cancer.

[0053] In some embodiments, the methods provided herein further include (iii) assessing the effectiveness of administration of Compound I, or a pharma- ceutical acceptable salt thereof, in combination with a PD-1 inhibitor by measuring levels of regulatory T cells (CD25hi FoxP3+ T cells) or effector T cells (e.g., CD8+ and CD4+ cells).

[0054] In some embodiments, levels of regulatory T cells (CD25hi FoxP3+ T cells) or effector T cells (e.g., CD8+ and CD4+ cells) that are about 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or 10% or less of baseline levels of regulatory T cells (CD25hi FoxP3+ T cells) or effector T cells (e.g., CD8+ and CD4+ cells) indicate that one or more treatment cycles of administration of a combination of Compound I or a pharma- ceutical acceptable salt thereof and a PD-1 inhibitor are efficacious.

[0055] In some embodiments, levels of regulatory T cells (CD25hi FoxP3+ T cells) or effector T cells (e.g., CD8+ and CD4+ cells) that are about 65% or less of baseline levels of regulatory T cells (CD25hi FoxP3+ T cells) or effector T cells (e.g., CD8+ and CD4+ cells) indicate that one or more treatment cycles of administration of a combination of Compound I, or a pharma- ceutical acceptable salt thereof, and a PD-1 inhibitor are efficacious.

[0056] In some embodiments, co-administration of Compound I, or a pharma- ceutically acceptable salt thereof, with a PD-1 inhibitor is effective in treating cancer.

[0057] In another aspect, provided herein is a method for treating cancer in a patient in need thereof, comprising the steps of: (i) administering to the patient compound I, or a pharma- ceutically acceptable salt thereof, on days 1-5 of each of the one or more treatment cycles; and (ii) administering to the patient a PD-1 inhibitor on day 22 of each of the treatment cycles, wherein each of the one or more treatment cycles is 6 weeks long, and wherein compound I is one of the following:

[0058] [ka] A method is provided having the structure:

[0059] In another aspect, provided herein is a method for treating cancer in a patient in need thereof, comprising the steps of: (i) administering to the patient compound I, or a pharma- ceutically acceptable salt thereof, on days 1-5 of each of the one or more treatment cycles; and (ii) administering to the patient a PD-1 inhibitor on day 14 of each of the treatment cycles, wherein each of the one or more treatment cycles is three weeks long, and wherein compound I is one of the following:

[0060] [ka] A method is provided having the structure:

[0061] In yet another aspect, provided herein is a method for treating cancer in a patient in need thereof, comprising: (i) administering to the patient compound I, or a pharma- ceutically acceptable salt thereof, during week 1 of an odd-numbered cycle (e.g., cycle 1) of one or more treatment cycles; and (ii) administering to the patient a PD-1 inhibitor during week 1 of each even-numbered cycle (e.g., cycle 2), wherein each of the one or more treatment cycles is 3 weeks, 6 weeks, or 9 weeks long, and wherein compound I is one of the following:

[0062] [ka] A method is provided having the structure:

[0063] In yet another aspect, provided herein is a method for treating cancer in a patient in need thereof, comprising the steps of: (i) administering to the patient compound I, or a pharma- ceutically acceptable salt thereof, during week 1 of each of the one or more treatment cycles; and (ii) administering to the patient a PD-1 inhibitor during week 2 of each of the treatment cycles, wherein each of the one or more treatment cycles is three weeks long, and wherein compound I is one of the following:

[0064] [ka] A method is provided having the structure:

[0065] In yet another aspect, provided herein is a method for treating cancer in a patient in need thereof, comprising the steps of: (i) administering to the patient compound I, or a pharma- ceutically acceptable salt thereof, once daily for 1, 2, 3, 4, or 5 days every 3, 6, or 9 weeks; and (ii) administering to the patient a PD-1 inhibitor once every 3 or 6 weeks, wherein compound I is one of the following:

[0066] [ka] A method is provided having the structure:

[0067] Incorporation by Reference 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]

[0068] The novel features of the present disclosure are set forth with particularity in the appended claims. The features and advantages of the present disclosure will be better understood by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which: [Figure 1] Figure 2 illustrates the Kaplan-Meier survival curves from Example 2a, in which a study was conducted to evaluate the efficacy of combination treatment of Compound I with a PD-1 inhibitor (RMP1-14) in the MC38 mouse adenocarcinoma model.The efficacy of two treatment cycles of combination treatment is shown compared to a single cycle of combination treatment or a single cycle of PD-1 inhibitor. [Diagram 2]Figure 1 illustrates Kaplan-Meier survival curves from Example 2a, in which a study was conducted to evaluate the efficacy of combination treatment of Compound I with a PD-1 inhibitor (RMP1-14) in the MC38 mouse adenocarcinoma model. The efficacy of two treatment cycles of combination treatment compared to a single cycle of combination treatment or a single cycle of combination treatment combined with an additional cycle of Compound I is shown. [Diagram 3] Figure 2 illustrates the Kaplan-Meier survival curves from Example 2a, in which a study was conducted to evaluate the efficacy of combination treatment of Compound I with a PD-1 inhibitor (RMP1-14) in the MC38 mouse adenocarcinoma model.The efficacy of two treatment cycles of combination treatment is shown compared to a single cycle of combination treatment, or a single cycle of combination treatment combined with an additional cycle of a PD-1 inhibitor. [Figure 4] 1 shows the study design for a clinical trial of Compound I in combination with pembrolizumab to treat certain cancer patients. [Diagram 5] Illustrates Level 1 (top) and Level 2 (bottom) dosing schedules for the study design of Compound I in combination with pembrolizumab. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0069] Provided herein is a method of treating proliferative diseases and disorders (e.g., cancer) in a patient in need of such treatment, in one or more treatment cycles, comprising administering, in each treatment cycle: i) a PI3K inhibitor, which is compound I or a pharma- ceutical acceptable salt thereof, and a PD-1 inhibitor (e.g., pembrolizumab).

[0070] definition To facilitate understanding of the disclosure set forth herein, a number of terms are defined below.

[0071] In general, the nomenclature used herein and the laboratory methods in organic chemistry, medicinal chemistry, and pharmacology described herein are those well known and commonly used in the art. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The term "subject" refers to an animal, including, but not limited to, a primate (e.g., a human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein when referring to a mammalian subject, such as, for example, a human subject, in one embodiment, a human.

[0072] The terms "treat," "treating," and "treatment" are meant to include alleviating or arresting a disorder, disease, or condition, or one or more of the symptoms associated with a disorder, disease, or condition, or alleviating or eradicating the cause of the disorder, disease, or condition itself.

[0073] The terms "prevent", "preventing" and "prevention" are meant to include methods of delaying and / or preventing the onset of a disorder, disease or illness and / or its attendant symptoms, or of barring a subject from contracting a disorder, disease or illness, or of reducing the risk that a subject will contract a disorder, disease or illness.

[0074] The terms "therapeutically effective amount" and "effective amount" are meant to include an amount of a compound that, upon administration, is sufficient to prevent the progression of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated. The terms "therapeutically effective amount" or "effective amount" also refer to an amount of a compound sufficient to elicit the biological or medical response in a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human that is being sought by a researcher, veterinarian, physician, or clinician.

[0075] The terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," and "physiologically acceptable excipient" refer to a pharma- ceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other components of a pharmaceutical formulation and suitable for use in contact with the tissues or organs of humans and animals without undue toxicity, irritation, allergic response, immunogenicity, or other problems or complications, and commensurate with a reasonable benefit-risk ratio. See Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd Edition, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2009.

[0076] The terms "about" and "approximately" refer to an acceptable error for a particular value as determined by one of ordinary skill in the art, which error depends in part on how the value is measured or determined. In certain embodiments, the terms "about" and "approximately" refer to within 1, 2, 3, or 4 standard deviations. In certain embodiments, the terms "about" and "approximately" refer to 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.

[0077] 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 pharma- ceutically acceptable excipients, to treat, prevent, or ameliorate one or more symptoms of a disorder, disease, or condition. As used herein, "active ingredient" and "active substance" may be optically active isomers of the compounds described herein.

[0078] The terms "drug," "therapeutic agent," and "chemotherapeutic agent" refer to a compound or pharmaceutical composition thereof that is administered to a subject to treat, prevent, or ameliorate one or more symptoms of a disorder, disease, or condition.

[0079] The terms "naturally occurring" and "native," when used in connection with biological materials such as nucleic acid molecules, polypeptides, host cells, and the like, refer to materials that are found in nature and that have not been manipulated by man. Similarly, the terms "non-naturally occurring" or "non-native" refer to materials that are not found in nature or that have been structurally modified or synthesized by man.

[0080] The term "PI3K" refers to a phosphoinositide 3-kinase or a mutant thereof that can phosphorylate the inositol ring of PI at the D-3 position. The term "PI3K mutant" is intended to include a protein that is substantially homologous to a native PI3K, i.e., has one or more naturally occurring or non-naturally occurring amino acid deletions, insertions, or substitutions (e.g., PI3K derivatives, homologs, and fragments) compared to the amino acid sequence of a native PI3K. The amino acid sequence of a PI3K mutant is at least about 80% identical, at least about 90% identical, or at least about 95% identical to a native 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. PI3Ks are 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, the PI3K is a class I kinase. In certain embodiments, the PI3K is p110α, p110β, p110δ, or p110γ. In certain embodiments, the PI3K is a variant of class I kinase. In certain embodiments, the PI3K is a mutant of p110α.Examples of mutants of p110α 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, the 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.

[0081] 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). In humans, the PD-1 protein is encoded by the PDCD1 gene. PD-1 is a cell surface receptor that plays a key role in downregulating the immune system and promoting self-tolerance by suppressing T-cell inflammatory activity. PD-1 is expressed on the surface of activated T cells and protects against autoimmunity through a dual mechanism that promotes apoptosis (programmed cell death) in antigen-specific T cells in lymph nodes while simultaneously reducing apoptosis in regulatory T cells (anti-inflammatory suppressive T cells). PD-1 inhibitors are used to treat some types of cancer by activating the immune system to attack tumors.

[0082] 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 on activated T cells, B cells, and myeloid cells), to regulate the activation or inhibition of T cell responses. PD-L1, the ligand for PD-1, is highly expressed in multiple cancers. Inhibition of the interaction between PD-1 and PD-L1 can enhance T cell responses against cancer cells or tumors, and thus may be useful in the treatment of cancer.

[0083] As used herein, the terms "synergy," "synergism," and "synergistic" refer to a combination of therapies (e.g., the use of a PI3K inhibitor, Compound I, 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 a combination of therapies allows one or more of the therapies to be used at lower doses and / or to be administered to a subject less frequently. The availability of lower doses of a therapy and / or the ability to administer the therapy less frequently reduces the toxicity associated with administering the therapy to a subject without reducing its effectiveness 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. Furthermore, synergy can improve the effectiveness of the therapies 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, synergy of a combination of therapies may avoid or reduce adverse or undesirable side effects associated with the use of any single therapy. The "synergy," "synergistic," or "synergistic" effect of a combination may be determined by the methods of Chou et al., and / or Clark et al., herein.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 for methods of determining "synergy," "synergism," or "additive" effects of a combination.

[0084] Compound I PI3K Inhibitor One therapeutic agent administered in the combination therapy provided herein is a PI3K inhibitor. In some embodiments, the PI3K inhibitor is Compound I or a pharma- ceutically acceptable salt or hydrate thereof; Compound I is as follows:

[0085] [ka] It has the structure:

[0086] PD-1 inhibitors Another therapeutic agent administered in the combination therapy provided herein is a PD-1 inhibitor.

[0087] The PD-1 (programmed cell death-1) receptor (also called CD279) is expressed on the surface of activated T cells. PD-1's ligand, PD-L1, is usually expressed on the surface of dendritic cells or macrophages. In some cases, the interaction of PD1 with PD-L1 halts 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 the production of cytokines and inhibits the proliferation of the T cell. In some cases, cancer cells or tumor cells exploit this signaling pathway as a mechanism to avoid detection and inhibit the immune response. In some cases, PD-L1 is overexpressed on cancer or tumor cells or on non-transformed cells within the tumor microenvironment. In some cases, PD-L1 expressed on tumor cells binds to the PD-1 receptor on activated T cells, resulting in the inhibition of cytotoxic T cells. These inactivated T cells remain inhibited within the tumor microenvironment. The PD1 / PD-L1 pathway represents an adaptive immune resistance mechanism mounted by cancer or tumor cells in response to intrinsic antitumor activity.

[0088] PD-1 inhibitors (or anti-PD-1 agents) and PD-1 inhibitors (or anti-PD-L1 agents) block the interaction between PD-1 and PD-L1 and increase the immune response against cancer cells. In some cases, blocking receptor binding results in the amplification of antigen-specific T cell responses against cancer cells. In some cases, antibodies that block PD-1 / PD-L1 interactions target lymphocyte receptors or their ligands to enhance intrinsic anti-tumor activity. In some cases, PD-1 inhibitors and PD-L1 inhibitors attenuate separate immune suppressive pathways within the tumor microenvironment. In some cases, PD-1 inhibitors and / or PD-L1 inhibitors are useful for treating cancer.

