Combination therapy of HDAC inhibitors and PD-1 inhibitors

Abstract

The invention relates to combination therapy of an HDAC inhibitor and a PD-1 inhibitor. Provided herein are combinations comprising HDACi and a PD-1 inhibitor useful for the treatment of cancer, including the reduction and / or prevention of cancer metastasis. The combination is also useful in the treatment of cancers that have been previously treated with a PD-L1 inhibitor.

Description

[0001] This application is a divisional application of the application with the filing date of May 11, 2017, application number 201780041694.5, and invention name "Combination Therapy of HDAC Inhibitor and PD-1 Inhibitor".

[0002] Cross-reference to related applications

[0003] This invention claims the priority of U.S. Provisional Application No. 62 / 335,044 filed on May 11, 2016 and U.S. Provisional Application No. 62 / 436,361 filed on December 19, 2016, which are hereby incorporated by reference in their entirety, including all tables, figures and technical solutions. Technical Field

[0004] This invention relates to combinations of HDACi and PD-1 inhibitors and the use of such combinations in the treatment of cancer. Background Art

[0005] Cancer is a major cause of morbidity and mortality worldwide. Although the standards of care for many different cancer types have improved significantly over the years, the current standards of care still do not meet the need for effective therapies to improve cancer treatment. The clinical application of immuno-oncology agents targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death receptor-1 (PD-1) and its ligand PD-L1 has improved over the standards of care in the treatment of many cancer types. Although these checkpoint inhibitors have produced improved clinical responses in some such cancers, durable clinical responses occur in only about 10 - 45% of patients. In addition, a large number of tumors are drug-resistant or become difficult to cure. Epigenetic modifiers, such as histone deacetylase inhibitors (HDACi), have successfully treated certain hematological malignancies, but although preclinical data show activity against solid tumors, this result has not translated to the clinic as a single therapy. Therefore, there is a need in the art for new therapies, including, for example, combination therapies for the treatment of cancer. Solutions to these and other problems in the art are provided herein. Summary of the Invention

[0006] Specifically provided herein is a combination comprising an HDAC inhibitor (HDACi) and a PD-1 inhibitor. The combination comprises a compound of formula I and a PD-1 inhibitor. In certain cases, the PD-1 inhibitor is a PD-1 antibody.

[0007] A first aspect is a combination comprising a therapeutically effective amount of a PD-1 inhibitor and a therapeutically effective amount of a compound of formula I:

[0008]

[0009] A is a phenyl or heterocyclic group optionally substituted with 1 to 4 substituents selected from the group consisting of: halogen, -OH, -NH2, -NO2, -CN, -COOH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino, C2-C4 acyl, C2-C4 acylamino, C1-C4 alkylthio, C1-C4 perfluoroalkyl, C1-C4 perfluoroalkoxy, C1-C4 alkoxycarbonyl, phenyl and heterocyclic group. B is a phenyl optionally substituted with 1 to 3 substituents selected from the group consisting of: halogen, -OH, -NH2, -NO2, -CN, -COOH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino, C2-C4 acyl, C2-C4 acylamino, C1-C4 alkylthio, C1-C4 perfluoroalkyl, C1-C4 perfluoroalkoxy, C1-C4 alkoxycarbonyl and phenyl. Y is a moiety containing -CO-, which is linear and the distances between the centroid (W1) of ring B, the centroid (W2) of ring A and the oxygen atom (W3) serving as a hydrogen bond acceptor in moiety Y are respectively: W1-W2 = about W1-W3 = about to about and W2-W3 = about to about Z is a single bond or C1-C4 alkylene, -O-, -S-, -NH-, -CO-, -CS-, -SO- or -SO2-. R 1 and R 2 are independently hydrogen or C1-C4 alkyl. R 3 is hydrogen or C1-C4 alkyl. R 4 is hydrogen or -NH2. X 1 、X 2 、X 3 or X 4 One of them is halogen, -OH, -NH2, -NO2, -CN, -COOH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino, C2-C4 acyl, C2-C4 acylamino, C1-C4 alkylthio, C1-C4 perfluoroalkyl, C1-C4 perfluoroalkoxy or C1-C4 alkoxycarbonyl, which is optionally substituted with halogen or C1-C4 alkyl, and the other X 1 、X 2 、X 3 or X 4 are independently hydrogen, provided that when R 4 is hydrogen, one of X 1 、X 2 、X 3 or X 4 is -NH2, aminoalkyl or alkylamino.

[0010] In some embodiments, Z is a single bond. In some embodiments, R 3 is hydrogen. In some embodiments, A is pyridinyl. In some embodiments, X 2 is a halogen, preferably -F. In some embodiments, R 1 and R 2 are independently hydrogen. In some embodiments, R 3 is hydrogen. In some embodiments, R 4 is -NH2. In some embodiments, Y is -C(O)NH-CH2.

[0011] In one embodiment, the compound of formula I is N-(2-amino-4-fluorophenyl)-4-[[[(2E)-1-oxo-3-(3-pyridinyl)-2-propen-1-yl]amino]methyl]benzamide, which is referred to herein as HBI-8000, or chidamide.

[0012] In another embodiment, the PD-1 inhibitor is a small molecule compound, nucleic acid, peptide, protein, antibody, peptibody, bispecific antibody, minibody, single-chain variable fragment (ScFv) or a fragment or variant thereof.

[0013] In another embodiment, the PD-1 inhibitor is an antibody.

[0014] In another embodiment, the PD-1 antibody is selected from nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR001, SHR-1210 or MEDI0680.

[0015] Another aspect is a pharmaceutical composition, which comprises the combination described herein and a pharmaceutically acceptable excipient.

[0016] Another aspect is a kit, which comprises the combination or pharmaceutical composition described herein.

[0017] Another aspect is a method of treating cancer by administering to a patient in need a therapeutically effective amount of the combination or pharmaceutical composition described herein.

[0018] In one embodiment, the combination included in the method comprises a compound of formula I and a PD-1 antibody. The PD-1 antibody can be nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR001, SHR-1210 or MEDI0680.

[0019] On the other hand, it is a method for reducing the level of myeloid-derived suppressor cells (MDSC) in a patient in need by administering a therapeutically effective amount of the combination or pharmaceutical composition described herein.

[0020] On the other hand, it is a method for reducing the level of regulatory T cells (Treg cells) in a patient in need by administering a therapeutically effective amount of the combination or pharmaceutical composition described herein.

[0021] On the other hand, it is a method for enhancing the activity of natural killer (NK) or cytotoxic T cell activity in a cancer patient by administering a therapeutically effective amount of the combination or pharmaceutical composition described herein.

[0022] On the other hand, it is a method for enhancing antibody-dependent cell-mediated cytotoxicity in a cancer patient by administering a therapeutically effective amount of the combination or pharmaceutical composition described herein.

[0023] On the other hand, it is a method for treating a disease, disorder or alleviating or eliminating the symptoms of a disease and disorder (such as cancer) using a combination of a therapeutically effective amount of a histone deacetylase inhibitor (HDAC inhibitor) and PD-1, said combination being administered to an individual in need of treatment and whose cancer has previously been treated with a PD-L1 inhibitor.

[0024] In other aspects, the methods disclosed herein reduce or prevent the metastasis of primary tumors in a subject.

[0025] The methods described herein include administering a therapeutically effective amount of a combination of a histone deacetylase inhibitor and a PD-1 inhibitor. In one aspect of this embodiment, the histone deacetylase inhibitor is one or more compounds of formula I. In some aspects of this embodiment, the compound of formula I has the following structure:

[0026]

[0027] In another aspect, the compound of formula I is N-(2-amino-4-fluorophenyl)-4-[[[(2E)-1-oxo-3-(3-pyridinyl)-2-propen-1-yl]amino]methyl]benzamide. In some aspects, the administered amount of the compound of formula I is greater than about 5 mg or in the range of about 5 to 50 mg.

[0028] In some aspects, the PD1 inhibitor is a small molecule compound, nucleic acid, peptide, protein, antibody, peptibody, bispecific antibody, minibody, single-chain variable fragment (ScFv) or a fragment or variant thereof. In some aspects, the PD-1 inhibitor is AMP-24 or an antibody, such as a monoclonal antibody, including a human antibody or a humanized antibody, such as nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In some aspects, the PD-1 antibody is administered in an amount of about 1 mg / kg, 2 mg / kg, 3 mg / kg or 5 mg / kg.

[0029] In some aspects, the cancer being treated is one or more of the following: prostate cancer, skin cancer, ovarian cancer; cancers of non-lymphoid parenchymal organs including the heart, placenta, skeletal muscle and lung; breast cancer; head and neck cancer, including various lymphomas such as mantle cell lymphoma, non-Hodgkin's lymphoma cell lymphoma, PTCL, adenoma, squamous cell carcinoma, laryngeal cancer, salivary gland cancer, thymoma and thymic carcinoma; leukemia; retinal cancer; esophageal cancer; multiple myeloma; melanoma; colorectal cancer; lung cancer; cervical cancer; endometrial cancer; gallbladder cancer; liver cancer; follicular thyroid cancer; gastric cancer; non-small cell lung cancer; glioma; urothelial carcinoma; bladder cancer; prostate cancer; renal cell carcinoma; invasive ductal carcinoma; and glioblastoma multiforme.

[0030] Other aspects are methods of using a combination of an HDAC inhibitor and a PD-1 inhibitor to reduce or prevent metastasis, wherein the combination is administered before, concurrently with, after, or in a combination of before, concurrently and after the treatment of the primary tumor. Treatment of the primary tumor can include one or more of radiation, surgery, chemotherapy, immunotherapy, targeted therapy, hormone therapy, stem cell transplantation, cryotherapy, laser therapy and precision medicine. The primary tumor can include, but is not limited to, breast cancer, lung cancer, bladder cancer, skin cancer, bowel cancer, colon cancer, kidney cancer, ovarian cancer, pancreatic cancer, prostate cancer, brain cancer, gastric cancer, thyroid cancer, head and neck cancer, gastroesophageal cancer, connective tissue or other non-epithelial tissue cancer, lymphocyte cancer or uterine cancer. In some embodiments, the primary tumor is breast cancer, which may be triple-negative progressive metastatic breast cancer. In some aspects, before using the combination treatment, the HDACi is administered alone to prime the tumor for a period of time. The priming time can be 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, greater than 1 week, 2 weeks, greater than 2 weeks, 3 weeks or greater than 3 weeks. In some aspects of priming, the HDACi is administered every two weeks or every three weeks for a period of time before starting the combination treatment.

[0031] In another aspect, the disclosure herein includes a kit for (i) reducing primary tumor metastasis; (ii) preventing or delaying cancer recurrence; (iii) prolonging disease - free or tumor - free survival; (iv) increasing overall survival; (v) reducing treatment frequency; (vi) alleviating one or more symptoms of cancer, and (vii) reducing tumor burden. The kit includes an HDACi and a PD - 1 inhibitor. In some aspects of the kit, the HDACi and the PD - 1 inhibitor comprise separate formulations. In some aspects, the PD - 1 inhibitor and the HDACi are in different containers. The kit may include instructions for use and / or reagents and medical devices for administration.

[0032] In another aspect, the disclosure herein provides a method of treating a subject having primary cancer with a combination of an HDACi and a PD - 1 inhibitor, wherein the treatment results in one or more of the following: (i) reducing or slowing tumor metastasis; (ii) preventing or delaying cancer recurrence; (iii) prolonging disease - free or tumor - free survival; (iv) increasing overall survival; (v) reducing treatment frequency; (vi) alleviating one or more symptoms of cancer or a combination of the above, and (vii) reducing tumor burden. In some embodiments of this method, the patient has been previously treated with a PD - L1 checkpoint inhibitor.

[0033] In some aspects of the methods disclosed herein, the reduced metastasis is metastasis to one or more of the adrenal gland, brain and / or spinal cord, bone, lung, liver and / or pleura, gastrointestinal tract, peritoneum, muscle, lymph nodes, and skin.

[0034] Other aspects of the methods disclosed herein are methods for reducing or preventing metastasis, wherein the primary or secondary tumor of the subject treated with the combination is breast cancer, lung cancer, bladder cancer, skin cancer, bowel cancer, colon cancer, kidney cancer, ovarian cancer, pancreatic cancer, prostate cancer, liver cancer, brain cancer, gastric cancer, thyroid cancer, head and neck cancer, gastroesophageal cancer, myeloma, lymphoma, connective tissue or other non - epithelial tissue cancer, and uterine cancer. In some aspects of this method, the cancer is triple - negative breast cancer.

[0035] In some aspects of the method, the method further comprises treating the subject with an E - selectin inhibitor or plerixafor or a combination of an E - selectin inhibitor and plerixafor. In some aspects of this method, the E - selectin inhibitor and / or plerixafor is given before, simultaneously with, or after the HDACi and PD - 1 combination, or in a combination before, simultaneously with, or after.

[0036] In some aspects of the method, the treatment further comprises treating the subject with an αv integrin inhibitor, or an antibody from the group consisting of etaracizumab, intetumumab, or abituzumab, or a combination of an αv integrin inhibitor and an antibody from the group consisting of etaracizumab, etaracizumab, intetumumab, or abituzumab. In other aspects of this embodiment, the treatment further comprises treating the subject with a matrix metalloproteinase inhibitor, wherein the matrix metalloproteinase inhibitor is administered before, concurrently with, or after the HDACi and the PD-1 inhibitor, or in a combination before, concurrently with, or after. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 Group tumor growth is illustrated as the median tumor volume (mm 3 , y-axis) over time (days, x-axis) for all groups in the study described in Example 1 herein.

[0038] Figure 2 Group tumor growth is illustrated as the median tumor volume (mm 3 , y-axis) over time (days, x-axis) for mice treated with 50 mg / kg of the compound (HBI-8000) in the study described in Example 1 herein.

[0039] Figure 3 Survival (Kaplan-Meier) for all groups tested in the study described in Example 1 herein is illustrated.

[0040] Figure 4 Survival (Kaplan-Meier) for mice treated with 50 mg / kg of the compound (HBI-8000) in the study described in Example 1 herein is illustrated.

[0041] Figure 5 Group tumor growth is shown as the median tumor volume (mm 3 , y-axis) over time (days, x-axis) for all groups in the study described in Example 2 herein.

[0042] Figure 6 Survival (Kaplan-Meier) for all groups tested in the study described in Example 2 herein is illustrated.

[0043] Figure 7 The individual study endpoint times for each animal in Example 2 herein are shown.

[0044] Figure 8 Survival (Kaplan-Meier) in the study described in Example 3 herein is illustrated.

[0045] Figure 9 Shows the individual study endpoint times for each animal in Example 3 of this article.

[0046] Figure 10 Shows the number of metastatic lung lesions of the study described in Example 4 of this article.

[0047] Figure 11 Shows the median tumor growth curves for all study groups. Detailed implementation mode

[0048] Definition

[0049] All patents, applications, published applications, and other publications are incorporated by reference in their entirety. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The chemical structures and chemical formulas described herein are constructed according to the standard rules of chemical valence known in the chemical art. If there is a difference between the depicted structure and the name given to the structure, the described structure will be given more weight. When the stereochemistry of a structure or a part of a structure is not indicated in the depicted structure or a part of the depicted structure, the depicted structure should be interpreted as including all its possible stereoisomers.

[0050] Any methods, devices, and materials similar or equivalent to those described herein can be used in the practice of this invention. The following definitions are provided to facilitate the understanding of certain terms frequently used herein and are not meant to limit the scope of this disclosure. Unless otherwise stated, in cases where a term has multiple definitions herein, the definitions in this section shall prevail. The headings used herein are for organizational purposes only and in no way limit the invention described herein.

[0051] The term "PD-1 inhibitor" refers to a moiety (e.g., a compound, nucleic acid, polypeptide, antibody) that reduces, inhibits, blocks, eliminates, or interferes with the activity or expression of PD-1 (e.g., programmed cell death protein 1; PD-1 (CD279); GI:145559515), including variants, isotypes, species homologs of human PD-1 (e.g., mouse), and analogs having at least one common epitope with PD-1. PD-1 inhibitors include molecules and macromolecules such as compounds, nucleic acids, polypeptides, antibodies, peptibodies, bispecific antibodies, minibodies, single-chain variable fragments (ScFv), and fragments or variants thereof. Thus, a PD-1 inhibitor as used herein refers to any moiety that antagonizes the activity or expression of PD-1. The efficacy of a PD-1 inhibitor can be determined, for example, by its inhibitor concentration at 50% (half-maximal inhibitory concentration or IC 50) Measured. PD-1 inhibitors include the exemplary compounds and compositions described herein. A PD-1 antibody refers to a PD-L1 inhibitor, which is a monoclonal or polyclonal antibody as described herein.

[0052] The terms "nivolumab", "pembrolizumab", "pidilizumab", "AMP-224", "REGN2810", "PDR001", "SHR-1210", "SAR-439684", and "MEDI0680" are used according to their ordinary and common meanings as understood in the art.

[0053] The terms "polypeptide" and "protein" are used interchangeably herein and refer to any molecule comprising at least 2 or more amino acids.

[0054] The term "effective amount" refers to the amount of a therapy (e.g., a combination provided herein or another active agent described herein, such as an anti-cancer agent as described herein) that is sufficient to achieve the stated purpose or otherwise achieve the effects of administering it. An effective amount may be sufficient to reduce and / or ameliorate the progression, development, recurrence, severity, and / or duration of a given disease, disorder, or condition and / or the symptoms associated therewith, or may be sufficient to reduce the activity level of a polypeptide (e.g., PD-1). An effective amount may be a "therapeutically effective amount", which refers to an amount sufficient to provide a therapeutic benefit, such as reducing or ameliorating the progression or progression of a given disease, disorder, or condition; reducing or ameliorating the recurrence, development, or onset of a particular disease, disorder, or condition; and / or improving or enhancing the prophylactic or therapeutic effect of another therapy. The compositions described herein in a therapeutically effective amount may enhance the therapeutic efficacy of another therapeutic agent.

[0055] The term "regimen" refers to a regimen for the administration and timing of administration of one or more therapies (e.g., a combination described herein or another active agent, such as an anti-cancer agent as described herein) for treating a disease, disorder, or condition described herein. A regimen may include an active administration period and a rest period known in the art. The active administration period includes the administration of the combinations and compositions described herein and the duration of the efficacy of such combinations and compositions. The rest period of the regimens described herein includes a period of time during which the compounds are not actively administered and, in some cases, includes a period of time during which the efficacy of such compounds may be minimized. The combination of active administration and rest in the regimens described herein may increase the efficacy and / or duration of administration of the combinations and compositions described herein.

[0056] The term "therapies / therapy" refers to any regimen, method, and / or agent that can be used to prevent, treat, manage, and / or ameliorate a disease, disorder, or condition or one or more symptoms thereof. In certain instances, the term refers to other active agents, such as the anti-cancer agents described herein. The term "therapy" can refer to antiviral therapy, antibacterial therapy, antifungal therapy, anti-cancer therapy, biologic therapy, supportive therapy, and / or other therapies known to those of skill in the art (e.g., medical professionals, such as physicians) applicable to treating, managing, preventing, or ameliorating a disease, disorder, or condition or one or more symptoms thereof.

[0057] The term "patient" or "subject" refers to a mammal, such as a human, cow, rat, mouse, dog, monkey, ape, goat, sheep, bovine, or deer. Typically, the patient as described herein is a human.

[0058] The term "inhibition / inhibit / inhibiting" refers to a decrease in the activity or expression of a polypeptide or a reduction or amelioration of a disease, disorder, or condition or its symptoms. Inhibition as used herein can include partial or complete blocking of a stimulus, reducing, preventing, or delaying activation, or inactivating, desensitizing, or downregulating protein or enzyme activity.

[0059] The antibodies described herein can be polyclonal or monoclonal and include xenogeneic, allogeneic, or syngeneic forms and modified forms thereof (e.g., humanized or chimeric). "Antibody" is intended to mean a polypeptide product of a B cell within the immunoglobulin class of polypeptides that is capable of binding a specific molecular antigen and is composed of two pairs of identical polypeptide chains, where each pair has one heavy chain (about 50 - 70 kDa) and one light chain (about 25 kDa) and each amino-terminal portion of each chain includes a variable region of about 100 to about 130 or more amino acids, and each carboxyl-terminal portion of each chain includes a constant region (see Borrebaeck (ed.) (1995) Antibody Engineering, 2nd ed., Oxford University Press; Kuby (1997) Immunology, 3rd ed., W.H. Freeman and Company, New York). Specific molecular antigens that can bind to the antibodies described herein include PD-1 and its epitopes.

[0060] The term "monoclonal antibody" refers to a population of antibody molecules that contain one antigen-binding site capable of immunoreacting with a specific epitope of an antigen, while the term "polyclonal antibody" refers to a population of antibody molecules that contain multiple antigen-binding sites capable of interacting with a specific antigen. Monoclonal antibodies typically exhibit a single binding affinity for the specific antigen with which they immunoreact. For example, the monoclonal antibodies used according to the present invention can be prepared by a variety of techniques, including, for example, the hybridoma method (e.g., Kohler and Milstein., Nature, 256:495-97 (1975); Hongo et al., Hybridoma, 14(3):253-260 (1995), Harlow et al., Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2nd ed 1988); Hammerling et al., Monoclonal Antibodies and T-Cell Hybridomas 563-681 (Elsevier, N.Y., 1981)), recombinant DNA methods (see, for example, U.S. Patent No. 4,816,567), phage display techniques (see, for example, Clackson et al., Nature, 352:624-628 (1991); Marks et al., J Mol. Biol. 222:581-597 (1992); Sidhu et al., J Mol. Biol. 338(2):299-310 (2004); Lee et al., J Mol. Biol. 340(5):1073-1093 (2004); Fellouse, Proc. Natl. Acad. Sci. USA 101(34):12467-12472 (2004); and Lee et al., J. Immunol. Methods 284(1-2):119-132 (2004), and techniques for generating human or human-like antibodies in animals having partial or all of the human immunoglobulin locus or genes encoding human immunoglobulin sequences (see WO 1998 / 24893; WO 1996 / 34096; WO 1996 / 33735; WO 1991 / 10741; Jakobovits et al., Proc. Natl. Acad. Sci. USA 90:2551 (1993); Jakobovits et al., Nature 362:255-258 (1993); Bruggemann et al., Year in Immunol.)》7:33(1993); U.S. Patent Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; and 5,661,016; Marks et al., 《Bio / Technology》10:779-783(1992); Lonberg et al., 《Nature》368:856-859(1994); Morrison, 《Nature》368:812-813(1994); Fishwild et al., 《Nature Biotechnol.》14:845-851(1996); Neuberger, 《Nature Biotechnol.》14:826(1996); and Lonberg and Huszar, 《Intern. Rev. Immunol.》13:65-93(1995).

[0061] The monoclonal antibodies of the present invention also include "chimeric" antibodies (immunoglobulins) in which a portion of the heavy and / or light chain is identical or homologous to the corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain is identical or homologous to the corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, provided that they exhibit the desired biological activity (U.S. Patent No. 4,816,567; Morrison et al., 《Proc. Natl. Acad. Sci. USA》, pp. 6851-6855(1984)). "Humanized antibodies" can be considered a subset of the chimeric antibodies described herein.

