Administration of sting agonist and checkpoint inhibitors

Abstract

To provide a medicament for treating cancer in patients in need thereof.SOLUTION: Provided is a medicament for treating cancer, comprising a compound having the following structure, or a pharmaceutically acceptable salt thereof, in combination with a checkpoint inhibitor, wherein the checkpoint inhibitor is an anti-PD-1 antibody, and wherein the cancer is classical Hodgkin lymphoma or primary mediastinal large B-cell lymphoma.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure relates to methods for treating cancer. Specifically, the present disclosure provides methods for treating various cancers by administering a STING (stimulator of interferon genes) agonist in combination with one or more checkpoint inhibitors. [Background technology]

[0002] In 2012, there were an estimated 14 million diagnosed cases of cancer worldwide, resulting in approximately 8.2 million deaths. The global cancer burden is growing at an alarming pace. In 2030 alone, approximately 21.3 million new cancer cases and 13.1 million cancer deaths are expected, due solely to population growth and aging. Cancer is the second most common cause of death in the United States, surpassed only by heart disease, accounting for nearly one-quarter of all deaths. The National Cancer Institute estimates that approximately 14.5 million Americans with a history of cancer were alive in 2014. While some of these individuals were cancer-free, others may still have evidence of cancer and have been treated. While medical advances have improved cancer survival rates, new and more effective treatments are continually needed.

[0003] Cancer treatment has primarily relied on surgery, radiation therapy, cytotoxic chemotherapy, and their combinations. However, within the past decade, targeted cancer therapy has ushered in a new era in the field of oncology. Targeted cancer therapy is a drug designed to interfere with specific molecules necessary for tumor growth and progression, and can include small molecules and larger chemical entities such as monoclonal antibodies (mAbs).

[0004] STING is a transmembrane receptor localized in the ER that recognizes and binds cyclic dinucleotides. Natural ligands recognized by STING include bacterial / protozoan-derived cyclic dinucleotides (CDNs) and 2',3'-cGAMP, synthesized upstream by cGAS (cyclic GMP-AMP synthase). See Trends in Immunology 35:88-93 (2014). One of the natural ligands, 2',3'-cGAMP, is degraded by the pyrophosphatase / phosphodiesterase ENPP1 (ecto-nucleotide pyrophosphatase / phosphodiesterase), while other CDNs are degraded by other phosphodiesterases. See Nat Chem Biol 10:1043-1048 (2014); Cell Res 25:539-550 (2015); Biochemistry 55:837-849 (2016). STING activation by these natural ligands induces phosphorylation of TBNK1 (TANK-binding kinase 1) and IRF3 (interferon regulatory factor 3), leading to activation of NFkB and type I interferon (IFN) responses, respectively. See Trends in Immunology 35:88-93 (2014).

[0005] The effect of STING on cancer cell growth control has been demonstrated using genetically engineered mice. It has been reported that STING-deficient and IRF3-deficient mice exhibit uncontrolled tumor growth compared to wild-type mice. (See Immunity 41:830-842(2014)). Additionally, it has been reported that cancer cell growth in tumor-allografted mice was suppressed by radiation therapy, whereas the efficacy of radiation therapy was reduced in mice genetically deficient in STING and IFNAR1 (interferon (alpha and beta) receptor 1, a receptor for type I IFN produced by downstream signaling). (See Immunity 41:843-852(2014)). Collectively, the above evidence suggests that STING plays an important role in suppressing cancer cell growth. Therefore, STING can be used as an anti-cancer agent. In addition, activation of STING can further enhance the immune effect of conventional vaccines due to STING's ability to activate both innate and adaptive immunity. See Ther Adv Vaccines 1:131-143 (2013). Therefore, STING agonists can also be used as adjuvants for various vaccines.

[0006] In addition to small molecules, targeted therapies include monoclonal antibodies. For example, among the many known monoclonal antibody targeted therapies are monoclonal antibodies against PD-1 (e.g., nivolumab / Opdivo® and pembrolizumab / Keytruda®), monoclonal antibodies against PD-L1 (e.g., atezolizumab / Tecentriq®, durvalumab / Imfinzi®, and avelumab / Bavencio®), and monoclonal antibodies against CTLA-4 (e.g., ipilimumab / Yervoy®). Thus, some cancers are PD-1 mediated disorders, PD-L1 The disorder may be a CD4+-mediated disorder, or a CTLA-4-mediated disorder. Additional monoclonal antibody targeted therapies include, but are not limited to, monoclonal antibodies against CD20 (e.g., rituximab / Rituxan®), CD52 (e.g., alemtuzumab / Campus®), VEGF (e.g., bevacizumab / Avastin®), HER2 (e.g., trastuzumab / Herceptin® for treating Her2+ breast cancer and gastric cancer), and EGFR (e.g., cetuximab / Erbitux® for treating colorectal cancer).

[0007] In order to extend the lifespan of patients while maintaining a high quality of life, new combinations of therapeutic agents that produce beneficial effects in cancer treatment are desirable. New combinations can provide increased benefits compared to each drug alone. In particular, combination treatment regimens can be useful for patients suffering from disease conditions, including proliferative disorders, autoimmune diseases, inflammatory diseases, fibrotic diseases, and kidney diseases, and may also reduce the recurrence rate or overcome the resistance to certain anticancer drugs that is sometimes seen in these patients. This is especially true when cancers may be resistant or resistant to currently available treatment regimens.

[0008] Therefore, new treatment regimens, including combination therapies, are needed. Summary of the Invention

[0009] In one aspect, the present disclosure relates to a method of treating cancer comprising administering a STING agonist in combination with a checkpoint inhibitor to a subject in need of such treatment.

[0010] In one aspect, the present disclosure provides a method of treating a cancer patient, comprising administering to a patient in need thereof Compound No. 14, having the structure:

[0011] [ka]

[0012] or a pharmaceutically acceptable salt thereof in combination with a checkpoint inhibitor.

[0013] In some embodiments, the checkpoint inhibitor is selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-CTLA-4 antibody.

[0014] In some embodiments, the checkpoint inhibitor is an anti-PD-1 antibody.

[0015] In some embodiments, the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, lambrolizumab, pidilizumab, BMS-936559, and AMP-224.

[0016] In some embodiments, the checkpoint inhibitor is an anti-PD-L1 antibody.

[0017] In some embodiments, the anti-PD-L1 antibody is selected from the group consisting of atezolizumab, durvalumab, avelumab, YW243.55.S70, MEDI-4736, MSB-0010718C, LY3300054, BMS-936559, MPDL3280A, and MDX-1105.

[0018] In some embodiments, the checkpoint inhibitor is an anti-CTLA-4 antibody.

[0019] In some embodiments, the anti-CTLA-4 antibody is selected from the group consisting of ipilimumab and tremelimumab.

[0020] In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered orally.

[0021] In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered intravenously.

[0022] In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered by intravenous infusion.

[0023] In some embodiments, the checkpoint inhibitor is administered intravenously.

[0024] In some embodiments, the checkpoint inhibitor is administered by intravenous infusion.

[0025] In some embodiments, the checkpoint inhibitor is administered by subcutaneous injection.

[0026] In some embodiments, the checkpoint inhibitor is administered subcutaneously.

[0027] In some embodiments, Compound No. 14 and the checkpoint inhibitor are administered simultaneously.

[0028] In some embodiments, Compound No. 14 and the checkpoint inhibitor are administered sequentially in separate pharmaceutical compositions.

[0029] In some embodiments, the cancer is a PD-1 positive cancer, a PD-L1 positive cancer, or a CTLA-4 positive cancer.

[0030] In some embodiments, the cancer is a solid tumor or a hematological malignancy. In some embodiments, the cancer is a metastatic solid tumor. In some embodiments, the cancer is an advanced solid tumor.

[0031] In some embodiments, the cancer is melanoma, lung cancer, kidney cancer, lymphoma, head and neck cancer, urothelial cancer, prostate cancer, bladder cancer, breast cancer, gastric cancer, colorectal cancer, leukemia, cervical cancer, microsatellite instability-high cancer, hepatocellular carcinoma, or Merkel cell carcinoma.

[0032] In some embodiments, the melanoma is metastatic melanoma, unresectable melanoma, or cutaneous melanoma.

[0033] In some embodiments, the lung cancer is non-small cell lung cancer or small cell lung cancer.

[0034] In some embodiments, the non-small cell lung cancer is metastatic non-small cell lung cancer, metastatic squamous non-small cell lung cancer, or metastatic non-squamous non-small cell lung cancer.

[0035] In some embodiments, the renal cancer is renal cell carcinoma.

[0036] In some embodiments, the lymphoma is classical Hodgkin's lymphoma or primary mediastinal large B-cell lymphoma.

[0037] In some embodiments, the head and neck cancer is head and neck squamous cell carcinoma.

[0038] In some embodiments, the urothelial cancer is urothelial carcinoma.

[0039] In some embodiments, the prostate cancer is hormone-refractory prostate cancer.

[0040] In some embodiments, the gastric cancer is gastroesophageal junction adenocarcinoma.

[0041] In some embodiments, the cancer is a microsatellite instability-high cancer.

[0042] In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered once every two weeks, once a week, twice a week, three times a week, or daily.

[0043] In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered twice a week.

[0044] In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered once a week.

[0045] In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered on days 1, 4, 8, and 11 of a 21-day cycle.

[0046] In some embodiments, the checkpoint inhibitors are administered separately once every 12 weeks, once every 4 weeks, once every 3 weeks, once every 2 weeks, once a week, twice a week, three times a week, or daily.

[0047] In some embodiments, the checkpoint inhibitor is administered once every two weeks.

[0048] In some embodiments, the checkpoint inhibitor is administered once every three weeks.

[0049] In some embodiments, the checkpoint inhibitor is administered once every four weeks.

[0050] In some embodiments, the checkpoint inhibitor is administered once every 12 weeks.

[0051] In some embodiments, the checkpoint inhibitor is administered on day 1 of the treatment cycle.

[0052] In some embodiments, the treatment cycle is 14 days, 21 days, 28 days, or 84 days.

[0053] In some embodiments, Compound No. 14, or a pharmaceutically acceptable salt thereof, and a checkpoint inhibitor are administered simultaneously once every 12 weeks, once every 4 weeks, once every 3 weeks, once every 2 weeks, once a week, twice a week, three times a week, daily, or on days 1, 4, 8, and 11 of a 21-day cycle.

[0054] In some embodiments, Compound No. 14, or a pharmaceutically acceptable salt thereof, is administered once every two weeks, once a week, twice a week, three times a week, daily, or on days 1, 4, 8, and 11 of a 21-day cycle, and a checkpoint inhibitor is separately administered once every 12 weeks, once every four weeks, once every three weeks, once every two weeks, once a week, twice a week, three times a week, or daily.

[0055] In one aspect, the present disclosure relates to a kit comprising a pharmaceutical agent for use in treating cancer in a subject in need thereof. The kit comprises a pharmaceutical agent comprising a STING agonist and instructions for administering the STING agonist and one or more checkpoint inhibitors, or the kit comprises a pharmaceutical agent comprising one or more checkpoint inhibitors and instructions for administering one or more checkpoint inhibitors and a STING agonist. The kit may comprise both a pharmaceutical agent comprising a STING agonist and a pharmaceutical agent comprising one or more checkpoint inhibitors, as well as instructions for administering the STING agonist and one or more checkpoint inhibitors. The kit may also comprise one or more additional therapeutic agents.

[0056] In one aspect, the present disclosure relates to a medicament for use in treating cancer in a subject in need thereof. The medicament comprises a STING agonist and one or more checkpoint inhibitors. The medicament can also comprise one or more additional therapeutic agents. [Brief explanation of the drawings]

[0057] [Figure 1a] 1 shows a Kaplan-Meier plot of progression-free survival of survival as a function of time in a mouse A20 syngeneic tumor model after administration of Compound No. 14, an anti-mouse PD-1 antibody ("anti-mPD-1"), a combination of Compound No. 14 and anti-mPD-1, and vehicle to mice. [Figure 1b] 1 shows plots of individual tumor volumes as a function of time in a murine A20 syngeneic tumor model after administration of Compound #14, anti-mPD-1, the combination of Compound #14 and anti-mPD-1, and vehicle to mice. [Figure 2a] 1 shows a Kaplan-Meier plot of progression-free survival of survival as a function of time in the murine L5178-R syngeneic tumor model after administration of Compound No. 14, anti-mPD-1, the combination of Compound No. 14 and anti-mPD-1, and vehicle to mice. [Figure 2b]1 shows plots of individual tumor volumes as a function of time in the murine L5178-R syngeneic tumor model after administration of Compound #14, anti-mPD-1, the combination of Compound #14 and anti-mPD-1, and vehicle to mice. [Figure 3a] 1 shows a Kaplan-Meier plot of progression-free survival of survival as a function of time in a murine WEHI-3 syngeneic tumor model after administration of Compound #14, anti-mPD-1, the combination of Compound #14 and anti-mPD-1, and vehicle to mice. [Figure 3b] 1 shows plots of individual tumor volumes as a function of time in a murine WEHI-3 syngeneic tumor model after administration of Compound #14, anti-mPD-1, a combination of Compound #14 and anti-mPD-1, and vehicle to mice. [Figure 4a] 1 shows a Kaplan-Meier plot of progression-free survival of survival as a function of time in the murine RM-1 syngeneic tumor model after administration of Compound #14, anti-mPD-1, the combination of Compound #14 and anti-mPD-1, and vehicle to mice. [Figure 4b] 1 shows plots of individual tumor volumes as a function of time in a murine RM-1 syngeneic tumor model after administration of Compound #14, anti-mPD-1, the combination of Compound #14 and anti-mPD-1, and vehicle to mice. [Figure 5a] 1 shows a Kaplan-Meier plot of progression-free survival of survival as a function of time in a murine L1210 syngeneic tumor model after administration of Compound #14, anti-mPD-1, the combination of Compound #14 and anti-mPD-1, and vehicle to mice. [Figure 5b] 1 shows plots of individual tumor volumes as a function of time in a murine L1210 syngeneic tumor model after administration of Compound #14, anti-mPD-1, the combination of Compound #14 and anti-mPD-1, and vehicle to mice. DETAILED DESCRIPTION OF THE INVENTION

[0058] Definitions and Abbreviations To facilitate understanding of this disclosure, certain abbreviations, terms, and phrases are defined below.