[0089] Any suitable PD-1 inhibitor may 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, variant, or biosimilar thereof. In some embodiments, the PD-1 inhibitor is a monoclonal antibody. In some embodiments, the method of treating cancer with a PI3K inhibitor described herein in combination with a PD-1 inhibitor described herein results in a temporary reduction in the level of systemic immunosuppression.

[0090] Some embodiments provided herein describe a pharmaceutical composition or a method of using the pharmaceutical composition comprising a PI3K inhibitor described herein in combination with a PD-1 inhibitor. The PD-1 inhibitors used in the pharmaceutical compositions and methods provided herein include, but are not limited to, nivolumab (Opdivo®), pembrolizumab (Keytruda®), 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 (Opdivo®), pembrolizumab (Keytruda®), MEDI0680 (AMP-514), AMP-224, AMP-514 (Amplimmune), or variants or biosimilars thereof. In some embodiments, the PD-1 inhibitor is pidilizumab (CT-011), or a variant or biosimilar thereof. In some embodiments, the PD-1 inhibitor is nivolumab (OPDIVO®), pembrolizumab (KEYTRUDA®), 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.

[0091] In a preferred embodiment, the PD-1 inhibitor is pembrolizumab (KEYTRUDA®), a pembrolizumab variant, or a pembrolizumab biosimilar.

[0092] In another embodiment, the PD-1 inhibitor is nivolumab (OPDIVO®), a nivolumab variant, or a nivolumab biosimilar.

[0093] How to use Provided herein is a method for treating cancer in a patient in need thereof with one or more treatment cycles, the method comprising: (i) administering to the patient compound I, or a pharma- ceutically acceptable salt thereof, for a first period of each of the one or more treatment cycles; and (ii) administering to the patient a PD-1 inhibitor (e.g., pembrolizumab) following administration of compound I, or a pharma- ceutically acceptable salt thereof.

[0094] In some embodiments, compound I or a pharma- ceutically acceptable salt thereof and a PD-1 inhibitor (e.g., pembrolizumab) are administered sequentially during each of one or more treatment cycles. In some embodiments of sequential administration, compound I or a pharma- ceutically 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 on which compound I or a pharma- ceutically acceptable salt thereof is administered). Sequential administration of Compound I, or a pharma- ceutically acceptable salt thereof, and a PD-1 inhibitor (e.g., pembrolizumab) is more effective than simultaneous administration of Compound I, or a pharma- ceutically acceptable salt thereof, and a PD-1 inhibitor (e.g., pembrolizumab), e.g., when Compound I, or a pharma- ceutically acceptable salt thereof, is administered sequentially and the PD-1 inhibitor (e.g., pembrolizumab) is also administered on one or more days on which Compound I, or a pharma- ceutically acceptable salt thereof, is administered.

[0095] As used herein, the term "intermittent" or "intermittently" is intended to mean to stop and start at regular or irregular intervals.For example, the intermittent administration of compound is administration for 5 days every 3-week treatment cycle, administration in treatment cycle (e.g., daily administration for 5 days every 3-week treatment cycle, followed by a rest period of 12 days without administration).

[0096] In some embodiments, compound I or a pharma- ceutically acceptable salt thereof exhibits higher affinity and bioactivity for PI3K (e.g., PI3Kδ) compared to other PI3K inhibitors, including but not limited to, idelalisib. In some embodiments, compound I or a pharma-ceutically acceptable salt thereof exhibits improved or superior drug distribution to blood cells compared to other PI3K inhibitors, including but not limited to, idelalisib.

[0097] In some embodiments, the combination therapy of a PD-1 inhibitor (e.g., pembrolizumab) with Compound I or a pharma- ceutically acceptable salt thereof exhibits reduced toxicity to normal cells. In various embodiments, the combination of a PD-1 inhibitor (e.g., pembrolizumab) with Compound I or a pharma- ceutically acceptable salt thereof is selectively toxic or more toxic to rapidly proliferating cells, such as cancerous tumors, than to normal cells.

[0098] 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) infections, neutropenia, (serious) diarrhea, colon inflammation, colitis, lung tissue inflammation (pneumonia), intestinal perforation, pneumonia, anemia, thrombocytopenia, nausea, fever, fatigue, cough, abdominal pain, chills, rash, vomiting, hypertriglyceridemia, hyperglycemia, elevated levels of liver enzymes (e.g., ALT and ALST), hepatotoxicity, limb edema, or combinations thereof in patients receiving the combination therapy. In certain embodiments, the combination therapy described herein avoids, reduces, or minimizes the occurrence of infections, including serious infections. In certain embodiments, the combination therapy described herein avoids, reduces, or minimizes the occurrence of neutropenia. In certain embodiments, the combination therapy described herein avoids, reduces, or minimizes the occurrence of diarrhea, including severe diarrhea. In certain embodiments, the combination therapy described herein avoids, reduces, or minimizes the occurrence of colon inflammation. In certain embodiments, the combination therapy described herein avoids, reduces, or minimizes the occurrence of colitis. In certain embodiments, the combination therapy described herein avoids, reduces, or minimizes the occurrence of pulmonary tissue inflammation (pneumonia). In certain embodiments, the combination therapy described herein avoids, reduces, or minimizes the occurrence of intestinal perforation. In certain embodiments, the combination therapy described herein avoids, reduces, or minimizes the occurrence of pneumonia. In certain embodiments, the combination therapy described herein avoids, reduces, or minimizes the occurrence of anemia. In certain embodiments, the combination therapy described herein avoids, reduces, or minimizes the occurrence of thrombocytopenia. In certain embodiments, the combination therapy described herein avoids, reduces, or minimizes the occurrence of nausea. In certain embodiments, the combination therapies described herein avoid, reduce, or minimize the occurrence of fever.In certain embodiments, the combination therapy described herein avoids, reduces, or minimizes the occurrence of fatigue. In certain embodiments, the combination therapy described herein avoids, reduces, or minimizes the occurrence of coughing. In certain embodiments, the combination therapy described herein avoids, reduces, or minimizes the occurrence of abdominal pain. In certain embodiments, the combination therapy described herein avoids, reduces, or minimizes the occurrence of chills. In certain embodiments, the combination therapy described herein avoids, reduces, or minimizes the occurrence of rash. In certain embodiments, the combination therapy described herein avoids, reduces, or minimizes the occurrence of vomiting. In certain embodiments, the combination therapy described herein avoids, reduces, or minimizes the occurrence of hypertriglyceridemia.

[0099] In certain embodiments, the combination therapy described herein avoids, reduces, or minimizes the occurrence of hyperglycemia. In certain embodiments, the combination therapy described herein avoids, reduces, or minimizes the occurrence of elevated levels of liver enzymes (e.g., ALT and ALST). In certain embodiments, the combination therapy described herein avoids, reduces, or minimizes the occurrence of liver toxicity. In certain embodiments, the combination therapy described herein avoids, reduces, or minimizes the occurrence of limb edema.

[0100] In some embodiments, the combination therapy described herein avoids or reduces harmful or undesirable side effects associated with chemotherapy, radiation therapy, or cancer therapy. In some examples, the combination therapy and / or composition described herein provides chemoprotective and / or radioprotective properties against non-cancerous cells. In further or additional embodiments, the low dose / low dosage of PI3K inhibitor reduces or minimizes any undesirable side effects associated with chemotherapy. Non-limiting examples of side effects associated with chemotherapy, radiation therapy, or cancer therapy include fatigue, anemia, appetite changes, bleeding problems, diarrhea, constipation, hair loss, nausea, vomiting, pain, peripheral neuropathy, swelling, skin and nail changes, urinary and bladder changes, and difficulty swallowing.

[0101] Some embodiments provided herein describe a method for treating or preventing a proliferative disease or disorder (e.g., cancer), comprising administering a PI3K inhibitor in combination with a PD-1 inhibitor (e.g., pembrolizumab). In certain embodiments, provided herein is a method for treating or preventing a disease, comprising administering a therapeutically effective amount of compound I or a pharma- ceutically acceptable salt thereof and a therapeutically effective amount of a PD-1 inhibitor (e.g., pembrolizumab). In some embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered at a dose that is less than the therapeutically effective amount of compound I or a pharma- ceutically acceptable salt thereof administered alone. In some embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered at a dose that is less than the therapeutically effective amount of the PD-1 inhibitor (e.g., pembrolizumab) administered alone. In some embodiments, co-administration of compound I or a pharma- ceutically acceptable salt thereof and a PD-1 inhibitor (e.g., pembrolizumab) is effective for treating cancer. In some embodiments, the PD-1 inhibitor is pembrolizumab or nivolumab. In a preferred embodiment, the PD-1 inhibitor is pembrolizumab.

[0102] In some embodiments, the proliferative disease or disorder is cancer. In certain embodiments, the proliferative disease or disorder is blood cancer. In certain embodiments, the proliferative disease or disorder is solid tumor. In certain embodiments, the proliferative disease or disorder is cancer of the breast, skin, prostate, cervix, uterus, ovary, testis, bladder, lung, liver, pharynx, oral cavity, colon and gastrointestinal tract (e.g., esophagus, stomach, pancreas), brain, thyroid, blood, and lymphatic system.

[0103] In certain embodiments, cancers treatable by the methods provided herein include: (1) leukemias, including acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia, such as myeloblastic, promyelocytic, myelomonocytic, monocytic, and erythroleukemic leukemias, and myelodysplastic syndromes or symptoms thereof (anemia, thrombocytopenia, neutropenia, bicytopenia, or pancytopenia), refractory anemia (RA), ring sideroblastic RA (RARS), RA with excess blasts (RAEB), transformed RAEB (RAEBT), preleukemia, and chronic myelomonocytic leukemia (CMML); and (2) chronic myelocytic (granulocytic) leukemia. (3) chronic leukemias, including but not limited to chronic lymphocytic leukemia, and hairy cell leukemia; (4) lymphomas, including but not limited to Hodgkin's disease and non-Hodgkin's disease; (5) multiple myelomas, including but not limited to smoldering multiple myeloma, nonsecretory myeloma, osteosclerotic myeloma, plasma cell leukemia, solitary plasmacytoma, and extramedullary plasmacytoma; (6) Waldenstrom's macroglobulinemia; (7) monoclonal gammopathy of undetermined significance; (8) benign monoclonal gammopathy; (9) heavy chain disease; (10) bone marrow sarcoma; sarcoma), osteosarcoma, chondrosarcoma, Ewing's sarcoma, malignant giant cell tumor, osteofibrosarcoma, chordoma, periosteal sarcoma, soft tissue sarcoma, angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, metastatic carcinoma, schwannoma, rhabdomyosarcoma, and synovial sarcoma, (11) glioma, astrocytoma, brain stem glioma, ependymoma, oligodendroglioma, non-glial tumor, acoustic neuroma, head (12) brain tumors, including but not limited to cerebrospinal fluid (PC), cerebrospinal fluid (CF), cerebrospinal fluid (EGF), cerebrospinal fluid (EC ...(15) pancreatic cancer, including but not limited to insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin-secreting tumors, and carcinoid or islet cell tumors; (16) pituitary cancer, including but not limited to Cushing's disease, prolactin-secreting tumors, acromegaly, and diabetes insipidus; (17) eye cancer, including but not limited to iris melanoma and ciliary body melanoma, and ocular melanoma such as retinoblastoma; (18) vaginal cancer, including but not limited to squamous cell carcinoma, adenocarcinoma, and melanoma; (19) squamous cell carcinoma, melanoma, and adenocarcinoma. (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, mucinous epidermoid carcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oat cell (small cell) cell tumor. (24) gastric cancer, including adenocarcinoma, granulomatous (polypoid), ulcerative, superficial spreading, diffuse spreading, malignant lymphoma, liposarcoma, fibrosarcoma, and carcinosarcoma; (25) colon cancer; (26) rectal cancer; (27) liver cancer, including but not limited to hepatocellular carcinoma 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 carcinoma; (31) Testicular cancer, including but not limited to germinal tumors, seminoma, undifferentiated, classical (classical), spermatocytic, nonseminoma, embryonal carcinoma, teratocytoma, and choriocarcinoma (yolk sac tumor); (32) prostate cancer, including but not limited to adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma; (33) penile 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 carcinoma;(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) kidney cancer, including but not limited to renal cell carcinoma, adenocarcinoma, adenocarcinoma, fibrosarcoma, and transitional cell carcinoma (renal pelvis and / or renal ureter); (40) Wilms' tumor; (41) bladder cancer, including but not limited to transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, and carcinosarcoma; (42) reproductive cancers, such as cervical, uterine, ovarian, or testicular cancer, (43) esophageal cancer, (44) laryngeal cancer, (45) head and neck cancer (such as cancer of the mouth, nose, throat, larynx, sinuses, or salivary glands), as well as other cancers, including, but not limited to, myxosarcoma, osteogenic sarcoma, endothelial sarcoma, lymphangioendothelial sarcoma, mesothelioma, synovium, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, and papillary adenocarcinoma (see Fishman et al., 1985, Medicine, 2d Ed., J.B. 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., USA). 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.