[0062] When used in reference to an antibody or a functional fragment thereof (e.g., a "humanized antibody"), the term "human" refers to an antibody or a functional fragment thereof having a human variable region or a portion thereof corresponding to a human germline immunoglobulin sequence. Such human germline immunoglobulin sequences are described by Kabat et al. (1991) 《Sequences of Proteins of Immunological Interest》, U.S. Department of Health and Human Services, National Institutes of Health (NIH) Publication No. 91-3242. In the context of the present invention, a human antibody can include an antibody that binds to PD-1 or a variant thereof as described herein.

[0063] In some cases, a human antibody is an antibody having an amino acid sequence corresponding to an antibody produced by a human and / or an antibody prepared using any of the techniques for preparing human antibodies disclosed herein. A variety of techniques known in the art can be used to generate human antibodies, including phage display libraries. Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991). Also useful for the preparation of human monoclonal antibodies are the methods described in Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boemer et al., J. Immunol., 147(1):86-95 (1991). See also van Dijk and van de Winkel, Curr. Opin. Pharmacol., 2:368-74 (2001). Human antibodies can be prepared by administering an antigen to a transgenic animal that has been modified to produce such antibodies in response to antigen challenge, but whose endogenous loci have been disabled, such as an immunized xenomouse (for XENOMOUSE technology, see, e.g., U.S. Patent Nos. 6,075,181 and 6,150,584). For human antibodies produced by human B cell hybridoma technology, see, e.g., Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006).

[0064] A "humanized antibody" refers to an antibody prepared from a non-human cell having a variable region or variable and constant regions that has been altered to more closely resemble an antibody prepared from a human cell. For example, by altering the non-human antibody amino acid sequence to incorporate amino acids found in the human germline immunoglobulin sequence. The humanized antibodies of the invention can include amino acid residues not encoded by the human germline immunoglobulin sequence (e.g., mutations induced by in vitro random or site-specific mutagenesis or introduced by in vivo somatic mutation), such as in the CDRs. Humanized antibodies can also include antibodies in which the CDR sequences derived from the germline of another mammalian species (e.g., mouse) have been grafted onto a human framework sequence.

[0065] Humanized forms of non-human (e.g., murine) antibodies are antibodies that contain minimal sequences derived from non-human immunoglobulins. In one embodiment, a humanized antibody is a human immunoglobulin (recipient antibody) in which the residues from the hypervariable regions of the recipient are replaced with residues from the hypervariable regions of a non-human species (donor antibody), such as a mouse, rat, rabbit, or non-human primate having the desired specificity, affinity, and / or capacity. In some instances, framework ("FR") residues of the human immunoglobulin are replaced with corresponding non-human residues. Additionally, a humanized antibody may contain residues not found in the recipient antibody or the donor antibody. These modifications can be made to further improve antibody properties, such as binding affinity. Typically, a humanized antibody will contain substantially all of at least one, and usually two, variable domains, where all or substantially all of the hypervariable loops correspond to those of the non-human immunoglobulin sequence, and all or substantially all of the FR regions are regions of the human immunoglobulin sequence, although the FR regions may include one or more individual FR residue substitutions that improve antibody properties, such as binding affinity, isomerization, immunogenicity, etc. The number of these amino acid substitutions in the FR is generally no more than 6 in the H chain and no more than 3 in the L chain. A humanized antibody optionally may also include at least a portion of the immunoglobulin constant region (Fc), which may be a human immunoglobulin. Exemplary methods and humanized antibodies include those described by Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992); Vaswani and Hamilton, Ann. Allergy. Asthma & Immunol. 1:105-115 (1998); Harris, Biochem. Soc. Transactions 23:1035-1038 (1995); Burle and Gross, Curr. Op. Biotech. 5:428-433 (1994); and U.S. Patent Nos. 6,982,321 and 7,087,409.

[0066] When used in reference to an antibody, the term "functional fragment" refers to a portion of an antibody, including a heavy or light chain polypeptide, which retains some or all of the binding activity of the antibody from which the fragment is derived. Such functional fragments can include, for example, Fd, Fv, Fab, F(ab'), F(ab)2, F(ab')2, single-chain Fv (ScFv), bispecific antibodies, trispecific antibodies, tetravalent antibodies, and minibodies. Other functional fragments can include, for example, heavy or light chain polypeptides, variable region polypeptides, or CDR polypeptides or portions thereof, so long as such functional fragments retain binding activity. Such antibody binding fragments can be found described, for example, in Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, New York (1989); Myers (ed.), Molecular Biology and Biotechnology: A Comprehensive Desk Reference, New York: VCH Publisher, Inc.; Huston et al., Cell Biophysics, 22:189-224 (1993); Plückthun and Skerra, Meth. Enzymol., 178:497-515 (1989); and Day, E.D., Advanced Immunochemistry, 2nd ed., Wiley-Liss, Inc., New York, NY (1990). Antibody Engineering, 2nd ed., Oxford University Press, 1995.

[0067] When used in reference to an antibody, the term "heavy chain" refers to a polypeptide chain of approximately 50-70 kDa, wherein the amino-terminal portion includes a variable region of approximately 120-130 or more amino acids and the carboxyl-terminal portion includes a constant region. Based on the amino acid sequence of the heavy chain constant region, the constant region can be one of five different types designated alpha (α), delta (δ), epsilon (ε), gamma (γ), and mu (μ). The different heavy chains vary in size: α, δ, and γ contain approximately 450 amino acids, while μ and ε contain approximately 550 amino acids. When combined with a light chain, these different types of heavy chains give rise to the five well-known classes of antibodies, IgA, IgD, IgE, IgG, and IgM, including the four subclasses of IgG, namely IgG1, IgG2, IgG3, and IgG4. The heavy chain can be a human heavy chain.

[0068] When used in reference to an antibody, the term "light chain" refers to a polypeptide chain of approximately 25 kDa, wherein the amino-terminal portion includes a variable region of about 100 to about 110 or more amino acids and the carboxyl-terminal portion includes a constant region. The approximate length of the light chain is 211 to 217 amino acids. There are two different types based on the amino acid sequence of the constant domain, called kappa (κ) and lambda (λ). The amino acid sequences of light chains are well known in the art. The light chain can be a human light chain.

[0069] The term "variable domain" or "variable region" refers to a portion of the light or heavy chain of an antibody that is generally located at the amino-terminus of the light or heavy chain and is about 120 to 130 amino acids in length in the heavy chain and about 100 to 110 amino acids in length in the light chain, and is responsible for the binding and specificity of each particular antibody for its particular antigen. The variable domains can vary widely in sequence between different antibodies. The variability in sequence is concentrated in the CDRs, while the portions of the variable domain with less variability are called framework regions (FRs). The CDRs of the light and heavy chains are primarily responsible for the interaction of the antibody with the antigen. The numbering of amino acid positions used herein is according to the EU index, as in Kabat et al. (1991) Sequences of Proteins of Immunological Interest (U.S. Department of Health and Human Services, Washington, D.C.), 5th ed. The variable region can be a human variable region.

[0070] CDR refers to one of the three hypervariable regions (H1, H2, or H3) in the non-framework region of the VH β-sheet framework of an immunoglobulin (Ig or antibody), or one of the three hypervariable regions (L1, L2, or L3) in the non-framework region of the VL β-sheet framework of an antibody. Thus, CDRs are variable region sequences interspersed within the framework region sequences. CDR regions are well-known to those skilled in the art and have been defined by, for example, Kabat as the regions of highest variability within the antibody variable (V) domain (Kabat et al., J. Biol. Chem. 252:6609-6616 (1977); Kabat, Adv. Prot. Chem. 32:1-75 (1978)). CDR region sequences have also been structurally defined by Chothia as those residues that do not belong to the conserved β-sheet framework and can thus adopt different conformations (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)). Both terms are well-recognized in the art. The positions of CDRs within the canonical antibody variable domain have been determined by comparing multiple structures (Al-Lazikani et al., J. Mol. Biol. 273:927-948 (1997); Morea et al., Methods 20:267-279 (2000)). Since the number of residues within the hypervariable regions varies among different antibodies, additional residues relative to the canonical positions are usually numbered with a, b, c, etc. adjacent to the residue numbers in the canonical variable domain numbering scheme (Al-Lazikani et al., supra (1997)). This nomenclature is also well-known to those skilled in the art.

[0071] For example, CDRs defined according to the Kabat (hypervariable), Chothia (structural), or MacCallum (J. Mol. Biol. 262:732-745 (1996)) nomenclatures are set forth in Table 1 below:

[0072] Table 1: CDR Definitions

[0073]

[0074] 1 Residue numbering follows the nomenclature of the aforementioned Kabat et al. reference

[0075] 2 Residue numbering follows the nomenclature of the aforementioned Chothia et al. reference

[0076] The term "cancer" refers to any physiological condition in mammals characterized by unregulated cell growth. Cancers described herein include solid tumors and hematological / blood cancers. "Hematological cancer" refers to any blood-borne cancer and includes, for example, myeloma, lymphoma, and leukemia. "Solid tumor" or "tumor" refers to a lesion and neoplastic cell growth and proliferation, whether malignant or benign, and all precancerous and cancerous cells and tissues that result in abnormal tissue growth. As used herein, "neoplastic" refers to any form of disordered or unregulated cell growth that results in abnormal tissue growth, whether malignant or benign.

[0077] The term "treating / treatment" refers to any sign of success or improvement in the progression, severity, and / or duration of a disease, pathology, or condition, including any objective or subjective parameter, such as reduction in emissions; remission; alleviation of symptoms or making an injury, pathology, or condition more tolerable to the patient; slowing the rate of degeneration or decline; making the ultimate point of degeneration less debilitating; or improving the physical and mental well-being of the patient.

[0078] The term "enhancement" refers to an increase or improvement in the function or activity of a protein or cell after administration or contact with a combination described herein compared to the protein or cell before administration or contact.

[0079] The term "administration" refers to the act of delivering a combination or composition described herein to a subject by a route such as oral, mucosal, topical, suppository, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal, or subcutaneous administration. Parenteral administration includes intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration. Administration typically occurs after the onset of a disease, disorder, or condition or its symptoms, but in some cases, it may occur before the onset of a disease, disorder, or condition or its symptoms (e.g., administration to a patient predisposed to such a disease, disorder, or condition).

[0080] The term "co - administration" refers to the administration of two or more agents (e.g., a combination as described herein and another active agent, such as an anti - cancer agent as described herein). The timing of co - administration depends in part on the combination and composition being administered and can include administration simultaneous with, immediately before, or immediately after the administration of one or more additional therapies, such as cancer therapies, like chemotherapy, hormone therapy, radiation therapy, or immunotherapy. The compounds of the present invention can be administered alone or can be co - administered to a patient. Co - administration is intended to include the simultaneous or sequential administration, either alone or in combination, of compounds (more than one compound or agent). Thus, when desired, the formulation can also be combined with other active substances (e.g., to reduce metabolic degradation). The compounds described herein can be used in combination with each other, in combination with other active agents known to be suitable for treating diseases associated with cells expressing a specific kinase as described herein, or in combination with adjuvants that are not effective alone but can enhance the efficacy of the active agent.

[0081] The term "anti - cancer agent" is used in its general ordinary meaning and refers to a composition having anti - tumor properties or the ability to inhibit cell growth or proliferation. In an embodiment, the anti - cancer agent is a chemotherapeutic agent. In an embodiment, the anti - cancer agent is an agent identified herein as useful in a method of treating cancer. In an embodiment, the anti - cancer agent is an agent approved by the FDA or a similar regulatory agency outside the United States for the treatment of cancer.

[0082] The term "chemotherapeutic / chemotherapeutic agent" is used in its general ordinary meaning and refers to a chemical composition or compound having anti - tumor properties or the ability to inhibit cell growth or proliferation. "Chemotherapy" refers to a therapy or protocol that includes the administration of a chemotherapeutic agent or anti - cancer agent as described herein.

[0083] The terms "halo", "halogen", and "halide" refer to - F, - Cl, - Br, and - I.

[0084] Unless otherwise specified, the term "alkyl", by itself or as part of another substituent, refers to a straight - chain (i.e., unbranched) or branched carbon chain (or carbon) or a combination thereof, which has no unsaturated groups and can include monovalent, divalent, and polyvalent groups. The alkyl as defined herein can be specified by its number of carbon atoms (i.e., C1 - C 10 means 1 - 10 carbons). The alkyl herein can include C1 - C 10 、C1 - C8, C1 - C6, and C1 - C4 lengths. "Perfluoroalkyl" refers to an alkyl in which all hydrogens in the alkyl chain have been replaced by fluorine.

[0085] The term "alkoxy" refers to an alkyl group (e.g., C1 - C 10, C1-C8, C1-C6, and C1-C4 alkyl groups). Exemplary alkoxy groups include groups having the formula -OR, where R is a branched or straight-chain alkyl group. The "perfluoroalkoxy" moiety refers to an alkoxy group in which all of the hydrogens in the alkyl chain have been replaced by fluorine.

[0086] The term "aminoalkyl" refers to an alkyl group in which one or more hydrogen atoms have been replaced by an amino group (e.g., C1-C 10 , C1-C8, C1-C6, and C1-C4 alkyl groups)

[0087] The term "alkylamino" refers to an alkyl group that is linked to the remainder of the molecule through a nitrogen linking group (-NR-) (e.g., C1-C 10 , C1-C8, C1-C6, and C1-C4 alkyl groups). Exemplary alkylamino groups include N-methylamino, N-ethylamino, N-isopropylamino, etc.

[0088] The term "acyl" refers to a moiety having the formula -C(O)R, where R is a substituted or unsubstituted alkyl, haloalkyl, or amino group. The term "acylamino" refers to an acyl moiety having an attached amino group and includes moieties such as acetylamino, propionylamino, butyrylamino, isobutyrylamino, etc.

[0089] The term "alkylthio" refers to an alkyl group that is linked to the remainder of the molecule through a sulfur linking group (-S-) (e.g., C1-C 10 , C1-C8, C1-C6, and C1-C4 alkyl groups). Exemplary alkylthio groups include methylthio, ethylthio, propylthio, etc.

[0090] The term "heterocycle" or "heterocyclic group" refers to a stable 3- to 15-membered monocyclic group that is saturated or unsaturated and contains one or more heteroatoms (e.g., N, O, or S). Exemplary heterocycles include, but are not limited to, morpholinyl, piperidinyl, piperazinyl, pyranyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, oxetanyl, azetidinyl, etc.

[0091] Compositions

[0092] Combinations (e.g., combination therapies and compositions) suitable for treating a variety of diseases, disorders, and their symptoms (including, for example, cancer) are provided herein. The combinations described herein include benzamide HDAC inhibitors of formula I and PD-1 inhibitors, such as those described below. One aspect is a combination comprising a therapeutically effective amount of a PD-1 inhibitor and a therapeutically effective amount of a compound of formula I:

[0093]

[0094] Wherein:

[0095] A is phenyl or heterocyclic group optionally substituted with 1 - 4 substituents selected from the group consisting of: halogen, -OH, -NH2, -NO2, -CN, -COOH, C1 - C4 alkyl, C1 - C4 alkoxy, C1 - C4 aminoalkyl, C1 - C4 alkylamino, C2 - C4 acyl, C2 - C4 acylamino, C1 - C4 alkylthio, C1 - C4 perfluoroalkyl, C1 - C4 perfluoroalkoxy, C1 - C4 alkoxycarbonyl, phenyl and heterocyclic group;

[0096] B is phenyl optionally substituted with 1 - 3 substituents selected from the group consisting of: halogen, -OH, -NH2, -NO2, -CN, -COOH, C1 - C4 alkyl, C1 - C4 alkoxy, C1 - C4 aminoalkyl, C1 - C4 alkylamino, C2 - C4 acyl, C2 - C4 acylamino, C1 - C4 alkylthio, C1 - C4 perfluoroalkyl, C1 - C4 perfluoroalkoxy, C1 - C4 alkoxycarbonyl and phenyl;

[0097] Y is a moiety containing -CO-, which is linear and the distances between the centroid (W1) of ring B, the centroid (W2) of ring A and the oxygen atom (W3) serving as a hydrogen bond acceptor in moiety Y are respectively: W1 - W2 = about W1 - W3 = about to about and W2 - W3 = about to about

[0098] Z is a single bond or C1 - C4 alkylene, -O-, -S-, -NH-, -CO-, -CS-, -SO- or -SO2-;

[0099] R 1 and R 2 are independently hydrogen or C1 - C4 alkyl;

[0100] R 3 is hydrogen or C1 - C4 alkyl;

[0101] R 4 is hydrogen or -NH2; and

[0102] X 1 、X 2 、X 3 or X 4wherein one of X is halogen, -OH, -NH2, -NO2, -CN, -COOH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino, C2-C4 acyl, C2-C4 acylamino, C1-C4 alkylthio, C1-C4 perfluoroalkyl, C1-C4 perfluoroalkoxy or C1-C4 alkoxycarbonyl, which is optionally substituted with halogen or C1-C4 alkyl, and the other X 1 , X 2 , X 3 or X 4 are independently hydrogen,

[0103] But the restriction is that when R 4 When X is hydrogen, 1 , X 2 , X 3 or X 4 One of them is -NH2, aminoalkyl or alkylamino.

[0104] In certain cases, A is phenyl or phenyl optionally substituted by halogen, -OH, -NH2, -NO2, -CN, -COOH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino, C2-C4 acyl, C2-C4 acylamino, C1-C4 alkylthio, C1-C4 perfluoroalkyl, C1-C4 perfluoroalkoxy, C1-C4 alkoxycarbonyl, phenyl or heterocyclyl. A can be a heterocyclyl (e.g., a 5- to 10-membered heterocyclyl) containing -N-, -S- or -O- moieties. In some cases, A is a 5 to 10-membered N-heterocyclic moiety having 1, 2, 3, 4 or more nitrogen heteroatoms, such as pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolyl, pyrazolidinyl, pyrazolyl, oxazolidinyl, oxazolyl, thiazolidinyl, thiazolyl, piperidinyl, pyridinyl, piperazinyl, diazinyl, tetrazolyl, triazinyl, tetrazinyl, azobenzene, diazinyl, azocyclooctyl or azocinyl. A can be a saturated or unsaturated 5 to 10-membered N-heterocyclic moiety. In some cases, A is a 6-membered N-heterocyclic moiety, such as pyridine.

[0105] In certain embodiments, B is phenyl. B can be phenyl optionally substituted with, for example, halogen, -OH, -NH2, -NO2, -CN, -COOH, or a small portion of C1-C4 alkyl. In some embodiments, B is phenyl substituted with halogen. In other embodiments, B is substituted with an electron donating group (EDG). In other embodiments, B is phenyl substituted with an electron withdrawing group (EWG). In another embodiment, B is phenyl substituted with C1-C4 alkyl. B can be phenyl substituted with methyl, ethyl, or propyl. B can be phenyl substituted with methoxy, ethoxy, or propoxy.

[0106] In some cases, Y is -C(O)NH-CH2-. In certain embodiments, Z is a single bond. Z can be a methylene, ethylene or propylene moiety. In some embodiments, Z is -O-, -S-, -NH-, -CO-, -CS-, -SO- or -SO2-.

[0107] R 1 and R 2 are both hydrogen in some cases. R 1 and R 2 can both be C1-C4 alkyl. For example, R 1 and R 2 can both be methyl, ethyl or propyl. In some cases, if one of R 1 or R 2 is hydrogen, then the other is C1-C4 alkyl (such as methyl). R 3 can be hydrogen. In other embodiments, R 3 is C1-C4 alkyl (such as methyl or ethyl).

[0108] R 4 can be -NH2. In some cases, R 4 is -NH2, where one of X 1 、X 2 、X 3 or X 4 is a halogen. When R 4 is -NH2, X 2 or X 3 can be a halogen. In one embodiment, R 4 is -NH2 and X 2 is a halogen. In such cases, X 2 can be -F.

[0109] In another embodiment, R 1 、R 2 and R 3 are hydrogen, where Z is a single bond, R 4 is -NH2 and Y is -C(O)NH-CH2-. In such embodiments, A can be a heterocyclic moiety as described above and B can be a phenyl group. X 1 、X 2 、X 3 or X 4 can be a halogen (such as -F) or -NH2.

[0110] The compound of formula I can be a compound substantially described in U.S. Patent Nos. 7,244,751 and 7,550,490, which are hereby incorporated by reference in their entireties for all purposes. In one embodiment, the compound of formula I is N-(2-amino-4-fluorophenyl)-4-[[[(2E)-1-oxo-3-(3-pyridinyl)-2-propen-1-yl]amino]methyl]benzamide. In another embodiment, the compound of formula I has formula Ia as set forth below:

[0111]

[0112] The compounds of formula I as described herein include their pharmaceutically acceptable salts, pharmaceutically acceptable stereoisomers, prodrugs, enantiomers, diastereomers, hydrates, co-crystals, and polymorphs.

[0113] In certain cases, the combination includes a compound of formula I (e.g., Ia) in an amount greater than about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg. The combination may include a compound of formula I in an amount greater than about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg. In certain cases, the amount of the compound of formula I is greater than about 5 mg or about 10 mg. The combination may include a compound of formula I in an amount greater than about 1 mg to about 10 mg, 1 mg to about 25 mg, 1 mg to about 50 mg, 5 mg to about 10 mg, 5 mg to about 25 mg, 5 mg to about 50 mg, 10 mg to about 25 mg, 10 mg to about 50 mg, 50 mg to about 100 mg, or 100 mg to about 200 mg.

[0114] The combination may include a compound present in an amount of at least about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg or 200 mg. The combination may include a Compound of Formula I present in an amount of at least about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg or 10 mg. In certain cases, the amount of the Compound of Formula I present is at least about 5 mg or about 10 mg. The combination may include a Compound of Formula I present in an amount of at least about 1 mg to about 10 mg, 1 mg to about 25 mg, 1 mg to about 50 mg, 5 mg to about 10 mg, 5 mg to about 25 mg, 5 mg to about 50 mg, 10 mg to about 25 mg, 10 mg to about 50 mg, 50 mg to about 100 mg or 100 mg to about 200 mg.

[0115] The combination may include a compound present in an amount of about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg or 200 mg. The combination may include a Compound of Formula I present in an amount of about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg or 10 mg. In certain cases, the amount of the Compound of Formula I present is about 5 mg or about 10 mg. The combination may include a Compound of Formula I present in an amount of about 1 mg to about 10 mg, 1 mg to about 25 mg, 1 mg to about 50 mg, 5 mg to about 10 mg, 5 mg to about 25 mg, 5 mg to about 50 mg, 10 mg to about 25 mg, 10 mg to about 50 mg, 50 mg to about 100 mg or 100 mg to about 200 mg.