[0059] [Table 1]

[0060] 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 disclosure belongs. All patents and publications mentioned herein are incorporated by reference in their entirety.

[0061] As used herein, the term "cancer" refers to a cellular disorder characterized by uncontrolled or dysregulated cell proliferation, reduced cell differentiation, inappropriate ability to invade surrounding tissues, and / or the ability to establish new growth in ectopic locations. The term "cancer" includes solid tumors and non-solid tumors, such as hematologic tumors. The term "cancer" encompasses diseases of the skin, tissues, organs, bone, cartilage, blood, and vasculature. The term "cancer" includes primary and metastatic It further includes metastatic cancers.

[0062] As used herein, the term "autoimmune disease" refers to a disorder resulting from an abnormal immune response against normal body parts. The term "autoimmune disease" encompasses disorders including, but not limited to, rheumatoid arthritis (RA), granulomatosis with polyglomerulitis (GPA) (Wegener's granulomatosis), and microscopic polyangiitis (MPA).

[0063] The term "PD-1" (also known as programmed cell death protein 1, PDCD1, CD279, SLEB2, or SLE1) refers to any native PD-1, unless otherwise indicated. The term "PD-1" encompasses "full-length," unprocessed PD-1, as well as any form of PD-1 that results from processing within cells. The term also encompasses naturally occurring variants of PD-1, such as splice variants, allelic variants, and isoforms.

[0064] The term "PD-L1" (also known as programmed cell death 1 ligand, unless otherwise indicated) refers to any naturally occurring PD-L1. The term "PD-L1" encompasses "full-length," unprocessed PD-L1, as well as any form of PD-L1 that results from processing within cells. The term also encompasses naturally occurring variants of PD-L1, such as splice variants, allelic variants, and isoforms.

[0065] The term "CTLA-4" (also known as cytotoxic T-lymphocyte-associated antigen 4) refers to any native CTLA-4, unless otherwise indicated. The term "CTLA-4" encompasses "full-length," unprocessed CTLA-4, as well as any form of CTLA-4 that results from processing within cells. The term also encompasses naturally occurring variants of CTLA-4, such as splice variants, allelic variants, and isoforms.

[0066] The term "antibody" refers to an immunoglobulin molecule that recognizes and binds to a target, such as a protein, polypeptide, peptide, carbohydrate, polynucleotide, lipid, or a combination thereof, via at least one antigen recognition site within the variable region of the immunoglobulin molecule. As used herein, the term "antibody" encompasses intact polyclonal antibodies, intact monoclonal antibodies, antibody fragments (such as Fab, Fab', F(ab')2, and Fv fragments), single-chain Fv (scFv) variants, multispecific antibodies, e.g., bispecific antibodies generated from at least two intact antibodies, chimeric antibodies, humanized antibodies, human antibodies, fusion proteins containing an antigenic determinant of an antibody, and any other modified immunoglobulin molecule containing an antigen recognition site, so long as the antibody exhibits the desired biological activity. Antibodies can be any of five major immunoglobulin classes, namely, IgA, IgD, IgE, IgG, and IgM, or their subclasses (isotypes) (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), based on the distinctive heavy chain constant domains, designated alpha, delta, epsilon, gamma, and mu, respectively. Different classes of immunoglobulins have distinct and well-known subunit structures and three-dimensional configurations. Antibodies can be naked or conjugated to other molecules, such as toxins, radioisotopes, etc.

[0067] A "blocking" or "antagonist" antibody is an antibody that inhibits or reduces the biological activity of the antigen to which it binds, e.g., PD-1, PD-L1, or CTLA-4. In certain embodiments, a blocking or antagonist antibody substantially or completely inhibits the biological activity of the antigen. Desirably, the biological activity is reduced by 10%, 20%, 30%, 50%, 70%, 80%, 90%, 95%, or even 100%.

[0068] The term "anti-PD-1 antibody" or "antibody that binds to PD-1" refers to an antibody that binds to PD-1. "Anti-PD-1" refers to an antibody that can bind to PD-1 with sufficient affinity to be useful as a diagnostic and / or therapeutic agent in targeting PD-1. The extent of binding of the anti-PD-1 antibody to unrelated, non-PD-1 proteins is less than about 10% of the binding of the antibody to PD-1, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, an antibody that binds to PD-1 has a dissociation constant (Kd) of 1 μM or less, 100 nM or less, 10 nM or less, 1 nM or less, or 0.1 nM or less.

[0069] The terms "anti-PD-L1 antibody" or "antibody that binds to PD-L1" refer to an antibody that can bind to PD-L1 with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent in targeting PD-L1. The extent of binding of the anti-PD-L1 antibody to unrelated, non-PD-L1 proteins is less than about 10% of the binding of the antibody to PD-L1, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, an antibody that binds to PD-L1 has a dissociation constant (Kd) of 1 μM or less, 100 nM or less, 10 nM or less, 1 nM or less, or 0.1 nM or less.

[0070] The terms "anti-CTLA-4 antibody" or "antibody that binds to CTLA-4" refer to an antibody that can bind to CTLA-4 with sufficient affinity so that the antibody is useful as a diagnostic and / or therapeutic agent in targeting CTLA-4. The extent of binding of the anti-CTLA-4 antibody to unrelated, non-CTLA-4 proteins is less than about 10% of the binding of the antibody to CTLA-4, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, an antibody that binds to CTLA-4 has a dissociation constant (Kd) of 1 μM or less, 100 nM or less, 10 nM or less, 1 nM or less, or 0.1 nM or less.

[0071] A "monoclonal" antibody refers to a homogeneous antibody that is involved in highly antigen-specific recognition and binding of a single antigenic determinant, i.e., epitope. This is in contrast to polyclonal antibodies, which typically include different antibodies directed against different antigenic determinants. The term "monoclonal" antibody encompasses intact, full-length monoclonal antibodies, as well as antibody fragments (e.g., Fab, Fab', F(ab')2, Fv), single-chain (scFv) variants, fusion proteins containing an antibody portion, and any other immunoglobulin molecule containing an antigen-recognition site. Furthermore, a "monoclonal" antibody refers to an antibody produced by any method, including, but not limited to, hybridoma, phage selection, recombinant expression, and transgenic animals.

[0072] The term "chimeric antibody" refers to an antibody in which the amino acid sequences of the immunoglobulin molecule are derived from two or more species. Typically, the variable regions of both the light and heavy chains correspond to the variable regions of antibodies from one species of mammal (e.g., mouse, rat, rabbit, etc.) having the desired specificity, affinity, and function, while the constant regions are homologous to the sequences of antibodies from another species (usually human) to avoid eliciting an immune response in that species.

[0073] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of a compound or a combination of one or more compounds that, when administered (e.g., sequentially or simultaneously), elicits a desired biological or pharmaceutical response, e.g., destroys target cancer cells or delays or arrests cancer progression in a patient. A therapeutically effective amount may vary depending on the intended use (in vitro or in vivo) or the patient and disease state being treated, e.g., the patient's weight and age, the severity of the disease state, the method of administration, etc., and can be readily determined by one of ordinary skill in the art. The term also applies to a dose that induces a specific response in target cells, e.g., reduced platelet adhesion and / or cell migration. For example, in some embodiments, a "therapeutically effective amount" as used herein refers to the amount of Compound No. 14, or a pharmaceutically acceptable salt thereof, and the amount of a checkpoint inhibitor, when administered separately or in combination, that has a beneficial effect. In some embodiments, the combined effect is additive. In some embodiments, the combination The combined effect is synergistic. Furthermore, one of skill in the art will recognize that in combination therapy, the amount of Compound No. 14, or a pharmaceutically acceptable salt thereof, and / or the amount of checkpoint inhibitor may be used in a "sub-therapeutic amount," i.e., an amount less than the therapeutically effective amount of Compound No. 14, or a pharmaceutically acceptable salt thereof, or the checkpoint inhibitor alone.

[0074] In any form or composition, the administered dose(s) or therapeutically effective (total) amount may be: (i) BSA, e.g., mg / m 2 or (ii) on a mass basis, e.g., as mg, of the amount(s) of therapeutic agent(s) per patient.

[0075] The term "about" refers to approximately, within a range, roughly, or around. When the term "about" is used in conjunction with a numerical value or numerical range, it means that the referenced numerical value or numerical range is approximate within experimental variability (or within statistical experimental error); thus, the numerical value or numerical range may vary, for example, by 1% to 15% of the stated numerical value or numerical range. Generally, the term "about" is used herein to modify numerical values above and below the stated value by a variance of ±10%.

[0076] As used herein, "patient" generally refers to a mammal (e.g., a human) who has been diagnosed with, exhibits, or is otherwise believed to be suffering from a disease, disorder, or condition (such as cancer).

[0077] As used herein, "body surface area" (BSA) is calculated using standard nomograms, e.g.,

[0078]

number

[0079] It is calculated using

[0080] The terms "co-administration," "administration in combination," and "administering a combination" refer to the administration of two or more pharmaceutically active ingredients, including, but not limited to, Compound No. 14, or a pharmaceutically acceptable salt thereof, and a checkpoint inhibitor disclosed herein, to a patient. Co-administration may refer to simultaneous or sequential administration of Compound No. 14, or a pharmaceutically acceptable salt thereof, and a checkpoint inhibitor disclosed herein.

[0081] The terms "concurrently" and "simultaneously" refer to administration of Compound No. 14, or a pharmaceutically acceptable salt thereof, and a checkpoint inhibitor disclosed herein to a patient at the same time or at two different times separated by no more than two hours. The co-administration of Compound No. 14, or a pharmaceutically acceptable salt thereof, and a checkpoint inhibitor may be in a single dosage form or in separate dosage forms.

[0082] The terms "sequential" and "sequentially" refer to the administration of Compound No. 14, or a pharmaceutically acceptable salt thereof, and a checkpoint inhibitor disclosed herein to a patient at two different time points separated by more than two hours, e.g., about 3 hours, about 4 hours, about 5 hours, about 8 hours, about 12 hours, more than 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or even more.

[0083] The term "interruption" refers to a period following administration of one or more specific pharmaceutically active ingredients to a patient in an intermittent regimen. The interruption refers to a drug-free period during which the specific pharmaceutically active ingredient is not administered for at least one day.

[0084] The term "synergism" refers to a situation in which the effect of combining two or more drugs is greater than the sum of the effects of each drug individually. This term includes not only the alleviation of symptoms of the disorder being treated, but also an improved side effect profile, improved tolerability, improved patient compliance, increased efficacy, or any other improvement in clinical outcome.

[0085] As used herein, the exemplary terms "include," "such as" and " Terms such as, "for example," "for example," and the like (and variations thereof, e.g., "includes," "including," "examples") are intended to be open-ended unless otherwise specified. That is, unless expressly stated otherwise, such terms are intended to imply "but not limited to," e.g., "including" means "including but not limited to."

[0086] Unless otherwise stated, structures depicted herein are meant to include chemical entities that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of a hydrogen atom by deuterium or tritium, or 13 C- or 14 Chemical substances having the present structures except for the replacement of a carbon atom with a C-enriched carbon are within the scope of this invention.

[0087] Unless a stereochemical configuration is indicated, structures depicted herein are meant to include all stereochemical forms of the structure, i.e., the R and S configurations for each asymmetric center. Thus, unless otherwise indicated, single stereochemical isomers as well as enantiomeric, racemic, and diastereomeric mixtures of the chemical compounds of the present invention are within the scope of the present invention. When the stereochemical configuration is indicated for a compound, the diastereomeric or enantiomeric excess of the compound is at least 99.0%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%.

[0088] STING agonists The present disclosure provides a combination treatment for a patient with cancer or an autoimmune disease, which treatment comprises, inter alia, administering to a subject in need thereof a therapeutically effective amount of at least one STING agonist.

[0089] In some embodiments, the STING agonist is a compound of Formula I, having the following structure, or a pharmaceutically acceptable salt thereof:

[0090] [ka]

[0091] In the formula, R 1 and R 2 are each independently a hydroxy group or a halogen atom, B 1 teeth,

[0092] [ka]

[0093] and R 18 is hydrogen or C 1~6 is alkyl, R 19 is a halogen atom, B 2 teeth,

[0094] [ka]

[0095] and Q 2 and Q 4 are each independently an oxygen atom or a sulfur atom.

[0096] In some embodiments, the STING agonist is Compound No. 14, having the following structure, or a pharmaceutically acceptable salt thereof:

[0097] [ka]

[0098] In some embodiments, the STING agonist is Compound No. 14, or a pharmaceutically acceptable salt thereof.

[0099] In some embodiments, the STING agonist is Compound No. 14.

[0100] Certain STING agonists disclosed herein are described, for example, in PCT Publication No. WO2018 / 100558. They can be prepared by methods known to those of skill in the art and / or according to the methods described in WO2018 / 100558, which is incorporated herein by reference in its entirety.

[0101] In some embodiments, the STING agonist is Compound No. 14, or a crystalline form thereof.

[0102] Checkpoint inhibitors The present disclosure provides, inter alia, combination therapies comprising administering to a subject in need thereof a therapeutically effective amount of at least one checkpoint inhibitor (e.g., nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, and ipilimumab). In some embodiments, the checkpoint inhibitor is an anti-PD-1 antibody. In some embodiments, the checkpoint inhibitor is an anti-PD-L1 antibody. In some embodiments, the checkpoint inhibitor is an anti-CTLA-4 antibody.

[0103] PD-1 is a type I transmembrane protein that is one of the major immune checkpoint molecules (Blank et al., 2005, Cancer Immunotherapy, 54:307-314). PD-1 is primarily expressed on activated T cells, where it interacts with its ligands PD-L1 (B7-H1 or CD274) and PD-L2 (B7-DC or CD273) to induce inhibitory signals that result in reduced T cell proliferation, cytokine production, and cytotoxic activity (Freeman et al., 2000, J. Exp. Med., 192:1027-34).