[0104] In certain embodiments, provided herein is a method of treating a hematological malignancy in a patient with a combination of an effective amount of Compound I or a pharma- ceutically acceptable salt thereof and an effective amount of a PD-1 inhibitor. In certain embodiments, the hematological malignancy is leukemia, lymphoma, myeloma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, T-cell malignancy, or 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.

[0105] In certain embodiments, the hematological malignancy is a T-cell malignancy. In certain embodiments, the T-cell malignancy is 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), blastoid NK-cell lymphoma, enteropathic T-cell lymphoma, hepatosplenic gamma-delta T-cell lymphoma, lymphoblastic lymphoma, nasal NK / T-cell lymphoma, or treatment-related T-cell lymphoma.

[0106] In certain embodiments, the hematological malignancy is a B-cell malignancy. In certain embodiments, the B-cell malignancy is selected from the group consisting of acute lymphocytic 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), primary macroglobulinemia, and the like. In certain embodiments, the B cell malignancy includes diffuse large B cell lymphoma (DLBCL). In certain embodiments, the hematological malignancy includes diffuse large B cell lymphoma (DLBCL). In certain embodiments, the hematological malignancy includes diffuse large B cell lymphoma (DLBCL). In certain embodiments, the hematological malignancy includes diffuse large B cell lymphoma (DLBCL). In certain embodiments, the hematological malignancy includes 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).

[0107] 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.

[0108] In other embodiments, the disease or disorder is a solid tumor cancer. In some embodiments, the solid tumor cancer is selected from the group consisting of carcinoma, adenocarcinoma, adrenocortical carcinoma, colon adenocarcinoma, colorectal adenocarcinoma, ductal cell carcinoma, lung cancer, thyroid cancer, nasopharyngeal carcinoma, melanoma, non-melanoma skin cancer, and lung cancer.

[0109] 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's lymphoma, Hodgkin's 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, or mesothelioma.

[0110] In one embodiment, the cancer is melanoma. In another embodiment, the cancer is lung cancer. In one particular 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 particular embodiment, the colorectal cancer is microsatellite instability high 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 high tumor mutation burden cancer.

[0111] In some embodiments of the methods provided herein, the methods further comprise (iii) assessing the effectiveness of administration of the combination of Compound I, or a pharma- ceutically acceptable salt thereof, and a PD-1 inhibitor by measuring levels of regulatory T cells (CD25hi FoxP3+ T cells) or effector T cells (e.g., CD8+ and CD4+ cells). In some embodiments, an effective treatment (e.g., combination treatment) is indicated if regulatory T cells (CD25hi FoxP3+ T cells) or effector T cells (e.g., CD8+ and CD4+ cells) are suppressed below a particular threshold (e.g., by at least 35%) compared to baseline levels. In some embodiments, levels of regulatory T cells (CD25hi FoxP3+ T cells) or effector T cells (e.g., CD8+ and CD4+ cells) that are about 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or 10% or less of baseline levels of regulatory T cells (CD25hi FoxP3+ T cells) or effector T cells (e.g., CD8+ and CD4+ cells) indicate that one or more treatment cycles of administration of a combination of Compound I, or a pharma- ceutical acceptable salt thereof, and a PD-1 inhibitor are efficacious. In some embodiments, levels of regulatory T cells (CD25hi FoxP3+ T cells) or effector T cells (e.g., CD8+ and CD4+ cells) that are about 65% or less of baseline levels of regulatory T cells (CD25hi FoxP3+ T cells) or effector T cells (e.g., CD8+ and CD4+ cells) indicate that one or more treatment cycles of administration of a combination of Compound I, or a pharma- ceutical acceptable salt thereof, and a PD-1 inhibitor are efficacious.

[0112] Depending on the disorder, disease, or condition being treated and the condition of the patient, Compound I or a pharma- ceutically acceptable salt or a PD-1 inhibitor (e.g., pembrolizumab) can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or topical) routes of administration, and can be formulated, alone or together, in suitable dosage units using pharma- ceutically acceptable excipients, carriers, adjuvants, and vehicles appropriate for each route of administration as described elsewhere herein.

[0113] Dosage and Administration Regimen In certain embodiments, the methods provided herein comprise administering to a patient compound I, or a pharma- ceutically acceptable salt thereof, and a PD-1 inhibitor (e.g., pembrolizumab), either simultaneously or sequentially. In a preferred embodiment, compound I, or a pharma- ceutically acceptable salt thereof, and a PD-1 inhibitor (e.g., pembrolizumab) are administered sequentially.

[0114] The suitability of a particular administration route for a particular active agent varies depending on the active agent itself (e.g., whether it can be orally administered without being decomposed before entering the bloodstream) and the disease to be treated.The recommended administration route for the second active agent is known to those skilled in the art.See, for example, Physicians'Desk Reference, 1755-1760 (56th ed.2002).

[0115] In certain embodiments, compound I or a pharma- ceutically acceptable salt thereof and a PD-1 inhibitor (e.g., pembrolizumab) are administered simultaneously, essentially simultaneously, or sequentially. When administration is sequential, the PD-1 inhibitor may be administered before or after administration of compound I or a pharma- ceutically acceptable salt thereof. In some preferred embodiments, the PD-1 inhibitor is administered after administration of compound I or a pharma- ceutically acceptable salt thereof. In some embodiments, the PD-1 inhibitor is administered simultaneously with compound I or a pharma- ceutically acceptable salt thereof. In some embodiments, the PD-1 inhibitor is administered before administration of compound I or a pharma- ceutically acceptable salt thereof.

[0116] In certain embodiments, compound I or a pharma- ceutically acceptable salt thereof and a PD-1 inhibitor (e.g., pembrolizumab) do not need to be administered by the same vehicle. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof and a PD-1 inhibitor (e.g., pembrolizumab) are administered in different vehicles. The PD-1 inhibitor (e.g., pembrolizumab) may be administered once or multiple times, and the number of administrations of each component of the combination may be the same or different. Furthermore, compound I or a pharma- ceutically acceptable salt thereof and a PD-1 inhibitor (e.g., pembrolizumab) do not need to be administered at the same site.

[0117] In another aspect, provided herein is a method for treating cancer in a patient in need thereof, comprising the steps of: (i) administering to the patient compound I, or a pharma- ceutically acceptable salt thereof, on days 1-5 of each of the one or more treatment cycles; and (ii) administering to the patient a PD-1 inhibitor on day 22 of each of the treatment cycles, wherein each of the one or more treatment cycles is 6 weeks long, and wherein compound I is one of the following:

[0118] [ka] A method is provided having the structure:

[0119] In another aspect, provided herein is a method for treating cancer in a patient in need thereof, comprising the steps of: (i) administering to the patient compound I, or a pharma- ceutically acceptable salt thereof, on days 1-5 of each of the one or more treatment cycles; and (ii) administering to the patient a PD-1 inhibitor on day 14 of each of the treatment cycles, wherein each of the one or more treatment cycles is three weeks long, and wherein compound I is one of the following:

[0120] [ka] A method is provided having the structure:

[0121] Treatment Cycle In some preferred embodiments, the method further comprises administering to a patient in need of administration compound I or a pharma- ceutically acceptable salt thereof and a PD-1 inhibitor (e.g., pembrolizumab) in one or more treatment cycles repeated on a regular schedule, optionally with a rest period between two treatment cycles. For example, in some cases, after the combination treatment provided herein is administered for 3 weeks, there is no rest period before the next treatment cycle. In some cases, after the combination treatment provided herein is administered for 6 weeks, there is no rest period before the next treatment cycle. In other embodiments, after the combination treatment provided herein is administered for 3 weeks, there is a rest period of 1 week before the next treatment cycle. In other embodiments, after the combination treatment provided herein is administered for 6 weeks, there is a rest period of 3 weeks before the next treatment cycle.

[0122] In some examples, the cycle includes administering Compound I or a pharma- ceutically acceptable salt thereof simultaneously with administration of a PD-1 inhibitor (e.g., pembrolizumab). In some examples, the treatment cycle includes administering Compound I or a pharma- ceutically acceptable salt thereof on a day that is different from the day that the PD-1 inhibitor (e.g., pembrolizumab) is administered. In some examples, compound I or a pharma- ceutically acceptable salt thereof and a PD-1 inhibitor (e.g., pembrolizumab) are administered about 1 day apart, about 2 days apart, about 3 days apart, about 4 days apart, about 5 days apart, about 6 days apart, about 7 days apart, about 8 days apart, about 9 days apart, about 10 days apart, about 11 days apart, about 12 days apart, about 13 days apart, about 14 days apart, about 15 days apart, about 16 days apart, about 17 days apart, about 18 days apart, about 19 days apart, about 20 days apart, about 21 days apart, about 22 days apart, about 23 days apart, about 24 days apart, about 25 days apart, about 26 days apart, about 27 days apart, or about 28 days apart.

[0123] In some examples, the treatment cycle includes administering compound I or a pharma- ceutically acceptable salt thereof for a first period, followed by a second period. In some embodiments, the administration of the PD-1 inhibitor occurs the day after the second period. In some examples, the first period 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 is 3 days, 4 days, 5 days, 6 days, or 1 week. In a preferred embodiment, the first period is 5 days.

[0124] In some embodiments, the first period begins on day 1, 2, 3, 4, 5, 6, 7, or 8 of each of one or more treatment cycles.

[0125] In some embodiments, the second 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 period is 16 days.In another embodiment, the second period is about 3 weeks.

[0126] In some embodiments, the PD-1 inhibitor is administered beginning the day after the second period of time, which is immediately following the first period of time.

[0127] 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. In a preferred embodiment, the PD-1 inhibitor is administered about 8 days after the first period of time. In another embodiment, the PD-1 inhibitor is administered about 16 days after the first period of time.

[0128] 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 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 24 weeks, 27 weeks, 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.

[0129] In some embodiments, the PD-1 inhibitor is administered intravenously (eg, by injection).

[0130] In some embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered in combination with pembrolizumab at a dose of about 400 mg for 5 days once each 6-week treatment cycle at about 60 mg / day. In some particular embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered in combination with pembrolizumab at a dose of about 400 mg on days 1-5 on day 22 of each 6-week treatment cycle at about 60 mg / day. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof and pembrolizumab are administered for 1-10 treatment cycles. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof and pembrolizumab are administered for 1 treatment cycle. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof and pembrolizumab are administered for 2 treatment cycles. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof and pembrolizumab are administered for 3 treatment cycles. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof and pembrolizumab are administered for 4 treatment cycles. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof and pembrolizumab are administered for 5 treatment cycles. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof and pembrolizumab are administered for 6 treatment cycles. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof and pembrolizumab are administered for 7 treatment cycles. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof and pembrolizumab are administered for 8 treatment cycles. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof and pembrolizumab are administered for 9 treatment cycles. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof and pembrolizumab are administered for 10 treatment cycles. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof and pembrolizumab are administered for more than 10 treatment cycles.

[0131] In some embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered in combination with pembrolizumab at a dose of about 200 mg for 5 days once each 3-week treatment cycle at about 60 mg / day. In some particular embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered in combination with pembrolizumab at a dose of about 200 mg on day 14 of each 3-week treatment cycle at about 60 mg / day on days 1-5. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof and pembrolizumab are administered for 1-10 treatment cycles. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof and pembrolizumab are administered for 1 treatment cycle. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof and pembrolizumab are administered for 2 treatment cycles. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof and pembrolizumab are administered for 3 treatment cycles. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof and pembrolizumab are administered for 4 treatment cycles. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof and pembrolizumab are administered for 5 treatment cycles. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof and pembrolizumab are administered for 6 treatment cycles. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof and pembrolizumab are administered for 7 treatment cycles. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof and pembrolizumab are administered for 8 treatment cycles. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof and pembrolizumab are administered for 9 treatment cycles. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof and pembrolizumab are administered for 10 treatment cycles. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof and pembrolizumab are administered for more than 10 treatment cycles.

[0132] In some embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered for 10 days at about 60 mg / day, twice during each 6-week treatment cycle, in combination with pembrolizumab at a dose of about 200 mg. In some particular embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered for 10 days 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 I or a pharma- ceutically acceptable salt thereof and pembrolizumab are administered for 1-10 treatment cycles. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof and pembrolizumab are administered for 1 treatment cycle. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof and pembrolizumab are administered for 2 treatment cycles. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof and pembrolizumab are administered for 3 treatment cycles. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof and pembrolizumab are administered for 4 treatment cycles. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof and pembrolizumab are administered for 5 treatment cycles. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof and pembrolizumab are administered for 6 treatment cycles. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof and pembrolizumab are administered for 7 treatment cycles. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof and pembrolizumab are administered for 8 treatment cycles. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof and pembrolizumab are administered for 9 treatment cycles. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof and pembrolizumab are administered for more than 10 treatment cycles. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof and pembrolizumab are administered for more than 10 treatment cycles.