[0116] The compound of formula I can be present in the combinations described herein relative to the body weight of the patient (i.e., mg / kg). In some cases, the amount of the compound of formula I present is equal to about 0.0001 mg / kg to about 200 mg / kg, 0.001 mg / kg to about 200 mg / kg, 0.01 mg / kg to about 200 mg / kg, 0.01 mg / kg to about 150 mg / kg, 0.01 mg / kg to about 100 mg / kg, 0.01 mg / kg to about 50 mg / kg, 0.01 mg / kg to about 25 mg / kg, 0.01 mg / kg to about 10 mg / kg or 0.01 mg / kg to about 5 mg / kg, 0.05 mg / kg to about 200 mg / kg, 0.05 mg / kg to about 150 mg / kg, 0.05 mg / kg to about 100 mg / kg, 0.05 mg / kg to about 50 mg / kg, 0.05 mg / kg to about 25 mg / kg, 0.05 mg / kg to about 10 mg / kg or 0.05 mg / kg to about 5 mg / kg, 0.5 mg / kg to about 200 mg / kg, 0.5 mg / kg to about 150 mg / kg, 0.5 mg / kg to about 100 mg / kg, 0.5 mg / kg to about 50 mg / kg, 0.5 mg / kg to about 25 mg / kg, 0.5 mg / kg to about 10 mg / kg or 0.5 mg / kg to about 5 mg / kg. In other cases, the amount of the compound of formula I present is equal to about 1 mg / kg to about 200 mg / kg, 1 mg / kg to about 150 mg / kg, 1 mg / kg to about 100 mg / kg, 1 mg / kg to about 50 mg / kg, 1 mg / kg to about 25 mg / kg, 1 mg / kg to about 10 mg / kg or 1 mg / kg to about 5 mg / kg.

[0117] PD-1 inhibitors suitable for the combinations described herein include any molecule capable of inhibiting, blocking, eliminating or interfering with the activity or expression of PD-1. In particular, the PD-1 inhibitor can be a small molecule compound, nucleic acid, polypeptide, antibody, peptibody, bispecific antibody, minibody, single-chain variable fragment (ScFv) or a functional fragment or variant thereof. In one case, the PD-1 inhibitor is a small molecule compound (e.g., a compound having a molecular weight of less than about 1000 Da). In other cases, the PD-1 inhibitors suitable in the combinations described herein include nucleic acids and polypeptides. The PD-1 inhibitor can be a polypeptide (e.g., a macrocyclic polypeptide), such as those exemplified in U.S. Patent Application Publication No.: 2014 / 0294898, which patent application is hereby incorporated by reference in its entirety and for all purposes. In one example, the PD-1 inhibitor is an antibody, peptibody, bispecific antibody, minibody, ScFv or a functional fragment thereof. In one example, the PD-1 inhibitor is AMP-224 (GSK).

[0118] AMP-224 is a recombinant fusion protein that includes the extracellular domain of the PD-1 ligand programmed cell death ligand 2 (PD-L2) and the Fc region of human IgG. Certain cancers can evade and suppress the immune system, in part and without being limited by any particular theory, through the interaction between PD-1 and B7-H1. AMP-224 appears to block this interaction and thus appears to overcome immunosuppression.

[0119] In another example, the PD-1 inhibitor is a PD-1 antibody. The PD-1 antibody can be a monoclonal or polyclonal antibody. In certain embodiments, the PD-1 antibody is a monoclonal antibody.

[0120] PD-1 antibodies include all known types of antibodies and their functional fragments, including but not limited to those exemplified herein, such as human antibodies, mouse antibodies, chimeric antibodies, humanized antibodies, or chimeric humanized antibodies.

[0121] In one embodiment, the PD-1 antibody is a human antibody. In another embodiment, the PD-1 antibody is a mouse antibody. In another embodiment, the PD-1 antibody is a chimeric antibody. In another embodiment, the PD-1 antibody is a humanized antibody. In another embodiment, the PD-1 antibody is a chimeric humanized antibody. The PD-1 antibody can be a human antibody or a humanized antibody. The PD-1 antibody can be nivolumab, pembrolizumab, pidilizumab, REGN2810, PDR 001, or MEDI0680. In some embodiments, two or more PD-1 antibodies are administered in combination with a compound of formula I as described herein.

[0122] The PD-1 antibody can be nivolumab. Nivolumab (sold as OPDIVO) is a fully human monoclonal antibody against PD-1 with immune-enhancing activity. Without being bound by any particular theory, nivolumab binds to PD-1 via its cognate ligand and blocks its activation, resulting in the activation of T cells and a cell-mediated immune response against tumor cells or pathogens.

[0123] The PD-1 antibody can be pembrolizumab. Pembrolizumab (MK-3475, sold as KEYTRUDA) is a humanized monoclonal IgG4 antibody against the human cell surface receptor PD-1 with potential immune-enhancing activity. Without being bound by any particular theory, pembrolizumab binds to PD-1, an inhibitory signaling receptor expressed on the surface of activated T cells, and blocks the binding and activation of PD-1 by its cognate ligand. Blocking of the binding and activity results in the activation of a T cell-mediated immune response against tumor cells.

[0124] The PD-1 antibody can be pidilizumab. Pidilizumab (CT-011) is a humanized monoclonal antibody against human PD-1, with immunomodulatory and antitumor activities. Without being bound by any particular theory, pidilizumab blocks the interaction between the receptor PD-1 and its ligand, resulting in a decrease in the apoptosis process in lymphocytes (mainly effector / memory T cells) and an increase in the antitumor activity of NK cells.

[0125] The PD-1 antibody can be REGN2810. REGN2810 is a human monoclonal antibody against PD-1, with potential immune checkpoint inhibition and antitumor activities. Without being bound by any particular theory, REGN2810 binds to PD-1, inhibits the binding to its cognate ligand, and blocks the activation of its downstream signaling pathway. This can restore immune function through the activation of cytotoxic T cells.

[0126] The PD-1 antibody can be PDR 001. PDR 001 is a fully humanized monoclonal antibody against PD-1, with immune checkpoint inhibition and antitumor activities. Without being bound by any particular theory, PDR 001 binds to PD-1 expressed on activated T cells and blocks the interaction with its cognate ligand. Inhibition of ligand binding blocks PD-1-mediated signaling and leads to T cell activation and induction of a T cell-mediated immune response against tumor cells.

[0127] The PD-1 antibody can be MEDI0680. MEDI0680 (AMP-514) is a monoclonal antibody against PD-1, with potential immunomodulatory and antitumor activities. Without being bound by any particular theory, MEDI0680 appears to inhibit PD-1 and the activation of its downstream signaling pathway. This inhibition can restore immune function through the activation of T cells and a cell-mediated immune response against tumor cells overexpressing PD-1.

[0128] The PD-1 antibody can be any antibody isotype. The term isotype refers to the antibody class encoded by the heavy chain constant region gene. The heavy chain of a given antibody or functional fragment determines the class of the antibody or functional fragment: IgM, IgG, IgA, IgD, or IgE. Each class can have a κ or λ light chain. The term subclass refers to the minor differences in the heavy chain amino acid sequences that distinguish subclasses. There are two IgA subclasses (subclass IgA1 and IgA2) in humans, and there are four IgG subclasses (subclass IgG1, IgG2, IgG3, and IgG4). These classes and subclasses are well known to those skilled in the art.

[0129] The applicable PD-1 antibody binds to PD-1 with sufficient strength to inhibit the activity of PD-1. As used herein, binding refers to the interaction between molecules to form a complex. The interaction can be, for example, a non-covalent interaction, including hydrogen bonding, ionic bonding, hydrophobic interaction, and / or van der Waals interaction. The complex can also include the binding of two or more molecules bound together by covalent or non-covalent bonds, interactions, or forces. The binding of the antibody or its functional fragment can be detected using, for example, enzyme-linked immunosorbent assay or any of the many methods well known to those skilled in the art.

[0130] The strength of the total non-covalent interaction between a single antigen-binding site on a PD-1 antibody or functional fragment and a single epitope of a target molecule (e.g., PD-1) is the affinity of the antibody or functional fragment for the epitope. The association (k1) of an antibody or its functional fragment with a monovalent antigen (k1 / k -1 ) and the dissociation (k -1 ) ratio is the association constant K, which is a measure of affinity. The value of K varies for different complexes of the antibody or functional fragment and the antigen and depends on k1 and k -1 . The association constant K of the antibody or functional fragment of the present invention can be determined using any method provided herein or any other method well known to those skilled in the art.

[0131] The affinity of a single binding site does not always reflect the true strength of the interaction between an antibody or functional fragment and an antigen. When a complex antigen containing multiple repeating antigenic determinants contacts an antibody containing multiple binding sites, the interaction of such an antibody or functional fragment with the antigen at one site will increase the likelihood of a reaction occurring at a second site. The strength of this multiple interaction between a multivalent antibody and an antigen is called avidity. The avidity of an antibody or functional fragment can be a better measure of its binding ability than the affinity of its individual binding sites. For example, high avidity can compensate for low affinity, as is sometimes found for pentameric IgM antibodies, which can have a lower affinity than IgG, but the high avidity of IgM due to multivalency enables it to bind antigen effectively.

[0132] The specificity of a PD-1 inhibitor antibody or its functional fragment refers to the ability of a single antibody or its functional fragment to react only with one antigen (e.g., a single epitope of PD-1). An antibody or functional fragment can be considered specific when it can distinguish differences in the primary, secondary, or tertiary structure of an antigen or an isoform of the antigen.

[0133] The PD-1 antibody may be present in an amount that is a measure relative to the body weight of a patient in need thereof. For example, the amount of the PD-1 antibody present may be from about 0.1 mg / kg to about 30 mg / kg, 0.1 mg / kg to about 25 mg / kg, 0.1 mg / kg to about 20 mg / kg, 0.1 mg / kg to about 15 mg / kg, 0.1 mg / kg to about 10 mg / kg, 0.1 mg / kg to about 7.5 mg / kg, 0.1 mg / kg to about 5 mg / kg, 0.1 mg / kg to about 2.5 mg / kg, or about 0.1 mg / kg to about 1 mg / kg. The amount of the PD-1 antibody present may be from about 0.5 mg / kg to about 30 mg / kg, 0.5 mg / kg to about 25 mg / kg, 0.5 mg / kg to about 20 mg / kg, 0.5 mg / kg to about 15 mg / kg, 0.5 mg / kg to about 10 mg / kg, 0.5 mg / kg to about 7.5 mg / kg, 0.5 mg / kg to about 5 mg / kg, 0.5 mg / kg to about 2.5 mg / kg, or about 0.5 mg / kg to about 1 mg / kg. The PD-1 antibody may be present in an amount from about 0.5 mg / kg to about 5 mg / kg or from about 0.1 mg / kg to about 10 mg / kg. The PD-1 antibody may be present in an amount from about 0.5 mg / kg to about 15 mg / kg or from about 0.1 mg / kg to about 20 mg / kg.

[0134] In other embodiments, the PD-1 antibody may be present in an amount of about 0.1 mg / kg, 0.5 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, or 30 mg / kg. The PD-1 antibody may be present in an amount of about 1 mg / kg, 2 mg / kg, 3 mg / kg, or 5 mg / kg.

[0135] The PD-1 antibody may be present in the combination in an amount of about 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg or 2000 mg. The PD-1 antibody may be present in the combination in an amount of about 1 mg to about 10 mg, 10 mg to about 20 mg, 25 mg to about 50 mg, 30 mg to about 60 mg, 40 mg to about 50 mg, 50 mg to about 100 mg, 75 mg to about 150 mg, 100 mg to about 200 mg, 200 mg to about 500 mg, 500 mg to about 1000 mg, 1000 mg to about 1200 mg, 1000 mg to about 1500 mg, 1200 mg to about 1500 mg or 1500 mg to about 2000 mg.

[0136] The PD-1 antibody may be present in the combination in an amount of about 0.1 mg / mL, 0.5 mg / mL, 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / ml, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 150 mg / mL, 200 mg / mL, 250 mg / mL, 300 mg / mL mL, 400 mg / mL or 500 mg / mL. In one embodiment, the PD-1 antibody is present in the combination in an amount of about 1 mg / mL to about 10 mg / mL, 5 mg / mL to about 10 mg / mL, 5 mg / mL to about 15 mg / mL, 10 mg / mL to about 25 mg / mL, 20 mg / mL to about 30 mg / mL, 25 mg / mL to about 50 mg / mL or 50 mg / mL to about 100 mg / mL.

[0137] In certain cases, a therapeutically effective amount of the PD-1 antibody is determined to be the amount provided in the package insert for the PD-1 antibody. The term package insert refers to the instructions that are typically included in the commercial drug package approved by the FDA or a similar regulatory agency outside the United States and that contain information about, for example, usage, dosage, administration, contraindications and / or warnings regarding the use of such a drug.

[0138] The compounds of Formula I as described herein can be provided in an amount synergistic with the amount of a PD-1 inhibitor. The term synergistic refers to a combination of the combinations (e.g., a compound of Formula I and a PD-1 inhibitor - including co-administration with another active agent, such as an anti-cancer agent as described herein) or regimens as described herein, such as those described herein, which are more effective than the additive effect of each therapy or regimen.

[0139] The synergistic effect of the combinations described herein can permit the use of lower doses of one or more components of the combination (e.g., a compound of Formula I or a PD-1 inhibitor). The synergistic effect can permit administration of at least one administered therapy (e.g., a compound of Formula I or a PD-1 inhibitor) to a subject having a disease, disorder, or condition as described herein at a lower frequency. Such lower doses and reduced frequency of administration can reduce the toxicity associated with administering at least one therapy (e.g., a compound of Formula I or a PD-1 inhibitor) to a subject without reducing the therapeutic efficacy. The synergistic effect as described herein avoids or reduces adverse or unwanted side effects associated with the use of any therapy.

[0140] Pharmaceutical composition

[0141] The combinations described herein can be provided as a pharmaceutical composition, the pharmaceutical composition being suitable for administration to a patient by any of the routes described herein, including but not limited to: oral, transmucosal (e.g., nasal, inhalation, pulmonary, sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intra-arterial), topical (e.g., eye drops or other ophthalmic formulations), transdermal, or percutaneous administration to a patient.

[0142] Examples of dosage forms include: tablets; cachets; capsules (e.g., gelatin capsules); lozenges; troches; suppositories; powders; gels; liquid dosage forms suitable for parenteral administration to a patient; and sterile solids (e.g., crystalline or amorphous solids) which can be reconstituted to provide a liquid dosage form suitable for parenteral administration to a patient.

[0143] The pharmaceutical compositions and dosage forms described herein generally include one or more excipients. Suitable excipients are well known to those skilled in the pharmaceutical art. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors, e.g., the intended route of administration to the patient. The pharmaceutical compositions described herein can include other agents, such as stabilizers, lubricants, buffering agents, and disintegrants, which can reduce the rate of decomposition of the active ingredient in a particular formulation.

[0144] The pharmaceutical compositions described herein can, in certain instances, include other active agents (e.g., anti-cancer agents, such as those described herein) in the amounts provided herein in addition to those in the combinations described herein.

[0145] In one embodiment, the compound of formula I is provided in an oral dosage form, such as a tablet or a capsule. In another embodiment, the compound of formula I is provided as a powder (e.g., a lyophilized powder) which can be resuspended in a liquid suitable for parenteral administration.

[0146] The PD-1 inhibitors described herein can be provided in a form that facilitates or promotes their administration to a patient. For example, when the PD-1 inhibitor is a PD-1 antibody as described herein, the PD-1 inhibitor can be formulated as a ready-to-use solution for parenteral administration. In other instances, the PD-1 inhibitor, including for example a PD-1 antibody, can be formulated as a powder (e.g., a lyophilized powder) which can be resuspended in a liquid suitable for parenteral administration. In one embodiment, the combination includes a PD-1 antibody formulated for intravenous administration. In another embodiment, the combination includes a compound of formula I formulated in an oral dosage form (e.g., a tablet or a capsule) and a PD-1 inhibitor formulated for intravenous administration.

[0147] The combinations described herein can be provided as controlled release pharmaceutical products, with the goal of improving a pharmaceutical therapy as compared to a drug therapy achieved by its non-controlled counterpart. Controlled release formulations can prolong the activity of the drug, reduce the frequency of dosing and increase patient compliance. Additionally, controlled release formulations can be used to affect the onset time of action or other characteristics, such as the blood level of the drug, and can therefore affect the occurrence of side effects (e.g., adverse effects).

[0148] Kit

[0149] The combinations and pharmaceutical compositions described herein can be provided as part of a kit. For example, such a kit can improve patient compliance or improve the accuracy of administering the combination or be easy to prepare. The kit includes a compound of formula I, wherein the compound is provided in a formulation as described herein. The kit also includes a PD-1 inhibitor as described herein. The kit can include AMP-224. In some embodiments, the kit includes a PD-1 antibody as described herein, such as nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. The kit can include package inserts or other information (e.g., prescription information) which can be used to administer the combination to a patient in need, such as a cancer patient as described herein.

[0150] The kits of the present invention may comprise the combinations described herein (e.g., a compound of Formula I and a PD-1 antibody) having the same or different formulations. Each component of the combinations described herein in the kit may be provided in separate containers. Alternatively or additionally, the components of the combinations described herein may be provided in a single container. In some embodiments, the compound of Formula I and the PD-1 inhibitor of the combination comprise different formulations. In such cases, the container may be a container ready for administration to a patient in need, such as an IV bag, an ampoule, or a syringe. In one embodiment, the compound of Formula I in the kit is formulated for oral administration (e.g., tablets, capsules, or sachets). The PD-1 inhibitor may be provided, for example, in the form of a powder (e.g., a lyophilized powder) or a solution for parenteral administration. In certain cases, the PD-1 inhibitor is a PD-1 antibody as described herein, which is formulated for parenteral administration, such as by intravenous administration.

[0151] The contents of the kits described herein may be provided in a sterile form. The kits and their contents may be provided in a form ready for administration to a subject in need. In such cases, the components of the kit combination are provided as a formulation and optionally in an administration device such that administration requires little further action by the user. Where the kit includes an administration device, such device includes devices known and understood by those skilled in the art for the administration routes described herein, such as but not limited to syringes, pumps, bags, cups, inhalers, droppers, patches, creams, or injectors. In some embodiments, the components in the kit are sterilized.

[0152] Method

[0153] The combinations, pharmaceutical compositions, and kits described herein can be used to treat diseases, disorders, or alleviate or eliminate the symptoms of diseases and disorders (e.g., cancer). It should be understood that the methods described herein involve the administration of the combinations and pharmaceutical compositions described herein, and such combinations and pharmaceutical compositions can be provided in the form of the kits described herein. Methods for treating cancer by administering a therapeutically effective amount of the combination described herein to a patient in need are provided herein. Methods for managing cancer by administering a therapeutically effective amount of the combination described herein to a patient in need are also provided herein.

[0154] Combinations suitable for the methods described herein include a compound of Formula I:

[0155]

[0156] Wherein:

[0157] A is a phenyl or heterocyclic group optionally substituted with 1 to 4 substituents selected from the group consisting of: halogen, -OH, -NH2, -NO2, -CN, -COOH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino, C2-C4 acyl, C2-C4 acylamino, C1-C4 alkylthio, C1-C4 perfluoroalkyl, C1-C4 perfluoroalkoxy, C1-C4 alkoxycarbonyl, phenyl and heterocyclic group;

[0158] B is a phenyl group optionally substituted with 1 to 3 substituents selected from the group consisting of: halogen, -OH, -NH2, -NO2, -CN, -COOH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino, C2-C4 acyl, C2-C4 acylamino, C1-C4 alkylthio, C1-C4 perfluoroalkyl, C1-C4 perfluoroalkoxy, C1-C4 alkoxycarbonyl and phenyl;

[0159] Y is a moiety containing -CO-, which is linear and the distances between the centroid (W1) of ring B, the centroid (W2) of ring A and the oxygen atom (W3) serving as a hydrogen bond acceptor in moiety Y are respectively: W1 - W2 = about W1 - W3 = about to about and W2 - W3 = about to about

[0160] Z is a single bond or C1-C4 alkylene, -O-, -S-, -NH-, -CO-, -CS-, -SO- or -SO2-;

[0161] R 1 and R 2 are independently hydrogen or C1-C4 alkyl;

[0162] R 3 is hydrogen or C1-C4 alkyl;

[0163] R 4 is hydrogen or -NH2; and

[0164] X 1 、X 2 、X 3 or X 4wherein one of X is halogen, -OH, -NH2, -NO2, -CN, -COOH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino, C2-C4 acyl, C2-C4 acylamino, C1-C4 alkylthio, C1-C4 perfluoroalkyl, C1-C4 perfluoroalkoxy or C1-C4 alkoxycarbonyl, which is optionally substituted with halogen or C1-C4 alkyl, and the other X 1 , X 2 , X 3 or X 4 are independently hydrogen,

[0165] But the restriction is that when R 4 When X is hydrogen, 1 , X 2 , X 3 or X 4 One of them is -NH2, aminoalkyl or alkylamino.

[0166] The compounds of Formula I useful in the methods described herein include compounds substantially as described above. In certain instances, the compounds of Formula I used in the methods provided herein for treating cancer include compounds wherein R 1 , R 2 and R 3 In some cases, Y is -C(O)NH-CH2-. In some cases, R 3 Can be C1-C4 alkyl as described above. A of formula I can be a 5-10 membered heterocyclic moiety. In particular, and as described above, useful embodiments of compounds of formula I include compounds wherein A is an N-heterocyclic ring, such as a 5-membered or 6-membered heterocyclic ring moiety. In some cases, A can be pyridyl.

[0167] Compounds of formula I suitable for use in the methods described herein may be those wherein R 4 is -NH2 and at least X 1 , X 2 , X 3 or X 4 In some cases, the compounds of Formula I used in the methods described herein include compounds wherein R 4 is -NH2 and X 1 , X 2 , X 3 or X 4 In one embodiment, the compound of formula I is a compound of formula Ia as described above.

[0168] The PD-1 inhibitors for use in the methods described herein are those PD-1 inhibitors described herein. For example, the PD-1 inhibitor can be a small molecule compound, nucleic acid, polypeptide, antibody, peptibody, bispecific antibody, minibody, single-chain variable fragment (ScFv) or a functional fragment or variant thereof. In one example, the PD-1 inhibitor is AMP-224. In other examples, the PD-1 inhibitor can be a PD-1 antibody as described above. In one example, the PD-1 antibody for use in the methods described herein is nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680.

[0169] It is to be understood that the Compound of Formula I and the PD-1 inhibitor that make up the combination for such methods include each therapy in the amounts described herein and are administered as described herein. For example, the Compound of Formula I can be present in the combination administered to a patient in need thereof in an amount of about 5 mg to about 50 mg or about 5 mg to about 100 mg. As another example, the PD-1 inhibitor can be a PD-1 antibody, which is present in an amount of about 0.1 mg / kg to about 10 mg / kg or about 0.1 mg / kg to about 20 mg / kg. These amounts are merely exemplary and do not in any way limit the amounts of each therapy that can be present in the combination as described herein.

[0170] It is also to be understood that the combination for use in the methods described herein can be provided as a kit as described above. Such a kit includes each component of the combination as described herein and optionally other kit components, including for example containers and administration devices, such as those described above.

[0171] The cancer can be a solid tumor. The cancer can be a hematological cancer. In certain cases, the cancer is a solid tumor selected from the group consisting of squamous cell carcinoma, non-squamous cell carcinoma, non-small cell lung cancer (NSCLC), small cell lung cancer, melanoma, hepatocellular carcinoma, renal cell carcinoma, ovarian cancer, head and neck cancer, urothelial cancer, breast cancer, prostate cancer, glioblastoma, colorectal cancer, pancreatic cancer, lymphoma, leiomyosarcoma, liposarcoma, synovial sarcoma or malignant peripheral nerve sheath tumor (MPNST).