[0104] In some embodiments, the anti-PD-1 antibody is a fully human monoclonal antibody. In some embodiments, the anti-PD-1 antibody is a humanized IgG monoclonal antibody.

[0105] In some embodiments, the anti-PD-1 antibody is a full-length (intact) antibody. In some embodiments, the anti-PD-1 antibody consists of an anti-PD-1 binding fragment, including, but not limited to, Fab, Fab', F(ab')2, and Fv fragments, single-chain Fv fragments, and single-chain domain fragments.

[0106] In some embodiments, the anti-PD-1 antibody is a derivatized antibody. In some embodiments, the anti-PD-1 antibody is derivatized by glycosylation, acetylation, PEGylation, phosphorylation, and amidation. In some embodiments, the anti-PD-1 antibody is derivatized by known protecting / blocking groups, proteolytic cleavage, or conjugation to a cellular ligand or other protein. In some embodiments, the derivatized anti-PD-1 antibody can also include one or more unnatural amino acids, for example, using ambrx technology (see, e.g., Wolfson, 2006, Chem. Biol. 13(10):1011-2).

[0107] In some embodiments, the anti-PD-1 antibody is nivolumab.

[0108] Nivolumab is a human monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Nivolumab is an IgG4 kappa immunoglobulin with a calculated molecular weight of 146 kDa. It is expressed in a recombinant Chinese hamster ovary (CHO) cell line. Nivolumab is approved by the FDA for the treatment of unresectable or metastatic melanoma, melanoma, metastatic non-small cell lung cancer, advanced renal cell carcinoma, classical Hodgkin lymphoma, head and neck squamous cell carcinoma, urothelial carcinoma, microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) metastatic colorectal cancer, and hepatocellular carcinoma. Nivolumab is commercially available as Opdivo®.

[0109] In some embodiments, the anti-PD-1 antibody is pembrolizumab.

[0110] Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. It is an IgG4 kappa immunoglobulin with a molecular weight of 149 kDa. Pembrolizumab is produced in recombinant Chinese hamster ovary (CHO) cells. Pembrolizumab has been approved by the FDA for the treatment of melanoma, non-small cell lung cancer, head and neck cancer, classical Hodgkin's lymphoma, primary mediastinal large B-cell lymphoma, urothelial carcinoma, microsatellite instability-high cancer, gastric cancer, and cervical cancer. Pembrolizumab is commercially available as Keytruda®.

[0111] In some embodiments, the anti-PD-1 antibody is cemiplimab.

[0112] Cemiplimab is a human monoclonal antibody that binds to PD-1 and blocks its interaction with PD-L1 and PD-L2. Cemiplimab is an IgG4 immunoglobulin with a molecular weight of approximately 146 kDa. It is produced by recombinant DNA technology in Chinese hamster ovary (CHO) cell suspensions. Cemiplimab is approved by the FDA for the treatment of metastatic cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC that are not candidates for curative surgery or curative radiation. Cemiplimab is commercially available as Libtayo®.

[0113] Additional anti-PD-1 antibodies include, for example, pidilizumab (Medivation), BMS-936559 (Bristol-Myers Squibb), and AMP-224.

[0114] In some embodiments, the anti-PD-1 antibody used in the methods (and kits) described herein is nivolumab or an anti-PD-1 antibody that binds to the same epitope as nivolumab. In some embodiments, the anti-PD-1 antibody is nivolumab.

[0115] In some embodiments, the anti-PD-1 antibody used in the methods (and kits) described herein is pembrolizumab or an anti-PD-1 antibody that binds to the same epitope as pembrolizumab. In some embodiments, the anti-PD-1 antibody is pembrolizumab.

[0116] PD-L1 is a type I transmembrane protein containing an extracellular Ig-V-like domain, an Ig-C-like domain, a transmembrane domain, and an intracellular C-terminal domain. PD-L1 is frequently expressed in a wide range of cancers, including on tumor cells and / or tumor-infiltrating immune cells, and may contribute to the inhibition of antitumor immune responses in the tumor microenvironment. In some cancers, PD-L1 expression is associated with reduced survival and poor prognosis. PD-L1 is expressed on many cell types, including T cells, B cells, endothelial, epithelial, and antigen-presenting cells, cells of lung, liver, and heart tissue, and several types of tumor cells. PD-L1 expression on the cell surface has also been shown to be upregulated through IFN-γ stimulation. At least four variants of PD-1 have been cloned from activated human T cells, including transcripts lacking (i) exon 2, (ii) exon 3, (iii) exons 2 and 3, or (iv) exons 2–4. See Nielsen et al., Cell. Immunol. 235:109-16 (2005). The amino acid sequence of human PD-L1 is represented by GenBank accession number NP054862.1.

[0117] In some embodiments, the anti-PD-L1 antibody is a full-length (intact) antibody. In some embodiments, the anti-PD-L1 antibody is comprised of an anti-PD-L1 binding fragment, including, but not limited to, Fab, F(ab')2, Fd, Fv, and dAb fragments, single-chain Fv fragments, and PD-L1 binding domain immunoglobulin fusion proteins.

[0118] In some embodiments, the anti-PD-L1 antibody is atezolizumab.

[0119] Atezolizumab is a programmed death-ligand 1 (PD-L1) blocking antibody. It is an Fc-engineered, humanized, non-glycosylated IgG1 kappa immunoglobulin with a calculated molecular weight of 145 kDa. Atezolizumab is approved by the FDA for the treatment of locally advanced or metastatic urothelial carcinoma and metastatic non-small cell lung cancer. Atezolizumab is commercially available as Tecentriq®.

[0120] In some embodiments, the anti-PD-L1 antibody is durvalumab.

[0121] Duravalimab is a programmed cell death ligand 1 (PD-L1) blocking antibody. It is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody produced by recombinant DNA technology in Chinese hamster ovary (CHO) cell suspension culture. It has been approved by the FDA for the treatment of urothelial carcinoma and non-small cell lung cancer. Duravalimab is commercially available as Imfinzi®.

[0122] In some embodiments, the anti-PD-L1 antibody is avelumab.

[0123] Avelumab is a programmed death-ligand-1 (PD-L1) blocking antibody. It is a human IgG1 lambda monoclonal antibody with a molecular weight of approximately 147 kDa. Avelumab has been approved by the FDA for the treatment of metastatic Merkel cell carcinoma and locally advanced or metastatic urothelial carcinoma. Avelumab is commercially available as BAVENCIO®.

[0124] Additional anti-PD-L1 antibodies include, for example, YW243.55.S70 (U.S. Patent No. 8,217,149), MEDI-4736, MSB-0010718C, LY3300054 (Eli Lilly and Co.), BMS-936559 (Bristol-Meyers Squibb), MPDL3280A, and MDX-1105.

[0125] In some embodiments, the anti-PD-L1 antibody used in the methods (and kits) described herein is atezolizumab or an anti-PD-L1 antibody that binds to the same epitope as atezolizumab, hi some embodiments, the anti-PD-L1 antibody is atezolizumab.

[0126] In some embodiments, the anti-PD-L1 antibody used in the methods (and kits) described herein is durvalumab or an anti-PD-L1 antibody that binds to the same epitope as durvalumab. In some embodiments, the anti-PD-L1 antibody is durvalumab.

[0127] In some embodiments, the anti-PD-L1 antibody used in the methods (and kits) described herein is avelumab or an anti-PD-L1 antibody that binds to the same epitope as avelumab. In some embodiments, the anti-PD-L1 antibody is avelumab.

[0128] CTLA-4 is a type I transmembrane protein encoded in humans by the CTLA-4 gene. CTLA-4 has been found to correlate with cancer growth and development due to its negative role in immune responses. CTLA-4 is expressed on the cell surface of activated CD4+ and CD8+ T cells and is an important negative regulator of T cell function. CTLA-4 has been shown to negatively regulate immune activation through both intrinsic and extrinsic mechanisms (Grosso and Kunkel, Cancer Immunity (2013) 13:5). Inhibition of CTLA-4 negative regulation promotes stimulation of adaptive immune responses and T cell activation. A representative amino acid sequence of human CTLA-4 can be found in GenBank Accession No. AAL07473.1, and a representative mRNA nucleic acid sequence encoding human CTLA-4 can be found in GenBank Accession No. AF414120.1.

[0129] In some embodiments, the anti-CTLA-4 antibody is a full-length (intact) antibody. In some embodiments, the anti-CTLA-4 antibody consists of an anti-CTLA-4 binding fragment, including, but not limited to, Fab, Fab', F(ab'), Fv, and single-chain fragments, diabodies, disulfide-stabilized Fv fragments (dsFv), (dsFv)2, bispecific dsFv (dsFv-dsFv'), disulfide-stabilized diabodies (ds diabodies), single-chain antibody molecules (scFv), scFv dimers (bivalent diabodies), multispecific antibodies, camelized single-domain antibodies, nanobodies, domain antibodies, and bivalent domain antibodies.

[0130] In some embodiments, the anti-CTLA-4 antibody is ipilimumab.

[0131] Ipilimumab is a recombinant human monoclonal antibody that binds to cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). Ipilimumab is an IgG1 kappa immunoglobulin with a molecular weight of approximately 148 kDa. Ipilimumab is produced in mammalian (Chinese hamster ovary) cell culture. Ipilimumab is approved by the FDA for the treatment of unresectable or metastatic melanoma, adjuvant treatment of melanoma, and advanced renal cell carcinoma. Ipilimumab is commercially available as Yervoy®.

[0132] Additional anti-CTLA-4 antibodies include, for example, tremelimumab.

[0133] In some embodiments, the anti-CTLA-4 antibody used in the methods (and kits) described herein is ipilimumab or an anti-CTLA-4 antibody that binds to the same epitope as ipilimumab, hi some embodiments, the anti-CTLA-4 antibody is ipilimumab.

[0134] Cancer treatment methods In some embodiments, the present disclosure relates to a method of treating cancer in a patient by administering to a patient in need of such treatment a combination of a STING agonist, or a pharmaceutically acceptable salt thereof, and one or more checkpoint inhibitors.

[0135] In some embodiments, the present disclosure relates to a method of treating cancer by administering to a patient in need thereof a combination of a STING agonist and a checkpoint inhibitor.

[0136] In some embodiments, the present disclosure relates to the use of a combination of a STING agonist and a checkpoint inhibitor for the treatment of cancer in a patient.

[0137] In some embodiments, the present disclosure relates to a composition comprising a STING agonist for use in treating cancer in a patient, wherein the patient is also treated with a checkpoint inhibitor. In some aspects, the present disclosure relates to a composition comprising a STING agonist for use in treating cancer in a patient, wherein the STING agonist is combined with a checkpoint inhibitor. In some embodiments, the STING agonist can be administered simultaneously or sequentially with the checkpoint inhibitor.

[0138] In some embodiments, the present disclosure relates to a method of treating cancer, the method comprising administering to a patient in need of such treatment therapeutically effective amounts of a STING agonist and a checkpoint inhibitor. The present invention relates to administering a combination of

[0139] In some embodiments, the present disclosure relates to methods of treating cancer by administering to a patient a combination of Compound No. 14, or a pharmaceutically acceptable salt thereof, and a checkpoint inhibitor.

[0140] In another aspect, the present disclosure relates to the use of Compound No. 14, or a pharmaceutically acceptable salt thereof, in combination with a checkpoint inhibitor for the treatment of cancer.

[0141] In some embodiments, the methods of treating cancer described herein can include a combination of a STING agonist, a checkpoint inhibitor, and one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents can be a chemotherapeutic agent. In some embodiments, the one or more additional therapeutic agents can include, but are not limited to, fludarabine, cyclophosphamide, doxorubicin, vincristine, methotrexate, anthracycline chemotherapy, prednisone, methylprednisolone, glucocorticoids, ibritumomab tiuxetan, acetaminophen, antihistamines, and combinations thereof. In another embodiment, the checkpoint inhibitor is co-administered with human hyaluronidase.

[0142] In some embodiments, the present disclosure relates to a method of treating a disorder, wherein the disorder is cancer.

[0143] In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a metastatic solid tumor. In some embodiments, the cancer is an advanced solid tumor. Non-limiting examples of solid tumors include pancreatic cancer; bladder cancer, including invasive bladder cancer; colorectal cancer, including microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer; thyroid cancer; gastric cancer; breast cancer, including metastatic breast cancer; prostate cancer, including androgen-dependent and androgen-independent prostate cancer; renal cancer, e.g., metastatic renal cell carcinoma and advanced renal cell carcinoma; urothelial carcinoma, including locally advanced or metastatic urothelial carcinoma; microsatellite instability-high cancer; liver cancer, e.g., hepatocellular carcinoma and intrahepatic cholangiocarcinoma; non-small cell lung cancer (NSCLC), squamous lung carcinoma, bronchioloalveolar carcinoma (BAC), adenocarcinoma of the lung, and small cell lung cancer. cancer of the lung and bronchus, including submucosal lung cancer (SCLC); ovarian cancer, including advanced epithelial and primary peritoneal cancer; uterine cancer, including cervical cancer, uterine corpus and cervix; endometrial cancer; esophageal cancer; head and neck cancer, including squamous cell carcinoma of the head and neck, nasopharyngeal carcinoma, oral cavity and pharynx; melanoma, including unresectable or metastatic melanoma, and adjuvant treatment of melanoma; metastatic Merkel cell carcinoma; neuroendocrine carcinoma, including metastatic neuroendocrine tumors; brain tumors, including glioma / glioblastoma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma; neuroendocrine carcinoma, including metastatic neuroendocrine tumors; osteosarcoma; gastroesophageal junction cancer, and soft tissue sarcoma.