[0133] In some examples, the cycle comprises only administration of compound I or its pharmaceutically acceptable salt. In some examples, compound I or its pharmaceutically acceptable salt 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 its pharmaceutically acceptable salt is administered for about 5 days. In another preferred embodiment, compound I or its pharmaceutically acceptable salt is administered for about 5 consecutive days.

[0134] In some embodiments, each of the one or more treatment cycles is 6 weeks, with compound I or a pharma- ceutically acceptable salt thereof being administered on days 1-5, and then the PD-1 inhibitor being administered once on day 22.

[0135] In some embodiments, each of the one or more treatment cycles is three weeks, with compound I or a pharma- ceutically acceptable salt thereof being administered on days 1-5, and then the PD-1 inhibitor being administered once on day 14.

[0136] In some cases, a treatment cycle includes administration of only a PD-1 inhibitor. In some cases, the PD-1 inhibitor is administered once, twice, three times, or four times during a treatment cycle. In a preferred embodiment, the PD-1 inhibitor is administered once during a treatment cycle.

[0137] In some examples, the method for multiple treatment cycles includes administering the second treatment cycle within about 60 days or about 3 months. In some examples, the method for multiple treatment cycles includes administering the second cycle within 50 days of the previous treatment cycle. In another example, 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 the additional treatment cycle is performed within 10 days of the previous treatment cycle. In some embodiments, the administration of the additional treatment cycle is performed within 9 days of the previous treatment cycle. In some embodiments, the administration of the additional treatment cycle is performed within 3 weeks of the previous treatment cycle. In some embodiments, the administration of the additional treatment cycle is performed within 7 days of the previous treatment cycle. In some embodiments, the administration of the additional treatment cycle is performed within 6 days of the previous treatment cycle. In some embodiments, administration of the additional treatment cycle occurs within 5 days of the previous treatment cycle. In some embodiments, administration of the additional treatment cycle occurs within 4 days of the previous treatment cycle. In some embodiments, administration of the additional treatment cycle occurs within 3 days of the previous treatment cycle. In some embodiments, administration of the additional treatment cycle occurs within 2 days of the previous treatment cycle. In some embodiments, administration of the additional treatment cycle occurs within 1 day of the previous treatment cycle.

[0138] The length of the treatment cycle varies depending on the treatment being performed. In some embodiments, the length of the treatment cycle ranges from 2 weeks to 6 weeks. In some embodiments, the length of the treatment cycle ranges from 4 weeks to 6 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 1 week, 2 weeks, 3 weeks, or 4 weeks. In some embodiments, the treatment cycle lasts 4 weeks. Additionally, the number of treatment doses scheduled in each cycle varies depending on the agent being administered.

[0139] In some examples, the multiple treatment cycle compound method includes administering Compound I, or a pharma- ceutically acceptable salt thereof, and a PD-1 inhibitor in alternating treatment cycles. In some embodiments, Compound I, or a pharma- ceutically 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.

[0140] In some examples, the method for administering multiple compounds is performed in a sequential order, and compound I or a pharma- ceutically acceptable salt thereof is administered before the PD-1 inhibitor (e.g., pembrolizumab). In another example, the PD-1 inhibitor (e.g., pembrolizumab) is administered before compound I or a pharma- ceutically acceptable salt thereof.

[0141] In some examples, the method for administering compound I 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 examples, the method for administering compound I 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 examples, the method for administering compound I or a pharmaceutically acceptable salt thereof is by injection, and the method for administering a PD-1 inhibitor (e.g., pembrolizumab) is by injection.

[0142] In some embodiments, compound I or its pharmaceutically acceptable salt is administered daily, 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, every other 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 I or its pharmaceutically acceptable salt is administered daily.

[0143] In some embodiments, the PD-1 inhibitor is administered daily, every other day, every 3 days, every 4 days, every 5 days, every 6 days, weekly, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every other week, 3 times a week, 4 times a week, 5 times a week, 6 times a week, monthly, 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).

[0144] In some embodiments, Compound I or a pharma- ceutically acceptable salt thereof, or a PD-1 inhibitor is optionally administered continuously, or alternatively, the dosage of the administered therapeutic agent (Compound I or a pharma- ceutically acceptable salt thereof, or a PD-1 inhibitor) is temporarily reduced or temporarily suspended for a period 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 drug holidays can be, by way of example only, 10% to 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%.

[0145] In certain embodiments, dosage levels of Compound I or a pharma- ceutically acceptable salt thereof in treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition described herein generally range from about 1 to about 1000 mg, about 1 to about 500 mg, about 5 to about 500 mg, about 5 to about 200 mg, about 5 to about 250 mg, or about 10 to about 150 mg, and may be administered in single or multiple doses. In certain embodiments, Compound I or a pharma- ceutically acceptable salt thereof may be administered in single or multiple doses, such as 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 ... It is administered in amounts of 5mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 450 or 500mg. In certain embodiments, Compound I or a pharma- ceutically acceptable salt thereof is administered at a dose of 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 mg / day, or about 130 mg / day. g / day, about 130 mg / day, about 135 mg / day, about 140 mg / day, about 145 mg / day, about 150 mg / day, about 155 mg / day, about 160 mg / day, about 165 mg / day, about 170 mg / day, about 175 mg / day, about 180 mg / day, about 185 mg / day, about 190 mg / day, about 195 mg / day, about 200 mg / day, about 225 mg / day, about 250 mg / day, about 275 mg / day, about 300 mg / day, about 325 mg / day, about 350 mg / day, about 375 mg / day, about 400 mg / day, about 450 mg / day, or about 500 mg / day.In certain embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered in an amount of about 30 mg / day. In certain embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered in an amount of about 45 mg / day. In certain embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered in an amount of about 60 mg / day. In certain embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered in an amount of about 90 mg / day. In certain embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered in an amount of about 120 mg / day. In certain embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered in a dose of about 150 mg / day. In certain embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered in an amount of about 180 mg / day. In some preferred embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered in an amount of about 60 mg / day.

[0146] For oral administration, the pharmaceutical compositions provided herein may contain about 1.0 to about 1,000 mg of Compound I or a pharma- ceutically acceptable salt thereof, and in one embodiment, may be formulated in the form of a tablet or capsule containing 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 a pharma- ceutically acceptable salt thereof for symptomatic adjustment of dosage to the patient being treated. In some preferred embodiments, the pharmaceutical compositions provided herein may be formulated in the form of a tablet containing about 60 mg of Compound I or a pharma- ceutically acceptable salt thereof. The pharmaceutical composition comprising Compound I or a pharma- ceutically acceptable salt thereof is administered in a regimen of once to four times per day, including once, twice, three times, or four times per day. In some preferred embodiments, Compound I or a pharma- ceutically acceptable salt thereof is administered once per day. In some embodiments, about 30 mg, about 45 mg, or about 60 mg of Compound I or a pharma- ceutically acceptable salt thereof is administered once per day. In some embodiments, Compound I or a pharma- ceutically acceptable salt thereof is administered to a patient in need of administration of Compound I or a pharma- ceutically acceptable salt thereof in an amount of about 60 mg daily for 1, 2, 3, 4, 5, 6, or 7 consecutive days. In some embodiments, Compound I or a pharma- ceutically acceptable salt thereof is administered to a patient in need of administration of Compound I or a pharma- ceutically acceptable salt thereof in an amount of about 60 mg daily for 5 consecutive days. In some embodiments, Compound I or a pharma- ceutically acceptable salt thereof is administered to a patient in need of administration of Compound I or a pharma- ceutically acceptable salt thereof in an amount of about 60 mg daily for two consecutive days in a treatment cycle. In some embodiments, Compound I or a pharma- ceutically acceptable salt thereof is administered to a patient in need of administration of Compound I or a pharma- ceutically acceptable salt thereof in an amount of about 60 mg daily for three consecutive days in a treatment cycle.In some embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered to a patient in need of administration of compound I or a pharma- ceutically acceptable salt thereof in an amount of about 60 mg daily for 4 consecutive days in a treatment cycle. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered to a patient in need of administration of compound I or a pharma- ceutically acceptable salt thereof in an amount of about 60 mg daily for 6 consecutive days in a treatment cycle. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered to a patient in need of administration of compound I or a pharma- ceutically acceptable salt thereof in an amount of about 60 mg daily for 7 consecutive days in a treatment cycle.

[0147] In some embodiments, the compound I or a pharma- ceutically acceptable salt thereof is administered in the first week of a treatment cycle. In some embodiments, the compound I or a pharma- ceutically acceptable salt thereof is administered in the second week of a treatment cycle. In some embodiments, the compound I or a pharma- ceutically acceptable salt thereof is administered in the third week of a treatment cycle. In some embodiments, the compound I or a pharma- ceutically acceptable salt thereof is administered in the fourth week of a treatment cycle. In some embodiments, the compound I or a pharma- ceutically acceptable salt thereof is administered in the fifth week of a treatment cycle. In some embodiments, the compound I or a pharma- ceutically acceptable salt thereof is administered in the sixth week of a treatment cycle. In some embodiments, the compound I or a pharma- ceutically acceptable salt thereof is administered in the seventh week of a treatment cycle. In some embodiments, the compound I or a pharma- ceutically acceptable salt thereof is administered in the eighth week of a treatment cycle. In some embodiments, the compound I or a pharma- ceutically acceptable salt thereof is administered in the ninth week of a treatment cycle. In some embodiments, the treatment cycle is 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, or 9 weeks.

[0148] In some embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered in week 1 of a three-week treatment cycle. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered in week 2 of a three-week treatment cycle. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered in week 3 of a three-week treatment cycle.

[0149] In some embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered in week 1 of a 6-week treatment cycle. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered in week 2 of a 6-week treatment cycle. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered in week 3 of a 6-week treatment cycle. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered in week 4 of a 6-week treatment cycle. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered in week 5 of a 6-week treatment cycle. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered in week 6 of a 6-week treatment cycle.

[0150] In some embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered in week 1 of a 9-week treatment cycle. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered in week 2 of a 9-week treatment cycle. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered in week 3 of a 9-week treatment cycle. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered in week 3 of a 9-week treatment cycle. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered in week 4 of a 9-week treatment cycle. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered in week 5 of a 9-week treatment cycle. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered in week 6 of a 9-week treatment cycle. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered in week 7 of a 9-week treatment cycle. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered in week 8 of a 9-week treatment cycle. In some embodiments, Compound I or a pharma- ceutically acceptable salt thereof is administered during week 9 of a 9-week treatment cycle.

[0151] In some embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered on 1, 2, 3, 4, 5, 6, or 7 consecutive days during the week in which compound I or a pharma- ceutically acceptable salt thereof is administered. In one embodiment, compound I or a pharma- ceutically acceptable salt thereof is administered on days 1-2 during the week in which compound I or a pharma- ceutically acceptable salt thereof is administered. In another embodiment, compound I or a pharma- ceutically acceptable salt thereof is administered on days 1-3 during the week in which compound I or a pharma- ceutically acceptable salt thereof is administered. In yet another embodiment, compound I or a pharma- ceutically acceptable salt thereof is administered on days 1-4 during the week in which compound I or a pharma- ceutically acceptable salt thereof is administered. In yet another embodiment, compound I or a pharma- ceutically acceptable salt thereof is administered on days 1-5 during the week in which compound I or a pharma- ceutically acceptable salt thereof is administered. In yet another embodiment, compound I or a pharma- ceutically acceptable salt thereof is administered on days 1-6 during the week in which compound I or a pharma- ceutically acceptable salt thereof is administered. In yet another embodiment, Compound I, or a pharma- ceutically acceptable salt thereof, is administered on days 1 to 7 of the week that Compound I, or a pharma- ceutically acceptable salt thereof, is administered.

[0152] In the methods of treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition described herein, suitable dosage levels of a PD-1 inhibitor (e.g., pembrolizumab) generally range from about 0.1 to 2000 mg per day, in some embodiments, 1 to 500 mg, one or more times per day, is effective to achieve the desired results.

[0153] In certain embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered once daily, twice daily, or three times daily. In certain embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered once daily. In certain embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is co-administered (e.g., in a single dosage form) once daily.

[0154] 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 2 weeks, 3 weeks, 4 weeks, or 5 weeks. In certain embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered by intravenous injection or direct injection. In a preferred embodiment, the PD-1 inhibitor is administered every 3 weeks.

[0155] In some embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered in week 1 of a treatment cycle. In some embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered in week 2 of a treatment cycle. In some embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered in week 3 of a treatment cycle. In some embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered in week 4 of a treatment cycle. In some embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered in week 5 of a treatment cycle. In some embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered in week 6 of a treatment cycle. In some embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered in week 7 of a treatment cycle. In some embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered in week 8 of a treatment cycle. In some embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered on 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.

[0156] In some embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered in week 1 of a three-week treatment cycle. In some embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered in week 2 of a three-week treatment cycle. In some embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered in week 3 of a three-week treatment cycle.

[0157] 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.

[0158] 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 (e.g., pembrolizumab) is administered in week 9 of a 9-week treatment cycle.