[0172] In certain embodiments, the cancer is a solid tumor selected from non-small cell lung cancer (NSCLC), hepatocellular carcinoma, melanoma, ovarian cancer, breast cancer, pancreatic cancer, renal cell carcinoma or colorectal cancer. The cancer can be non-small cell lung cancer (NSCLC). The cancer can be hepatocellular carcinoma. The cancer can be melanoma. The cancer can be ovarian cancer. The cancer can be breast cancer. The cancer can be pancreatic cancer. The cancer can be renal cell carcinoma. The cancer can be colorectal cancer.

[0173] The present invention provides methods of treating NSCLC by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of formula I and a PD-1 antibody selected from: nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210, or MEDI0680. On the other hand, the methods comprise treating NSCLC by administering a combination of AMP-224 and a compound of formula I described herein. In some embodiments, the NSCLC is stage IIA or IIB. The NSCLC can be stage IIIA or IIIB cancer. The NSCLC can be stage IV cancer. The staging of cancer as described herein is described by classification according to the American Joint Committee on Cancer TNM cancer staging symbols well known in the art. Those skilled in the art will readily appreciate that other staging classification systems are available and applicable to the methods described herein. In certain instances, the method is a method of treating stage IIIA or IIIB NSCLC by administering the combination described herein, the combination comprising a compound of formula I and a PD-1 antibody selected from: nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210, or MEDI0680. On the other hand, the methods comprise treating stage IIIA or IIIB NSCLC by administering a combination of AMP-224 and a compound of formula I described herein. On the other hand is a method of treating stage IV NSCLC by administering the combination described herein, the combination comprising a compound of formula I and a PD-1 antibody selected from: nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210, or MEDI0680. In another aspect, the methods comprise treating stage IV NSCLC by administering a combination of AMP-224 and a compound of formula I described herein.

[0174] The present invention further provides methods for treating hepatocellular carcinoma by administering a therapeutically effective amount of the combinations described herein, wherein the combinations comprise a compound of Formula I and a PD-1 antibody selected from: nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In another aspect, the methods comprise treating hepatocellular carcinoma by administering a combination of AMP-224 and a compound of Formula I described herein. In some embodiments, the hepatocellular carcinoma is stage II cancer. In another embodiment, the hepatocellular carcinoma is stage IIIA, IIIB or IIIC cancer. In another embodiment, the hepatocellular carcinoma is stage IVA or IVB cancer. In one aspect, the method is a method for treating stage III (e.g., IIIA, IIIB or IIIC) hepatocellular carcinoma by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from: nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In another aspect, the method comprises treating stage III (e.g., IIIA, IIIB or IIIC) hepatocellular carcinoma by administering a combination of AMP-224 and a compound of Formula I described herein. In another aspect is a method for treating stage IV (e.g., IVA or IVB) hepatocellular carcinoma by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from: nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In another aspect, the method comprises treating stage IV (e.g., IVA or IVB) hepatocellular carcinoma by administering a combination of AMP-224 and a compound of Formula I described herein.

[0175] The present invention further provides methods for treating melanoma by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from: nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. On the other hand, the methods comprise treating melanoma by administering a combination of AMP-224 and a compound of Formula I described herein. In some embodiments, the melanoma is a stage IIA, IIB or IIC cancer. In another embodiment, the melanoma is a stage IIIA, IIIB or IIIC cancer. In another embodiment, the melanoma is a stage IV cancer. In one aspect, the method is a method for treating stage II (e.g., stage IIA, IIB or IIC) melanoma by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from: nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. On the other hand, the methods comprise treating stage II (e.g., stage IIA, IIB or IIC) melanoma by administering a combination of AMP-224 and a compound of Formula I described herein. In one aspect, the method is a method for treating stage III (e.g., stage IIIA, IIIB or IIIC) melanoma by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from: nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. On the other hand, the methods comprise treating stage III (e.g., stage IIIA, IIIB or IIIC) melanoma by administering a combination of AMP-224 and a compound of Formula I described herein. On the other hand, there is provided a method for treating stage IV melanoma by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from: nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. On the other hand, the methods comprise treating stage IV melanoma by administering a combination of AMP-224 and a compound of Formula I described herein.

[0176] On the other hand, there is provided a method for treating ovarian cancer by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from: nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. On the other hand, the method comprises treating ovarian cancer by administering a combination of AMP-224 and a compound of Formula I described herein. In some embodiments, the ovarian cancer is stage I cancer as defined by the FIGO ovarian cancer staging criteria. The ovarian cancer can be stage IA, IB or IC (e.g., IC1, IC2 or IC3) cancer. In another embodiment, the ovarian cancer is stage II cancer. The ovarian cancer can be stage IIA or IIB cancer. In one aspect, the method is a method for treating stage I (e.g., stage IA, IB, IC1, IC2 or IC3) ovarian cancer by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from: nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. On the other hand, the method comprises treating stage I (e.g., stage IA, IB, IC1, IC2 or IC3) ovarian cancer by administering a combination of AMP-224 and a compound of Formula I described herein. On the other hand, the method is a method for treating stage II (e.g., stage IIA or IIB) ovarian cancer by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from: nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. On the other hand, the method comprises treating stage II (e.g., stage IIA or IIB) ovarian cancer by administering a combination of AMP-224 and a compound of Formula I described herein.

[0177] The present invention also provides methods for treating breast cancer by administering a therapeutically effective amount of the combinations described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In another aspect, the method comprises treating breast cancer by administering a combination of AMP-224 and a compound of Formula I described herein. The breast cancer can be HER2-negative breast cancer. The breast cancer can be HER2-positive breast cancer. The breast cancer can be triple-negative breast cancer. In some embodiments, the breast cancer is stage IA or IB cancer. In another embodiment, the breast cancer is stage IIA or IIB cancer. In another embodiment, the breast cancer is stage IIIA, IIIB or IIIC cancer. In another embodiment, the breast cancer is stage IV cancer. In one aspect, the method is a method for treating stage I (e.g., stage IA or IB) breast cancer by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In another aspect, the method comprises treating stage I (e.g., stage IA or IB) breast cancer by administering a combination of AMP-224 and a compound of Formula I described herein. In another aspect, the method is a method for treating stage II (e.g., stage IIA or IIB) breast cancer by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In another aspect, the method comprises treating stage II (e.g., stage IIA or IIB) breast cancer by co-administering AMP-224 and a compound of Formula I described herein. In another aspect, the method is a method for treating stage III (e.g., stage IIIA, IIIB or IIIC) breast cancer by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In another aspect, the method comprises treating stage III (e.g., stage IIIA, IIIB or IIIC) breast cancer by administering a combination of AMP-224 and a compound of Formula I described herein.On the other hand, there is provided a method for treating stage IV breast cancer by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In another aspect, the method comprises treating stage IV breast cancer by administering a combination of AMP-224 and a compound of Formula I described herein.

[0178] The present invention provides methods for treating pancreatic cancer. In one aspect, the methods include treating pancreatic cancer by administering a therapeutically effective amount of a combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In another aspect, the methods include treating pancreatic cancer by administering a combination of AMP-224 and a compound of Formula I described herein. In some embodiments, the pancreatic cancer is locally advanced, resected or unresected pancreatic cancer or metastatic pancreatic cancer. In some embodiments, the pancreatic cancer is stage IA or IB cancer. In another embodiment, the pancreatic cancer is stage IIA or IIB cancer. In another embodiment, the pancreatic cancer is stage III cancer. In another embodiment, the pancreatic cancer is stage IV cancer. In one aspect, the method is a method for treating stage I (e.g., stage IA or IB) pancreatic cancer by administering a therapeutically effective amount of a combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In another aspect, the methods include treating stage I (e.g., stage IA or IB) pancreatic cancer by administering a combination of AMP-224 and a compound of Formula I described herein. In another aspect, the method is a method for treating stage II (e.g., stage IIA or IIB) pancreatic cancer by administering a therapeutically effective amount of a combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In another aspect, the methods include treating stage II (e.g., stage IIA or IIB) pancreatic cancer by administering a combination of AMP-224 and a compound of Formula I described herein. Another aspect is a method for treating stage III pancreatic cancer by administering a therapeutically effective amount of a combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In another aspect, the methods include treating stage III pancreatic cancer by administering a combination of AMP-224 and a compound of Formula I described herein.On the other hand, there is provided a method for treating stage IV pancreatic cancer by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of formula I and a PD-1 antibody selected from nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In another aspect, the method comprises treating stage IV pancreatic cancer by administering a combination of AMP-224 and a compound of formula I described herein.

[0179] The present invention further provides a method for treating renal cell carcinoma by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from: nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In another aspect, the method comprises treating renal cell carcinoma by administering a combination of AMP-224 and a compound of Formula I described herein. In some embodiments, the renal cell carcinoma is stage I cancer. In another embodiment, the renal cell carcinoma is stage II cancer. In another embodiment, the renal cell carcinoma is stage III cancer. In another embodiment, the renal cell carcinoma is stage IV cancer. In one aspect, the method is a method for treating stage I renal cell carcinoma by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from: nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In another aspect, the method comprises treating stage I renal cell carcinoma by administering a combination of AMP-224 and a compound of Formula I described herein. In another aspect, the method is a method for treating stage II renal cell carcinoma by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from: nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In another aspect, the method comprises treating stage II renal cell carcinoma by administering a combination of AMP-224 and a compound of Formula I described herein. Another aspect is a method for treating stage III renal cell carcinoma by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from: nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In another aspect, the method comprises treating stage III renal cell carcinoma by administering a combination of AMP-224 and a compound of Formula I described herein. In another aspect, the method is a method for treating stage IV renal cell carcinoma by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from: nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In another aspect, the method comprises treating stage IV renal cell carcinoma by administering a combination of AMP-224 and a compound of Formula I described herein.

[0180] The present invention also provides methods for treating colorectal cancer by administering a therapeutically effective amount of the combinations described herein, wherein the combinations comprise a compound of formula I and a PD-1 antibody selected from nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In another aspect, the method comprises treating colorectal cancer by administering a combination of AMP-224 and a compound of formula I described herein. In some embodiments, the colorectal cancer is stage I cancer. In another embodiment, the colorectal cancer is stage IIA, IIB or IIC cancer. In another embodiment, the colorectal cancer is stage IIIA, IIIB or IIIC cancer. In another embodiment, the colorectal cancer is stage IVA or IVB cancer. In certain cases, the colorectal cancer is further characterized by the grade of the cancer. In any of the stages provided herein, the colorectal cancer can be grade 1, 2, 3 or 4 cancer. In one aspect, the method is a method for treating stage I colorectal cancer by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of formula I and a PD-1 antibody selected from nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR001, SHR-1210 or MEDI0680. In another aspect, the method comprises treating stage I colorectal cancer by administering a combination of AMP-224 and a compound of formula I described herein. In another aspect, the method is a method for treating stage II (e.g., IIA, IIB or IIC) colorectal cancer by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of formula I and a PD-1 antibody selected from nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In another aspect, the method comprises treating stage II (e.g., IIA, IIB or IIC) colorectal cancer by administering a combination of AMP-224 and a compound of formula I described herein. In another aspect, the method is a method for treating stage III (e.g., IIIA, IIIB or IIIC) colorectal cancer by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of formula I and a PD-1 antibody selected from nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In another aspect, the method comprises treating stage III (e.g., IIIA, IIIB or IIIC) colorectal cancer by administering a combination of AMP-224 and a compound of formula I described herein.Another aspect is a method of treating stage IV (e.g., stage IVA or IVB) colorectal cancer by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In another aspect, the method comprises treating stage IV (e.g., stage IVA or IVB) colorectal cancer by administering a combination of AMP-224 and a compound of Formula I described herein.

[0181] In other embodiments, the cancer is a hematological cancer selected from lymphoma, non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma, Reed-Sternberg disease, multiple myeloma (MM), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL) or chronic lymphocytic leukemia (CLL). In certain embodiments, the cancer is Hodgkin's lymphoma or Reed-Sternberg disease.

[0182] In certain embodiments, a method of treating cancer comprises a method of treating NHL by administering a therapeutically effective amount of a combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from: nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210, or MEDI0680. In another aspect, the method comprises treating NHL by administering a combination of AMP-224 and a compound of Formula I described herein. NHL can be characterized by its stage, for example, according to the Ann Arbor staging system. NHL can be indolent NHL (e.g., follicular lymphoma (FL); lymphoplasmacytic lymphoma (LL); marginal zone lymphoma (MZL) or primary cutaneous anaplastic large cell lymphoma) or aggressive NHL (e.g., diffuse large B-cell lymphoma (DLBCL)); follicular large cell lymphoma, stage III; anaplastic large cell lymphoma; extranodal NK- / T-cell lymphoma; lymphomatoid granulomatosis; angioimmunoblastic T-cell lymphoma; peripheral T-cell lymphoma; intravascular large B-cell lymphoma; Burkitt lymphoma; lymphoblastic lymphoma; adult T-cell leukemia / lymphoma; or mantle cell lymphoma). In some embodiments, NHL is stage I (e.g., stage I(I) (thymus) or stage I(E) (lymphatic system)) cancer. In another embodiment, NHL is stage II (e.g., stage II(I) (lymph nodes) or stage II(E) (adjacent organs)) cancer. In another embodiment, NHL is stage III (e.g., stage III(I) (lymph nodes), stage III(E) (adjacent organs), stage III(S) (spleen) or stage III(ES) (adjacent organs and spleen)) cancer. In another embodiment, NHL is stage IV cancer. In one aspect, the method is a method of treating stage I (e.g., stage I(I) or I(E)) NHL by administering a therapeutically effective amount of a combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from: nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210, or MEDI0680. In another aspect, the method comprises treating stage I (e.g., stage I(I) or I(E)) NHL by administering a combination of AMP-224 and a compound of Formula I described herein. In another aspect, the method is a method of treating stage II (e.g., stage II(I) or II(E)) NHL by administering a therapeutically effective amount of a combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from: nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210, or MEDI0680.In another aspect, the method includes treating stage II (e.g., stage II(I) or II(E)) NHL by administering a combination of AMP-224 and a compound of formula I as described herein. In another aspect, the method is a method of treating stage III (e.g., stage III(I), III(E), III(S), or III(ES)) NHL by administering a therapeutically effective amount of a combination as described herein, wherein the combination includes a compound of formula I and a PD-1 antibody selected from: nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210, or MEDI0680. In another aspect, the method includes treating stage III (e.g., stage III(I), III(E), III(S), or III(ES)) NHL by administering a combination of AMP-224 and a compound of formula I as described herein. Another aspect is a method of treating stage IV NHL by administering a therapeutically effective amount of a combination as described herein, wherein the combination includes a compound of formula I and a PD-1 antibody selected from: nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210, or MEDI0680. In another aspect, the method includes treating stage IV NHL by administering a combination of AMP-224 and a compound of formula I as described herein.

[0183] On the other hand, there is provided a method for treating Hodgkin's lymphoma by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In another aspect, the method comprises treating Hodgkin's lymphoma by administering a combination of AMP-224 and a compound of Formula I described herein. Hodgkin's lymphoma can be classical or nodular lymphocyte predominant. In some embodiments, Hodgkin's lymphoma includes Reed-Sternberg cells and can cause Reed-Sternberg disease. In some embodiments, Hodgkin's lymphoma is stage I cancer. In another embodiment, Hodgkin's lymphoma is stage II cancer. In another embodiment, Hodgkin's lymphoma is stage III cancer. In another embodiment, Hodgkin's lymphoma is stage IV cancer. In one aspect, the method is a method for treating stage I Hodgkin's lymphoma by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In another aspect, the method comprises treating stage I Hodgkin's lymphoma by administering a combination of AMP-224 and a compound of Formula I described herein. In another aspect, the method is a method for treating stage II Hodgkin's lymphoma by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In another aspect, the method comprises treating stage II Hodgkin's lymphoma by administering a combination of AMP-224 and a compound of Formula I described herein. In another aspect, the method is a method for treating stage III Hodgkin's lymphoma by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In another aspect, the method comprises treating stage III Hodgkin's lymphoma by administering a combination of AMP-224 and a compound of Formula I described herein.On the other hand, there is provided a method for treating stage IV Hodgkin's lymphoma by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of formula I and a PD-1 antibody selected from nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In another aspect, the method comprises treating stage IV Hodgkin's lymphoma by administering a combination of AMP-224 and a compound of formula I described herein.

[0184] On the other hand, there is provided a method for treating chronic lymphocytic leukemia (CLL) by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from: nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210, or MEDI0680. In another aspect, the method comprises treating CLL by administering a combination of AMP-224 and a compound of Formula I described herein. CLL can be staged according to the Rai system or the Binet system. For example, in one embodiment, CLL is Rai stage I cancer. In another embodiment, CLL is Rai stage II cancer. In another embodiment, CLL is Rai stage III cancer. In another embodiment, CLL is Rai stage IV cancer. In another embodiment, CLL is Binet stage A cancer. CLL can be Binet stage B cancer. CLL can be Binet stage C cancer. In one aspect, the method is a method for treating Rai stage I CLL by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from: nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210, or MEDI0680. In another aspect, the method comprises treating Rai stage I CLL by administering a combination of AMP-224 and a compound of Formula I described herein. In one aspect, the method is a method for treating Rai stage II CLL by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from: nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210, or MEDI0680. In another aspect, the method comprises treating Rai stage II CLL by administering a combination of AMP-224 and a compound of Formula I described herein. In one aspect, the method is a method for treating Rai stage III CLL by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from: nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210, or MEDI0680. In another aspect, the method comprises treating Rai stage III CLL by administering a combination of AMP-224 and a compound of Formula I described herein.In one aspect, the method is a method for treating Rai stage IV CLL by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of formula I and a PD-1 antibody selected from: nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In another aspect, the method comprises treating Rai stage IV CLL by administering a combination of AMP-224 and a compound of formula I described herein. In one aspect, the method is a method for treating Binet stage A CLL by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of formula I and a PD-1 antibody selected from: nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In another aspect, the method comprises treating Binet stage A CLL by administering a combination of AMP-224 and a compound of formula I described herein. In one aspect, the method is a method for treating Binet stage B CLL by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of formula I and a PD-1 antibody selected from: nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In another aspect, the method comprises treating Binet stage B CLL by administering a combination of AMP-224 and a compound of formula I described herein. In one aspect, the method is a method for treating Binet stage C CLL by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of formula I and a PD-1 antibody selected from: nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In another aspect, the method comprises treating Binet stage C CLL by administering a combination of AMP-224 and a compound of formula I described herein.

[0185] On the other hand, there is provided a method for treating acute lymphoblastic leukemia (ALL) by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In another aspect, the method comprises treating ALL by administering a combination of AMP-224 and a compound of Formula I described herein. ALL can be characterized according to the World Health Organization (WHO) classification. ALL can be T-cell lymphoblastic leukemia. ALL can be B-cell lymphoblastic leukemia. ALL can be B-cell lymphoblastic leukemia with recurrent genetic abnormalities selected from:

[0186] B-lymphoblastic leukemia / lymphoma with t(9;22)(q34;q11.2), BCR-ABL1;

[0187] B-lymphoblastic leukemia / lymphoma with t(v;11q23); MLL rearrangement;

[0188] B-lymphoblastic leukemia / lymphoma with t(12;21)(p13;q22) TEL-AML1 (ETV6-RUNX1);

[0189] B-lymphoblastic leukemia / lymphoma with hyperdiploidy;

[0190] B-lymphoblastic leukemia / lymphoma with hypodiploidy;

[0191] B-lymphoblastic leukemia / lymphoma with t(5;14)(q31;q32) IL3-IGH; or

[0192] B-lymphoblastic leukemia / lymphoma with t(1;19)(q23;p13.3) TCF3-PBX1.

[0193] On the other hand, there is provided a method for treating chronic myelogenous leukemia (CML) by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In another aspect, the method comprises treating CML by administering a combination of AMP-224 and a compound of Formula I described herein. CML can be characterized by the stage of the disease. In one embodiment, CML is in the chronic phase (e.g., having less than about 10% blast cells in the patient's blood or bone marrow). In another embodiment, CML is in the accelerated phase (e.g., the patient has (1) more than 10% blast cells but less than 20% blast cells in their blood or bone marrow; (2) a basophil count that comprises at least about 20% of the white blood cell (WBC) count; (3) a high WBC count; (4) a high or low platelet count; or (5) chromosomal changes in the leukemic cells). In another embodiment, CML is in the blast phase (e.g., having more than 20% blast cells in the patient's blood or bone marrow). In one aspect, the method is a method for treating chronic-phase CML by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In another aspect, the method comprises treating chronic-phase CML by administering a combination of AMP-224 and a compound of Formula I described herein. In another aspect, the method is a method for treating accelerated-phase CML by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In another aspect, the method comprises treating accelerated-phase CML by administering a combination of AMP-224 and a compound of Formula I described herein. In another aspect, the method is a method for treating blast-phase CML by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In another aspect, the method comprises treating blast-phase CML by administering a combination of AMP-224 and a compound of Formula I described herein.

[0194] The present invention also provides methods for treating AML by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from the group consisting of nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210, or MEDI0680. In another aspect, the method comprises treating AML by administering a combination of AMP-224 and a compound of Formula I described herein. AML can be characterized, for example, by the WHO classification system. In one embodiment, AML is characterized by having certain genetic abnormalities, including those provided below:

[0195] AML with a translocation between chromosomes 8 and 21;

[0196] AML with a translocation or inversion in chromosome 16;

[0197] AML with a translocation between chromosomes 9 and 11;

[0198] APL (M3) with a translocation between chromosomes 15 and 17;

[0199] AML with a translocation between chromosomes 6 and 9;

[0200] AML with a translocation or inversion in chromosome 3; or

[0201] AML with a translocation between chromosomes 1 and 22 (megakaryocytic).

[0202] AML can be characterized as having myelodysplasia-related changes. AML can be characterized as being related to a previous anti-cancer therapy (e.g., chemotherapy or radiotherapy). AML can be characterized as AML that is not considered to belong to the above WHO groups and includes, for example:

[0203] AML with minimal differentiation (M0);

[0204] AML without maturation (M1);

[0205] AML with maturation (M2);

[0206] Acute myelomonocytic leukemia (M4);

[0207] Acute monocytic leukemia (M5);

[0208] Acute erythroleukemia (M6);

[0209] Acute megakaryoblastic leukemia (M7);

[0210] Acute basophilic leukemia; or

[0211] Acute panmyelosis with myelofibrosis.

[0212] The combinations described herein can be administered to a cancer patient at any time after diagnosis. For example, the cancer patient can be untreated (i.e., not receiving a cancer therapy for the diagnosed cancer). The cancer patient can be one who has not undergone treatment for one cancer but may be diagnosed with one or more other cancers, such as cancers caused by cancer metastasis or malignancy. The cancer patient can be one who has not undergone immune checkpoint therapy for one or more cancers. The cancer patient may have refractory cancer. In certain cases, the combinations described herein are administered to a patient in need as a first-line therapy (e.g., the first therapy administered to an untreated cancer patient). In some embodiments, the cancer patient is untreated for non-small cell lung cancer (NSCLC), hepatocellular carcinoma, melanoma, ovarian cancer, breast cancer, pancreatic cancer, renal cell carcinoma, or colorectal cancer.