[0144] In some embodiments, the cancer is a hematological cancer. Non-limiting examples of hematological malignancies that can be treated with the methods of the present disclosure include acute myeloid leukemia (AML); chronic myeloid leukemia (CML), including accelerated phase CML and blastic phase of CML (CML-BP); acute lymphoblastic leukemia (ALL); chronic lymphoblastic leukemia (CLL); Hodgkin lymphoma (HL), including classical Hodgkin lymphoma; B-cell lymphoma, T-cell lymphoma, follicular lymphoma (FL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL). non-Hodgkin's lymphoma (NHL), including primary mediastinal large B-cell lymphoma, and Burkitt's lymphoma; multiple myeloma (MM); amyloidosis; Waldenstrom's macroglobulinemia; myelodysplastic syndromes (MDS), including refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess blasts (RAEB), and accelerated RAEB (RAEB-T); and myeloproliferative syndromes. In some embodiments, the cancer is chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma (NHL), primary mediastinal large B-cell lymphoma, and Burkitt's lymphoma. lymphoma, or non-Hodgkin's lymphoma, including follicular lymphoma (FL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and Burkitt lymphoma.

[0145] In some embodiments, the cancer is melanoma, lung cancer, kidney cancer, lymphoma, head and neck cancer, urothelial cancer, prostate cancer, bladder cancer, breast cancer, gastric cancer, colorectal cancer, leukemia, cervical cancer, microsatellite instability-high cancer, hepatocellular carcinoma, or Merkel cell carcinoma.

[0146] In some embodiments, the melanoma is metastatic melanoma, unresectable melanoma, or cutaneous melanoma.

[0147] In some embodiments, the lung cancer is non-small cell lung cancer or small cell lung cancer.

[0148] In some embodiments, the non-small cell lung cancer is metastatic non-small cell lung cancer, metastatic squamous non-small cell lung cancer, or metastatic non-squamous non-small cell lung cancer.

[0149] In some embodiments, the renal cancer is renal cell carcinoma.

[0150] In some embodiments, the lymphoma is classical Hodgkin's lymphoma or primary mediastinal large B-cell lymphoma.

[0151] In some embodiments, the head and neck cancer is head and neck squamous cell carcinoma.

[0152] In some embodiments, the urothelial cancer is urothelial carcinoma.

[0153] In some embodiments, the prostate cancer is hormone-refractory prostate cancer.

[0154] In some embodiments, the gastric cancer is gastroesophageal junction adenocarcinoma.

[0155] In some embodiments, the cancer is a microsatellite instability-high cancer.

[0156] In some embodiments, the cancer is recurrent. In some embodiments, a recurrent cancer is a cancer that has returned after a period of time during which the cancer was not detected.

[0157] In some embodiments, the cancer is refractory. In one aspect, a refractory cancer does not respond to cancer treatment and is also known as a resistant cancer. In some embodiments, the cancer is resistant to rituximab. In some embodiments, the cancer does not respond to rituximab treatment. In some embodiments, the cancer is melanoma or colon cancer. In some embodiments, the patient has become refractory to a rituximab-containing regimen. In some embodiments, the tumor is unresectable. In some embodiments, an unresectable tumor cannot be removed by surgery. In some embodiments, the cancer has not been previously treated. In some embodiments, the cancer is locally advanced. In some embodiments, "locally advanced" refers to a cancer that is somewhat widespread but still limited to one area. In some cases, "locally advanced" can refer to a small tumor that has not spread but has invaded nearby organs or tissues, making it difficult to remove by surgery alone. In some embodiments, the cancer is metastatic. In some embodiments, a metastatic cancer is a cancer that has spread from the part of the body where it began (the primary site) to other parts of the body.

[0158] In some embodiments, the present disclosure relates to a method of treating a disorder, wherein the disorder is an autoimmune disease. do.

[0159] In some embodiments, the disorder is a STING-mediated disorder.

[0160] In some embodiments, the disorder is a PD-1 positive cancer. PD-1 positive cancers include cancers in which PD-1 is expressed in the cancer cells.

[0161] In some embodiments, the disorder is a PD-L1 positive cancer. PD-L1 positive cancers include cancers in which PD-L1 is expressed on the cancer cells.

[0162] In some embodiments, the disorder is a CTLA-4 positive cancer. CTLA-4 positive cancers include cancers in which CTLA-4 is expressed in the cancer cells.

[0163] Pharmaceuticals In some embodiments, the present disclosure relates to a medicament for use in treating cancer in a patient in need of such treatment, the medicament comprising a STING agonist and a checkpoint inhibitor, in a single dosage form or in separate dosage forms.

[0164] In some embodiments, the medicaments described herein may include a combination of a STING agonist, a checkpoint inhibitor, and optionally one or more additional therapeutic agents.

[0165] In some embodiments, the present disclosure relates to the use of a STING agonist in the manufacture of a medicament for treating cancer, wherein the STING agonist is administered together with a checkpoint inhibitor, and the medicaments are in a single dosage form or separate dosage forms. In some embodiments, the STING agonist is administered together with a checkpoint inhibitor and one or more additional therapeutic agents.

[0166] In some embodiments, the disclosure relates to the use of a STING agonist for the manufacture of a medicament in the treatment of cancer in a patient, wherein the patient is also treated with a checkpoint inhibitor and, optionally, one or more additional therapeutic agents. In some embodiments, the STING agonist can be administered simultaneously or sequentially with the checkpoint inhibitor. In some aspects, the disclosure relates to the use of a STING agonist for the manufacture of a medicament in the treatment of cancer in a patient, wherein the STING agonist is combined with a checkpoint inhibitor and, optionally, one or more additional therapeutic agents. In some embodiments, the STING agonist is present in the same composition as the checkpoint inhibitor. In some embodiments, the STING agonist is present in a separate composition as the checkpoint inhibitor. In some embodiments, the STING agonist is present in the same composition as the one or more additional therapeutic agents. In some embodiments, the STING agonist is present in the same composition as the checkpoint inhibitor and, optionally, one or more additional therapeutic agents. In some embodiments, the STING agonist is present in a separate composition as the one or more additional therapeutic agents. In some embodiments, the STING agonist is present in a separate composition as the one or more additional therapeutic agents. In some embodiments, the STING agonist is present in a separate composition from the checkpoint inhibitor and, optionally, one or more additional therapeutic agents.

[0167] In another aspect, the disclosure relates to the use of Compound No. 14, or a pharmaceutically acceptable salt thereof, in combination with a checkpoint inhibitor in the manufacture of a medicament for use in the treatment of cancer. In some embodiments, the disclosure relates to the use of Compound No. 14, or a pharmaceutically acceptable salt thereof, in combination with a checkpoint inhibitor, and optionally one or more additional therapeutic agents, in the manufacture of a medicament for use in the treatment of cancer.

[0168] In another aspect, the present disclosure relates to the use of Compound No. 14, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer, wherein Compound No. 14, or a pharmaceutically acceptable salt thereof, is administered together with a checkpoint inhibitor, and optionally one or more additional therapeutic agents.

[0169] In some embodiments, the one or more additional therapeutic agents can be chemotherapeutic agents. In some embodiments, the one or more additional therapeutic agents can include, but are not limited to, fludarabine, cyclophosphamide, doxorubicin, vincristine, methotrexate, anthracycline chemotherapeutic agents, prednisone, methylprednisolone, glucocorticoids, ibritumomab tiuxetan, acetaminophen, antihistamines, and combinations thereof. In another embodiment, the checkpoint inhibitor is co-administered with human hyaluronidase.

[0170] Combination Administration Compound No. 14, or a pharmaceutically acceptable salt thereof, may be administered in combination with a checkpoint inhibitor, and optionally one or more additional therapeutic agents, in a single dosage form or as separate dosage forms. In some embodiments, when administered as a separate dosage form, the checkpoint inhibitor may be administered before, simultaneously with, or after administration of Compound No. 14, or a pharmaceutically acceptable salt thereof. In some embodiments, when administered as a separate dosage form, one or more doses of Compound No. 14, or a pharmaceutically acceptable salt thereof, may be administered before the checkpoint inhibitor. In some embodiments, the checkpoint inhibitor is administered before administration of Compound No. 14, or a pharmaceutically acceptable salt thereof. As used herein, administration of Compound No. 14, or a pharmaceutically acceptable salt thereof, a checkpoint inhibitor, and optionally one or more additional therapeutic agents in "combination" refers not only to simultaneous or sequential administration of the agents, but also to administration of the agents during a single treatment cycle, as will be understood by those skilled in the art. When Compound No. 14, or a pharmaceutically acceptable salt thereof, is administered in combination with a checkpoint inhibitor, and optionally one or more additional therapeutic agents, a therapeutically effective amount of the combination is administered.

[0171] The STING agonist can be administered by any method known to those of skill in the art. For example, in some embodiments, the STING agonist can be administered in the form of a pharmaceutical composition of the STING agonist and a pharmaceutically acceptable carrier, such as those described herein. In some embodiments, the pharmaceutical composition is suitable for oral administration. In some embodiments, the pharmaceutical composition is a tablet or capsule suitable for oral administration. In some other embodiments, the pharmaceutical composition is a liquid dosage form suitable for oral administration. In some embodiments, the pharmaceutical composition is suitable for parenteral administration. In some embodiments, the pharmaceutical composition is suitable for intravenous administration. In some embodiments, the pharmaceutical composition is suitable for intravenous infusion. In some embodiments, the pharmaceutical composition is suitable for injection. In some embodiments, the pharmaceutical composition is suitable for intravenous injection. In some embodiments, the pharmaceutical composition is suitable for subcutaneous injection. In some embodiments, these compositions optionally further comprise one or more additional therapeutic agents.

[0172] The checkpoint inhibitor can be administered by any method known to one of skill in the art. In some embodiments, the checkpoint inhibitor is administered intravenously (iv). In some embodiments, the checkpoint inhibitor is administered subcutaneously (sc). In some embodiments, the checkpoint inhibitor is administered orally. For example, the checkpoint inhibitor can be administered in the form of a second composition, in some embodiments, a pharmaceutical composition of a checkpoint inhibitor, such as those described herein, and a pharmaceutically acceptable carrier. In one aspect, the pharmaceutical composition is suitable for oral administration. In some embodiments, the pharmaceutical composition is a tablet or capsule that is suitable for oral administration. In some other embodiments, the checkpoint inhibitor can be administered intravenously (iv). In some embodiments, the checkpoint inhibitor is administered subcutaneously (sc). In some other embodiments, the checkpoint inhibitor can be administered orally. In embodiments, the pharmaceutical compositions are in liquid form suitable for oral administration. In some embodiments, these compositions optionally further comprise one or more additional therapeutic agents.

[0173] Such pharmaceutical compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intraperitoneal, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. In some embodiments, the checkpoint inhibitor is administered orally, intravenously, or subcutaneously. In some embodiments, the checkpoint inhibitor is administered orally. In some embodiments, the checkpoint inhibitor is administered intravenously. In some embodiments, intravenous administration can be intravenous infusion or intravenous injection. In some embodiments, the checkpoint inhibitor is administered by intravenous infusion. In some embodiments, the checkpoint inhibitor is administered by intravenous injection. In some embodiments, the checkpoint inhibitor is administered by subcutaneous injection. In some embodiments, the checkpoint inhibitor is administered by intravenous infusion followed by subcutaneous injection. In another embodiment, the checkpoint inhibitor is co-administered subcutaneously with human hyaluronidase. These administration methods may be designed to be short-acting, fast-releasing, or long-acting. Furthermore, the checkpoint inhibitor can be administered in a local manner, such as by injection at the tumor site, rather than systemically.

[0174] In some embodiments, the checkpoint inhibitor may be administered by nasal aerosol or inhalation. The checkpoint inhibitor may be prepared according to techniques well known in the art and may be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0175] The amount or suitable dose of the disclosed methods depends on several factors, including the nature of the severity of the condition being treated, the particular inhibitor, the route of administration, and the age, weight, overall health, and response of the individual subject. In some embodiments, a suitable dose level is one that achieves a therapeutic response as measured by tumor regression or other standard measures of disease progression, progression-free survival, or overall survival. In some embodiments, a suitable dose level is one that achieves a therapeutic response while minimizing any side effects associated with the administration of the therapeutic agent. A suitable dose level may be one that prolongs the therapeutic response and / or prolongs lifespan.

[0176] It will be understood that the suitable doses of the STING agonist, checkpoint inhibitor, and optionally one or more additional therapeutic agents may be taken at any time of the day or night. In some embodiments, the suitable dose of each agent is administered in the morning. In some other embodiments, the suitable dose of each agent is administered in the evening. In some embodiments, the suitable dose of each agent is administered both in the morning and evening. It will be understood that the suitable dose of each agent may be administered with or without food. In some embodiments, the suitable dose of each agent is administered with a meal. In some embodiments, the suitable dose of each agent is administered on an empty stomach.

[0177] In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered on a daily schedule. In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered every other day. In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered once every three days. In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered in three doses, once every three days. In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered twice a week. In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered on a three times per week schedule. In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered on a once per week schedule. In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered on a once every two weeks schedule.

[0178] In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered once daily. In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered twice daily. In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered three times daily.

[0179] In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered at least three times every other day within a seven-day cycle. In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered on days 1 and 4 within a seven-day cycle. In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered consecutively within a seven-day cycle, followed by a break. In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered for two consecutive days, followed by a break for five days within at least one seven-day cycle. In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered for three consecutive days, followed by a break for four days within at least one seven-day cycle. In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered for four consecutive days, followed by a break for three days within at least one seven-day cycle. In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered for five consecutive days, followed by a break for two days within at least one seven-day cycle. In some embodiments, there will be a drug holiday between one or more 7 day treatment cycles. In some embodiments, there will be a drug holiday between one or more 7 day treatment cycles.