[0159] In some embodiments, the PD-1 inhibitor (e.g., pembrolizumab) is administered on day 1, 2, 3, 4, 5, 6, or 7 of the week that 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 that the PD-1 inhibitor (e.g., pembrolizumab) is administered.

[0160] In certain embodiments, the PD-1 inhibitor is pembrolizumab, and the amount of pembrolizumab administered is about 10 mg / day to 1000 mg / day (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 daily is about 200 mg or about 400 mg. In some embodiments, pembrolizumab is administered once every three weeks (Q3W) at a dose of 200 mg. In some embodiments, pembrolizumab is administered once every six weeks (Q6W) at a dose of 400 mg.

[0161] In certain embodiments, the methods described herein further comprise administering pembrolizumab intravenously at a dose of 1-10 mg / kg every 3 weeks. In certain embodiments, pembrolizumab is administered intravenously at a dose of 2 mg / kg every 3 weeks. In certain embodiments, 2 mg / kg pembrolizumab is administered as an intravenous infusion over 30 minutes at 200 mg every 3 weeks or 400 mg every 6 weeks.

[0162] In some embodiments, compound I or a pharma- ceutically acceptable salt thereof and a PD-1 inhibitor (e.g., pembrolizumab) are not administered at the same time, but instead the two compounds are administered at different times. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof and a PD-1 inhibitor (e.g., pembrolizumab) are administered at least once during a treatment cycle. As used herein, a treatment cycle refers to a period during which each therapeutic agent is administered at least once. A treatment cycle can be about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, or 30 days. In some embodiments, the treatment cycle is 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks. In certain embodiments, the treatment cycle is at least 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks.

[0163] However, it will be understood that the specific dose level and frequency of administration for any particular patient may vary and will depend on a variety of factors, including the activity of the particular compound used, the metabolic stability and duration of action of that compound, age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular disease, and the host being treated. Dosages can be determined by standard clinical techniques. The precise dose to be employed in the formulation will also vary depending on the route of administration, the disease or severity of the disease, and in some embodiments should be determined according to the judgment of the practitioner and each patient's circumstances.

[0164] The dosage administered to the subject in the context of the present disclosure should be sufficient to affect therapeutic effect.Those skilled in the art will recognize that dosage varies according to various factors, including the efficacy of specific compound, age, disease, and weight of patient, and stage / severity of disease.Dosage is also determined by route of administration (dosage form), timing of administration, and frequency of administration.

[0165] Additional combination therapy Also, in certain embodiments, the methods of combination therapy comprising compound I, or a pharma- ceutically acceptable salt thereof, and a PD-1 inhibitor (e.g., pembrolizumab) can be used or administered in combination with a third agent or therapy useful for the treatment, prevention, or amelioration of one or more symptoms of a proliferative disorder, disease, or condition.

[0166] Suitable third therapeutic agents include: (1) alpha adrenergic agonists; (2) antiarrhythmics; (3) antiatherosclerotic agents, such as ACAT inhibitors; (4) antibiotics, such as anthracyclines, bleomycin, mitomycin, dactinomycin, and plicamycin; (5) anticancer and cytotoxic agents, e.g., alkylating agents, such as nitrogen mustards, alkyl sulfonates, nitrosoureas, ethylenimines, and triazenes; (6) acenocoumarol, argatroban, and bivalirudin. (7) anticoagulants such as lepirudin, fondaparinux, heparin, phenindione, warfarin, and ximelagatran; (8) biguanides (e.g., metformin), glucosidase inhibitors (e.g., acarbose), insulin, meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride, glyburide, and glipizide), thiazolidinediones (e.g., troglitazone, rosiglitazone, and pioglitazone), PPAR-gamma agonists (PPAR-gamma agonists), and cyclosporine inhibitors (CTAs). monists), (8) antifungal drugs such as amorolfine, amphotericin B, anidulafungin, bifonazole, butenafine, butoconazole, caspofungin, ciclopirox, clotrimazole, econazole, fenticonazole, filipin, fluconazole, isoconazole, itraconazole, ketoconazole, micafungin, miconazole, naftifine, natamycin, nystatin, oxiconazole, ravuconazole, posaconazole, rimocidin, sertaconazole, sulconazole, terbinafine, tioconazole, voriconazole, (9) anti-inflammatory drugs, e.g. acetonitrile, ... Clofenac, acemetacin, amoxiprine, aspirin, azapropazone, benorylate, bromfenac, carprofen, celecoxib, choline magnesium salicylate, diclofenac, diflunisal, etodolac, etoricoxib, phythramine, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, lumiracoxib, meclofenamic acid, mefenamic acid, meloxicam, metamizole, methyl salicylate, magnesium salicylate, nabumetone, naproxen, nimesulide, oxyphenbutazone,(10) antimetabolites such as folate antagonists, purine analogs, and pyridine analogs; (11) antiplatelet agents such as GPIIb / IIIa 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) aP2 inhibitors; (15) beta-adrenergic agonists such as carvedilol and metoprolol; (16) bile acid sequestrants such as questran; (17) calcium channel blockers such as amlodipine besylate; (18) chemotherapeutic agents; (19) cyclooxygenase-2 (COX-2) inhibitors such as celecoxib and rofecoxib; (20) ) cyclosporine, (21) cytotoxic drugs such as azathioprine and cyclophosphamide, (22) diuretics such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzothiazide, ethacrynic acid, ticrynafen, chlorthalidone, furosenide, muzolimine, bumetanide, triamterene, amiloride, and spironolactone, (23) endothelin-converting enzyme (ECE) inhibitors such as phosphoramidone. inhibitors, (24) enzymes such as L-asparaginase, (25) factor VIIa inhibitors and factor Xa inhibitors, (26) farnesyl-protein transferase inhibitors, (27) fibrates, (28) growth factor inhibitors such as modulators of PDGF activity, (29) growth hormone secretagogues, (30) pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (also known as itavastatin, nisvastatin, or nisbastatin), ZD-4522 (rosuvastatin,(31) hormonal agents such as glucocorticoids (e.g., cortisone), estrogens / antiestrogens, androgens / antiandrogens, progestins, luteinizing hormone-releasing hormone antagonists, and octreotide acetate; (32) immunosuppressants; (33) mineralocorticoid receptor antagonists such as spironolactone and eplerenone; (34) microtubule disruptors such as ecteinascidins; (35) microtubule stabilizers such as pacitaxel, docetaxel, and epothilone AF; (36) MTP inhibitors; (37) niacin; (38) PDE III inhibitors (e.g., cilostazol) and PDE (39) phosphodiesterase inhibitors such as V inhibitors (e.g., sildenafil, tadalafil, vardenafil), (40) plant-derived products such as vinca alkaloids, epipodophyllotoxins, and taxanes, (41) platelet-activating factor (PAF) antagonists, (42) platinum coordination compounds such as cisplatin, satraplatin, and carboplatin, (43) potassium channel openers, (44) prenyl-protein transferase inhibitors, (45) protein tyrosine kinase inhibitors, (46) renin inhibitors, (47) squalene synthetase inhibitors, (48) aldosterone, beclomethasone, betamethasone, deoxycorticosterone acetate, fludrocortisone, hydrocortisone (cortisol), prednisolone, prednisolone, (48) steroids such as nisone, methylprednisolone, dexamethasone, and triamcinolone; (49) TNF-alpha inhibitors such as tenidap; (50) thrombin inhibitors such as hirudin; (51) thrombolytic agents such as anistreplase, reteplase, tenecteplase, tissue plasminogen activator (tPA), recombinant tPA, streptokinase, urokinase, pro-urokinase, and anisoylated plasminogen streptokinase activator complex (APSAC); (52) thromboxane receptor antagonists such as ifetroban; (53) topoisomerase inhibitors; (54) vasopeptidase inhibitors (dual NEP-ACE inhibitors) such as omapatrilat and gemopatriat; (55) hydroxyurea.and various other agents such as, but not limited to, procarbazine, mitotein, hexamethylmelamine, and gold compounds.

[0167] In certain embodiments, third treatments that may 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, tumor necrosis factor (TNF)), hyperthermia, cryotherapy, and agents to reduce any side effects (e.g., antiemetics).

[0168] In certain embodiments, third therapeutic agents that may be used in combination with the compounds provided herein include alkylating agents (mechlorethamine, chlorambucil, cyclophosphamide, melphalan, and ifosfamide), antimetabolites (cytarabine (also known as cytosine arabinoside or Ara-C) and methotrexate), purine antagonists, pyrimidine antagonists (6-mercaptopurine, 5-fluorouracil, cytarabine, and gemcitabine), spindle inhibitors (vinblastine, These include, but are not limited to, cyclophosphamide, vincristine, and vinorelbine, podophyllotoxins (etoposide, irinotecan, and topotecan), antibiotics (daunorubicin, doxorubicin, bleomycin, and mitomycin), nitrosoureas (carmustine and lomustine), enzymes (asparaginase), hormones (tamoxifen, leuprolide, flutamide, and megestrol), imatinib, adriamycin, dexamethasone, and cyclophosphamide. For a more comprehensive discussion of current cancer treatments, see the list of FDA-approved oncology drugs at http: / / www.nci.nih.gov / , http: / / www.fda.gov / cder / cancer / dniglistframe.htm, and The Merck Manual, Seventeenth Ed. 1999, the entire contents of which are incorporated herein by reference.

[0169] In another embodiment, the method provided herein includes administering compound I or a pharma- ceutically acceptable salt thereof and a PD-1 inhibitor (e.g., pembrolizumab) in combination with one or more chemotherapeutic agents and / or treatments selected from alkylating agents (e.g., cisplatin, carboplatin), antimetabolites (e.g., methotrexate and 5-FU), antitumor antibiotics (e.g., adriamycin and bleomycin), antitumor plant alkaloids (e.g., taxol and etoposide), antitumor hormones (e.g., dexamethasone and tamoxifen), antitumor immune agents (e.g., interferon alpha, beta, and gamma), radiation therapy, and surgery. In certain embodiments, the one or more chemotherapeutic agents and / or treatments are administered to the subject before, during, or after administration of compound I or a pharma- ceutically acceptable salt thereof and a PD-1 inhibitor (e.g., pembrolizumab).

[0170] Such other agents or drugs can be administered simultaneously with Compound I or its pharma- ceutically acceptable salt and PD-1 inhibitor (e.g., pembrolizumab) or sequentially, by commonly used routes and amounts. When Compound I or its pharma- ceutically acceptable salt and PD-1 inhibitor (e.g., pembrolizumab) are used simultaneously with one or more other agents, a pharmaceutical composition containing such other agents in addition to Compound I or its pharma- ceutically acceptable salt and PD-1 inhibitor (e.g., pembrolizumab) can be utilized, but is not required. Thus, the pharmaceutical compositions provided herein include pharmaceutical compositions that also contain one or more other active ingredients or therapeutic agents in addition to Compound I or its pharma- ceutically acceptable salt.

[0171] Pharmaceutical Compositions and Routes of Administration Provided herein is a pharmaceutical composition comprising compound I or a pharma- ceutically acceptable salt thereof, a PD-1 inhibitor (e.g., pembrolizumab), and a pharma- ceutically acceptable excipient, adjuvant, carrier, buffer, or stabilizer. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof and the PD-1 inhibitor (e.g., pembrolizumab) are present in the same pharmaceutical composition. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof and the PD-1 inhibitor (e.g., pembrolizumab) are present in different pharmaceutical compositions.

[0172] In some embodiments, the first pharmaceutical composition comprises Compound I or a pharma- ceutically acceptable salt thereof and a first pharma- ceutically acceptable excipient or carrier. In some embodiments, the second pharmaceutical composition comprises a PD-1 inhibitor (e.g., pembrolizumab) and a second pharma- ceutically acceptable excipient or carrier.

[0173] In one embodiment, the pharmaceutical composition is provided in a dosage form for oral administration, which comprises a compound provided herein and one or more pharma- ceutically acceptable excipients or carriers. The pharmaceutical composition provided herein formulated for oral administration may be in tablet, capsule, powder, or liquid form. In some embodiments, the tablet comprises a solid carrier or adjuvant. Liquid pharmaceutical compositions typically comprise a liquid carrier, such as water, petroleum, animal or vegetable oils, mineral oil, or synthetic oil. Saline solution, dextrose, or other saccharide solution, or glycols, such as ethylene glycol, propylene glycol, or polyethylene glycol, may also be included. In some embodiments, the capsule comprises a solid carrier, such as gelatin.

[0174] In another embodiment, the pharmaceutical composition is provided in a dosage form for parenteral administration, which comprises the compound provided herein and one or more pharma- ceutically acceptable excipients or carriers.When the pharmaceutical composition can be formulated for intravenous, cutaneous or subcutaneous injection, the active ingredient is in the form of a parenterally acceptable aqueous solution that is pyrogen-free and has suitable pH, isotonicity and stability.Those skilled in the art can fully prepare suitable solutions using isotonic vehicles such as, for example, sodium chloride injection, Ringer's injection or lactated Ringer's injection.In some embodiments, preservatives, stabilizers, buffers, antioxidants and / or other additives are included as necessary.