[0213] However, cancer incidence and mortality are generally associated with ineffective treatment or cancers that are resistant to or have become refractory to one or more cancer therapies. Accordingly, the combinations described herein can be administered to a patient in need as second, third, fourth, fifth, sixth, or more line therapy. The combinations described herein can be administered to a cancer patient who has been treated with at least one anti-cancer therapy or anti-cancer agent. In certain cases, the patient has received at least one anti-cancer therapy, including, for example, chemotherapy, radiation therapy, surgery, targeted therapy, immunotherapy, or combinations thereof. The patient may have a cancer that is resistant / refractory to treatment with at least one anti-cancer agent.

[0214] The methods of treating cancer in this article include treating a subject who has been treated with a PD-L1 checkpoint inhibitor and has experienced no response to treatment, or a partial response or stable disease, but then develops resistance to the treatment and the disease progresses or has experienced a complete response to the treatment, but then develops resistance to the treatment and the disease progresses (as defined by RECIST or other criteria). In some embodiments, the cancer after treatment with a PD-L1 inhibitor results in a partial response, but then develops resistance to PD-L1 as the disease progresses. In some embodiments, the cancer after treatment with a PD-L1 inhibitor results in stable disease, but then develops resistance to PD-L1 as the disease progresses. In some embodiments, the cancer after treatment with a PD-L1 inhibitor results in a complete response, but then develops resistance to PD-L1 as the disease progresses. In some embodiments, the cancer after treatment with a PD-L1 inhibitor does not respond to the treatment. Resistance is defined as disease progression during treatment or lack of response to treatment. This failure of PD-L1 inhibitor antibody treatment can be treated with a combination of a PD-1 and an HDAC inhibitor, such as but not limited to HBI-8000 or an HDAC inhibitor that inhibits one or more cancer-related class I HDACs selected from HDAC1, HDAC2, or HDAC3. In certain cases, the HDAC inhibitor also inhibits class IIb HDAC10. It has been reported that HBI-8000 inhibits HDAC 1, 2, 3, and 10 at low nanomolar concentrations (see Zhi-Qiang Ning et al., Cancer Chemother Pharmacol (2012) 69:901-909). It also has activity at HDAC 8 and 11. Ning et al. also reported that HBI-8000 is more active than Entinostat at HDAC 1, 2, 3, 8, 10, and 11. In addition, HBI-8000 has favorable pharmacokinetic and safety profiles that allow for continuous dosing - oral administration pK(t 1 / 2 ~17 hours). In some embodiments, the HDAC inhibitor is selected from one or more of the group consisting of vorinostat, romidepsin, panobinostat, belinostat, entinostat, mocetinostat, givinostat, practinostat, quisinostat, abexinostat, chr-3996, and AR-42.

[0215] The present invention provides a method for reducing the metastasis of a primary tumor in a subject, wherein the treatment comprises administering a therapeutically effective amount of a combination of a histone deacetylase inhibitor and a PD-1 inhibitor.

[0216] The present invention provides a method for reducing the metastasis of a primary tumor in a subject, wherein the treatment comprises administering a therapeutically effective amount of the combination described herein to the subject in need of treatment.

[0217] In some embodiments, the HDAC inhibitor is selected from one or more of the group consisting of vorinostat, romidepsin, panobinostat, belinostat, entinostat, mocetinostat, givinostat, practinostat, quisinostat, abexinostat, chr-3996, and AR-42.

[0218] The present invention provides a method for treating a primary or secondary cancer in a subject, wherein the treatment results in one or more of the following: (i) a reduction in the number of cancer cells; (ii) a decrease in tumor volume; (iii) an increased rate of tumor regression; (iv) a reduction or slowing of the infiltration of cancer cells into peripheral organs; (v) a reduction or slowing of tumor metastasis; (vi) a reduction or inhibition of tumor growth; (vii) prevention or delay of the occurrence and / or recurrence of the cancer and / or an extension of disease-free or tumor-free survival; (viii) an increase in overall survival; (ix) a reduction in the frequency of treatment; (x) a reduction in cancer burden, and (xi) alleviation of one or more symptoms associated with the cancer, wherein the treatment comprises administering a therapeutically effective amount of the combination described herein to the subject in need of treatment.

[0219] In some embodiments, the combination is administered before, simultaneously with, after, or in a combination of before, simultaneously, and after the treatment of the primary tumor. In some embodiments, the treatment of the primary tumor comprises one or more of the group consisting of radiation, surgery, chemotherapy, immunotherapy, targeted therapy, hormone therapy, stem cell transplantation, cryotherapy, laser therapy, and precision medicine. In some embodiments, the HDAC inhibitor is administered as a single agent for a period of time before administering the combination. In some embodiments, the primary tumor is breast cancer, lung cancer, bladder cancer, skin cancer, intestinal cancer, colon cancer, kidney cancer, liver cancer, brain cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, thyroid cancer, head and neck cancer, gastroesophageal cancer, connective tissue or other non-epithelial tissue cancer, myeloid cell cancer, lymphocytic cell cancer, and uterine cancer.

[0220] Response criteria

[0221] RECIST:

[0222] RECIST is a set of established guidelines or criteria that are internationally recognized for evaluating patient response, stability, and progression in clinical trials and clinical practice. First published in 2000 and revised in 2009 (Eisenhauer EA et al; New response criteria in solid tumours: revised RECIST guideline (version 1.1); Eur J Cancer 2009; 45:228-47), as a joint effort of the European Organisation for Research and Treatment of Cancer, the National Cancer Institute of the United States, and the Clinical Trials Group of the National Cancer Institute of Canada, RECIST has traditionally been used to evaluate response to chemotherapy.

[0223] Assessment of target lesions:

[0224] Complete response (CR): All target lesions disappear; Partial response (PR): The sum of the LD (longest diameter) of target lesions is reduced by at least 30%, with the sum of LD at baseline as the reference; Stable disease (SD): Neither sufficient reduction to qualify for PR nor sufficient increase to qualify for PD, with the minimum sum of LD since the start of treatment as the reference; Progressive disease (PD): The sum of the LD of target lesions is increased by at least 20%, with the minimum sum of LD recorded since the start of treatment or the appearance of one or more new lesions as the reference

[0225] Assessment of non-target lesions

[0226] Complete response (CR): All non-target lesions disappear and tumour marker levels normalize; Incomplete response / Stable disease (SD): Persistence of one or more non-target lesions and / or maintenance of tumour marker levels above the normal limit; Progressive disease (PD): Appearance of one or more new lesions and / or definite progression of existing non-target lesions.

[0227] Other response criteria

[0228] Other response criteria include immune-related response criteria or iRECIST, as defined by Wolchok et al. in 2009 (Wolchok JD et al.; Guidelines for the Evaluation of Immune Therapy Activity in Solid Tumors: Immune-Related Response Criteria. Clin Cancer Res 2009;15(23):7412-20) and the Revised International Working Group Response Criteria (Cheson BD et al., Revised response criteria for malignant lymphoma. J Clin Oncol 2007;25:579-586).

[0229] Methods of treating cancer include methods of inhibiting cell growth by administering a therapeutically effective amount of a combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 inhibitor described herein. In one example, the PD-1 inhibitor is AMP-224. In another example, it is a method of inhibiting cell growth by administering a therapeutically effective amount of a combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from: nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680.

[0230] Also provided herein are methods of inhibiting cancer metastasis in a patient in need thereof by administering a therapeutically effective amount of a combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 inhibitor described herein. In one example, the PD-1 inhibitor is AMP-224. In another example, it is a method of inhibiting cancer metastasis in a patient in need thereof by administering a therapeutically effective amount of a combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from: nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In some embodiments, cancer metastasis is inhibited by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%.

[0231] On the other hand, there is a method for reducing pre-existing tumor metastasis in a cancer patient in need thereof by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of formula I described herein and a PD-1 inhibitor. In one example, the PD-1 inhibitor is AMP-224. In another example, there is a method for reducing pre-existing tumor metastasis in a cancer patient in need thereof by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of formula I and a PD-1 antibody selected from: nivolumab, pidilizumab, pembrolizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In some embodiments, the pre-existing tumor metastasis is reduced by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%.

[0232] On the other hand, the method for treating cancer further provides a method for reducing an individual's tumor burden by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of formula I described herein and a PD-1 inhibitor. In some embodiments, the method for treating cancer reduces the tumor or tumor burden of the patient. In one example, the PD-1 inhibitor is AMP-224. In another example, there is a method for reducing an individual's tumor burden by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of formula I and a PD-1 antibody selected from: nivolumab, pidilizumab, pembrolizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In some embodiments, the tumor burden is reduced by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%.

[0233] On the other hand, the method for treating cancer further provides a method for reducing an object's tumor burden by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of formula I and a PD-1 inhibitor described herein. In one example, the PD-1 inhibitor is AMP-224. In another example, there is a method for reducing an individual's tumor burden by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of formula I and a PD-1 antibody selected from: nivolumab, pidilizumab, pembrolizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210 or MEDI0680. In some embodiments, the tumor burden is reduced by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%.

[0234] The methods for treating cancer described herein also provide methods for increasing or otherwise prolonging the time to disease progression for certain stages, including advanced stages of cancer, such as stage III and stage IV cancers as described herein. By administering a therapeutically effective amount of the combination described herein, the time to disease progression in a patient can be prolonged, wherein the combination comprises a compound of formula I and a PD-1 inhibitor described herein. In one example, the PD-1 inhibitor is AMP-224. In another example, it is a method for increasing the time to disease progression in a patient by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of formula I and a PD-1 antibody selected from: nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210, or MEDI0680. In some embodiments, the increase is a comparison between the time to disease progression without treatment and with treatment with the combination described herein. In some embodiments, the methods described herein prolong the time to disease progression by at least 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, or longer, including the values therein.

[0235] The methods for treating cancer described herein also provide methods for increasing or otherwise prolonging the survival period (including overall survival) of a patient diagnosed with cancer as described herein. The survival period of a patient can be prolonged by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of formula I and a PD-1 inhibitor described herein. In one example, the PD-1 inhibitor is AMP-224. In another example, it is a method for prolonging the survival period of a patient by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of formula I and a PD-1 antibody selected from: nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210, or MEDI0680. In some embodiments, the increase is a comparison between the survival period without treatment and with treatment with the combination described herein. In some embodiments, the methods described herein prolong the survival period by at least 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, or longer, including the values therein.

[0236] The methods of treating cancer described herein also provide methods for increasing the progression-free survival of a patient diagnosed with cancer as described herein. The progression-free survival of a patient can be extended by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of Formula I described herein and a PD-1 inhibitor. In one example, the PD-1 inhibitor is AMP-224. In another example, it is a method for increasing the progression-free survival of a patient diagnosed with cancer by administering a therapeutically effective amount of the combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from the group consisting of nivolumab, pidilizumab, pirilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210, or MEDI0680. In some embodiments, the increase is a comparison between the progression-free survival without treatment and the progression-free survival with treatment with the combination described herein. In some embodiments, the methods described herein increase the progression-free survival by at least 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, or longer, including the values therein.

[0237] The present invention also provides a method for reducing the level of myeloid-derived suppressor cells (MDSC) in a patient in need thereof by administering an effective amount of the combination described herein, wherein the combination comprises a compound of Formula I described herein and a PD-1 inhibitor. In another example, it is a method for reducing the level of myeloid-derived suppressor cells (MDSC) in a patient in need thereof compared to administering the compound of Formula I or the PD-1 inhibitor alone by administering an effective amount of the combination described herein, wherein the combination comprises a compound of Formula I and a PD-1 antibody selected from the group consisting of nivolumab, pidilizumab, pirilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210, or MEDI0680. The reduction of MDSC can be beneficial for the treatment of cancer described herein. The level of MDSC in a human patient can be measured before, during, and after administration of the combination described herein. In some embodiments, it may be useful to compare the amount of MDSC before and after administration in a patient. A reduction in the amount, level, or number of MDSC after administration can indicate the effectiveness of the combination in, for example, treating cancer described herein. The MDSC level can be monitored using the combination described herein during the course of the treatment or protocol described herein. In this case, determining the MDSC level at various points during administration can indicate the effectiveness of the protocol.

[0238] The present invention also provides methods for reducing the percentage or level of Treg cells in a patient in need thereof. Such methods include administering an effective amount of a combination described herein, wherein the combination includes a compound of formula I described herein and a PD-1 inhibitor. In one example, the PD-1 inhibitor is AMP-224. In another example, a method for reducing the percentage or level of Treg cells in a patient in need thereof by administering to the patient an effective amount of a combination described herein, wherein the combination includes a compound of formula I and a PD-1 antibody selected from the group consisting of nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210, or MEDI0680, wherein the administration reduces the percentage or level of Treg cells in the patient as compared to the level prior to administration. The reduction of Treg cells can be beneficial for the treatment of cancer described herein. The level of Treg cells in a human patient can be measured before, during, and after administration of the combination described herein. In some embodiments, it may be useful to compare the amount of Treg cells before and after administration in a patient. A decrease in the amount, level, or number of Treg cells after administration may indicate the effectiveness of the combination in treating, for example, cancer described herein. The level of Treg cells can be monitored using the combination described herein during the course of a treatment or protocol described herein. In such cases, determining the level of Treg cells at various points during administration can indicate the effectiveness of the protocol.

[0239] The combinations described herein can be used in methods for enhancing natural killer (NK) cell activity. The combinations described herein can also be used in methods for enhancing cytotoxic T cell activity. The enhancing methods include contacting NK cells or cytotoxic T cells with a combination described herein, wherein the combination enhances the activity of NK cells or cytotoxic T cells relative to the activity prior to contact. In some embodiments, the enhanced activity of NK cells or cytotoxic T cells is in a cancer patient who has been administered a combination as described herein. Such combinations suitable for enhancing the activity of NK cells or cytotoxic T cells can include AMP-224. In other examples, the combinations for the methods described herein for enhancing the activity of NK cells or cytotoxic T cells include a PD-1 selected from the group consisting of nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210, or MEDI0680.

[0240] The combinations described herein can also enhance antibody-dependent cell-mediated cytotoxicity in a cancer patient after administration of the combination described herein.

[0241] The combinations described herein may include the administration of each therapy (e.g., a compound of Formula I and a PD-1 inhibitor), wherein the administrations are performed simultaneously or sequentially (in either order). In one embodiment, the compound of Formula I and the PD-1 inhibitor are administered simultaneously (e.g., within at least 1 to 5 minutes of each other). In another embodiment, the compound of Formula I and the PD-1 inhibitor are administered sequentially (e.g., within at least 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 5 hours, 10 hours, 12 hours, 1 day, 2 days, 5 days, 7 days, 14 days, or 21 days of each other).

[0242] In one instance, the compound of Formula I is administered simultaneously with a PD-1 antibody selected from nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as SAR-439684), PDR 001, SHR-1210, or MEDI0680. In another instance, the compound of Formula I may be administered before nivolumab. In another instance, the compound of Formula I may be administered before pembrolizumab. In another instance, the compound of Formula I may be administered before pidilizumab. In another instance, the compound of Formula I may be administered before REGN2810 (also known as SAR-439684). In another instance, the compound of Formula I may be administered before PDR 001. In another instance, the compound of Formula I may be administered before MEDI0680. In another instance, the compound of Formula I may be administered after nivolumab. In another instance, the compound of Formula I may be administered after pembrolizumab, atezolizumab, or SHR-1210. In another instance, the compound of Formula I may be administered after pidilizumab, atezolizumab, or SHR-1210. In another instance, the compound of Formula I may be administered after REGN2810 (also known as SAR-439684). In another instance, the compound of Formula I may be administered after PDR 001. In another instance, the compound of Formula I may be administered after MEDI0680.

[0243] In another instance, the compound of Formula I is administered simultaneously with AMP-224. In another instance, the compound of Formula I is administered before AMP-224. In another instance, the compound of Formula I is administered after AMP-224

[0244] The compound of formula I can be administered, for example, once daily (QD), twice daily (BID), once weekly (QW), twice weekly (BIW), three times a week (TIW), or monthly (QM). For example, the compound of formula I can be administered BID. The compound of formula I can be administered TIW. In certain cases, the compound of formula I is administered 2 to 3 times per week. In some embodiments, the compound of formula I is administered daily. In another embodiment, the compound of formula I is administered QD. The compound can be administered QD for about 1 day to about 7 days, 1 day to about 14 days, 1 day to about 21 days, 1 day to about 28 days, or daily until disease progression or unacceptable toxicity. Administration of the compound of formula I can depend in part on the patient's tolerance, where greater tolerance may permit a greater amount or more frequent administration. Alternatively, when a patient shows poor tolerance to the compound of formula I, a smaller amount of the compound or a lower frequency of administration can be carried out. Administration of the compound can also be stopped when the maximum therapeutic effect is reached and then resumed when further administration is needed, although there are alternative regimens and dosages. The compound of formula I can be administered according to any of the regimens described herein. In some embodiments, the PD-1 inhibitor and the compound of formula I are co-administered on day 1 of the administration regimen.

[0245] For example, the compound of Formula I can be administered in an amount of about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg or 200 mg QD. For example, the compound of Formula I can be administered in an amount of about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg or 200 mg BIW. For example, the compound of Formula I can be administered in an amount of about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg or 200 mg TIW. For example, the compound of Formula I can be administered in an amount of about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg or 200 mg QW. For example, the compound of Formula I can be administered in an amount of about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg or 200 mg Q2W. For example, the compound of Formula I can be administered in an amount of about 5 mg or about 10 mg QD. For example, the compound of Formula I can be administered in an amount of about 5 mg or about 10 mg BIW. For example, the compound of Formula I can be administered in an amount of about 5 mg or about 10 mg TIW. For example, the compound of Formula I can be administered in an amount of about 5 mg or about 10 mg QW. For example, the compound of Formula I can be administered in an amount of about 5 mg or about 10 mg Q2W. The administration of the compound of Formula I can be continuous. The administration of the compound of Formula I can be intermittent.

[0246] For example, the compound of formula I can be administered in an amount of about 1 mg to about 10 mg, 1 mg to about 25 mg, 1 mg to about 50 mg, 5 mg to about 10 mg, 5 mg to about 25 mg, 5 mg to about 50 mg, 10 mg to about 25 mg, 10 mg to about 50 mg, 50 mg to about 100 mg, or 100 mg to about 200 mg QD. For example, the compound of formula I can be administered in an amount of about 1 mg to about 10 mg, 1 mg to about 25 mg, 1 mg to about 50 mg, 5 mg to about 10 mg, 5 mg to about 25 mg, 5 mg to about 50 mg, 10 mg to about 25 mg, 10 mg to about 50 mg, 50 mg to about 100 mg, or 100 mg to about 200 mg BIW. For example, the compound of formula I can be administered in an amount of about 1 mg to about 10 mg, 1 mg to about 25 mg, 1 mg to about 50 mg, 5 mg to about 10 mg, 5 mg to about 25 mg, 5 mg to about 50 mg, 10 mg to about 25 mg, 10 mg to about 50 mg, 50 mg to about 100 mg, or 100 mg to about 200 mg TIW. For example, the compound of formula I can be administered in an amount of about 1 mg to about 10 mg, 1 mg to about 25 mg, 1 mg to about 50 mg, 5 mg to about 10 mg, 5 mg to about 25 mg, 5 mg to about 50 mg, 10 mg to about 25 mg, 10 mg to about 50 mg, 50 mg to about 100 mg, or 100 mg to about 200 mg QW. For example, the compound of formula I can be administered in an amount of about 1 mg to about 10 mg, 1 mg to about 25 mg, 1 mg to about 50 mg, 5 mg to about 10 mg, 5 mg to about 25 mg, 5 mg to about 50 mg, 10 mg to about 25 mg, 10 mg to about 50 mg, 50 mg to about 100 mg, or 100 mg to about 200 mg Q2W. The administration of the compound of formula I can be continuous. The administration of the compound of formula I can be intermittent.

[0247] For example, the compound of formula I can be administered in an amount of about 0.0001 mg / kg to about 200 mg / kg, 0.001 mg / kg to about 200 mg / kg, 0.01 mg / kg to about 200 mg / kg, 0.01 mg / kg to about 150 mg / kg, 0.01 mg / kg to about 100 mg / kg, 0.01 mg / kg to about 50 mg / kg, 0.01 mg / kg to about 25 mg / kg, 0.01 mg / kg to about 10 mg / kg or 0.01 mg / kg to about 5 mg / kg QD. For example, the compound of formula I can be administered in an amount of about 0.0001 mg / kg to about 200 mg / kg, 0.001 mg / kg to about 200 mg / kg, 0.5 mg / kg to about 200 mg / kg, 0.5 mg / kg to about 150 mg / kg, 0.5 mg / kg to about 100 mg / kg, 0.5 mg / kg to about 50 mg / kg, 0.5 mg / kg to about 25 mg / kg, 0.5 mg / kg to about 10 mg / kg or 0.5 mg / kg to about 5 mg / kg BIW. For example, the compound of formula I can be administered in an amount of about 0.0001 mg / kg to about 200 mg / kg, 0.001 mg / kg to about 200 mg / kg, 0.5 mg / kg to about 200 mg / kg, 0.5 mg / kg to about 150 mg / kg, 0.5 mg / kg to about 100 mg / kg, 0.5 mg / kg to about 50 mg / kg, 0.5 mg / kg to about 25 mg / kg, 0.5 mg / kg to about 10 mg / kg or 0.5 mg / kg to about 5 mg / kg TIW.For example, the compound of formula I can be administered in an amount of about 0.0001 mg / kg to about 200 mg / kg, 0.001 mg / kg to about 200 mg / kg, 0.5 mg / kg to about 200 mg / kg, 0.5 mg / kg to about 150 mg / kg, 0.5 mg / kg to about 100 mg / kg, 0.5 mg / kg to about 50 mg / kg, 0.5 mg / kg to about 25 mg / kg, 0.5 mg / kg to about 10 mg / kg, or 0.5 mg / kg to about 5 mg / kg of QW. For example, the compound of formula I can be administered in an amount of about 0.0001 mg / kg to about 200 mg / kg, 0.001 mg / kg to about 200 mg / kg, 0.5 mg / kg to about 200 mg / kg, 0.5 mg / kg to about 150 mg / kg, 0.5 mg / kg to about 100 mg / kg, 0.5 mg / kg to about 50 mg / kg, 0.5 mg / kg to about 25 mg / kg, 0.5 mg / kg to about 10 mg / kg, or 0.5 mg / kg to about 5 mg / kg of Q2W. The administration of the compound of formula I can be continuous. The administration of the compound of formula I can be intermittent.