[0180] The present description contemplates administration of a STING agonist for one or more treatment cycles, e.g., 1, 2, 3, 4, 5, 6, or more treatment cycles. In some embodiments, the treatment cycle is about 7 days to about 56 days, or more. In some embodiments, the treatment cycle is 7, 14, 21, 28, 35, 42, 49, or 56 days. In some embodiments, the treatment cycle is 21 or 28 days. In some embodiments, there will be a drug holiday within or between one or more treatment cycles. For example, in some embodiments, there is a drug holiday at the end of a treatment cycle. In some embodiments, there is a drug holiday between the second and third treatment cycles, but not between the first and second treatment cycles. In another embodiment, there may be a drug holiday between the first and second treatment cycles, but not between the second and third treatment cycles. Dosing schedules include, for example, administering the STING agonist once during the treatment schedule, e.g., on day 1 of a 21-day cycle, twice during the treatment schedule, e.g., on days 1 and 15 of a 21-day cycle, or on days 1 and 15 of a 28-day cycle, three times during the treatment schedule, e.g., on days 1, 8, and 15 of a 21-day cycle, or on days 1, 8, and 15 of a 28-day cycle, and four times during the treatment schedule, e.g., on days 1, 4, 8, and 11 of a 21-day cycle, or on days 1, 4, 8, and 11 of a 28-day cycle. Other dosing schedules are encompassed by the invention.

[0181] In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered within a 21 day cycle. In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered at least four times within a 21 day cycle. In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered on day 1 within a 21 day cycle. In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered on day 1 within a 21 day cycle. In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered on day 4 within a 21-day cycle. In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered on day 8 within a 21-day cycle. In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered on day 11 within a 21-day cycle. In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered on days 1, 4, 8, and 11 within a 21-day cycle.

[0182] In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered within a 21 day cycle. In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered at least twice within a 21 day cycle. In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered on day 1 within a 21 day cycle. In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered on day 8 within a 21 day cycle. In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered on days 1 and 8 within a 21 day cycle.

[0183] In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered for a period of one year or less. In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered for a period of one year or more.

[0184] In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 0.5 mg to about 1000 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 0.5 mg to about 300 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 1 mg to about 300 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 3 mg to about 300 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 0.5 mg to about 200 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 1 mg to about 200 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 10 mg to about 200 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 0.5 mg to about 100 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 0.5 mg to about 50 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 0.5 mg to about 10 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 0.5 mg to about 5 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 1 mg to about 3 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 2 mg to about 5 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 5 mg to about 10 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is from about 5 mg to about 15 mg.In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 10 mg to about 20 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 15 mg to about 25 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 20 mg to about 30 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 25 mg to about 35 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 30 mg to about 4. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 35 mg to about 45 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 40 mg to about 50 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 55 mg to about 65 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 50 mg to about 100 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 90 mg to about 150 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 140 mg to about 200 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 190 mg to about 250 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 240 mg to about 300 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 290 mg to about 350 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 340 mg to about 400 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 390 mg to about 450 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 440 mg to about 500 mg.

[0185] In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 0.5 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 1 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 2 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 3 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 4 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 6 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 8 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 10 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 12 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 16 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 20 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is 30 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 40 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 50 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 60 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 70 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 80 mg.In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 90 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 100 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 150 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 200 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 250 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 300 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 350 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 400 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 450 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 500 mg. All dosage amounts refer to the amount of Compound No. 14 administered and do not include the weight amount of any pharmaceutically acceptable salt.

[0186] In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 0.1 mg to about 3.5 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 0.2 mg to about 3.5 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 0.1 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 0.2 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 0.4 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 0.8 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 1.2 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 1.8 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 2.25 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 2.8 mg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 3.5 mg.

[0187] In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 0.01 mg / kg to about 100 mg / kg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 0.01 mg / kg to about 50 mg / kg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 0.01 mg / kg to about 20 mg / kg.

[0188] In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 0.01 mg / kg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 0.05 mg / kg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 0.1 mg / kg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 1 mg / kg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 2 mg / kg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 4 mg / kg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 6 mg / kg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 8 mg / kg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 10 mg / kg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 12 mg / kg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 14 mg / kg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 16 mg / kg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 18 mg / kg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 20 mg / kg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 30 mg / kg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 40 mg / kg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 50 mg / kg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 60 mg / kg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 70 mg / kg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 80 mg / kg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 90 mg / kg. In some embodiments, the amount of Compound No. 14 or a pharmaceutically acceptable salt thereof administered on each day of administration is about 100 mg / kg.

[0189] In some embodiments, the checkpoint inhibitor is administered on a daily schedule. In some embodiments, the checkpoint inhibitor is administered every other day. In some embodiments, the checkpoint inhibitor is administered once every three days. In some embodiments, the checkpoint inhibitor is administered on a twice-weekly schedule. In some embodiments, the checkpoint inhibitor is administered on a three-times-weekly schedule. In some embodiments, the checkpoint inhibitor is administered on a weekly schedule. In some embodiments, the checkpoint inhibitor is administered on a once-every-two-weekly schedule. In some embodiments, the checkpoint inhibitor is administered on a once-every-three-weekly schedule. In some embodiments, the checkpoint inhibitor is administered on a once-every-four-weekly schedule. In some embodiments, the checkpoint inhibitor is administered on a once-every-eight-weekly schedule. In some embodiments, the checkpoint inhibitor is administered on a once-every-twelve-weekly schedule.

[0190] In some embodiments, the checkpoint inhibitor is administered every other day at least three times within a 7-day cycle. In some embodiments, the checkpoint inhibitor is administered on day 1 of the treatment cycle. In certain embodiments, the proteasome inhibitor is administered on days 1 and 4 of the 7-day cycle. In some embodiments, the checkpoint inhibitor is administered consecutively within a 7-day cycle followed by a discontinuation. In some embodiments, the checkpoint inhibitor is administered for two consecutive days followed by a discontinuation for five consecutive days within at least one 7-day cycle. In some embodiments, the checkpoint inhibitor is administered for three consecutive days followed by a discontinuation for four consecutive days within at least one 7-day cycle. In some embodiments, the checkpoint inhibitor is administered for four consecutive days followed by a discontinuation for three consecutive days within at least one 7-day cycle. In some embodiments, the checkpoint inhibitor is administered for five consecutive days followed by a discontinuation for two consecutive days within at least one 7-day cycle.

[0191] In some embodiments, the checkpoint inhibitor is administered on day 1 of a 21-day treatment cycle. In some embodiments, the checkpoint inhibitor is administered on day 2 of a 21-day treatment cycle. In some embodiments, the checkpoint inhibitor is administered on day 2 of the first 21-day treatment cycle and on day 1 of each 21-day treatment cycle thereafter.

[0192] The present description contemplates administration of a checkpoint inhibitor for one or more treatment cycles, e.g., 1, 2, 3, 4, 5, 6, or more treatment cycles. In some embodiments, the treatment cycle is about 7 days to about 84 days, or more. In some embodiments, the treatment cycle is 7, 14, 21, 28, 35, 42, 49, 56, or 84 days. In some embodiments, the treatment cycle is 21 or 28 days. In some embodiments, there will be a drug holiday within or between one or more treatment cycles. For example, in some embodiments, there is a drug holiday at the end of a treatment cycle. In some embodiments, there is a drug holiday between the second and third treatment cycles, but not between the first and second treatment cycles. In other embodiments, there may be a drug holiday between the first and second treatment cycles, but not between the second and third treatment cycles. Dosing schedules include, for example, administering the checkpoint inhibitor once during the treatment schedule, e.g., on day 1 of a 21 day cycle, twice during the treatment schedule, e.g., on days 1 and 15 of a 21 day cycle, or on days 1 and 15 of a 28 day cycle, three times during the treatment schedule, e.g., on days 1, 8, and 15 of a 21 day cycle, or on days 1, 8, and 15 of a 28 day cycle, and four times during the treatment schedule, e.g., on days 1, 4, 8, and 11 of a 21 day cycle, or on days 1, 4, 8, and 11 of a 28 day cycle. Other dosing schedules are encompassed by the invention.

[0193] In some embodiments, the checkpoint inhibitor is administered by subcutaneous injection. In some embodiments, the checkpoint inhibitor is administered by intravenous infusion followed by one or more subsequent subcutaneous injections. In some embodiments, the intravenous infusion and one or more subsequent subcutaneous injections are administered according to the dosing schedules and methods disclosed herein.

[0194] In some embodiments, both Compound No. 14 and the checkpoint inhibitor are administered on day 1 of a 21-day treatment cycle. In some embodiments, Compound No. 14 is administered first on day 1 of a 21-day treatment cycle, followed by administration of the checkpoint inhibitor. In some embodiments, Compound No. 14 is administered on day 1 of a 21-day treatment cycle, and the checkpoint inhibitor is administered on day 1 of the 21-day treatment cycle one hour after administration of Compound No. 14.

[0195] In some embodiments, Compound No. 14 is administered as a 60±10 minute intravenous infusion.

[0196] In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 0.5 mg to about 1000 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 0.5 mg to about 900 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 0.5 mg to about 800 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 0.5 mg to about 700 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 0.5 mg to about 600 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 0.5 mg to about 500 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 1 mg to about 500 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 10 mg to about 500 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 50 mg to about 500 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 100 mg to about 500 mg. In some embodiments, The amount of anti-PD-1 antibody administered on each day of administration is about 150 mg to about 500 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 200 mg to about 500 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 220 mg to about 500 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 240 mg to about 500 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 260 mg to about 500 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 280 mg to about 500 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 300 mg to about 500 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 320 mg to about 500 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 340 mg to about 500 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 360 mg to about 500 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 380 mg to about 500 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 400 mg to about 500 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 200 mg to about 480 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 200 mg to about 460 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 200 mg to about 440 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 200 mg to about 420 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 200 mg to about 400 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 200 mg to about 380 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 200 mg to about 360 mg.In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 200 mg to about 340 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 200 mg to about 320 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 200 mg to about 300 mg.

[0197] In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 100 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 120 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 140 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 160 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 180 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 200 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 220 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 240 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 260 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 280 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 300 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 320 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 340 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 360 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 380 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 400 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 420 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 440 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 460 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 480 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 500 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 600 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 700 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 800 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 900 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 1000 mg.

[0198] In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 200 mg.

[0199] In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 0.5 mg / kg to about 10 mg / kg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 0.5 mg / kg to about 7.5 mg / kg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 0.5 mg / kg to about 5 mg / kg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 1 mg / kg to about 4 mg / kg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 1 mg / kg to about 3 mg / kg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 0.5 mg / kg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 1 mg / kg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 1.5 mg / kg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 2 mg / kg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 2.5 mg / kg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 3 mg / kg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 3.5 mg / kg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 4 mg / kg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 4.5 mg / kg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 5 mg / kg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 7.5 mg / kg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is about 10 mg / kg.

[0200] In some embodiments, the anti-PD-1 antibody is nivolumab or a pharmaceutically acceptable salt thereof. In some embodiments, the anti-PD-1 antibody is pembrolizumab or a pharmaceutically acceptable salt thereof. In some embodiments, the anti-PD-1 antibody is cemiplimab or a pharmaceutically acceptable salt thereof.

[0201] In some embodiments, administration of nivolumab, pembrolizumab, and cemiplimab is in accordance with their prescribing information approved by a health authority, such as that issued by the FDA or EMA, which information is incorporated herein in its entirety.

[0202] In some embodiments, the anti-PD-1 antibody is pembrolizumab or a pharmaceutically acceptable salt thereof. In some embodiments, the amount of pembrolizumab administered on each day of administration is about 200 mg. In some embodiments, pembrolizumab is administered in an amount of 200 mg on day 1 of a 21-day cycle.

[0203] In some embodiments, the anti-PD-1 antibody is pembrolizumab, or a pharmaceutically acceptable salt thereof, and pembrolizumab is administered in combination with Compound No. 14. In some embodiments, pembrolizumab is administered on day 1 of a 21 day cycle and compound number 14 is administered on days 1, 8, and 15 of the 21 day cycle. In some embodiments, pembrolizumab is administered in an amount of 200 mg on day 1 of a 21 day cycle and compound number 14 is administered in an amount of 0.1 mg on days 1, 8, and 15 of the 21 day cycle. In some embodiments, pembrolizumab is administered in an amount of 200 mg on day 1 of a 21 day cycle and compound number 14 is administered in an amount of 0.2 mg on days 1, 8, and 15 of the 21 day cycle. In some embodiments, pembrolizumab is administered in an amount of 200 mg on day 1 of a 21 day cycle and compound number 14 is administered in an amount of 0.2 mg or greater on days 1, 8, and 15 of a 21 day cycle. In some embodiments, pembrolizumab is administered in an amount of 200 mg on day 1 of a 21 day cycle and compound number 14 is administered in an amount of 0.1 mg to 3.5 mg on days 1, 8, and 15 of a 21 day cycle. In some embodiments, pembrolizumab is administered in an amount of 200 mg on day 1 of a 21 day cycle and compound number 14 is administered in an amount of 0.1 mg to 1.2 mg on days 1, 8, and 15 of a 21 day cycle. In some embodiments, pembrolizumab is administered in an amount of 200 mg on day 1 of a 21 day cycle and compound number 14 is administered in an amount of 0.2 mg to 3.5 mg on days 1, 8, and 15 of a 21 day cycle. In some embodiments, pembrolizumab is administered in an amount of 200 mg on day 1 of a 21 day cycle and compound number 14 is administered in an amount of 0.2 mg to 1.2 mg on days 1, 8, and 15 of a 21 day cycle. In some embodiments, pembrolizumab is administered in an amount of 200 mg on day 1 of a 21 day cycle and compound number 14 is administered in an amount of 0.1 mg, 0.2 mg, 0.4 mg, 0.8 mg, 1.2 mg, 1.6 mg, 2.0 mg, 2.5 mg, 3.0 mg, or 3.5 mg on days 1, 8, and 15 of a 21 day cycle.

[0204] In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 0.5 mg to about 2000 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 0.5 mg to about 1800 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 0.5 mg to about 1600 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 0.5 mg to about 1400 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 0.5 mg to about 1200 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 0.5 mg to about 1000 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 1 mg to about 2000 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 10 mg to about 2000 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 100 mg to about 2000 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 200 mg to about 2000 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 400 mg to about 2000 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 600 mg to about 2000 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 800 mg to about 2000 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 1000 mg to about 2000 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 1200 mg to about 2000 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 1500 mg to about 2000 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 1000 mg to about 2000 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 1000 mg to about 1800 mg.In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 1000 mg to about 1600 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 1000 mg to about 1400 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 1000 mg to about 1400 mg. The amount of anti-PD-L1 antibody administered on each day of administration is about 1000 mg to about 1200 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 1200 mg to about 1400 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 1100 mg to about 1300 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 1100 mg to about 1200 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 1200 mg to about 1300 mg.