[0175] In another embodiment, the pharmaceutical composition is provided in a dosage form for topical administration, which comprises a compound provided herein and one or more pharma- ceutically acceptable excipients or carriers.

[0176] Pharmaceutical compositions can also be formulated as modified release dosage forms, including delayed release, extended release, sustained release, extended release, pulsed release, controlled release, accelerated release, immediate release, targeted release and programmed release, 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., Eds., Marcel Dekker, Inc.: New York, NY, 2008).

[0177] The pharmaceutical compositions provided herein can be provided in unit dosage form or multiple dosage form. As used herein, unit dosage form refers to a unit suitable for administration to human and animal subjects that is physically separated and packaged separately as known in the art. Each unit dose contains a predetermined amount of active ingredient sufficient to produce the desired therapeutic effect, together with the required pharmaceutical carrier or excipient. Examples of unit dosage forms include ampoules, syringes, and individually packaged tablets and capsules. A unit dosage form may be administered in fractions or multiples thereof. A multiple dosage form is a plurality of identical unit dosage forms packaged in a single container that are administered in separate unit dosage form. Examples of multiple dosage forms include vials, bottles of tablets or capsules, or bottles of pints or gallons.

[0178] The pharmaceutical composition provided herein can be administered once or multiple times at intervals.It should be understood that the exact dosage and duration of treatment may vary according to the age, weight and health condition of the patient undergoing treatment, and can be determined empirically using known testing protocols or by inference from in vivo or in vitro test data or diagnostic data.It should also be understood that for any particular individual, a particular dosage regimen must be adjusted over time according to the individual's needs and the professional judgment of the person administering or supervising the administration of the formulation.

[0179] In certain embodiments, the pharmaceutical compositions provided herein further comprise one or more chemotherapeutic agents as defined herein.

[0180] A. Oral Administration The pharmaceutical compositions for oral administration provided herein can be provided in solid, semi-solid, or liquid dosage forms for oral administration. As used herein, oral administration also includes buccal, lingual, and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, fast melts, chewable tablets, capsules, pills, strips, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, mixed powders, effervescent or non-effervescent powders or granules, oral mists, solutions, emulsions, suspensions, wafers, sprinkles, elixirs, and syrups. In addition to the active ingredient, pharmaceutical compositions can contain one or more pharma- ceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, colorants, dye-migration inhibitors, sweeteners, flavoring agents, emulsifiers, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and a source of carbon dioxide.

[0181] Binders or granulating agents impart cohesiveness to the tablet and ensure that the tablet remains intact after compression. Suitable binders or granulating agents include starches such as corn starch, potato starch, pregelatinized starch (e.g., STARCH 1500), gelatin, sugars such as sucrose, glucose, dextrose, molasses, and lactose, acacia, alginic acid, alginates, Irish moss extract, Panwar gum, ghatti gum, mucilage of isabgol husk, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum®, larch arabinogalactan (larch arabinogalactan), glyceryl stearate, ... Suitable fillers include, but are not limited to, natural and synthetic gums such as arabogalactan, powdered tragacanth, and guar gum, celluloses such as ethyl cellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), microcrystalline celluloses 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 from about 50 to about 99% by weight in the pharmaceutical compositions provided herein.

[0182] Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.Some diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, when present in sufficient amounts, can impart properties to some compressed tablets that allow them to disintegrate in the mouth by chewing.Such compressed tablets can be used as chewable tablets.The amount of diluent in the pharmaceutical compositions provided herein varies according to the type of formulation, and can be easily discerned by those skilled in the art.

[0183] Suitable disintegrants include, but are not limited to, agar, bentonite, celluloses such as methylcellulose and carboxymethylcellulose, wood products, natural sponges, cation exchange resins; gums such as alginic acid, guar gum and Veegum HV, citrus pulp, cross-linked celluloses such as croscarmellose, cross-linked polymers such as crospovidone, cross-linked starch, calcium carbonate, microcrystalline celluloses such as sodium starch glycolate, polacrilin potassium, starches such as corn starch, potato starch, tapioca starch, and pregelatinized starch, clays; 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 by 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 by one of ordinary skill in the art. The pharmaceutical compositions provided herein may contain about 0.5 to about 15% by weight, or about 1 to about 5% by weight of disintegrant.

[0184] Suitable lubricants include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycols such as glycerin, sorbitol, mannitol, glycerol 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, soybean oil, zinc stearate, ethyl oleate, ethyl laureate, agar, starch, lycopodium, silica or silica gel such as AEROSIL® 200 (WR Grace Co., Baltimore, MD) and CAB-O-SIL® (Cabot Co., Boston, MA), and mixtures thereof. The pharmaceutical compositions provided herein may contain about 0.1 to about 5% by weight of a lubricant.

[0185] Suitable glidants include, but are not limited to, colloidal silicon dioxide, CAB-O-SIL® (Cabot Co., Boston, Massachusetts), and asbestos-free talc. Suitable coloring agents include, but are not limited to, any of the approved and certified water-soluble FD&C dyes, water-insoluble FD&C dyes suspended on alumina hydrate, dye lakes, and mixtures thereof. Dye lakes are the combination by adsorption of a water-soluble dye to a hydrous oxide of a heavy metal, resulting in an insoluble form of the dye. Suitable flavoring agents include, but are not limited to, natural flavoring agents extracted from plants such as fruits, and synthetic blends of compounds that provide a pleasant taste, such as peppermint and methyl salicylate. Suitable sweetening agents include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerin, and artificial sweetening agents such as saccharin and aspartame. Suitable emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan 80 monooleate (TWEEN® 80), and triethanolamine oleate. Suitable suspending and dispersing agents include: Examples of suitable emulsions include, but are not limited to, sodium carboxymethylcellulose, pectin, gum tragacanth, Veegum®, acacia, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable preservatives include, but are not limited to, glycerin, methyl and propylparaben, benzoic add, sodium benzoate, and alcohol. Suitable humectants include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, polyoxyethylene lauryl ether. Suitable solvents include, but are not limited to, glycerin, sorbitol, ethyl alcohol, and syrup. Suitable non-aqueous liquids utilized 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 carbon dioxide sources include, but are not limited to, sodium bicarbonate and sodium carbonate.

[0186] It will be understood that many carriers and excipients may serve different functions within the same formulation.

[0187] The pharmaceutical compositions for oral administration provided herein can be provided as compressed tablets, powder tablets, chewable lozenges, fast dissolving tablets, multiple compressed tablets, or enteric coated, sugar-coated, or coated tablets. Enteric coated tablets are compressed tablets coated with a substance that resists the action of stomach acid but dissolves or disintegrates in the intestine, thus protecting the active ingredients from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylates, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which can be beneficial in masking unpleasant tastes or odors and protecting the tablets from oxidation. 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 phthalates. Film coatings impart the same general properties 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.

[0188] Tablet dosage forms can be prepared from the active ingredient in powdered, crystalline, or granular form, either alone or in combination with one or more carriers or excipients, including binders, disintegrants, controlled release polymers, lubricants, diluents, and / or colorants. Flavoring and sweetening agents are particularly useful in the formation of chewable tablets and lozenges.

[0189] The pharmaceutical compositions provided herein for oral administration can be provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate. Hard gelatin capsules, also known as dry-filled capsules (DFC), consist of two pieces, one sliding over the other, completely enclosing the active ingredient. Elastic soft capsules (SEC) are soft, spherical shells, such as gelatin shells, plasticized by the addition of glycerin, sorbitol, or similar polyols. Soft gelatin shells may contain preservatives to prevent microbial growth. Suitable preservatives are those described herein, including methyl and propyl parabens, and sorbic acid. The liquid, semi-solid, and solid dosage forms provided herein may be encapsulated in capsules. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such a solution can be prepared as described in U.S. Patent Nos. 4,328,245, 4,409,239, and 4,410,545. The capsules may be coated by methods known to those skilled in the art to moderate or maintain dissolution of the active ingredient.

[0190] 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 the form of small globules throughout another liquid, which may be oil-in-water or water-in-oil. Emulsions may contain a pharma-ceutically acceptable non-aqueous liquid or solvent, an emulsifier, and a preservative. Suspensions may contain a pharma-ceutically acceptable suspending agent and a preservative. Aqueous alcoholic solutions may contain a pharma-ceutically acceptable acetal, such as a di(lower alkyl)acetal of a lower alkyl aldehyde (e.g., acetaldehyde diethyl acetal), and a water-miscible solvent with one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweet-tasting hydroalcoholic solutions. Syrups are concentrated aqueous solutions of a sugar (e.g., sucrose), and may also contain a preservative. For a liquid dosage form, for example, the solution in a polyethylene glycol may be diluted with a sufficient quantity of a pharma- ceutically acceptable liquid carrier, e.g., water, to be measured conveniently for administration.

[0191] Other useful liquid and semisolid dosage forms include, but are not limited to, the active ingredients provided herein and dialkylated mono- or polyalkylene glycols, including 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, where 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol. These formulations may further include one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfites, sodium pyrosulfite, thiodipropionic acid and its esters, and dithiocarbamates.

[0192] The pharmaceutical compositions for oral administration provided herein can also be provided in the form of liposomes, micelles, microspheres, or nanosystems. Micelle dosage forms can be prepared as described in U.S. Patent No. 6,350,458.

[0193] The pharmaceutical compositions provided herein for oral administration can be provided as non-effervescent or effervescent granules and powders that are reconstituted into liquid dosage forms.The pharma-ceutically acceptable carriers and excipients used in non-effervescent granules or powders may include diluents, sweeteners, and wetting agents.The pharma-ceutically acceptable carriers and excipients used in effervescent granules or powders may include organic acids and carbon dioxide sources.

[0194] Coloring and flavoring agents may be used in all of the above dosage forms.

[0195] The pharmaceutical compositions provided herein for oral administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release dosage forms.

[0196] B. Parenteral Administration 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.

[0197] The pharmaceutical compositions provided herein for parenteral administration can be formulated into any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid dosage forms suitable for liquid solution or suspension prior to injection.Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmacy (see Remington: The Science and Practice of Pharmacy, supra).

[0198] Pharmaceutical compositions intended for parenteral administration may contain one or more pharma- ceutically 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, solubility enhancers, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, viscosity enhancing agents, pH adjusting agents, and inert gases.

[0199] Suitable aqueous vehicles include, but are not limited to, water, saline, saline or phosphate buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, dextrose and lactate Ringer's injection.Non-aqueous vehicles include, but are not limited to, fixed oils of vegetable 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 medium-chain triglycerides of coconut oil, and palm seed oil.Water-miscible vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl 1-2-pyrrolidone, N,N-dimethylacetamide, and dimethyl sulfoxide.

[0200] Suitable antimicrobial or preservative agents include, but are not limited to, phenol, cresol, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl and propyl parabens, and sorbic acid. Suitable isotonicity agents include, but are not limited to, sodium chloride, glycerin, and dextrose. Suitable buffering agents include, but are not limited to, phosphates and citrates. Suitable antioxidants are those described herein, including bisulfites and sodium metabisulfite. Suitable local anesthetic agents include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are those described herein, including sodium carboxymethylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agents are those described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to, EDTA. Suitable pH adjusting agents 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, sulfobutylether-β-cyclodextrin, and sulfobutylether 7-β-cyclodextrin (CAPTISOL® CyDex, Lenexa, Kansas).

[0201] When the pharmaceutical compositions provided herein are formulated for multiple dose administration, the multiple dose parenteral formulations must contain antibacterial agents in bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile, as is known and practiced in the art.

[0202] 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 powders and hypodermic tablets, which are reconstituted with a vehicle before use. In yet another embodiment, the pharmaceutical composition is provided as a ready-to-use sterile suspension. In yet another embodiment, the pharmaceutical composition is provided as a sterile dry insoluble product, which is reconstituted with a vehicle before use. In yet another embodiment, the pharmaceutical composition is provided as a ready-to-use sterile emulsion.

[0203] The pharmaceutical compositions provided herein for parenteral administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release dosage forms.

[0204] The pharmaceutical compositions provided herein for parenteral administration can be formulated as a suspension, solid, semi-solid, or thixotropic liquid for administration as an implanted depot. In one embodiment, the pharmaceutical compositions provided herein are dispersed in a solid internal matrix surrounded by an external polymeric membrane that is insoluble in body fluids but allows the active ingredient in the pharmaceutical composition to diffuse.

[0205] 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 and methacrylic acid, collagen, crosslinked polyvinyl alcohol, and crosslinked partially hydrolyzed polyvinyl acetate.

[0206] Suitable outer polymeric membranes include, but are not limited to, polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomeric polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, and ethylene / vinyloxyethanol copolymers.

[0207] C. Topical Administration The pharmaceutical compositions provided herein can be administered topically to the skin, orifices, or mucous membranes. As used herein, topical administration includes (intradermal) dermal, conjunctival, intracorneal, intraocular, ocular, otic, transdermal, nasal, vaginal, urethral, ​​respiratory, and rectal administration.