[0248] For example, the compound of formula I can be administered in an amount of about 1 mg / kg to about 200 mg / kg, 1 mg / kg to about 150 mg / kg, 1 mg / kg to about 100 mg / kg, 1 mg / kg to about 50 mg / kg, 1 mg / kg to about 25 mg / kg, 1 mg / kg to about 10 mg / kg, or 1 mg / kg to about 5 mg / kg QD. For example, the compound of formula I can be administered in an amount of about 1 mg / kg to about 200 mg / kg, 1 mg / kg to about 150 mg / kg, 1 mg / kg to about 100 mg / kg, 1 mg / kg to about 50 mg / kg, 1 mg / kg to about 25 mg / kg, 1 mg / kg to about 10 mg / kg, or 1 mg / kg to about 5 mg / kg BIW. For example, the compound of formula I can be administered in an amount of about 1 mg / kg to about 200 mg / kg, 1 mg / kg to about 150 mg / kg, 1 mg / kg to about 100 mg / kg, 1 mg / kg to about 50 mg / kg, 1 mg / kg to about 25 mg / kg, 1 mg / kg to about 10 mg / kg, or 1 mg / kg to about 5 mg / kg TIW. For example, the compound of formula I can be administered in an amount of about 1 mg / kg to about 200 mg / kg, 1 mg / kg to about 150 mg / kg, 1 mg / kg to about 100 mg / kg, 1 mg / kg to about 50 mg / kg, 1 mg / kg to about 25 mg / kg, 1 mg / kg to about 10 mg / kg, or 1 mg / kg to about 5 mg / kg QW. For example, the compound of formula I can be administered in an amount of about 1 mg / kg to about 200 mg / kg, 1 mg / kg to about 150 mg / kg, 1 mg / kg to about 100 mg / kg, 1 mg / kg to about 50 mg / kg, 1 mg / kg to about 25 mg / kg, 1 mg / kg to about 10 mg / kg, or 1 mg / kg to about 5 mg / kg Q2W. In one example, the compound of formula I can be administered in an amount of about 15 mg / kg to about 75 mg / kg QD. In another example, the compound of formula I can be administered in an amount of about 20 mg / kg to about 50 mg / kg. In another example, the compound of formula I can be administered in an amount of about 0.001 mg / kg, 0.01 mg / kg, 0.05 mg / kg, 0.1 mg / kg, 0.5 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 40 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, 100 mg / kg, 125 mg / kg, 150 mg / kg, 175 mg / kg, or 200 mg / kg. The administration of the compound of formula I can be continuous.Administration of the compound of formula I can be intermittent.

[0249] As used herein, the term daily is intended to mean that the therapeutic compound (such as the compound of formula I) of the combination described herein is administered one or more times per day for a period of time. The term continuous is intended to mean that the therapeutic compound (such as the compound of formula I) of the combination described herein is administered daily for an uninterrupted period of at least 10 days to 52 weeks. The term intermittent or intermittently as used herein is intended to mean stopping and starting at regular or irregular intervals. For example, intermittent administration of the therapeutic compound (such as the compound of formula I) of the combination described herein includes administering 1 - 6 days per week (such as 2 to 3 times per week or QD), administering cyclically (such as administering daily for 2 to 8 consecutive weeks followed by a rest period of at least one day without administration), or administering every other day, for example.

[0250] When the PD-1 inhibitor is a PD-1 antibody, it can be administered according to an established protocol, such as the protocol provided in the package insert. The PD-1 antibody can be administered in the amounts described herein and can be administered QW, once every two weeks (Q2W), or once every three weeks (Q3W). In one embodiment, the PD-1 antibody is administered every two or three weeks. In another embodiment, the PD-1 antibody is administered Q2W. In another embodiment, the PD-1 antibody is administered Q3W. In another embodiment, the PD-1 antibody is administered BIW for at least 3 weeks.

[0251] For example, nivolumab can be administered in an amount of about 0.1 to about 10 mg / kg (including, for example, 0.1 mg / kg, 0.3 mg / kg, 0.5 mg / kg, 0.7 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg) QW. For example, nivolumab can be administered in an amount of about 0.1 to about 10 mg / kg (including, for example, 0.1 mg / kg, 0.3 mg / kg, 0.5 mg / kg, 0.7 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg) Q2W. For example, nivolumab can be administered in an amount of about 0.1 to about 10 mg / kg (including, for example, 0.1 mg / kg, 0.3 mg / kg, 0.5 mg / kg, 0.7 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg) Q4W. For example, nivolumab can be administered in an amount of about 0.1 to about 10 mg / kg (including, for example, 0.1 mg / kg, 0.3 mg / kg, 0.5 mg / kg, 0.7 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg), B4W (twice every 4 weeks). For example, nivolumab can be administered in an amount of about 0.1 to about 10 mg / kg (including, for example, 0.1 mg / kg, 0.3 mg / kg, 0.5 mg / kg, 0.7 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg) Q3W. Administration of nivolumab can be continuous. Administration of nivolumab can be intermittent.

[0252] Nivolumab can be administered as an intravenous infusion over about 10, 20, 30, 40, 50 or 60 minutes or longer. Nivolumab can be administered as an intravenous infusion over about 60 minutes once every 1, 2, 3, 4, 5 or more weeks. Nivolumab can be administered as an intravenous infusion over about 60 minutes once every two weeks. Nivolumab can be administered as an intravenous infusion over about 60 minutes once every three weeks. Nivolumab can be administered as an intravenous infusion over about 60 minutes once every four weeks. Nivolumab can be administered as an intravenous infusion in accordance with the package insert. Administration of nivolumab can be continuous. Administration of nivolumab can be intermittent.

[0253] For example, pembrolizumab can be administered in an amount of about 0.5 to about 20 mg / kg (including, for example, 0.5 mg / kg, 0.7 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 15 mg / kg). For example, pembrolizumab can be administered in an amount of about 0.5 to about 20 mg / kg (including, for example, 0.5 mg / kg, 0.7 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 15 mg / kg) QW. For example, pembrolizumab can be administered in an amount of about 0.5 to about 20 mg / kg (including, for example, 0.5 mg / kg, 0.7 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 15 mg / kg) Q2W. For example, pembrolizumab can be administered in an amount of about 0.5 to about 20 mg / kg (including, for example, 0.5 mg / kg, 0.7 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 15 mg / kg) Q3W. For example, pembrolizumab can be administered in an amount of about 0.5 to about 20 mg / kg (including, for example, 0.5 mg / kg, 0.7 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 15 mg / kg) Q4W. The administration of pembrolizumab can be continuous. The administration of pembrolizumab can be intermittent.

[0254] Pembrolizumab can be administered as an intravenous infusion over about 10, 20, 30, 40, 50 or 60 minutes or longer. Pembrolizumab can be administered as an intravenous infusion over about 60 minutes once every 1, 2, 3, 4, 5 or more weeks. Pembrolizumab can be administered as an intravenous infusion over about 60 minutes once every two weeks. Pembrolizumab can be administered as an intravenous infusion over about 60 minutes once every three weeks. Pembrolizumab can be administered as an intravenous infusion over about 60 minutes once every four weeks. Pembrolizumab can be administered according to the provided package insert. The administration of pembrolizumab can be continuous. The administration of pembrolizumab can be intermittent.

[0255] For example, pirtobrutinib can be administered in an amount of about 0.1 to about 30 mg / kg (including, for example, 0.1 mg / kg, 0.3 mg / kg, 0.5 mg / kg, 0.7 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg) QW. For example, pirtobrutinib can be administered in an amount of about 0.1 to about 30 mg / kg (including, for example, 0.1 mg / kg, 0.3 mg / kg, 0.5 mg / kg, 0.7 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg) Q2W. For example, pirtobrutinib can be administered in an amount of about 0.1 to about 30 mg / kg (including, for example, 0.1 mg / kg, 0.3 mg / kg, 0.5 mg / kg, 0.7 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg) Q3W. For example, pirtobrutinib can be administered in an amount of about 0.1 to about 30 mg / kg (including, for example, 0.1 mg / kg, 0.3 mg / kg, 0.5 mg / kg, 0.7 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg) Q4W. The administration of pirtobrutinib can be continuous. The administration of pirtobrutinib can be intermittent.

[0256] Pirtobrutinib can be administered as an intravenous infusion over about 10, 20, 30, 40, 50, or 60 minutes or longer. Pirtobrutinib can be administered as an intravenous infusion over about 60 minutes once every 1, 2, 3, 4, 5, or more weeks. Pirtobrutinib can be administered as an intravenous infusion over about 60 minutes once every two weeks. Pirtobrutinib can be administered as an intravenous infusion over about 60 minutes once every three weeks. Pirtobrutinib can be administered as an intravenous infusion over about 60 minutes once every four weeks. The administration of pirtobrutinib can be continuous. The administration of pirtobrutinib can be intermittent.

[0257] For example, AMP-224 can be administered in an amount of about 1 to about 50 mg / kg (including, for example, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg) QW. For example, AMP-224 can be administered in an amount of about 1 to about 50 mg / kg (including, for example, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg) Q2W. For example, AMP-224 can be administered in an amount of about 1 to about 50 mg / kg (including, for example, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg) Q3W (for example, by subcutaneous administration). For example, AMP-224 can be administered in an amount of about 1 to about 50 mg / kg (including, for example, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg) Q4W (for example, by subcutaneous administration). The administration of AMP-224 can be continuous. The administration of AMP-224 can be intermittent.

[0258] AMP-224 can be administered as an intravenous infusion over about 10, 20, 30, 40, 50 or 60 minutes or longer. AMP-224 can be administered as an intravenous infusion over about 60 minutes once every 1, 2, 3, 4, 5 or more weeks. AMP-224 can be administered as an intravenous infusion over about 60 minutes once every two weeks. AMP-224 can be administered as an intravenous infusion over about 60 minutes twice every three weeks. AMP-224 can be administered as an intravenous infusion over about 60 minutes three times every six weeks. The administration of AMP-224 can be continuous. The administration of AMP-224 can be intermittent.

[0259] For example, REGN2810 (also known as SAR-439684) can be administered in an amount of about 0.1 to about 30 mg / kg (including, for example, 0.1 mg / kg, 0.3 mg / kg, 0.5 mg / kg, 0.7 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg) Q2W. For example, REGN2810 (also known as SAR-439684) can be administered in an amount of about 0.1 to about 30 mg / kg (including, for example, 0.1 mg / kg, 0.3 mg / kg, 0.5 mg / kg, 0.7 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg) Q4W. For example, REGN2810 (also known as SAR-439684) can be administered in an amount of about 0.1 to about 30 mg / kg (including, for example, 0.1 mg / kg, 0.3 mg / kg, 0.5 mg / kg, 0.7 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg) B4W. For example, REGN2810 (also known as SAR-439684) can be administered in an amount of about 0.1 to about 30 mg / kg (including, for example, 0.1 mg / kg, 0.3 mg / kg, 0.5 mg / kg, 0.7 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg) QW. The administration of REGN2810 (also known as SAR-439684) can be continuous. The administration of REGN2810 can be intermittent.

[0260] REGN2810 (also known as SAR-439684) can be administered as an intravenous infusion over about 10, 20, 30, 40, 50, or 60 minutes or longer. REGN2810 (also known as SAR-439684) can be administered as an intravenous infusion over about 60 minutes once every 1, 2, 3, 4, 5, or more weeks. REGN2810 (also known as SAR-439684) can be administered as an intravenous infusion over about 60 minutes once every two weeks. REGN2810 (also known as SAR-439684) can be administered as an intravenous infusion over about 60 minutes twice every three weeks. REGN2810 (also known as SAR-439684) can be administered as an intravenous infusion over about 60 minutes three times every six weeks. Administration of REGN2810 (also known as SAR-439684) can be continuous. Administration of REGN2810 (also known as SAR-439684) can be intermittent.

[0261] For example, PDR 001 can be administered in an amount of about 0.5 to about 30 mg / kg (including, for example, 0.1 mg / kg, 0.3 mg / kg, 0.5 mg / kg, 0.7 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg) QW. For example, PDR 001 can be administered in an amount of about 0.5 to about 30 mg / kg (including, for example, 0.1 mg / kg, 0.3 mg / kg, 0.5 mg / kg, 0.7 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg) Q2W. For example, PDR 001 can be administered in an amount of about 0.5 to about 30 mg / kg (including, for example, 0.1 mg / kg, 0.3 mg / kg, 0.5 mg / kg, 0.7 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg) Q3W. For example, PDR 001 can be administered in an amount of about 0.5 to about 30 mg / kg (including, for example, 0.1 mg / kg, 0.3 mg / kg, 0.5 mg / kg, 0.7 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg) Q4W. The administration of PDR 001 can be continuous. The administration of PDR 001 can be intermittent.

[0262] PDR 001 can be administered as an intravenous infusion over about 10, 20, 30, 40, 50 or 60 minutes or longer. PDR 001 can be administered as an intravenous infusion over about 60 minutes once every 1, 2, 3, 4, 5 or more weeks. PDR 001 can be administered as an intravenous infusion over about 60 minutes once every two weeks. PDR 001 can be administered as an intravenous infusion over about 60 minutes twice every three weeks. PDR 001 can be administered as an intravenous infusion over about 60 minutes once every three weeks. The administration of PDR 001 can be continuous. The administration of PDR 001 can be intermittent.

[0263] For example, MEDI0680 can be administered in an amount of about 0.5 to about 30 mg / kg (including, for example, 0.1 mg / kg, 0.3 mg / kg, 0.5 mg / kg, 0.7 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg) QW. For example, MEDI0680 can be administered in an amount of about 0.5 to about 30 mg / kg (including, for example, 0.1 mg / kg, 0.3 mg / kg, 0.5 mg / kg, 0.7 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg) Q2W. For example, MEDI0680 can be administered in an amount of about 0.5 to about 30 mg / kg (including, for example, 0.1 mg / kg, 0.3 mg / kg, 0.5 mg / kg, 0.7 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg) Q3W. For example, MEDI0680 can be administered in an amount of about 0.5 to about 30 mg / kg (including, for example, 0.1 mg / kg, 0.3 mg / kg, 0.5 mg / kg, 0.7 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg) Q4W. The administration of MEDI0680 can be continuous. The administration of MEDI0680 can be intermittent.

[0264] MEDI0680 can be administered as an intravenous infusion over about 10, 20, 30, 40, 50 or 60 minutes or longer. MEDI0680 can be administered as an intravenous infusion over about 60 minutes once every 1, 2, 3, 4, 5 or more weeks. MEDI0680 can be administered as an intravenous infusion over about 60 minutes once every two weeks. MEDI0680 can be administered as an intravenous infusion over about 60 minutes twice every three weeks. MEDI0680 can be administered as an intravenous infusion over about 60 minutes once every three weeks. The administration of MEDI0680 can be continuous. The administration of MEDI0680 can be intermittent.

[0265] For example, SHR-1210 can be administered in an amount of about 0.5 to about 20 mg / kg (including, for example, 0.1 mg / kg, 0.3 mg / kg, 0.5 mg / kg, 0.7 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg) QW. For example, SHR-1210 can be administered in an amount of about 0.5 to about 20 mg / kg (including, for example, 0.1 mg / kg, 0.3 mg / kg, 0.5 mg / kg, 0.7 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg) Q2W. For example, SHR-1210 can be administered in an amount of about 0.5 to about 20 mg / kg (including, for example, 0.1 mg / kg, 0.3 mg / kg, 0.5 mg / kg, 0.7 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg) Q3W. For example, SHR-1210 can be administered in an amount of about 0.5 to about 20 mg / kg (including, for example, 0.1 mg / kg, 0.3 mg / kg, 0.5 mg / kg, 0.7 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg) Q4W. The administration of SHR-1210 can be continuous. The administration of SHR-1210 can be intermittent.

[0266] SHR-1210 can be administered as an intravenous infusion over about 10, 20, 30, 40, 50 or 60 minutes or longer. SHR-1210 can be administered as an intravenous infusion over about 60 minutes once every 1, 2, 3, 4, 5 or more weeks. SHR-1210 can be administered as an intravenous infusion over about 60 minutes once every two weeks. SHR-1210 can be administered as an intravenous infusion over about 60 minutes twice every three weeks. SHR-1210 can be administered as an intravenous infusion over about 60 minutes once every three weeks. The administration of SHR-1210 can be continuous. The administration of SHR-1210 can be intermittent.

[0267] The combinations described herein can be administered according to a regimen. The regimen can be constructed to provide a therapeutically effective amount of a compound of formula I and a PD-1 inhibitor (e.g., a PD-1 antibody) over a predetermined period of time (e.g., the administration period). The regimen can be constructed to limit or prevent side effects or undesirable complications of each component of the combinations described herein. The regimen can be constructed in a manner that results in an increased (e.g., synergistic) effect of the two therapies of the combination. A regimen suitable for treating cancer can include any number of days of administration that can be repeated as necessary. The administration period can be broken by including a rest period during which at least one therapy is not administered. For example, the regimen can include an administration period that includes 2, 3, 5, 7, 10, 15, 21, 28 or more days. These periods can be repeated. For example, the regimen can include a set number of days as previously described, where the regimen is repeated 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or more times.

[0268] The regimen can include a rest period of at least 1, 2, 3, 5, 7, 10 or more days during which at least one therapy is no longer administered to the patient. The rest period can be determined, for example, by monitoring the patient's response to the drug or by measuring the therapeutic efficacy. The rest period can be applicable to a single therapy such that only one therapy of the combinations described herein is stopped during the rest period, but the other therapies are still administered. The rest period can be applied to all therapies administered to the subject such that the subject does not receive therapy for a set period of time during the rest period. In some embodiments, the combinations described herein are administered to the patient according to a regimen.

[0269] The regimens described herein for using the combinations described herein to treat cancer can continue until disease progression or unacceptable toxicity.

[0270] Regimens for administering the combinations described herein include, for example, administering a compound of Formula I and a PD-1 inhibitor at BIW or TIW. For example, the compound of Formula I can be administered QD for about 21 days, and the PD-1 antibody described herein can be administered Q2W or Q4W). For example, the compound of Formula I can be administered BIW or TIW, and the PD-1 antibody described herein can be administered Q2W. In another exemplary regimen, the compound of Formula I can be administered BIW or TIW, and the PD-1 antibody can be administered BIW for 2 or 3 weeks. In another exemplary regimen, the compound of Formula I can be administered BIW or TIW, and the PD-1 antibody can be administered Q3W. In another exemplary regimen, the compound of Formula I can be administered BIW, and the PD-1 inhibitor described herein can be administered QW, Q2W or Q3W. In certain cases, such regimens include administering the PD-1 antibody at QW, Q2W or Q3W. In another exemplary regimen, the compound of Formula I can be administered TIW, and the PD-1 inhibitor described herein can be administered QW, Q2W or Q3W. In certain cases, such regimens include administering the PD-1 antibody at QW, Q2W or Q3W. In certain cases, such regimens include administering the compound of Formula I at QD. In certain cases, such regimens include administering the compound of Formula I at QD for at least 21 days. In another exemplary regimen, the compound of Formula I can be administered QD or QW, and the PD-1 inhibitor (e.g., PD-1 antibody) is administered at QW, Q2W or Q3W. In some embodiments, the compound of Formula I of the combination described herein is administered 2 to 3 times per week and the PD-1 antibody is administered once every 2 to 3 weeks. In some embodiments, the compound of Formula I of the combination described herein is administered QD for 21 days and the PD-1 antibody is administered once every 2 to 3 weeks.

[0271] The regimen can be a regimen of administering pembrolizumab in combination with a compound of formula I as described herein. In one exemplary regimen that includes pembrolizumab, the compound of formula I can be administered BIW or TIW, and pembrolizumab is administered according to the prescription information provided, for example, in the package insert. In another exemplary regimen, on day 1 of the regimen, pembrolizumab is administered in an amount of about 1 mg / kg to about 10 mg / kg, and then administered BIW for at least three weeks until disease progression or unacceptable toxicity, and the compound of formula I is administered BIW or TIW during the same period. In another exemplary regimen, on day 1 of the regimen, pembrolizumab is administered in an amount of about 1 mg / kg to about 10 mg / kg, and then administered Q3W until disease progression or unacceptable toxicity, and the compound of formula I is administered BIW or TIW during the same period. Pembrolizumab can be administered BIW for 3 weeks in combination with the compound of formula I, wherein the compound of formula I is administered during such a regimen, for example, BIW or TIW. Pembrolizumab can be administered QW for 3 weeks in combination with the compound of formula I, wherein the compound of formula I is administered during such a regimen, for example, BIW or TIW. In another exemplary regimen, pembrolizumab can be administered QW for 3 weeks in combination with the compound of formula I, wherein the compound of formula I is administered during such a regimen, for example, QD or QW. These regimens can be repeated as described above (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more times).

[0272] In another exemplary regimen that includes pembrolizumab, the compound of formula I can be administered QD, and pembrolizumab is administered according to the prescription information provided, for example, in the package insert. In another exemplary regimen, on day 1 of the regimen, pembrolizumab is administered in an amount of about 1 mg / kg to about 10 mg / kg, and then administered BIW for at least three weeks until disease progression or unacceptable toxicity, and the compound of formula I is administered QD during the same period. In another exemplary regimen, on day 1 of the regimen, pembrolizumab is administered in an amount of about 1 mg / kg to about 10 mg / kg, and then administered Q3W until disease progression or unacceptable toxicity, and the compound of formula I is administered QD during the same period. Pembrolizumab can be administered BIW for 3 weeks in combination with the compound of formula I, wherein the compound of formula I is administered during such a regimen, for example, QD. Pembrolizumab can be administered QW for 3 weeks in combination with the compound of formula I, wherein the compound of formula I is administered during such a regimen, for example, QD. These regimens can be repeated as described above (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more times).

[0273] The regimen can be a regimen of administering nivolumab in combination with a compound of formula I described herein. In one exemplary regimen comprising nivolumab, the compound of formula I can be administered BIW or TIW, and nivolumab is administered according to the prescribing information provided, for example, in the package insert. In another exemplary regimen, on day 1 of the regimen, nivolumab is administered at a dose of about 1 mg / kg to about 5 mg / kg, and then administered BIW for 3 weeks until disease progression or unacceptable toxicity, and the compound of formula I is administered BIW or TIW during the same period. In another exemplary regimen, on day 1 of the regimen, nivolumab is administered at a dose of about 1 mg / kg to about 5 mg / kg, and then administered Q2W until disease progression or unacceptable toxicity, and the compound of formula I is administered BIW or TIW during the same period. In another exemplary regimen, nivolumab can be administered Q2W, wherein the compound of formula I is administered during such a regimen, for example, BIW or TIW. In another exemplary regimen, nivolumab can be administered Q2W, wherein the compound of formula I is administered during such a regimen, for example, QD or QW. These regimens can be repeated as described above (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more times).

[0274] In another exemplary regimen comprising nivolumab, the compound of formula I can be administered QD, and nivolumab is administered according to the prescribing information provided, for example, in the package insert. In another exemplary regimen, on day 1 of the regimen, nivolumab is administered at a dose of about 1 mg / kg to about 5 mg / kg, and then administered BIW for 3 weeks until disease progression or unacceptable toxicity, and the compound of formula I is administered QD during the same period. In another exemplary regimen, on day 1 of the regimen, nivolumab is administered at a dose of about 1 mg / kg to about 5 mg / kg, and then administered Q2W until disease progression or unacceptable toxicity, and the compound of formula I is administered QD during the same period. In another exemplary regimen, nivolumab can be administered Q2W, wherein the compound of formula I is administered during such a regimen, for example, QD. These regimens can be repeated as described above (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more times).