[0205] In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 100 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 200 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 300 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 400 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 500 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 600 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 700 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 800 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 900 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 1000 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 1100 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 1200 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 1300 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 1400 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 1500 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 1600 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 1700 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 1800 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 1900 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 2000 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 2500 mg.In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 3000 mg.

[0206] In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 0.5 mg / kg to about 20 mg / kg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 1 mg / kg to about 20 mg / kg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 5 mg / kg to about 20 mg / kg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 5 mg / kg to about 15 mg / kg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 5 mg / kg to about 10 mg / kg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 6 mg / kg to about 10 mg / kg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 7 mg / kg to about 10 mg / kg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 8 mg / kg to about 10 mg / kg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 9 mg / kg to about 10 mg / kg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 10 mg / kg to about 15 mg / kg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 10 mg / kg to about 1 In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 10 mg / kg to about 13 mg / kg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 10 mg / kg to about 12 mg / kg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 10 mg / kg to about 11 mg / kg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 1 mg / kg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 2 mg / kg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 3 mg / kg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 4 mg / kg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 5 mg / kg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 6 mg / kg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 7 mg / kg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 8 mg / kg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 9 mg / kg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 10 mg / kg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 11 mg / kg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 12 mg / kg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 13 mg / kg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 14 mg / kg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 15 mg / kg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 16 mg / kg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 17 mg / kg.In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 18 mg / kg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 19 mg / kg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is about 20 mg / kg.

[0207] In some embodiments, the anti-PD-L1 antibody is atezolizumab or a pharmaceutically acceptable salt thereof. In some embodiments, the anti-PD-L1 antibody is durvalumab or a pharmaceutically acceptable salt thereof. In some embodiments, the anti-PD-L1 antibody is avelumab or a pharmaceutically acceptable salt thereof.

[0208] In some embodiments, administration of atezolizumab, durvalumab, and avelumab is in accordance with their prescribing information approved by a health authority, such as that issued by the FDA or EMA, which information is incorporated herein in its entirety.

[0209] In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 0.5 mg to about 2000 mg. In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 1 mg to about 2000 mg. In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 10 mg to about 2000 mg. In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 50 mg to about 2000 mg. In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 100 mg to about 2000 mg. In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 1 mg. In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 10 mg. In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 100 mg. In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 200 mg. In some embodiments, the anti-CTLA-4 antibody administered on each day of administration The amount of anti-CTLA-4 antibody administered on each day of administration is about 400 mg. In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 600 mg. In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 800 mg. In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 1000 mg. In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 1200 mg. In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 1400 mg. In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 1600 mg. In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 1800 mg. In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 2000 mg.

[0210] In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 0.5 mg / kg to about 20 mg / kg. In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 1 mg / kg to about 20 mg / kg. In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 1 mg / kg to about 18 mg / kg. In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 1 mg / kg to about 16 mg / kg. In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 1 mg / kg to about 14 mg / kg. In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 1 mg / kg to about 12 mg / kg. In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 1 mg / kg to about 10 mg / kg. In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 1 mg / kg. In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 2 mg / kg. In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 3 mg / kg. In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 4 mg / kg. In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 5 mg / kg. In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 6 mg / kg. In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 7 mg / kg. In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 8 mg / kg. In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 9 mg / kg. In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 10 mg / kg. In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 11 mg / kg. In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 12 mg / kg.In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 13 mg / kg. In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 14 mg / kg. In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 15 mg / kg. In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 16 mg / kg. In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 17 mg / kg. In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 18 mg / kg. In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 19 mg / kg. In some embodiments, the amount of anti-CTLA-4 antibody administered on each day of administration is about 20 mg / kg.

[0211] In some embodiments, the anti-CTLA-4 antibody is ipilimumab or a pharmaceutically acceptable salt thereof.

[0212] In some embodiments, administration of ipilimumab is in accordance with a regulatory approval issued by the FDA or EMA. and in accordance with its prescribing information approved by health authorities, such as that published in the National Institute of Infectious Diseases (NIID) No. 10 / 1999, filed on March 1, 2002, which is incorporated herein in its entirety.

[0213] Pharmaceutical Compositions The STING agonists and checkpoint inhibitors used in the methods and kits described herein can be formulated into pharmaceutical compositions suitable for administration. Pharmaceutical compositions may contain pharmaceutically acceptable excipients. As used herein, pharmaceutically acceptable excipients include, but are not limited to, any solvent, dispersion medium, or other liquid vehicle, dispersion or suspension aid, diluent, granulating and / or dispersing agent, surfactant, isotonicity agent, thickener or emulsifier, preservative, binder, lubricant or oil, colorant, sweetener or flavoring agent, stabilizer, antioxidant, antibacterial or antifungal agent, osmolality adjuster, pH adjuster, buffer, chelating agent, cryoprotectant, and / or bulking agent, suitable for the particular dosage form desired. Various excipients for formulating pharmaceutical compositions and techniques for preparing compositions are known in the art (see, for example, Remington: The Science and Practice of Pharmacy, 21, incorporated by reference in its entirety). st Ed., A.R. Gennaro (Lippincott, Williams & Wilkins, Baltimore, MD), 2006).

[0214] Any of the therapeutic agents described herein may take the form of a pharmaceutically acceptable salt. In some embodiments, such salts are derived from inorganic or organic acids or bases. For reviews of suitable salts, see, for example, Berge et al., J.Pharm.Sci., 1977, 66, 1-19, and Remington: The Science and Practice of Pharmacy, 20th Ed., A. Gennaro (ed.), Lippincott Williams & Wilkins (2000).

[0215] Examples of suitable acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenyl-propionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate salts.

[0216] Examples of suitable base addition salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, dicyclohexylamine salts, salts with organic bases such as N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and the like.

[0217] For example, Berge lists the following FDA-approved commercially available salts: acetate, besylate (benzenesulfonate), benzoate, bicarbonate, bitartrate, bromide, calcium edetate (ethylenediaminetetraacetate), camsylate (camphorsulfonate), carbonate, chloride, citrate, dihydrochloride, edetate (ethylenediaminetetraacetate), edisylate (1,2-ethanedisulfonate), estolate (lauryl sulfate), esylate (ethanesulfonate), fumarate, gluceptate (glucoheptonate), gluconate, glutamate, glycolylarsanilate (glycolamidophenylarsonate), hexylresorcinol, ... cinate), hydrabamine (N,N'-di(dehydroabietyl)ethylenediamine), hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate (2-hydroxyethanesulfonate), lactate, lactobionate, malate, maleate, mandelate, mesylate (methanesulfonate), methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate (2-naphthalenesulfonate), nitrate, pamoate (embonate), pantothenate, phosphate / diphosphate , polygalacturonate, salicylate, stearate, acetate, succinate, sulfate, tannate, tartrate, teoclate (8-chlorotheophyllinate), and triethiodide; organic cations benzathine (N,N'-dibenzylethylenediamine), chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine; and metal cations aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc.

[0218] Berge further lists the following non-FDA approved commercially available (outside the United States) salts: the anions adipate, alginate, aminosalicylate, anhydromethylene citrate, arecoline, aspartate, bisulfate, butyl bromide, camphorate, digluconate, dihydrobromide, disuccinate, glycerophosphate, hemisulfate, hydrogen fluoride, hydroiodide, methylene bis(salicylate), napadisilate (1,5-naphthalenedisulfonate), oxalate, and pectin. salts, persulfates, phenylethylbarbiturates, picrates, propionates, thiocyanates, tosylates, and undecanoates; the organic cations benethamine (N-benzylphenethylamine), clemizole (1-p-chlorobenzyl-2-pyrrolidin-1'-ylmethylbenzimidazole), diethylamine, piperazine, and tromethamine (tris(hydroxymethyl)aminomethane); and the metal cations barium and bismuth.

[0219] The pharmaceutical composition may include a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" refers to a substance that is compatible with the recipient subject (human) and suitable for delivering the active agent to the target site without terminating the activity of the agent. If any, the toxicity or adverse effects associated with the carrier are preferably commensurate with a reasonable risk-benefit ratio for the intended use of the active agent.

[0220] Pharmaceutically acceptable carriers that may be used in these compositions include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates or carbonates, saturated vegetable fatty acids such as glycine, sorbic acid, potassium sorbate, protamine sulfate, water, salts, or partial glyceride mixtures of electrolytes, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic materials, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0221] Pharmaceutical compositions for use in the methods of the present disclosure can be prepared by methods well known in the art, such as conventional granulation, mixing, dissolving, encapsulation, lyophilization, or emulsification processes, among others. The compositions can be produced in a variety of forms, including granules, precipitates, or particulates, powders, including freeze-dried, rotary-dried, or spray-dried powders, amorphous powders, tablets, capsules, syrups, suppositories, injections, emulsions, elixirs, suspensions, or solutions. Formulations may contain stabilizers, pH adjusters, surfactants, solubilizers, bioavailability modifiers, and combinations thereof. These pharmaceutical compositions are formulated for pharmaceutical administration to humans. Such compositions can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intraperitoneal, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. In some embodiments, the composition is administered orally, intravenously, or subcutaneously. In some embodiments, the composition is administered orally. In some embodiments, the composition is administered intravenously. In some embodiments, intravenous administration can be intravenous infusion or intravenous injection. In some embodiments, the composition is administered by intravenous infusion. In some embodiments, the composition is administered by intravenous injection. In some embodiments, the composition is administered by subcutaneous injection. In some embodiments, the composition is administered by intravenous infusion followed by subcutaneous injection. In another embodiment, the checkpoint inhibitor is co-administered subcutaneously with human hyaluronidase. These formulations can be designed to be short-acting, fast-releasing, or long-acting. Additionally, the composition can be administered in a local manner, such as by administration (e.g., by injection) at the tumor site, rather than systemically.

[0222] Pharmaceutical formulations can be prepared as liquid suspensions or solutions using liquids such as oil, water, alcohol, and combinations thereof. Solubilizers such as cyclodextrins can be included. Pharmaceutically suitable surfactants, suspending agents, or emulsifiers can be added for oral or parenteral administration. Suspensions can include oils such as peanut oil, sesame oil, cottonseed oil, corn oil, and olive oil. Suspension formulations can also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides, and acetylated fatty acid glycerides. Suspension formulations can include alcohols such as ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol, and propylene glycol, ethers such as poly(ethylene glycol), petroleum hydrocarbons such as mineral oil and mineral oil, and water.

[0223] Sterile injectable forms of these pharmaceutical compositions may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and physiological saline solution. Additionally, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland fixed oil may be used, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, particularly in their polyoxyethylated versions. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants, commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions or suspensions. Other commonly used surfactants, such as sorbitan alkyl esters, such as Tween or Span, and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, can also be used for formulation purposes. The composition can be formulated for parenteral administration by injection, for example, bolus injection or continuous infusion. The unit dosage form for injection can be in ampoules or multi-dose containers.

[0224] These pharmaceutical compositions can be orally administered in any orally acceptable dosage form, including capsules, tablets, aqueous suspensions or solutions. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweeteners, flavorings, or coloring agents can also be added. For oral administration in capsule form, useful diluents include lactose and dried cornstarch. For tablets for oral use, commonly used carriers include lactose and cornstarch. Lubricants such as magnesium stearate are also typically added. Coatings are used for various purposes, for example, to mask the taste. Coatings may be applied to tablets or to granulated particles for use in capsules, to affect the site of dissolution or absorption, or to prolong the action of a drug.

[0225] Alternatively, these pharmaceutical compositions can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore melts in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0226] These pharmaceutical compositions may also be administered topically, particularly when the target of treatment includes areas or organs readily accessible by topical application, such as diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0227] Topical application for the lower intestinal tract can be achieved with a rectal suppository formulation (see above) or a suitable enema formulation. A topical transdermal patch can also be used. For topical application, the pharmaceutical composition can be formulated into a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present disclosure include mineral oil, liquid mineral oil, white mineral oil, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutical composition can be formulated into a suitable lotion or cream containing the active ingredient(s) suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0228] For ophthalmic use, the pharmaceutical composition may be formulated as a micronized suspension in isotonic, pH-adjusted, sterile saline, or preferably as a solution in isotonic, pH-adjusted, sterile saline, either with or without a preservative, such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated into an ointment, such as petrolatum.

[0229] Pharmaceutical compositions may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation, and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0230] In one embodiment, Compound No. 14 is formulated as a solution for intravenous infusion. In some embodiments, Compound No. 14 is formulated in a solution containing 3 mg / 3 mL of Compound No. 14 as the free base. In one embodiment, the solution of Compound No. 14 can be diluted prior to infusion.

[0231] kit In some embodiments, the STING agonists or checkpoint inhibitors described herein can be manufactured for inclusion in a kit. A "kit" is any article of manufacture (e.g., package or container) containing at least one reagent or chemotherapeutic agent. Kits for use in the methods herein can include a STING agonist, e.g., Compound No. 14, or a pharmaceutically acceptable salt thereof. In some embodiments, the kit can further include a checkpoint inhibitor and, optionally, one or more additional therapeutic agents. In some embodiments, the kit can include Compound No. 14, or a pharmaceutically acceptable salt thereof, a checkpoint inhibitor, and, optionally, one or more additional therapeutic agents. In some embodiments, the kit can include one or more STING agonists or a pharmaceutically acceptable salt thereof. In some embodiments, the kit may include one or more checkpoint inhibitors.

[0232] In some embodiments, the present disclosure relates to kits containing medicaments for use in treating cancer in patients in need of such treatment. The kit includes a medicament comprising a STING agonist and instructions for administering the STING agonist and a checkpoint inhibitor, or the kit includes a medicament comprising a checkpoint inhibitor and instructions for administering the checkpoint inhibitor and a STING agonist. The kit may include a medicament comprising a STING agonist and a checkpoint inhibitor and instructions for administering the STING agonist and the checkpoint inhibitor, where the medicaments are in a single dosage form or separate dosage forms. In some embodiments, the kit optionally includes one or more additional therapeutic agents.