[0208] The pharmaceutical compositions provided herein can be formulated into any dosage form suitable for topical administration for local or systemic effect, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dustings, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, irrigations, sprays, suppositories, bandages, and skin patches. Topical formulations of the pharmaceutical compositions provided herein can also include liposomes, micelles, microspheres, nanosystems, and mixtures thereof.

[0209] 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 against microbial growth, stabilizers, solubility enhancers, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, and inert gases.

[0210] Pharmaceutical compositions may also be administered locally by electroporation, iontophoresis, phonophoresis, sonophoresis, and microneedle or needle-free injection, such as POWDERJECT™ (Chiron Corp., Emeryville, Calif.), and BIOJECT™ (Bioject Medical Technologies Inc., Tualatin, Oregon).

[0211] The pharmaceutical composition provided herein can be provided in the form of ointment, cream, and gel.Suitable ointment vehicles include lard, benzoin lard, olive oil, cottonseed oil, and other oils, oily or hydrocarbon vehicles including white petrolatum, emulsifiable or absorbent vehicles such as hydrophilic petrolatum, hydroxystearin sulfate, and anhydrous lanolin, water-removable vehicles such as hydrophilic ointments, water-soluble ointment vehicles including polyethylene glycols of varying molecular weight, emulsion vehicles, either 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 emollients, but usually require the addition of antioxidants and preservatives.

[0212] Suitable cream bases can be oil-in-water or water-in-oil. Suitable cream vehicles can be water-washable and include an oil phase, an emulsifier, and an aqueous phase. The oil phase, also referred to as the "internal" phase, is generally composed of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol. The aqueous phase is usually, but not necessarily, larger in volume than the oil phase and generally contains a humectant. In some embodiments, the emulsifier in the cream formulation is a nonionic, anionic, cationic, or amphoteric surfactant.

[0213] Gels are semi-solid, suspension-type systems. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the liquid carrier. Suitable gelling agents include, but are not limited to, cross-linked acrylic polymers such as carbomer, carboxypolyalkylene, and CARBOPOL®, hydrophilic polymers such as polyethylene oxide, polyoxyethylene-polyoxypropylene copolymers, and polyvinyl alcohol, cellulose polymers such as hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, and methylcellulose, gums such as tragacanth and xanthan gum, sodium alginate, and gelatin. To prepare a homogeneous gel, dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by grinding, mechanical mixing, and / or stirring.

[0214] The pharmaceutical compositions provided herein may be administered rectally, urethrally, vaginally, or perivaginally in the form of a suppository, pessary, bougie, poultice or cataplasm, paste, powder, dressing, cream, salve, contraceptive, ointment, solution, emulsion, suspension, tampon, gel, foam, spray, or enema. These dosage forms may be manufactured using conventional processes as described in Remington: The Science and Practice of Pharmacy, supra.

[0215] Rectal, urethral and vaginal suppositories are solid bodies for insertion into the orifices of the body, solid at ordinary temperatures but melt or soften at body temperature to release the active ingredient(s) inside the orifice. Pharmaceutically acceptable carriers utilized in rectal and vaginal suppositories include bases or vehicles such as stiffening agents that produce a melting point near body temperature when formulated with the pharmaceutical compositions provided herein, and antioxidants as described herein, including bisulfites and sodium metabisulfite. Suitable vehicles include, but are not limited to, cocoa butter (oil of the cacao), glycerin-gelatin, carbowax (polyoxyethylene glycol), spermaceti, paraffin, white and yellow wax, and suitable mixtures of mono-, di- and triglycerides of fatty acids, hydrogels such as polyvinyl alcohol, hydroxyethyl methacrylate, polyacrylic acid, etc. Combinations of various vehicles may be used. Rectal and vaginal suppositories may be prepared by compression or molding. The typical weight of a rectal and vaginal suppository is about 2 to about 3 g.

[0216] The pharmaceutical compositions provided herein may be administered ophthalmically in the form of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solution, gels, ocular inserts and implants.

[0217] The pharmaceutical compositions provided herein can be administered intranasally or by inhalation into the respiratory tract.The pharmaceutical compositions can be provided in the form of aerosol or solution for delivery using a pressurized container, pump, spray, atomizer such as an atomizer that uses electrohydrodynamics to generate a fine mist, or nebulizer, alone or in combination with a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane.The pharmaceutical compositions can also be provided as dry powders for insufflation, alone or in combination with an inert carrier such as lactose or phospholipids, and as nasal drops.For intranasal use, the powders can include bioadhesive agents, including chitosan or cyclodextrin.

[0218] Solutions or suspensions for use in pressurized containers, pumps, sprays, atomizers, or nebulizers can be formulated to contain ethanol, aqueous ethanol, or a suitable substitute, a propellant as a solvent, and / or a surfactant, such as sorbitan trioleate, oleic acid, or oligolactic acid, to disperse, solubilize, or extend the release of the active ingredients provided herein.

[0219] The pharmaceutical compositions provided herein can be micronized to a size suitable for delivery by inhalation, such as about 50 μm or less, or about 10 μm or less. Such size particles can be prepared using comminution 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.

[0220] Capsules, blisters, and cartridges for use in inhalers or insufflators can be formulated to contain a powder mix of the pharmaceutical composition provided herein, a suitable powder base such as lactose or starch, and a performance modifier such as l-leucine, mannitol, or magnesium stearate. Lactose may be in anhydrous or monohydrate form. 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 may further contain a suitable flavoring agent, such as menthol and levomenthol, and / or a sweetening agent, such as saccharin and saccharin sodium.

[0221] Pharmaceutical compositions provided herein for topical administration can be formulated to be immediate or modified release, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release.

[0222] D. Modified release The pharmaceutical compositions provided herein can be formulated as modified release dosage forms. As used herein, the term "modified release" refers to a dosage form in which the release rate or location of the active ingredient(s) is different from that of an immediate dosage form when administered by the same route. Modified release dosage forms include, but are not limited to, delayed release, extended release, sustained release, extended release, pulsed release, controlled release, accelerated release, immediate release, targeted release, and programmed release, and gastric retention dosage forms. Modified release dosage forms of pharmaceutical compositions can be prepared using various 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, multiparticulate controlled release devices, ion exchange resins, enteric coatings, multilayer coatings, microspheres, liposomes, and combinations thereof. The release rate of the active ingredient(s) can also be modified by changing the particle size and polymorphism of the active ingredient(s).

[0223] Examples of modified release compositions are 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, 5,891,474, 5,922,3 56, 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.

[0224] 1. Matrix Controlled Release Devices The controlled release dosage forms of the pharmaceutical compositions provided herein can be prepared 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).

[0225] In certain embodiments, the pharmaceutical compositions provided herein in modified release dosage form are formulated using erodible matrix devices that are water-swellable, erodible, or soluble polymers, including, but not limited to, synthetic polymers and naturally occurring polymers and derivatives, such as polysaccharides and proteins.

[0226] Materials useful in forming an erodible matrix include chitin, chitosan, dextran, and pullulan, agar gum, gum arabic, karaya gum, locust bean gum, tragacanth gum, carrageenan, ghatti gum, guar gum, xanthan gum, and scleroglucan, starches such as dextrin and maltodextrin, hydrocolloids such as pectin, phosphatides such as lecithin, alginates, propylene glycol alginate, gelatin, collagen; and ethyl cellulose (EC), methyl ethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hyaluronan, cellulose acetate, cellulose esters ... Cellulose derivatives such as 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), polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol fatty acid esters, polyacrylamide, polyacrylic acid, copolymers of ethacrylic acid or methacrylic acid (EUDRAGIT®, Rohm Examples of suitable acrylic acid derivatives include, but are not limited to, 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.

[0227] In certain embodiments, the pharmaceutical composition is formulated with a non-erodible matrix device: the active ingredient(s) are dissolved or dispersed in the inert matrix and, once administered, are released primarily by diffusion through the inert matrix. Suitable materials for use as the non-erodible matrix device include 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, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomeric polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, ethylene / vinyloxyethanol copolymers, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubber, polydimethylsiloxane, and silicone carbonate copolymers; hydrophilic polymers such as ethyl cellulose, cellulose acetate, crospovidone, and partially hydrolyzed crosslinked polyvinyl acetate; and carnauba wax (camauba Examples of suitable fatty compounds include, but are not limited to, fatty acids such as wax, microcrystalline wax, and triglycerides.

[0228] In a matrix controlled release system, the desired release kinetics can be controlled, for example, via the type of polymer used, the polymer viscosity, the particle size of the polymer and / or the active ingredient(s), the ratio of active ingredient(s) to polymer, as well as other excipients or carriers in the composition.

[0229] The pharmaceutical compositions provided herein in modified release dosage form can be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, melt granulation followed by compression.

[0230] product The compounds provided herein can also be provided as products 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 that is suitable for the formulation selected and the intended mode of administration and treatment.

[0231] Also provided herein is a kit that, when used by a physician, can simplify the administration of an appropriate amount of active ingredient to a subject. In certain embodiments, the kit provided herein includes one or more containers and dosage forms of Compound I or a pharma- ceutically acceptable salt thereof and a PD-1 inhibitor (e.g., pembrolizumab).

[0232] In certain embodiments, the kit provided herein comprises one or more containers and dosage forms of compound I or its pharma- ceutically acceptable salt and PD-1 inhibitor (e.g., pembrolizumab).The kit provided herein may further comprise a device used to administer the active ingredient.Examples of such devices include, but are not limited to, syringes, needleless syringes, drip bags, patches, and inhalers.

[0233] The kits provided herein may further comprise a pharma- ceutically acceptable vehicle that can be used to dispense 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 comprise a sealed container of a suitable vehicle in which the active ingredient can dissolve to form a particulate-free sterile solution suitable for parenteral administration.Examples of pharma-ceutically acceptable vehicles include, but are not limited to, aqueous vehicles including, but not limited to, Water for Injection USP, Sodium Chloride Injection, Ringer's Solution, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles including, but not limited to, ethyl alcohol, 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. EXAMPLES

[0234] As used herein, the symbols and conventions used in these processes, schemes, and examples are consistent with those used in modern scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry, regardless of whether a specific abbreviation is specifically specified.Specifically, but not limited to, the following abbreviations may be used in the examples and throughout this specification: g (gram), mg (milligram), mL (milliliter), μL (microliter), M (mole), mM (millimol), μM (micromol), eq. (equivalent), mmol (millimol), Hz (Hertz), MHz (Megahertz), hr or hrs (hours), min (minutes), and MS (mass spectrometry).

[0235] For all of the following examples, standard work-up and purification methods known to those skilled in the art can be utilized. Unless otherwise indicated, all temperatures are in degrees Celsius. Unless otherwise noted, all reactions were carried out at room temperature. The synthetic methods illustrated herein are intended to illustrate the available chemical reactions through the use of specific examples and are not indicative of the scope of the present disclosure.

[0236] 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-triazin-2-amine, compound I The synthesis of Compound I is described in US Pat. No. 9,056,852 B2, which is incorporated herein by reference for the present disclosure.

[0237] 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) were stirred at room temperature for 1 h. The crude product was purified by preparative HPLC to give compound I (11 mg, 13% yield) as a white solid: purity 99% (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.

[0238] Example 2: MC38 Mouse Colon Cancer Model for Combination of PI3K and PD-1 Inhibitors The combination of a PI3K inhibitor (Compound I) and a PD-1 inhibitor (RMP1-14) was evaluated utilizing the MC38 mouse colon cancer syngenic model in female immunocompetent C57BL / 6 mice. The study was designed to plot the survival time of mouse subjects when treated with the combination of Compound I and a PD-1 inhibitor.

[0239] Compound I dosing solutions were prepared weekly. Compound I formulations were prepared by adding the 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 obtain a 5 mg / mL dosing solution. This solution provided a dose of 50 mg / kg in a dosing volume of 10 mL / kg. Compound I dosing solutions were stored at 4° C. when not in use.

[0240] PD-1 inhibitor (anti-PD-1 antibody clone RMP1-14, lot number 5792-599016J1) was purchased from CR Discovery Services from Bio X Cell and stored at 4° C. upon receipt. Anti-PD-1 antibody dosing solution was prepared by diluting an aliquot of stock (6.37 mg / mL) to 0.5 mg / mL in sterile PBS to obtain a dose of 100 μg / mouse in a fixed dose volume of 0.2 mL per mouse.

[0241] Tumors were measured twice weekly. Treatment response was assessed from tumor growth delay (TGD), increase in median time to endpoint (TTE) in treated versus control mice, and comparison of survival curves using logrank analysis. Each animal was cultured until tumors reached 1000 mm 3 Tumor progression was marked upon reaching a volume endpoint of 0.01 mg / kg / day, and animals that did not reach said endpoint were euthanized at the end of the study and assigned a TTE value equal to the last day of the study (day 45).

[0242] The median TTE in control arm 1 was 19.0 days, establishing a maximum TGD of 137% for the study. All treatments evaluated in the study were acceptably tolerated, with acceptable mean BW loss and no treatment-related (TR) deaths.