[0275] It should also be understood that the combinations for treating cancer described herein can be co-administered with other active agents (such as anti-cancer agents) in addition to those present in the combinations described herein. The regimens for administering the combinations described herein can be modified as needed, including the above exemplary regimens, to include the administration of such active agents. The administration of such active agents (such as anti-cancer agents) can be carried out QD, QW, QM, BID, BIW, TIW, Q2W, Q3W, or Q4W, or according to the prescribing information of such anti-cancer agents as set forth, for example, in the package insert. Exemplary anti-cancer agents include, but are not limited to: ABRAXANE; abiraterone; ace-11; aclarubicin; acivicin; acodazole hydrochloride; acronine; actinomycin; acylfulvene; adenocyclopentanol; adozelesin; adriamycin; aldesleukin; all-trans retinoic acid (ATRA); altretamine; ambamustine; ambramycin; ametantrone acetate; amidox; amifostine; aminoglutethimide; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; antarelix; anthramycin; aphidicolin glycinate; depurinating acid; ara-CDP-DL-PTBA; arginine deiminase; ARRY-162; ARRY-300; ARRY-142266; AS703026; asparaginase; atelocollagen; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; diazo-tyrosine; azacitidine; AZD8330; azetepa; azotomycin; balanol; batimastat; BAY 11-7082; BAY 43-9006; BAY 869766; bendamustine; benzoporphyrin; benzodepa; benzoyl staurosporine; beta-alethine; beta-clarithromycin B; betulinic acid; b-FGF inhibitor; bicalutamide; bisantrene; bisaziridinyl spermine; bisnafide; bisnafide dimethanesulfonate; bistratene A;Bisantrene hydrochloride; Bleomycin; Bleomycin sulfate; Busulfan; Bizelesin; Breflate; Bortezomib; Brequinar sodium; Bropirimine; Budotitane; Buthionine sulfoximine; Bryostatin; Actinomycin C; Dimethandrolone; Calcipotriol; Calponin C; Camptothecin derivatives; Capecitabine; Formamide-amino triazole; Carboxyamidotriazole; CaRest M3; CARN700; Caracemide; Carbetimer; Carboplatin; Carmustine; Carubicin hydrochloride; Carzelesin; Castanospermine; Cecropin B; Cedefingol; Celecoxib; Cetrorelix; Chlorin; Chlorquinoxaline sulfonamide; Cicaprost; Chlorambucil; Chlorofusin; Cirolemycin; Cisplatin; CI-1040; Cis-porphyrin; Cladribine; Clomifene analogs; Clotrimazole; Collismycin A; Collismycin B; Combretastatin A4; Combretastatin analogs; Conagenin; Crambescidin 816; Crisnatol; Crisnatol mesylate; Nostocyclamide 8; Nostocyclamide A derivatives; Curacin A; Cyclopentanthraquinone; Cycloplatam; Cypemycin; Cyclophosphamide; Cytarabine; Cytarabine ocfosfate; Cytolytic factors; Cytostatin; Decarbazine; Dactinomycin; Daunomycin; Daunomycin hydrochloride; Decarbazine; Dacliximab; Dasatinib; Decitabine; Dehydrodidemnin B; Deslorelin; Dexamethasone; Ifosfamide; Dexrazoxane; Dexverapamil; Dexormaplatin; Dezaguanine; Dezaguanine mesylate; Diaziquone; Didemnin B; Didox; Diethylnorspermine;Dihydro-5-azacytidine; docetaxel; 9-dioxamycin; diphenylspiromustine; behenyl alcohol; dolasetron; docetaxel; doxorubicin; doxorubicin hydrochloride; doxifluridine; droloxifene; droloxifene citrate; methyltestosterone propionate; dronabinol; bizelesin; p-carzinophilin SA; ebselen; ecomustine; edelfosine; edrecolomab; edatrexate; eflornithine hydrochloride; eflornithine; elemene; emitefur; elsamitrucin; enloplatin; empenthrate; epipropidine; epirubicin; epirubicin hydrochloride; epristeride; erbulozole; eribulin; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etazolate; etoposide; etoposide phosphate; etoprine; exemestane; fadrozole; fadrozole hydrochloride; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fluorouracil; fludarabine phosphate; fludarabine; fludarabine phosphate; fludarubicin hydrochloride; forfenimex; formestane; fluorouracil; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitor; gemcitabine; geldanamycin; gossypol; GDC-0973; GSK1120212 / trametinib; herceptin; hydroxyurea; hepsulfam; amphiregulin; hexamethylenediacetamide; hypericin; ibandronic acid; ibrutinib; idamycin; idamycin hydrochloride;Ifosfamide; Conphosfamide; Ilmofosine; Iproplatin; Idoxifene; Idramantone; Ilmofosine; Ilomastat; Imidazacridone; Imatinib (e.g., GLEEVEC); Imiquimod; Iobenguane; Iodoxorubicin; Ipomeanol; Irinotecan; Irinotecan Hydrochloride; Irsogladine; Isobenzoguanazole; Isohomohalicondrin B; Itasetron; Iimofosine; Interleukin IL-2 (including recombinant interleukin II; or rlL.sub.2); Interferon α-2a; Interferon α-2b; Interferon α-n1; Interferon α-n3; Interferon β-1a; Interferon γ-1b; Jasplakinolide; Kahalalide F; Calyculin A Triacetate; Lanreotide; Leinamycin; Lenograstim; Lentinan Sulfate; Leptolstatin; Letrozole; Leuprorelin; Levamisole; Lenalidomide; Lenvatinib; Liaozole; Lissoclinamide 7; Lobaplatin; Lumbrokinase Phospholipid; Lometrexol; Lonidamine; Losoxantrone; Lovastatin; Loxoribine; Lurtotecan; Lutetium Texaphyrin; Lysofylline; Lanreotide Acetate; Lapatinib; Letrozole; Folinic Acid; Leuprorelin Acetate; Liaozole Hydrochloride; Lometrexol Sodium; Lomustine; Losoxantrone Hydrochloride; Pomalidomide; LY294002; Maitansine; Mannostatin A; Marimastat; Masoprocol; Breast Secretory Proteinase Inhibitor; Matrilysin Inhibitor; Menogaril; Merbarone; Meterelin; Methioninase; Metoclopramide; MIF Inhibitor; Mifepristone; Miltefosine; Mirimostim; Mitoguazone; Mitobromol; Mitonafide; Mitoxantrone; Mofarotene;Molgramostim; Mopidamol; Indian Ocean sponge B; Myriaporone; Maytansine; Mechlorethamine Hydrochloride; Megestrol Acetate; Methylene Estradiol Acetate; Melphalan; Mercaptopurine; Methotrexate; Methotrexate Sodium; Clopidogrel; Meturedepa; Mitindomide; Mitocarcin; Mitocromin; Mitogillin; Mitomalcin; Mitomycin; Mitosper; Mitotane; Mitoxantrone Hydrochloride; Mycophenolic Acid; Nafarelin; Nagrestip; Napavin; Naphterpin; Nartograstim; Nedaplatin; Nemorubicin; Neridronic Acid; Nilutamide; Nisamycin; Nitric Oxide Modulator; Nitrogen Oxide Antioxidant; Nitrullyn; Nocodazole; Nocardicin; Genasense; Octreotide; Oxyquin; Oligonucleotide; Onapristone; Ondansetron; Ondansetron; Oracin; Oral Cytokine Inducer; Ormaplatin; Oxisuran; Oxaliplatin; Osaterone; Oxaliplatin; Ernomycin; Barasubamide; Palmitoyl Zoxisine; Pamidronic Acid; Panaxatriol; Panomifene; Parabactin; Pazelliptine; Pegaspargase; Peldesine; Sodium Pentosan Polysulfate; Pentostatin; Pantoprazole; Perflubron; Pipophosfamide; Perillyl Alcohol; Phenamycin; Phenylacetate; Phosphatase Inhibitor; Picibanil; Pilocarpine Hydrochloride; Pirarubicin; Piritrexim; Placetin A; Placetin B; Porfiromycin; Prednisone; Prostaglandin J2; Pyrazoloacridine; Paclitaxel; PD035901; PD184352; PD318026; PD98059; Peliomycin; Pentamustine; Peplomycin Sulfate; PKC412;Piperbromide; Piposulfan; Pyroxyquinone Hydrochloride; Plicamycin; Plomestane; Podophyllotoxin; Polyphenol E; Porfimer Sodium; Porfiromycin; Prednimustine; Procarbazine; Procarbazine Hydrochloride; Puromycin; Puromycin Hydrochloride; Pyrazofurin; Raltitrexed; Ramosetron; Demethylretelliptine; Rhizoxin; Rituximab; RII Retinamide; Rogletimide; Rohitukine; Romurtide; Roquinimex; Rubiginone B1; Ruboxyl; Riboadenosine; Romidepsin; Safingol; Safingol Hydrochloride; Saintopin; Sarcophytol A; Sargramostim; Semustine; Sizofiran; Sobuzoxane; Borocaptate Sodium; Sodium Phenylacetate; Sovilol; Sonermin; Sorafenib; Sunitinib; Sparfosic Acid; Scabramycin D; Spiromustine; Splenopentin; Spongistatin 1; Spongistatin 2; Spongistatin 3; Spongistatin 4; Spongistatin 5; Spongistatin 6; Spongistatin 7; Spongistatin 8; and Spongistatin 9; Squalamine; Stiamide; Matrix Metalloproteinase Inhibitor; Sulfinosine; Suradista; Suramin; Swainsonine; SB239063; Selumetinib / AZD6244; Simtrazene; SP600125; Spisulosulfone Sodium; Sparomycin; Helix Germanium Hydrochloride; Spiroplatinum; Streptonigrin; Streptozotocin; Sulfachlorophenamide; Tallimustine; Tamoxifen Methiodide; Tauromustine; Tazarotene; Tecogalan Sodium; Tegafur; Telluropyranium; Temoporfin; Temozolomide; Teniposide; Tetrachloro Decoxide; Tetrazomine; Thaliblastine; Thiocoraline; Thrombopoietin; Thymalfasin; Thymopoietin Receptor Agonist; Thymotrinan;Tirapazamine; Titanium dichloride bis(cyclopentadienyl); Topsentin; Toremifene; Tretinoin; Triacetyluridine; Triciribine; Trimetrexate; Triptorelin; Tropisetron; Turosteride; Tyrphostins; Telithromycin; TAK-733; Taxotere; Ftorafur; Tirapazamine; Toremifene citrate; Trastuzumab; Trestolone acetate; Triciribine phosphate; Trimetrexate; Trimetrexate glucuronate; Triptorelin; Tubulozole hydrochloride; Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL); UBC inhibitor; Ubenimex; U0126; Uracil mustard; Uredepa; Vapreotide; Variolin B; Velaresol; Veramine; Verteporfin; Vinorelbine; Vinxaltine; Vitaxin; Vinblastine; Vinblastine sulfate; Vincristine sulfate; Vindesine; Vindesine sulfate; Vinepidine sulfate; Vinleurosine sulfate; Vinorelbine tartrate; Vinrosidine sulfate; Vinzolidine sulfate; Vorozole; Wortmannin; XL518; Zanoterone; Zeniplatin; Zilascorb; Zinostatin stimalamer; Zinostatin; and Zorubicin hydrochloride.

[0276] Other exemplary anti-cancer agents include Erbulozole (e.g., R-55104); Dolastatin 10 (e.g., DLS-10 and NSC-376128); Mivobulin isethionate (e.g., CI-980); NSC-639829; Discodermolide (e.g., NVP-XX-A-296); ABT-751 (Abbott; e.g., E-7010); Altorhyrtin A; Altorhyrtin C; Cemadotin hydrochloride (e.g., LU-103793 and NSC-D-669356); Epothilone A; Epothilone B; Epothilone C; Epothilone D; Epothilone E; Epothilone F; Epothilone B N-oxide; Epothilone A N-oxide; 16-Aza-Epothilone B; 21-Amino-Epothilone B; 21-Hydroxy-Epothilone D; 26-Fluoro-Epothilone; Auristatin PE (e.g., NSC-654663); Soblidotin (e.g., TZT-1027); LS-4559-P (Pharmacia; e.g., LS-4577); LS-4578 (Pharmacia; e.g., LS-477-P); LS-4477 (Pharmacia); LS-4559 (Pharmacia); RPR-112378 (Aventis); DZ-3358 (Daiichi); FR-182877 (Fujisawa; e.g., WS-9265B); GS-164 (Takeda); GS-198 (Takeda); KAR-2 (Hungarian Academy of Sciences); BSF-223651 (BASF; e.g., ILX-651 and LU-223651); SAH-49960 (Lilly / Novartis); SDZ-268970 (Lilly / Novartis); AM-97 (Armad / Kyowa Hakko); AM-132 (Armad); AM-138 (Armad / Kyowa Hakko); IDN-5005 (Indena); Nostocyclamide 52 (e.g., LY-355703); AC-7739 (Ajinomoto; e.g., AVE-8063A and CS-39.HCl); AC-7700 (Ajinomoto; e.g., AVE-8062; AVE-8062A; CS-39-L-Ser.HCl; and RPR-258062A); Vintafolide; Tubulysin A; Canertinib; CA-170 (Curis, Inc.);Cyanidin (e.g., NSC-106969); T-138067 (Tularik; e.g., T-67; TL-138067 and TI-138067); COBRA-1 (Parker Hughes Institute; e.g., DDE-261 and WHI-261); H10 (Kansas State University); H16 (Kansas State University); Oncocidin A1 (e.g., BTO-956 and DIME); DDE-313 (Parker Hughes Institute); Fijianolide B; Laulimalide; SPA-2 (Parker Hughes Institute); SPA-1 (Parker Hughes Institute; e.g., SPIKET-P); 3-IAABU (Cytoskeleton / Mt. Sinai School of Medicine; e.g., MF-569); Narcosine (e.g., NSC-5366); Noscapine; D-24851 (Asta Medica); A-105972 (Abbott); Hemiasterlin; 3-BAABU (Cytoskeleton / Mt. Sinai School of Medicine; e.g., MF-191); TMPN (Arizona State University); Bis(cyclopentadienyl)vanadium acetylacetonate; T-138026 (Tularik); Monsatrol; Inanocine (e.g., NSC-698666); 3-IAABE (Cytoskeleton / Mt. Sinai School of Medicine); A-204197 (Abbott); T-607 (Tuiarik; e.g., T-900607); RPR-115781 (Aventis); Sarcodictyins (e.g., demethylisocaryophyllene; deacetylisocaryophyllene; isocaryophyllene A; and Z-isocaryophyllene); Caribaeoside; Caribaeolin; Halichondrin B; D-64131 (Asta Medica); D-68144 (Asta Medica); Diazonamide A; A-293620 (Abbott); NPI-2350 (Nereus); Tacamonolide A; TUB-245 (Aventis); A-259754 (Abbott);Diozostatin; (-)-phenylastatin (e.g., NSCL-96F037); D-62638 (Asta Medica); D-62636 (Asta Medica); myostatin B; D-43411 (Zentaris; e.g., D-81862); A-289099 (Abbott); A-318315 (Abbott); HTI-286 (e.g., SPA-110; trifluoroacetate) (Wyeth); D-82317 (Zentaris); D-82318 (Zentaris); SC-12983 (NCI); sodium resverastatin phosphate; BPR-OY-007 (National Health Research Institutes); and SSR-250411 (Sanofi)); goserelin; leuprolide; triptolide; homoharringtonine; topotecan; itraconazole; deoxyadenosine; sertraline; pitavastatin; clofazimine; 5-nonyloxytriptamine; vemurafenib; dabrafenib; gefitinib (IRESSA); erlotinib (TARCEVA); cetuximab (ERBITUX); lapatinib (TYKERB); panitumumab (VECTIBIX); vandetanib (CAPRELSA); afatinib / BIBW2992; CI-1033 / canertinib; neratinib / HKI-272; CP-724714; TAK-285; AST-1306; ARRY334543; ARRY-380; AG-1478; dacomitinib / PF299804; OSI-420 / demethyl erlotinib; AZD8931; AEE726; pelitinib / EKB-569; CUDC-101; WZ8040; WZ4002; WZ3146; AG-490; XL647; PD153035; 5-thioguanine; 5-aza-2'-deoxycytidine; 17-N-allylamino-17-demethoxygeldanamycin (17-AAG); 20-epi-1,25-dihydroxyvitamin D3; 5-ethynyluracil; and BMS-599626.;

[0277] In certain embodiments, the combinations described herein are co-administered with the above-mentioned anti-cancer agents, wherein the anti-cancer agents have known activity against specific cancers (e.g., gemcitabine co-administered with the combination for treating pancreatic cancer described herein). The above anti-cancer agents may be approved for treating certain indications (e.g., certain cancers) at concentrations, amounts, and using treatment regimens known in the art.

[0278] It should be understood that modifications that do not substantially affect the activity of the various embodiments of the present invention are also included within the definition of the present invention provided herein. Therefore, the following examples are intended to illustrate and not limit the present invention.

[0279] Examples:

[0280] Example 1:

[0281] In this example, HBI-8000 was tested as a single therapy and in combination with 5 mg / kg of anti-PD-1. The experiments included a vehicle-treated group and a PD-1 inhibitor antibody single-therapy group, which served as control groups for analyzing efficacy. Tumors were measured twice weekly until the study ended on day 47. When the tumors reached the end-point tumor volume of 1000 mm 3 or on the last day of the study (whichever came first), each animal was euthanized and the end-point time (TTE) of each mouse was calculated. Treatment response was determined by analysis of the percent tumor growth delay (%TGD), defined as the percent increase in the median end-point time (TTE) of treated mice relative to control mice; and by the logrank significance of the difference in survival and regression responses between groups.

[0282] Mice: Female C57BL / 6 mice (Charles River Laboratories) were 8 weeks old and had a body weight (BW) range of 15.4 to 22.0 grams on day 1 of the study. Animals were provided water ad libitum (reverse osmosis, 1 ppm Cl), and NIH 31 modified and irradiated Lab consisting of 18.0% crude protein, 5.0% crude fat, and 5.0% crude fiber. The mice were housed in static micro-isolation cages in irradiated Enrich-o'cobs TM laboratory animal bedding at 20 - 22 °C (68 - 72 °F) and 40 - 60% humidity on a 12-hour light cycle.

[0283] Tumor cells: MC38 murine colon cancer cells were maintained in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum, 2 mM glutamine, 100 U / mL penicillin G sodium, 100 μg / mL streptomycin sulfate, and 25 μg / mL gentamicin. Cell cultures were maintained in tissue culture flasks in a humidified incubator at 37 °C in an atmosphere of 5% CO2 and 95% air.

[0284] Tumor implantation: Cells were harvested during exponential growth and resuspended in cold DMEM. Each mouse was inoculated subcutaneously in the right flank with 1 × 10 6 cells (0.1 mL cell suspension). As the average volume approached the desired range of 100 - 150 mm 3 , the tumor was measured in two dimensions to monitor growth. Tumor burden was calculated using the following formula:

[0285]

[0286] where w = width of the tumor and l = length of the tumor (mm). It was assumed that 1 mg was equivalent to 1 mm 3 tumor volume to estimate tumor weight. Fourteen days after tumor implantation (designated as day 1 of the study), animals with individual tumor volumes between 75 and 221 mm 3 were divided into 11 groups (n = 10 / group), with a group mean tumor volume of 130 - 133 mm 3 .

[0287] Test article: HBI-8000 (lot number 1384:0033) provided by HUYA Bioscience International. The antibody anti-PD-1 RMP1-14 (lot number 5611-10 / 0615) was purchased from BioXcell.

[0288] Administration solution: The antibody administration solution was freshly prepared daily and stored at 4 °C. HBI-8000 was dissolved in 0.2% CMC (carboxymethyl cellulose): 0.1% Tween 80. The anti-PDL-1 antibody administration solution was prepared by diluting an aliquot of the stock solution (6.48 mg / mL) in sterile PBS to 0.5 mg / mL to yield a 5 mg / kg dose in a 10 mL / kg dose volume.

[0289] Six groups of C57BL / 6 mice were dosed according to the regimens shown in Table 2. All doses were prepared as described above. HBI-8000 was administered orally (p.o.) once daily for 21 days (qd×21). The dose was adjusted according to the animal body weight. The antibody regimen was administered intraperitoneally (i.p.) at 5 mg / kg twice weekly for three weeks (biwk×3), and the dose was adjusted according to the animal body weight.

[0290] Table 2:

[0291]

[0292]

[0293] Tumor growth delay: Tumors were measured twice weekly using calipers, and each animal was euthanized when the tumor reached a volume of 1000 mm 3 or at the end of the study (D47) (whichever came first). Animals that withdrew from the tumor volume endpoint study were recorded as euthanized for tumor progression (TP), along with the date of euthanasia. The time to endpoint (TTE) for each mouse for analysis was calculated using the following equation:

[0294]

[0295] where TTE is expressed in days, the endpoint volume is expressed in mm 3 b is the intercept, and m is the slope of the line obtained from the linear regression of the log-transformed tumor growth data set. The data set consisted of the first observation beyond the endpoint volume used in the analysis and three consecutive observations made immediately prior to reaching this endpoint volume. The calculated TTE was generally less than the TP date, i.e., the day the animal was euthanized due to tumor burden. Animals with tumors that did not reach the endpoint volume were assigned a TTE value equal to the last day of the study. In cases where the TTE calculated by log transformation preceded the day of reaching the endpoint or exceeded the day of reaching the tumor volume endpoint, linear interpolation was performed to approximate the TTE. Any animal classified as having died from NTR (non-treatment related) causes due to accident (NTRa) or due to unknown etiology (NTRu) was excluded from the TTE calculation (and all further analysis). Animals classified as having died from TR (treatment related) or NTRm (non-treatment related death due to metastasis) were assigned a TTE value equal to the day of death.

[0296] Treatment outcome: Treatment outcome was evaluated from tumor growth delay (TGD), defined as the increase in median time to endpoint (TTE) in the treatment group compared to the control group:

[0297] TGD = T - C

[0298] Expressed as number of days, or as a percentage of the median TTE of the control group:

[0299]

[0300] where T = median TTE of the treatment group and C = median TTE of the designated control group.

[0301] Therapeutic efficacy: Therapeutic efficacy can be determined from the tumor volume of the animals remaining in the study on the last day. MTV(n) is defined as the median tumor volume (n) of the remaining number of animals (n) on the last day of the study, where the tumors of the animals did not reach the endpoint volume. Therapeutic efficacy can also be determined based on the incidence and extent of regression responses observed during the study. Treatment may cause partial regression (PR) or complete regression (CR) of the tumors in the animals. In a PR response, during three consecutive measurements during the course of the study, the tumor volume is 50% or less of its volume on Day 1, and for one or more of these three measurements, the tumor volume is equal to or greater than 13.5 mm 3 . In a CR response, the tumor volume measured three consecutive times during the course of the study is less than 13.5 mm 3 . Animals with a C response at the end of the study are additionally classified as tumor-free survivors (TFS). The regression responses of the animals are monitored.

[0302] Statistics: Prism (GraphPad) for Windows 6.07 was used for graphical display and statistical analysis. The log-rank test for evaluating overall survival was used to analyze the significance of the difference between the TTE values of the two groups. The log-rank analysis included data for all animals in a group, except those evaluated as having died of NTR. A two-tailed statistical analysis was performed at a significance level of P = 0.05. The group median tumor volume was plotted as a function of time. When an animal withdrew from the study due to tumor burden, the final tumor volume recorded for the animal was included in the data used to calculate the median volume at subsequent time points. The Kaplan-Meier plot shows the percentage of animals remaining in each group in the study as a function of time.