[0233] In some embodiments, a kit comprising a STING agonist and a checkpoint inhibitor may further comprise another component or reagent. In some embodiments, a reagent in the kit may be a diluent for preparing the STING agonist for administration. In some embodiments, a reagent in the kit may be a diluent for preparing the checkpoint inhibitor for administration. In some embodiments, a component in the kit may be a container for mixing the combination of the STING agonist and the checkpoint inhibitor.

[0234] In another aspect, the present disclosure relates to a kit for treating cancer, the kit comprising at least one medicament comprising at least one dose of Compound No. 14 or a pharmaceutically acceptable salt thereof, and at least one medicament comprising at least one dose of a checkpoint inhibitor, the kit for treating cancer further comprising administration instructions for administering the medicaments for treatment of a patient certified in need thereof. [Example]

[0235] In order that this disclosure may be more fully understood, the following examples are set forth. These examples are illustrative only and are not intended to limit the scope of the disclosure in any way.

[0236] [Table 2]

[0237] Example 1: In vivo tumor efficacy Common analytical methods Unless otherwise stated, 1 H NMR spectra were obtained using a Varian 300 MHz. Unless otherwise stated, HPLC was obtained on an Agilent 1100 series and UPLC was obtained by Water Acuity Systems.

[0238] As used in the examples below, Compound No. 14 can be synthesized according to the procedures listed in Example 14 in PCT Publication No. WO2018 / 100558.

[0239] General experimental conditions for antitumor efficacy in mouse tumor models Mouse syngeneic tumor model The following syngeneic models were utilized in each of Studies 1-5, as specified below.

[0240] A20 Study 1: A20 is a murine B-cell lymphoma cell line. The A20 mouse syngeneic tumor model was established in approximately 9-week-old female BALB / c mice (Vital River Laboratories, ory Animal Technology Co., Ltd., Beijing, China) 6 A20 cells (cell suspension) were inoculated subcutaneously into the flank of the mouse. The average tumor volume was approximately 55 mm. 3 When tumor size reached 100 mg / kg, the animals were randomized into one vehicle control group and three treatment groups (n=10 / group). Mice were then administered PBS, Compound No. 14, anti-mouse PD-1 antibody, or Compound No. 14 + anti-mouse PD-1 antibody for 31 days. Tumor growth and body weight were measured twice weekly during the treatment and post-treatment periods, and mice were humanely euthanized after they reached the humane endpoint.

[0241] L5178-R Study 2: L5178-R is a mouse lymphoma cell line. The L5178-R mouse syngeneic tumor model was injected into approximately 12-week-old female DBA / 2 mice (Vital River Laboratory Animal Technology Co., Ltd., Beijing, China) at 0.2 × 10 6 L5178-R cells (cell suspension) were inoculated subcutaneously into the flank of the mouse. The average tumor volume was approximately 65 mm. 3When tumor size reached 100 mg / kg, the animals were randomized into one vehicle control group and four treatment groups (n=10 / group). Mice were then administered 10 mg / kg of PBS, Compound No. 14, anti-mouse PD-1 antibody, or Compound No. 14 + anti-mouse PD-1 antibody for 10 days (Q3D x 3 & QW x 3). Tumor growth and body weight were measured twice a week during the treatment and post-treatment periods, and the mice were humanely euthanized after they reached the humane endpoint.

[0242] WEHI-3 Study 3: WEHI-3 is a murine myelomonocytic leukemia cell line. The WEHI-3 mouse syngeneic tumor model was established in approximately 11-week-old female BALB / c mice (Vital River Laboratory Animal Technology Co., Ltd., Beijing, China) at a dose of 0.1 × 10 6 WEHI-3 cells (cell suspension) were inoculated subcutaneously into the flank. The average tumor volume was approximately 60 mm. 3 When tumor size reached 100 mg / kg, animals were randomized into one vehicle control group and four treatment groups (n=10 / group). Mice were then administered PBS, Compound No. 14, anti-mouse PD-1 antibody, or Compound No. 14 + anti-mouse PD-1 antibody for 21 days. Tumor growth and body weight were measured twice weekly during the treatment and post-treatment periods, and mice were humanely euthanized after they reached the humane endpoint.

[0243] RM-1 Study 4: RM-1 is a mouse prostate cancer cell line. The RM-1 mouse syngeneic tumor model was inoculated into approximately 10-week-old female C57BL / 6 mice (Vital River Laboratory Animal Technology Co., Ltd., Beijing, China) with 0.8 × 10 6 RM-1 cells (cell suspension) were subcutaneously inoculated into the flank of the mouse. The average tumor volume was approximately 60 mm. 3When tumor size reached 100 mg / kg, animals were randomized into one vehicle control group and four treatment groups (n=10 / group). Mice were then administered PBS, Compound No. 14, anti-mouse PD-1 antibody, or Compound No. 14 + anti-mouse PD-1 antibody for 19 days. Tumor growth and body weight were measured twice weekly during the treatment and post-treatment periods, and mice were humanely euthanized after reaching the humane endpoint.

[0244] L1210 Study 5: L1210 is a murine leukemia cell line. The L1210 mouse syngeneic tumor model was inoculated into approximately 11-week-old female DBA / 2 mice (Vital River Laboratory Animal Technology Co., Ltd., Beijing, China) with 0.02 × 10 6 L1210 cells (cell suspension) were inoculated subcutaneously into the flank. The average tumor volume was approximately 50 mm. 3 When the PD-1 antibody response reached 1.0, the animals were randomized into one vehicle control group and four treatment groups (n=10 / group). Mice were then treated with PBS, Compound No. 14, anti-mouse PD-1 antibody, or Compound No. 14 + anti-PD-1 antibody. The mouse PD-1 antibody was administered for 15 days. Tumor growth and body weight were measured twice weekly during the treatment and post-treatment periods, and the mice were humanely euthanized after they reached the humane endpoint.

[0245] Test drug The following test medications were utilized in each of Studies 1-5, as specified below.

[0246] A20 Study 1: A 0.025 mg / mL stock solution of Compound No. 14 was formulated in phosphate buffered saline (PBS) and administered intravenously (IV) using a dose volume of 10 mL / kg body weight based on the exact animal weight on each day of treatment. The final dose was 0.25 mg / kg. Compound No. 14 dose was 0.2 mL. Anti-mouse PD1 antibody (anti-mPD-1) (Bio X Cell, 10 Technology Drive, Suite 100, San Diego, CA) was used. Anti-mPD-1 (Compound No. 14, Pharmacy No. 2B, West Lebanon, NH 03784) was formulated at 2 mg / mL in phosphate-buffered saline (PBS) prior to each injection, resulting in a 10 mg / kg dose using a 5 mL / kg dose volume, and administered intraperitoneally (IP) based on accurate body weight on each day of treatment. The dose volume of anti-mPD-1 was 0.1 mL. Compound No. 14 was administered to the single-agent and combination treatment groups on a Q3D schedule for three cycles through day 6 (days 0, 3, and 6), and anti-mPD-1 was administered to the single-agent and combination treatment groups on a Q3D schedule for three cycles through day 6 and a QW schedule for three weeks through day 27 (days 0, 3, 6, 13, 20, and 27).

[0247] L5178-R Study 2: A 0.025 mg / mL stock solution of Compound No. 14 was formulated in phosphate-buffered saline (PBS) and administered intravenously (IV) using a dose volume of 10 mL / kg body weight based on the exact animal weight each day of treatment. The final dose was 0.25 mg / kg. The dose volume of Compound No. 14 was 0.2 mL. Anti-mouse PD1 antibody (anti-mPD-1) (Bio X Cell, 10 Technology Drive, Suite 2B, West Lebanon, NH 03784) was formulated at 2 mg / mL in phosphate-buffered saline (PBS) prior to each injection, resulting in a 10 mg / kg dose using a dose volume of 5 mL / kg, and administered intraperitoneally (IP) based on the exact body weight each day of treatment. The dose volume of anti-mPD-1 was 0.1 mL. Compound No. 14 was administered to the single-agent and combination treatment groups on a Q3D schedule for three cycles through day 6 (days 0, 3, and 6), and anti-mPD-1 was administered to the single-agent and combination treatment groups on a Q3D schedule for three cycles through day 6 (days 0, 3, and 6).

[0248] WEHI-3 Study 3: A 0.025 mg / mL stock solution of Compound No. 14 was formulated in phosphate-buffered saline (PBS) and administered intravenously (IV) using a dose volume of 10 mL / kg body weight based on the exact animal weight on each day of treatment. The final dose was 0.25 mg / kg. The dose volume of Compound No. 14 was 0.2 mL. Anti-mouse PD1 antibody (anti-mPD-1) (Bio X Cell, 10 Technology Drive, Suite 2B, West Lebanon, NH 03784) was formulated at 2 mg / mL in phosphate-buffered saline (PBS) prior to each injection, resulting in a 10 mg / kg dose using a dose volume of 5 mL / kg, and administered intraperitoneally (IP) based on the exact body weight on each day of treatment. The dose volume of anti-mPD-1 was 0.1 mL. Compound No. 14 was administered to the single-agent and combination treatment groups on a Q3D schedule for three cycles through day 6 (days 0, 3, and 6), and anti-mPD-1 was administered to the single-agent and combination treatment groups on a Q3D schedule for three cycles through day 6 and a QW schedule for one week through day 13 (days 0, 3, 6, and 13).

[0249] RM-1 Study 4: A 0.025 mg / mL stock solution of Compound No. 14 was dissolved in phosphate-buffered saline. The compounds were formulated in saline (PBS) and administered intravenously (IV) using a dose volume of 10 mL / kg body weight based on the exact animal weight each day of treatment. The final dose was 0.25 mg / kg. The dose volume of Compound No. 14 was 0.2 mL. Anti-mouse PD1 antibody (anti-mPD-1) (Bio X Cell, 10 Technology Drive, Suite 2B, West Lebanon, NH 03784) was formulated at 2 mg / mL in phosphate buffered saline (PBS) prior to each injection and administered intraperitoneally (IP) using a dose volume of 5 mL / kg to provide a dose of 10 mg / kg based on the exact animal weight each day of treatment. The dose volume of anti-mPD-1 was 0.1 mL. Compound No. 14 was administered to the single-agent and combination treatment groups on a Q3D schedule for three cycles through day 6 (days 0, 3, and 6), and anti-mPD-1 was administered to the single-agent and combination treatment groups on a Q3D schedule for three cycles through day 6 and a QW schedule for one week through day 13 (days 0, 3, 6, and 13).

[0250] L1210 Study 5: A 0.025 mg / mL stock solution of Compound No. 14 was formulated in phosphate-buffered saline (PBS) and administered intravenously (IV) using a dose volume of 10 mL / kg body weight based on the exact animal weight each day of treatment. The final dose was 0.25 mg / kg. The dose volume of Compound No. 14 was 0.2 mL. Anti-mouse PD1 antibody (anti-mPD-1) (Bio X Cell, 10 Technology Drive, Suite 2B, West Lebanon, NH 03784) was formulated at 2 mg / mL in phosphate-buffered saline (PBS) prior to each injection, resulting in a 10 mg / kg dose using a dose volume of 5 mL / kg, and administered intraperitoneally (IP) based on the exact body weight each day of treatment. The dose volume of anti-mPD-1 was 0.1 mL. Compound No. 14 was administered to the single-agent and combination treatment groups on a Q3D schedule for three cycles through day 6 (days 0, 3, and 6), and anti-mPD-1 was administered to the single-agent and combination treatment groups on a Q3D schedule for three cycles through day 6 and a QW schedule for one week through day 13 (days 0, 3, 6, and 13).

[0251] Tumor Measurements: Tumors were measured twice weekly using calipers. Tumor volume was calculated using the standard equation: V = W 2 × L / 2 (where V = volume, W = width, and L = length for tumors). For Study 1, the mean tumor volume was approximately 55 mm 3 When Research 2 reaches 65mm 3 , 60mm for Study 3 3 , 60mm for Study 4 3 , 50mm for Research 5 3 Mice were randomized into four groups (n=10 / group) in Studies 1-5 and administered vehicle (PBS), Compound No. 14, anti-mPD-1, or a combination of Compound No. 14 and anti-mPD-1 at various doses and schedules. Tumor size and body weight were measured twice weekly throughout the study. Mice were euthanized when their tumor volume reached more than 10% of the animal's body weight or when individual tumors exceeded the humane endpoint in size (tumor length >2 cm).

[0252] Statistical analysis of comparison of different treatments in a mouse syngeneic tumor model The following statistical analysis methods were utilized in Studies 1-5.

[0253] All tumor volumes were multiplied by a factor of 5 before logarithmic transformation. After transformation, linear interpolation was used to determine the tumor volume of each mouse within 1000 mm. 3 The time (in days) from randomization for mice to reach a tumor size of 1000 mm was estimated. 3 The event of tumor progression reaching 1000 mm was considered a "tumor progression" event, and the estimated time was called the time to progression (TTP). 3 If the TTP was not reached, the last day of the mouse on study was recorded and right-censored. For each treatment pair of interest, a parametric survival model was assumed using a Weibull distribution for TTP to estimate the hazard ratio (HR) between the two treatment arms. HRs were calculated based on the difference between the two treatment arms. The HR reflects the hazard ratio of experiencing a progression event at any time throughout the study. An HR between treatment A and treatment B less than 1 suggests that treatment A is more effective than treatment B. Standard errors (SE) and 95% confidence intervals (CI) were also calculated to account for the uncertainty of the estimated HR. Finally, to assess the statistical significance of the difference between the two treatments, two types of tests were used to calculate P values: 1) Wald test p-values from the Weibull survival model; 2) nonparametric log-rank test.

[0254] result A20 Study 1: The combination arm of Compound #14 and anti-mouse PD-1 antibody provided combination benefit during the 31-day treatment phase of the A20 study when compared with either Compound #14 or the anti-mouse PD-1 antibody alone arm. The anti-mouse PD-1 antibody alone arm achieved one complete response that was maintained over 31 days, and the Compound #14 arm also achieved one complete response. In contrast, the Compound #14 and anti-mouse PD-1 antibody combination arm saw four complete responses. The Weibull regression hazard ratio was significant compared with both control arms, but was not significantly different for Compound #14 with anti-mouse PD-1 antibody compared with Compound #14 alone as assessed by the log-rank test (p=0.067).