[0243] Tumor growth delay (TGD) analysis Animals were monitored individually for tumor growth until day 45. The study protocol defined a tumor growth delay assay based on the median time to endpoint (TTE) in the treatment versus control groups. Each animal was cultured until tumors reached 1000 mm 3 Tumor progression (TP) was marked when the tumor reached a volumetric endpoint of 0.01 mg / kg / day. The TTE for each mouse was calculated using the following equation:

[0244]

number

[0245] On day 45, MTV(n) was defined as the median tumor volume of the n number of animals that survived to the last day and whose tumors did not reach the volumetric endpoint. Any animal determined to have died due to TR was assigned a TTE value equal to the day of death. Any animal that died due to NTR was excluded from the analysis. Treatment outcomes were assessed from the TGD, which was compared to the control group to show the increase in median TTE for the treatment group: TGD=TC Defined as, expressed in days, or as a percentage of median TTE in the control group:

[0246]

number

[0247] Survival analysis was performed by the Kaplan-Meinr method. The logrank (Mantel-Cox) and Gehan-Breslow-Wilcoxon tests measured the significance of the difference between the overall survival experience (survival curves) of the two groups based on the TTE values. Scatter plots were constructed to show the TTE values ​​for individual mice per group. Group median tumor volumes were plotted as a function of time. If an animal was removed from the study due to tumor size, the final tumor volume recorded for that animal was included in the data used to calculate the median volume at the later time point. Kaplan-Meier plots were constructed to show the percentage of animals remaining on study in each group versus time.

[0248] Example 2a Dosing began on study day 1 in four groups of C57BL / 6 mice (n=10 for control and PD-1 monotherapy, n=20 for combination therapy). Compound I was administered by oral gavage (po) at a dose of 50 mg / kg in a dose volume of 10 mL / kg and adjusted according to the most recent body weight measurements. PD-1 inhibitors were administered intraperitoneally (ip) at a dose of 100 μg / mouse in a fixed dose volume of 0.2 mL / mouse.

[0249] Group 1 was left untreated and served as the TGD% control group.

[0250] Group 2 was treated ip with PD-1 inhibitor at a dose of 100 μg / mouse, twice weekly for 2 weeks.

[0251] Group 3 was administered Compound I po at 50 mg / kg qdx7 starting on day 1. This group was then treated ip with the PD-1 inhibitor biwkx2 at 100 μg / animal starting on day 8.

[0252] Group 4 received Compound I po at 50 mg / kg qdx7 starting on day 1. Starting on day 8, this group was treated ip with PD-1 inhibitor at 100 μg / animal biwkx2, with the last dose given on day 18. On day 22, treatment with Compound I was resumed at 50 mg / kg once daily for 5 days (qdx5, starting on day 22).

[0253] Group 5 received Compound I po at 50 mg / kg qdx7 starting on day 1. These animals received PD-1 inhibitor at 100 μg / animal biwkx2 on day 8 with a final dose on day 18. A second course of PD-1 inhibitor was administered biwkx2 starting on day 27.

[0254] Group 6 received Compound I po at 50 mg / kg qdx7 starting on day 1. The animals received PD-1 inhibitor at 100 μg / animal biwkx2 on day 8 with a final dose on day 18. Treatment with Compound I resumed on day 22 at 50 mg / kg qdx5. A second course of PD-1 inhibitor was administered biwkx2 starting on day 27.

[0255] Group 7 was dosed with Compound I 50 mg / kg po qdx7 starting on day 1, then combined with PD-1 inhibitor 100 μg / mouse ip biwkx2 starting on day 8, again for 7 days starting on day 22 (qdx7, starting on day 22).

[0256] Treatment with compound I and PD-1 inhibitors was well tolerated. All of the compound I / PD-1 inhibitor combinations provided statistically significant survival benefits. 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 shown in Figure 1.

[0257] The combination regimen of compound I and PD-1 inhibitor administered in two treatment cycles was more effective than administering one cycle of combination treatment and administering one treatment cycle of compound I (group 6 vs. group 4), and was more effective than administering a single cycle of combination treatment of compound I and PD-1 inhibitor (group 6 vs. group 3). The results are shown in Figure 2.

[0258] The combination regimen of Compound I and PD-1 inhibitor administered in two treatment cycles was more effective than administering one combination cycle and administering one treatment cycle of PD-1 inhibitor (Group 6 vs. Group 5), and was more effective than administering a single cycle of combination treatment of Compound I and PD-1 inhibitor (Group 6 vs. Group 3). The results are shown in Figure 3.

[0259] Example 3: Clinical trial of combination treatment of Compound I with pembrolizumab This example concerns a three-cohort clinical trial of Compound I in combination with anti-PD-1 therapy with pembrolizumab in subjects with advanced renal cell carcinoma, or advanced melanoma, advanced hepatocellular carcinoma. This study includes a DLT window of 42 days (6 weeks). The study design is described in Figure 4.

[0260] Study design and dosing schedule The study involves administering Compound I in combination with pembrolizumab to three patient cohorts (N=20-30): Cohort 1: patients with advanced renal cell carcinoma (RCC), specifically advanced RCC of the clear cell subtype; Cohort 2: patients with melanoma; and Cohort 3: patients with advanced hepatocellular carcinoma (HCC).

[0261] The dosing schedule of the study design is shown in Figure 5.

[0262] In level 1 of the study, compound I is administered for 5 days on days 1-5, followed by a 16-day break during the first 3 weeks (cycle 1) and not administered during cycle 2. Compound I is administered once daily (qd) at a dose of 60 mg / day. Pembrolizumab is administered starting on day 1 of week 4 (day 1 of cycle 2, C2D1) and not administered during cycle 3, when compound I is administered. Pembrolizumab is administered by injection at a dose of 400 mg. Compound I administration is then repeated in cycles 3, 5, 7, ... and pembrolizumab administration is repeated in cycles 4, 6, 8, ..., with each cycle being 3 weeks (21 days).

[0263] In level 2 of the study, compound I is administered once daily (qd) at a dose of 60 mg / day on days 1-5 for 5 days followed by 16 days off in each 3-week treatment cycle. Pembrolizumab is administered by single infusion at a dose of 400 mg on day 14 of each 3-week treatment cycle. Compound I and pembrolizumab are then repeated in cycles 2, 3, 4, 5, 7, 8, ... each of the cycles is 3 weeks (21 days).

[0264] Responses are assessed by iRECIST. CT scans are repeated every 12 weeks to confirm CR or PD. For example, CT scans can be reviewed by blinded independent central review.

[0265] Study endpoints The primary endpoint of the study included overall response rate (ORR, commissioned CT scan imaging collection for blinded independent central review).

[0266] Secondary endpoints of the study include ORR (investigator assessment), duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

[0267] From the foregoing, it will be understood that, although specific embodiments have been described herein for purposes of illustration, various modifications may be made without departing from the spirit and scope of what is provided herein. All documents referred to above are incorporated herein by reference in their entireties. TIFF2025507901000013.tif514

Claims

1. 1. A method for treating cancer in a patient in need thereof with one or more treatment cycles, comprising: (i) administering to said patient Compound I, or a pharma- ceutically acceptable salt thereof, during a first period of each of said one or more treatment cycles; (ii) administering to the patient a PD-1 inhibitor following administration of Compound I or a pharma- ceutical acceptable salt thereof; Including, Compound I is 【Chemistry 1】 A method having the structure of:

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

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

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

5. 2. 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. 6. The method 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. 6. The method of claims 1, 2, 4, and 5, wherein each of the one or more treatment cycles is about three 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. 9. The method of claim 8, wherein the first period of time is five days.

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

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

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

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

14. The method of any one of claims 1 to 13, wherein said Compound I or a pharma- ceutically acceptable salt thereof is administered daily during said first period of time.

15. 10. The method of claim 1, wherein the compound I or a pharma- ceutically acceptable salt thereof is administered to the patient on an intermittent dosing schedule.

16. 16. The method of claim 15, wherein compound I or a pharma- ceutically acceptable salt thereof is administered only during the first time period of each of the one or more treatment cycles and not after the first time period, and wherein the first time period is shorter than each of the one or more treatment cycles.

17. 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 according to any one of claims 1 to 18, wherein the compound I or a pharma- ceutically 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 the compound I or a pharma- ceutically acceptable salt thereof is administered orally.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

38. 38. The method of any one of claims 1-37, wherein the first 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. 39. The method of any one of claims 1-38, wherein the first period begins on day 1 of each of the one or more treatment cycles.

40. 2. The method of claim 1, wherein each of the one or more treatment cycles is 6 weeks and wherein the compound I or a pharma- ceutically acceptable salt thereof is administered on days 1-5, and then the PD-1 inhibitor is administered once on day 22.

41. 2. The method of claim 1, wherein each of the one or more treatment cycles is three weeks and wherein the compound I or a pharma- ceutically acceptable salt thereof is administered on days 1-5, and then the PD-1 inhibitor is administered once on day 14.

42. 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's lymphoma, Hodgkin's lymphoma, colorectal cancer, urothelial carcinoma, gastric cancer, cervical cancer, hepatocellular carcinoma, Merkel cell carcinoma, esophageal cancer, endometrial cancer, squamous cell carcinoma, or mesothelioma.

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

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

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

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

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

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

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

50. 50. The method of any one of claims 1 to 49, further comprising: (iii) assessing the effectiveness of administration of the combination of compound I, or a pharma- ceutically acceptable salt thereof, and the PD-1 inhibitor by measuring levels of regulatory T cells (CD25hi FoxP3+ T cells) or effector T cells (e.g., CD8+ and CD4+ cells).

51. 51. The method of claim 50, wherein levels of regulatory T cells (CD25hi FoxP3+ T cells) or effector T cells (e.g., CD8+ and CD4+ cells) that are less than or equal to about 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or 10% of baseline levels of the regulatory T cells (CD25hi FoxP3+ T cells) or effector T cells (e.g., CD8+ and CD4+ cells) indicate that the one or more treatment cycles of administration of a combination of Compound I or a pharma- ceutically acceptable salt thereof and the PD-1 inhibitor are efficacious.

52. 52. The method of claim 50 or 51, wherein a level of regulatory T cells (CD25hi FoxP3+ T cells) or effector T cells (e.g., CD8+ and CD4+ cells) that is about 65% or less of a baseline level of the regulatory T cells (CD25hi FoxP3+ T cells) or effector T cells (e.g., CD8+ and CD4+ cells) indicates that the one or more treatment cycles of administration of a combination of compound I, or a pharma- ceutically acceptable salt thereof, and the PD-1 inhibitor is efficacious.

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

54. 1. A method for treating cancer in a patient in need thereof with one or more treatment cycles, comprising: (i) administering to said patient Compound I, or a pharma- ceutically acceptable salt thereof, on days 1-5 of each of said one or more treatment cycles; (ii) administering to the patient a PD-1 inhibitor on day 22 of each of the treatment cycles. Including, each of said one or more treatment cycles is 6 weeks; Compound I is 【Chemistry 2】 A method having the structure of:

55. 1. A method for treating cancer in a patient in need thereof with one or more treatment cycles, comprising: (i) administering to said patient Compound I, or a pharma- ceutically acceptable salt thereof, on days 1 to 5 of each of said one or more treatment cycles; (ii) administering to the patient a PD-1 inhibitor on day 14 of each of the treatment cycles. Including, each of said one or more treatment cycles is three weeks; Compound I is 【Chemistry 3】 A method having the structure of:

56. 1. A method for treating cancer in a patient in need thereof with one or more treatment cycles, comprising: (i) administering to said patient Compound I or a pharma- ceutically acceptable salt thereof during week 1 of an odd-numbered cycle (e.g., cycle 1) of said one or more treatment cycles; (ii) administering to the patient a PD-1 inhibitor during week 1 of each even-numbered cycle (e.g., cycle 2) of the treatment cycle; Including, each of said one or more treatment cycles is 3 weeks, 6 weeks, or 9 weeks; Compound I is 【Chemistry 4】 A method having the structure of:

57. 1. A method for treating cancer in a patient in need thereof with one or more treatment cycles, comprising: (i) administering to the patient Compound I, or a pharma- ceutically acceptable salt thereof, during week 1 of each of one or more treatment cycles; (ii) administering to the patient a PD-1 inhibitor during week 2 of each of the treatment cycles. Including, each of said one or more treatment cycles is three weeks; Compound I is 【Chemistry 5】 A method having the structure of:

58. 1. A method for treating cancer in a patient in need thereof, comprising: (i) administering to said patient Compound I or a pharma- ceutically acceptable salt thereof once daily for 1, 2, 3, 4, or 5 days every 3, 6, or 9 weeks; (ii) administering a PD-1 inhibitor to the patient once every three or six weeks. Including, Compound I is 【Chemistry 6】 A method having the structure of:

59. below: 【Chemistry 7】 or a pharma- ceutical composition for use in treating cancer in a patient in combination with a PD-1 inhibitor, comprising Compound I having the structure: (i) Compound I, or a pharma- ceutically acceptable salt thereof, is administered to said patient during a first period of each of one or more treatment cycles; (ii) The pharmaceutical composition, wherein said PD-1 inhibitor is administered to said patient following administration of compound I or a pharma- ceutically acceptable salt thereof.

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