[0303] Treat the animals in Example 1 according to the protocol described in Table 1. Figure 1 The median tumor growth curves for all study groups are shown, and Figure 2 the median tumor volume of the combination of 50 mg / kg of HBI-8000 plus the PD-1 inhibitor antibody relative to the single agents and vehicle control is shown. The combination of 50 mg / kg of HBI-8000 with the PD-1 inhibitor antibody produces a statistically significant inhibition of tumor growth. Figure 3 The Kaplan Meier plots for all groups are depicted, Figure 4Depicts the Kaplan Meier plot of the combination of 50 mg / kg of HBI-8000 plus a PD-1 inhibitor antibody relative to single-agent controls. The combination of 50 mg / kg of HBI-8000 plus a PD-1 inhibitor antibody produced a statistically significant survival benefit. Table 3 describes the values calculated for TTE and %TGD.

[0304] Table 3: Median TTE and %TGD (Example 1)

[0305]

[0306] Example 2:

[0307] In this example, HBI-8000 was tested as a single therapy and in combination with 5 mg / kg of a PD-1 inhibitor antibody. The experiments included a vehicle treatment group and a PD-1 inhibitor antibody single-therapy group, which served as control groups for efficacy analysis. Tumors were measured twice weekly until the study ended on day 50. When the tumor reached the end-point tumor volume of 1000 mm 3 or on the last day of the study (whichever came first), each animal was euthanized and the end-point time (TTE) for each mouse was calculated. Treatment response was determined by analysis of the percentage tumor growth delay (%TGD), defined as the percentage increase in the median end-point time (TTE) of treated mice relative to control mice; and by the log rank significance of the difference in survival and regression responses between groups.

[0308] Mice: Details of the animals used in this example can be found in paragraph

[00201] .

[0309] Tumor cell culture: Details of the tumor cells used in this example can be found in paragraph

[00217] .

[0310] Tumor implantation and measurement: Details of the tumor implantation and tumor growth measurement used in this example can be found in paragraph

[00218] . In this example, each mouse was inoculated subcutaneously in the right flank with 5×10 5 cells (0.1 mL cell suspension).

[0311] Test article: Details of the test article used in this example can be found in paragraph

[00219] .

[0312] Administration solution: Details of the administration solution used in this example can be found in paragraph

[00220] .

[0313] Treatment: Four groups of C57BL / 6 mice (n = 10) were administered drugs according to the protocol in Table 4. Unless otherwise specified, drug administration started on Day 1. HBI-8000 was administered orally at 50 mg / kg. The PD-1 inhibitor antibody was administered intraperitoneally at 5 mg / kg. The vehicle (0.2% carboxymethyl cellulose: 0.1% Tween 80 in deionized water) was administered orally. All drugs were delivered at a dose volume of 10 mL / kg, adjusted according to the body weight of individual animals.

[0314] Table 4:

[0315]

[0316] Tumor growth delay: Details of the measurement and calculation of tumor growth delay can be found in paragraph

[00223] .

[0317] Treatment outcome: Details of the measurement and calculation of treatment outcome can be found in paragraph

[00224] .

[0318] Treatment efficacy: Details of the measurement and calculation of treatment efficacy can be found in paragraph

[00225] .

[0319] Statistics: Details of the statistics and software used in this study can be found in paragraph

[00226] . Figure 5 The median tumor volume measurements for all groups are shown, Figure 6 and the Kaplan-Meier plots are shown, which depict the percentage of animals remaining in each group in the study relative to time. Table 6 describes the values of TTE and %TGD calculated for each treatment group.

[0320] Treat the animals in Example 2 according to the protocol described in Table 4. Figure 5 The median tumor growth curves for all study groups are shown; in terms of tumor growth inhibition, the combination of 50 mg / kg of HBI-8000 plus the PD-1 inhibitor antibody was close to statistical significance. Figure 6 The Kaplan-Meier plots for all groups are depicted; the combination of 50 mg / kg of HBI-8000 plus the PD-1 inhibitor antibody produced a statistically significant survival benefit relative to the vehicle and the single agents. Figure 7 The individual endpoint times for all groups in Example 7 are depicted. Table 5 describes the values calculated for TTE and %TGD.

[0321] Table 5: Median TTE and %TGD (Example 2)

[0322]

[0323]

[0324] Example 3

[0325] In this model, a portion of the animals undergoing first-line treatment with a PD-L1 checkpoint inhibitor antibody experienced complete tumor regression. However, a similar proportion of the animals undergoing first-line treatment with a PD-L1 inhibitor antibody experienced rapid tumor progression. The remaining animals treated in this manner experienced slow tumor progression or stable disease, which is a result of the situation of many human cancer patients receiving PD-L1 inhibitor antibody therapy, that is, they experienced a transient partial response, including disease stabilization, but then developed resistance and rapidly progressed, and the PD-1 inhibitor antibody therapy failed. In this example, the efficacy of HBI-8000 alone and in combination with the PD-1 inhibitor antibody RMPI-14 as a second-line therapy was evaluated to assess the ability to cause tumor growth delay (TGD) in animals in which tumors progressed after first-line therapy with a PD-L1 inhibitor antibody in an immunocompetent C57BL / 6 mouse MC38 murine colon cancer syngeneic model. Thus, the need of human patients with failed PD-L1 inhibitor antibody therapy clinically was addressed.

[0326] Female C57BL / 6 mice bearing subcutaneous MC38 tumors (mean tumor volume at the start of treatment: 114 mm 3 ) were treated with first-line therapy with a PD-L1 inhibitor antibody, administered intraperitoneally (i.p.) at 5 mg / kg twice weekly for two weeks (biwk×2). When the tumors met the failure criteria and showed a two-consecutive increase in tumor volume and the tumor volume < 500 mm 3 , these were then re-enrolled in the second-line therapy efficacy study, which consisted of six groups (n = 10 per group) of mice. Administration started on D1, which represents the recruitment date and varied between the mice (this was standardized for each group). The second-line therapy was as follows. The vehicle was administered orally (p.o.). HBI-8000 was administered orally at 50 mg / kg. The PD-1 inhibitor antibody and anti-PDL-1 were administered intraperitoneally (i.p) at 5 mg / kg. The mice in Group 1 served as a control and received 0.2% carboxymethylcellulose: 0.1% Tween 80 in deionized water (vehicle) once daily for 21 days (qd×21). Group 2 received HBI-8000 qd×21. Group 3 received a second course of the PD-L1 inhibitor antibody biwk×2. Group 4 received HBI-8000 qd×21 and the PD-L1 inhibitor antibody biwk×2. Group 5 received anti-PD-1 biwk×2. Group 6 received HBI-8000 qd×21 and anti-PD-1 biwk×2. The study endpoint was a tumor volume of 1500 mm 3 or 45 days, whichever came first. Tumor measurements were performed twice weekly until D44, at which point individual animals left the study after reaching the tumor volume endpoint.

[0327] Mouse: At the start of initial PD-1 inhibitor antibody treatment, female C57BL / 6 mice (Charles River) were 8 weeks old and had a BW range of 18.1 - 24.1 g. Animals were provided with water ad libitum (reverse osmosis, 1 ppm Cl) and NIH 31 modified and irradiated Lab diet consisting of 18.0% crude protein, 5.0% crude fat, and 5.0% crude fiber Mice were housed in irradiated Enrich-o'cobs in static microisolator cages on bedding at 20 - 22 °C (68 - 72 °F) and 40 - 60% humidity on a 12-hour light cycle TM on bedding

[0328] Tumor Implantation and Measurement: Details of the tumor implantation and tumor growth measurement used in this example can be found in paragraph

[00218] . In this example, each mouse was inoculated subcutaneously in the right flank with 5 × 10 5 cells (0.1 mL cell suspension).

[0329] Test Articles: HBI-8000 (lot number 1384:0033) provided by HUYA Bioscience International. The PD-1 inhibitor antibody RMPI-14 (lot number 5611-10 / 0615) and the PDL-1 antibody 10F.9G2 (anti-PDL-1, lot number 5786-7-8 / 0815) were purchased from Bio X cell (West Lebanon, NH). All reagents were prepared according to the protocol specifications

[0330] Formulation Solutions: HBI-8000 was prepared by dilution in 0.2% CMC:0.1% Tween 80 to obtain a 5 mg / mL formulation solution. Fresh formulation solution was prepared weekly and stored at 4 °C. The PDL-1 inhibitor antibody formulation solution was prepared by diluting an aliquot of the stock solution (8.62 mg / mL) in sterile PBS to 0.5 mg / mL. The formulation solution was prepared twice a week and stored at 4 °C. The anti-PDL-1 antibody formulation solution was prepared by diluting an aliquot (5.37 mg / mL) in sterile PBS to 0.5 mg / mL. The anti-PDL-1 antibody formulation solution was prepared twice a week and stored at 4 °C

[0331] Treatment: For the initial PD-L1 inhibitor antibody failure portion of this study, 150 C57BL / 6 mice were administered the first-line PD-L1 inhibitor antibody intraperitoneally at 5 mg / kg, biwk×2. Animals meeting the re-entry criteria were included in the efficacy study; this included animals with a two consecutive increase in tumor volume and a tumor volume below 500 mm 3Animals. The first 60 animals to become available were placed in six efficacy groups in order until the groups were filled; this occurred on day 16 or day 22 after the start of the first-line dosing. For the efficacy study, six groups of C57BL / 6 mice (n = 10) were dosed according to the protocol in Table 6. The second-line treatment started on day 1, which was the day each animal was enrolled.

[0332] Table 6:

[0333]

[0334] Tumor growth delay: Details of the measurements and calculations of tumor growth delay used in the study are found in paragraph

[00223] .

[0335] Treatment outcome: Details of the measurements and calculations of treatment outcome used in the study are found in paragraph

[00224] .

[0336] Treatment efficacy: Details of the measurements and calculations of treatment efficacy used in the study are found in paragraph [002225].

[0337] Statistics: Details of the statistics and software used in this study can be found in paragraph

[00226] . The responses of each group to the therapies received were listed and classified as non-responder (NR), partial responder (PR), and complete responder (CR). Mean tumor volume measurements were obtained for all groups, and data for Kaplan-Meier plots were obtained, which show the percentage of animals remaining in each group in the study relative to time.

[0338] Treat the animals in Example 3 according to the protocol described in Table 6. Figure 8 The median tumor growth curves for all study groups are shown. Figure 8 Kaplan Meier plots for all groups are depicted; the combination of 50 mg / kg of HBI-8000 plus the anti-PD-1 inhibitor antibody produced a statistically significant survival benefit relative to the vehicle and the single agents. Figure 9 The individual endpoint times for all groups in Example 3 are depicted. Table 7 describes the values calculated for TTE and %TGD.

[0339] Table 7

[0340] Treatment group Median TTE Average T-C %TGD NR PR CR Vehicle 9.8 0.0 0.0 8 2 0 HBI-8000 11.4 3.0 31.8 8 1 1 PD-1Ab 13.8 10.4 106.3 6 2 2 PD-1Ab + HBI-8000 24.2 10.1 103.3 3 1 6 PD-L1 Ab 17.7 8.5 86.7 5 3 2 PD-L1 Ab + HBI-8000 14.7 3.8 39.2 6 4 0

[0341] Example 4

[0342] In this Example 4, the anti-tumor responses induced by HBI-8000 administered alone and in combination with anti-PD-1 RMP1-14 (anti-PD-1) were characterized in a 4T1 murine breast cancer xenograft model of BALB / c mice. The effects of these therapies on lung metastasis were evaluated.

[0343] In BALB / c mice bearing established 4T1 tumors, treatment was initiated on Day 1 (D1). HBI-8000 was administered orally (p.o.) at a single dose level, and anti-PD-1 was administered intraperitoneally (i.p.). Test agents were administered alone and in combination with HBI-8000. Control animals received vehicle. The study was terminated on D14 as the endpoint for metastases was reached. Treatment response was determined based on the metastasis counts obtained from the remaining animals on D14.

[0344] Mice: Female BALB / c mice (BALB / c AnNcr1, Charles River) were 7 weeks old at D1 of the study and had a body weight (BW) range of 14.7 to 20.7 g. Animals were provided water ad libitum (reverse osmosis, 1 ppm Cl) and NIH 31 modified and irradiated LabDiet consisting of 18.0% crude protein, 5.0% crude fat, and 5.0% crude fiber. Mice were housed in irradiated Enrich-o'cobs in static microisolator cages on irradiated bedding at 20 - 22 °C (68 - 72 °F) and 40 - 60% humidity on a 12-hour light cycle. TM Bedding.

[0345] Tumor cell culture: The 4T1 breast cancer cell line was grown to mid-logarithmic phase in RPMI medium containing 10% fetal bovine serum, 2 mM glutamine, 100 U / ml penicillin G sodium, 25 μg / mL gentamicin, and 100 μg / mL streptomycin sulfate. Cells were cultured in tissue culture flasks in a humidified incubator at 37 °C, 5% CO2, and 95% air.

[0346] In vivo implantation and tumor growth: 4T1 tumor cells were harvested during exponential growth and resuspended in PBS. Each test mouse was injected with 1 × 106 cells (0.1 mL cell suspension) in situ into the mammary fat pad. Tumor growth was monitored when the average size of the tumors approached the target range of 80 - 120 mm3.

[0347] Test agents: HBI-8000 (Lot No. 1384:0033) provided by HUYA Bioscience International, LLC. Anti-PD-1 RMP-14 (anti-PD-1, Lot No. 5792-599016J1) was purchased from Bio X cell (West Lebanon, NH). All reagents were prepared according to the protocol instructions. The vehicle used in this study was 0.2% carboxymethyl cellulose: 0.1% Tween 80 in deionized water. HBI-8000 was prepared by dilution in 0.2% CMC: 0.1% TW80 to obtain a dosing solution of 5 mg / mL. The dosing solution was freshly prepared weekly and stored at 4°C. The anti-PD-1 antibody dosing solution was prepared by diluting an aliquot (6.37 mg / mL) in sterile PBS to 0.5 mg / mL. The dosing solution was prepared on each day of dosing and stored at 4°C.

[0348] Treatment: On D1 of the study, mice bearing established 4T1 tumors were initiated on treatment according to the treatment plan outlined below. All agents were administered at a dose volume of 10 mL / kg; the volume was adjusted according to the individual BW.

[0349] Group 1 served as the efficacy control and received vehicle orally daily for thirteen days (qd×13).

[0350] Group 2 received 50 mg / kg of HBI-8000 orally, qd×13.

[0351] Group 3 received 5 mg / kg of anti-PD-1 intraperitoneally twice weekly for two weeks (biwk×2).

[0352] Group 4 received 50 mg / kg of HBI-8000, p.o., qd×13 and 5 mg / kg of anti-PD-1, i.p., biwk×2.

[0353] Endpoint: Metastasis count

[0354] Results were analyzed by counting the pulmonary metastases on D14, the last day of the study. Animals were euthanized at the endpoint using isoflurane anesthesia and necropsied to identify metastases. The total count was obtained by adding the number of lesions counted in the upper, middle, lower, and posterior lobes of the right lung to the number of lesions counted in the left lung. The % inhibition was defined as the difference between the number of metastatic lesions in the designated control group and the number of metastatic lesions in the drug-treated group, expressed as a percentage of the number of metastatic lesions in the designated control group:

[0355]

[0356] Results: The pulmonary metastasis count on day 14 for control animals in Group 1 was 35.0 ± 2.17 ( Figure 10)。Monotherapy with HBI-8000 produced a non-significant inhibition of -26%. Treatment with anti-PD-1 monotherapy resulted in 30% inhibition. The combination therapy of HBI-8000 and anti-PD-1 produced a lesion inhibition of 72%, which was statistically significant. The results are shown in Figure 10 in.

[0357] Example 5

[0358] In this example, HBI-8000 was tested as a monotherapy and in combination with 10 mg / kg of anti-PD-1 antibody or 10 mg / kg of PD-L1 antibody. The model used was the RENCA syngeneic model of renal cell carcinoma (RCC). The experiment included a vehicle treatment group, as well as monotherapy groups of the PD-1 inhibitor antibody and the PD-L1 inhibitor antibody, which served as control groups for analyzing efficacy. Tumors were measured twice a week until the study ended on day 25. Treatment response was determined by analysis of the percent tumor growth delay (%TGD).

[0359] Mice: Details of the animals used in this example were similar to those found in paragraph

[00216] .

[0360] Tumor cell culture: Details of the tumor cells used in this example were similar to those found in paragraph

[00217] .

[0361] Tumor implantation and measurement: Details of the tumor implantation and tumor growth measurement used in this example were similar to those found in paragraph

[00218] . In this example, each mouse was inoculated subcutaneously in the right flank with 1×10 6 RENCA cells (0.1 mL cell suspension).

[0362] Test articles: Details of the test articles used in this example can be found in paragraph

[00219] .

[0363] Administration solutions: Details of the administration solutions used in this example can be found in paragraph

[00220] .

[0364] Treatment: Six groups of female BALB / c mice bearing subcutaneous RENCA tumors (mean tumor volume at the start of treatment: 62 mm3) were treated according to the protocol in Table 8. Unless otherwise stated, administration began on day 1. HBI-8000 was administered orally at 50 mg / kg. The PD-1 and PD-L1 inhibitor antibodies were administered intraperitoneally at 10 mg / kg. Vehicle (0.2% carboxymethyl cellulose: 0.1% Tween 80 in deionized water) was administered orally. All agents were delivered at a dose volume of 10 mL / kg, adjusted according to the body weight of the individual animal.

[0365] Table 8:

[0366]

[0367] Tumor growth delay: Details of the measurement and calculation of tumor growth delay used in the study are found in paragraph

[00223] .

[0368] Therapeutic outcome: Details of the measurement and calculation of therapeutic outcome used in the study are found in paragraph

[00224] .

[0369] Therapeutic efficacy: Details of the measurement and calculation of therapeutic efficacy used in the study are found in paragraph

[00225] .

[0370] Statistics: Details of the statistics and software used in this study can be found in paragraph

[00226] . The responses of each group to the therapy received were listed and classified as non - responder (NR), partial responder (PR), and complete responder (CR). Mean tumor volume measurements were obtained for all groups, and data for the Kaplan - Meier plot were obtained, which shows the percentage of animals remaining in each group in the study relative to time.

[0371] Treat the animals in Example 5 according to the protocol described in Table 8. Figure 11 The median tumor growth curves for all study groups are shown; in terms of tumor growth inhibition, the combination of 50 mg / kg of HBI - 8000 plus the PD - 1 inhibitor antibody was statistically significant and different from the vehicle (P = 0.026) or PD - 1 antibody monotherapy (P = 0.036).

[0372] Example 6 - HDAC Enzyme Inhibition Assay

[0373] Use human recombinant HDAC proteins and perform an analysis of the selectivity and potency of the inhibition of HDAC isoforms by chidamide as described in Ning et al. Incubate all enzyme reactants at room temperature for 17 hours in a 50 μl reaction mixture containing a predefined concentration of HDAC assay buffer (BPS catalog number 50031), 5 μg BSA, HDAC substrate, purified recombinant HDAC enzyme, and the test compound. After the enzyme reaction, add 50 μl of 29HDAC developer (BPS catalog number 50030) to each well and incubate the plate at room temperature for an additional 20 minutes. Measure the fluorescence intensity using a Synergy TM 2 microplate reader at an excitation of 360 nm and an emission of 460 nm. Perform each compound concentration in duplicate. Determine the IC 50 value.

[0374] Although the present invention has been described with reference to the disclosed embodiments, those skilled in the art will readily understand that the specific examples and studies detailed above are only illustrative of the present invention. It should be understood that various modifications can be made without departing from the spirit of the present invention. Therefore, the present invention is only limited by the following claims.

Claims

1. A compound of the following formula: or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament for treating cancer in a patient in need in combination with a PD-1 inhibitor; wherein the PD-1 inhibitor is the PD-1 antibody RMP1-14 and wherein the cancer is melanoma.

2. The use according to claim 1, wherein the medicament is prepared for administration in combination with the PD-1 inhibitor after treatment with at least one anti-cancer therapy.

3. The use according to claim 2, wherein the anti-cancer therapy is chemotherapy, radiotherapy, surgery, targeted therapy, immunotherapy or a combination thereof.

4. The use according to claim 1, wherein the cancer is resistant to at least one anti-cancer agent.

5. The use according to any one of claims 1 to 4, wherein the medicament is prepared for simultaneous or sequential administration with the PD-1 inhibitor.

6. The use according to any one of claims 1 to 5, wherein the medicament is prepared for administering the compound 2 to 3 times per week.

7. The use according to claim 6, wherein the medicament is prepared for administering the compound in an amount of 20 mg, 30 mg, or 40 mg BIW.

8. The use according to claim 1, wherein the medicament is prepared for administering the compound daily.

9. The use according to claim 1, wherein the medicament is prepared for concomitant administration of the compound with the PD-1 inhibitor on day 1 of the dosing regimen.

10. The use according to claim 1, wherein the medicament is prepared for use in combination with the PD-1 inhibitor as a regimen.

11. The use according to claim 10, wherein the regimen is repeated until disease progression or unacceptable toxicity.

12. The use according to claim 10, wherein the regimen comprises at least a 1-day rest period between consecutive dosing periods.

13. The use according to claim 10, wherein the regimen comprises administering the medicament 2 to 3 times per week and administering the PD-1 antibody every 2 to 3 weeks.

14. The use according to claim 10, wherein the regimen comprises administering the medicament for 21 days at QD and administering the PD-1 antibody every 2 to 3 weeks.

15. The use according to claim 1, wherein the treatment of cancer inhibits cancer metastasis in the patient.

16. The use according to claim 1, wherein the treatment of cancer reduces the tumor or tumor burden in the patient.

17. The use according to claim 1, wherein the treatment of cancer inhibits pre-existing cancer metastasis in the patient.

18. The use according to claim 1, wherein the treatment of cancer prolongs the time to disease progression of the cancer in the patient.

19. The use according to claim 1, wherein the treatment of cancer prolongs the survival period of the patient.

20. The use according to claim 1, wherein the treatment of cancer increases the progression-free survival period of the patient.

21. Use according to claim 1, wherein the patient has been previously treated with a PD-L1 inhibitor, and the cancer after treatment with the PD-L1 inhibitor results in a partial response, but subsequently develops resistance to the PD-L1 inhibitor as the disease progresses.

22. Use according to claim 1, wherein the patient has been previously treated with a PD-L1 inhibitor, and the cancer after treatment with the PD-L1 inhibitor results in disease stability, but subsequently develops resistance to the PD-L1 inhibitor as the disease progresses.

23. Use according to claim 1, wherein the patient has been previously treated with a PD-L1 inhibitor, and the cancer after treatment with the PD-L1 inhibitor results in a complete response, but subsequently develops resistance to the PD-L1 inhibitor as the disease progresses.

24. Use according to claim 1, wherein the patient has been previously treated with a PD-L1 inhibitor, and the cancer after treatment with the PD-L1 inhibitor does not respond to the treatment.

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