[0255] Treatment groups from Study 1 are shown in Table 1a. The combined effect of treatment duration is also shown in Table 1a. Kaplan-Meier curves for progression-free survival during the treatment period are shown in Figure 1a. Tumor growth curves during the treatment period are shown in Figure 1b.

[0256] L5178-R Study 2: The Compound #14 and anti-mouse PD-1 antibody combination arm provided combination benefit during the 6-day treatment phase of the L5178-R study when compared to the anti-mouse PD-1 antibody-only arm, but not when compared to the Compound #14 arm. No complete responses were seen in this study. The Weibull regression hazard ratio was significant compared to the anti-mouse PD-1 antibody control arm.

[0257] Treatment groups from Study 2 are shown in Table 1a. The combined effect of treatment duration is also shown in Table 1a. Kaplan-Meier curves for progression-free survival during the treatment period are shown in Figure 2a. Tumor growth curves during the treatment period are shown in Figure 2b.

[0258] WEHI-3 Study 3: The Compound #14 and anti-mouse PD-1 antibody combination arm provided a combination benefit during the 14-day treatment phase of the WEHI-3 study when compared to the anti-mouse PD-1 antibody alone arm, but not when compared to the Compound #14 arm. No complete responses were seen in this study. The Weibull regression hazard ratio was significant compared to the anti-mouse PD-1 antibody control arm.

[0259] Treatment groups from Study 3 are shown in Table 1a. The combined effect of treatment duration is also shown in Table 1a. Kaplan-Meier curves for progression-free survival during the treatment period are shown in Figure 3a. Tumor growth curves during the treatment period are shown in Figure 3b.

[0260] RM-1 Study 4: The Compound #14 and anti-mouse PD-1 antibody combination arm provided combination benefit during the 14-day treatment phase of the RM-1 study when compared to the anti-mouse PD-1 antibody alone arm, but not when compared to the Compound #14 arm. No complete responses were seen in this study. The Weibull regression hazard ratio was significant compared to the anti-mouse PD-1 antibody control arm.

[0261] Treatment groups from Study 4 are shown in Table 1a. The combined effect of treatment duration is also shown in Table 1a. Kaplan-Meier curves for progression-free survival during treatment are shown in Figure 4a. The growth curves are shown in Figure 4b.

[0262] L1210 Study 5: The Compound #14 and anti-mouse PD-1 antibody combination arm provided combination benefit during the 11-day treatment phase of the L1210 study when compared to either the Compound #14 or anti-mouse PD-1 antibody alone arms. No complete responses were seen in this study. Weibull regression hazard ratios were significant compared to both control arms.

[0263] Treatment groups from Study 5 are shown in Table 1a. The combined effect of treatment duration is also shown in Table 1a. Kaplan-Meier curves for progression-free survival during the treatment period are shown in Figure 5a. Tumor growth curves during the treatment period are shown in Figure 5b.

[0264] [Table 3-1]

[0265] [Table 3-2]

[0266] Additional mouse syngeneic studies Unlike the A20, L5178-R, WEHI-3, RM-1, and L1210 syngeneic models, mouse mammary carcinoma 4T1, mouse melanoma B16F10, mouse leukemia C1498, mouse colon adenocarcinoma Colon26, mouse colon adenocarcinoma CT26, mouse lymphoma E.G7-OVA, mouse lymphoma EL4, mouse mammary carcinoma EMT6, mouse hepatocellular carcinoma H22, mouse plasmacytoma J558, mouse mammary adenocarcinoma JC, mouse lung carcinoma KLN205, mouse Lewis lung carcinoma LLC, and mouse In the Lewis lung carcinoma LLC-1 luc, mouse colon adenocarcinoma MC38, mouse lymphoma P388D1, mouse pancreatic ductal carcinoma PANC02, and mouse renal carcinoma RENCA models, no benefit was observed from the combination of Compound No. 14 and an anti-mouse PD-1 antibody under similar experimental conditions and procedures in Studies 1 to 5.

[0267] Example 2: Clinical Trial Evaluating Compound No. 14 in Combination with an Anti-PD-1 Antibody in the Treatment of Patients with Metastatic Solid Tumors A Phase 1, open-label, parallel-group, dose-escalation study will be conducted to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of Compound 14 as a single agent (SA) and in combination with pembrolizumab in adult patients with metastatic solid tumors. This information will be used to independently assess both the pharmacologically effective dose (PAD) and maximum tolerated dose (MTD) to establish a recommended Phase 2 dose (RP2D) for SA and in combination with pembrolizumab. Dose escalation may be stopped after determination of the PAD but before determination of the MTD, based on discussion of safety data by the investigator and sponsor.

[0268] Approximately 100 patients will be enrolled in this study. Once enrolled, patients will receive Compound #14 intravenously (IV) on days 1, 4, 8, and 11 of a 21-day dosing cycle in both the Compound #14 SA and the combination arm with pembrolizumab. All patients will remain hospitalized for treatment and monitoring until at least day 9 of cycle 1. Patients may be discharged 24 hours after the day 8 infusion if there are no clinical issues (i.e., fever, hypotension, or other clinical safety issues). If clinical safety, PK, and pharmacodynamics support this, the dosing schedule may be modified to deemphasize the intensive dosing of Compound #14 on days 1 and 8 of the 21-day cycle without requiring a protocol amendment. Alternative dosing schedules may also be considered if collective safety, PK, and pharmacodynamic data support it. Additionally, patients experiencing clinical benefit may be switched to this less frequent schedule after cycle 6 by the investigator, in agreement with the patient, if continuing the intensive schedule is deemed to be detrimental to the patient's health.

[0269] Single-agent compound number 14 arm The proposed initial exploratory dose range is 0.2 to 3.5 mg (if the 0.2 mg starting dose is not tolerated, a 0.1 mg dose level [DL] is defined). The starting dose will be calculated using a combination of the estimated minimum effective dose (MABEL) and nonclinical toxicity approaches. If the final DL is deemed safe and tolerable, doses above 3.5 mg can be explored. The upper DL of 3.5 mg roughly corresponds to a human equivalent dose slightly above the MTD in monkeys. For the first three patients at a given DL, patient enrollment will be staggered with a planned 4-day hold between each patient. This hold may not be necessary if more than three patients are enrolled on a DL or if tapering is indicated, provided there are no clinically significant safety findings suggestive of infusion reactions or cytokine release syndrome. During the trial, this 4-day hold may be reconsidered in discussions with the investigator and sponsor.

[0270] Compound No. 14 in combination with pembrolizumab arm The second arm will evaluate the safety, tolerability, PK, and pharmacodynamics of Compound No. 14 in combination with the approved dose and schedule of pembrolizumab (200 mg Q3W). This second arm will be initiated only if at least two DLs of Compound No. 14 in SA have been evaluated and deemed safe and tolerable. If there is no need for dose reduction to DL-1 in the SA arm, the starting dose of Compound No. 14 in this arm will be 0.2 mg (Compound No. 14 MABEL) administered on days 1, 4, 8, and 11 in combination with 200 mg pembrolizumab administered Q3W. Cycle 1 alone will be used for a better evaluation of safety. In this cycle, Compound No. 14 will be administered on day 1 and pembrolizumab will be administered on day 2. For the remaining dosing periods beginning on day 1 of cycle 2, both drugs will be administered on day 1, starting with Compound No. 14, followed by pembrolizumab with a 1-hour interval between the two drugs. If clinical safety and / or PK / pharmacodynamic data support it, less frequent dosing of Compound No. 14 in combination with pembrolizumab may be considered, such as dosing on days 1 and 8 of a 21-day cycle. Alternative dosing schedules may also be considered if the collective safety, PK, and pharmacodynamic data support it.

[0271] The study design consists of a dose escalation portion followed by dose expansion cohorts for both the SA and combination arms of Compound #14. Dose escalation of Compound #14 as SA and in combination with pembrolizumab will follow an adaptive design using Bayesian logistic regression modeling (BLRM). BLRM with an overdose control will be used to inform dose escalation decisions and MTD estimation for the SA and combination arms, while a combination of PK and pharmacodynamic data will be used to estimate the PAD. Once the PAD for Compound #14 as SA or in combination with pembrolizumab is determined, either the SA or combination expansion cohorts of Compound #14 can be initiated without specifying the SA or combination MTD, respectively. In both the SA and combination arms, three patients will be enrolled in the initial DL, followed by a 3 + 3 + 3 dose escalation rule. Starting with a patient's second DL, BLRM with an overdose control will be used for all subsequent dose recommendations for both the SA and combination arms, along with consideration of other non-dose-limiting toxicity (DLT) safety and available PK data. The final decision regarding the next DL will be made jointly by the sponsor and participating investigators within the DL boundaries, taking into account the output of the BLRM and other available clinical or translational information.

[0272] Once the MTD and / or PAD are determined for Compound #14 as SA or in combination with pembrolizumab, an expansion cohort of approximately 15 patients treated with Compound #14 as SA or in combination with pembrolizumab may be initiated to better evaluate safety and tolerability at that dose. Expansion cohorts may be initiated after PADs are identified and do not need to await MTD determination. If the dose escalation phase does not resolve the MTD or PAD, the ability to expand to more than one dose may be agreed upon between the sponsor and the investigator. In principle, these cohorts will enroll the same patient population as the dose escalation phase; however, some enrichment strategies may be implemented for these expansion cohorts if supported by either literature / publications, nonclinical / validation work, or evidence of antitumor activity during the escalation phase. A formal sample size calculation will not be performed for expansion cohorts.

[0273] Toxicity will be assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. DLTs will be defined as any well-described treatment-emergent adverse event (TEAE), including but not limited to, that occurs during cycle 1 and that the investigator considers to be at least possible related to Compound No. 14 as a SA or in combination with pembrolizumab. TEAEs meeting the DLT definition occurring in subsequent cycles will be considered in determining the PAD and RP2D of Compound No. 14, both as a SA and in combination with pembrolizumab, which may be at or below the MTD.

[0274] Patients who tolerate treatment with Compound No. 14 well at their initially assigned dose (i.e., complete at least Cycle 1 without DLT) and who would benefit from the study treatment based on the investigator's assessment may have their dose of Compound No. 14 increased in a treatment cycle following discussion with the sponsor. This means that all patients in the next DL cohort will This can only be considered if patients have not experienced DLT-like toxicity or discontinued due to adverse events after 3 cycles of treatment, and it has been determined that this DL does not exceed the MTD. If any patient in the next DL cohort progresses during the first 3 cycles of treatment, this does not prohibit intrapatient dose escalation from the previous dose.

[0275] During dose escalation, patients who do not receive their scheduled dose in Cycle 1 for reasons other than a DLT will be replaced.

[0276] The study will enroll up to approximately 100 subjects.

[0277] Primary endpoint Primary endpoints for this Phase 1 trial may include the frequency and severity of TEAEs, the number of patients with DLTs, the number / proportion of patients with one or more serious adverse events, and the number / proportion of patients with one or more TEAEs leading to dose modification and treatment discontinuation.

[0278] The trial will be conducted in accordance with good clinical practice standards.

[0279] Example 3: Clinical Trial Evaluating Compound No. 14 in Combination with an Anti-PD-1 Antibody in the Treatment of Patients with Metastatic Solid Tumors A Phase 1, open-label, parallel-group, dose-escalation study will be conducted to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of Compound 14 as a single agent (SA) and in combination with pembrolizumab in adult patients with metastatic solid tumors. This information will be used to independently assess both the pharmacologically effective dose (PAD) and maximum tolerated dose (MTD) to establish a recommended Phase 2 dose (RP2D) for SA and in combination with pembrolizumab. Dose escalation may be stopped after determination of the PAD but before determination of the MTD, based on discussion of safety data by the investigator and sponsor.

[0280] Approximately 100 patients will be enrolled in this study. Once enrolled, patients will receive Compound #14 as an intravenous (IV) infusion on days 1, 8, and 15 of a 21-day dosing cycle in both the Compound #14 SA and the combination arm with pembrolizumab. All patients will remain hospitalized for treatment and monitoring until at least day 9 of cycle 1. Patients may be discharged 24 hours after the day 8 infusion if there are no clinical issues (i.e., fever, hypotension, or other clinical safety issues). If clinical safety, PK, and pharmacodynamics support this, the dosing schedule may be modified to deemphasize the intensive dosing of Compound #14 on days 1 and 8 of the 21-day cycle without requiring a protocol amendment. Alternative dosing schedules may also be considered if collective safety, PK, and pharmacodynamic data support it. Additionally, patients who demonstrate clinical benefit may be switched to this less frequent schedule after cycle 6 by the investigator, in agreement with the patient, if continuing the intensive schedule is deemed to be detrimental to the patient's health.

[0281] Single-agent compound number 14 arm The proposed initial exploratory dose range is 0.2 to 3.5 mg (if the 0.2 mg starting dose is not tolerated, a 0.1 mg dose level [DL] is defined). The starting dose will be calculated using a combination of the estimated minimum effective dose (MABEL) and nonclinical toxicity approaches. If the final DL is deemed safe and tolerable, doses above 3.5 mg can be explored. The upper DL of 3.5 mg roughly corresponds to a human equivalent dose slightly above the MTD in monkeys. For the first three patients at a given DL, patient enrollment will be staggered with a planned four-day hold between each patient. If more than three patients are enrolled in a DL, If a 4-day hold is necessary, or if tapering is indicated, and there are no clinically significant safety findings suggestive of an infusion reaction or cytokine release syndrome, this 4-day hold may not be necessary. During the trial, this 4-day hold may be reconsidered in discussion with the investigator and sponsor.

[0282] Compound No. 14 in combination with pembrolizumab arm The second arm will evaluate the safety, tolerability, PK, and pharmacodynamics of Compound No. 14 in combination with the approved dose and schedule of pembrolizumab (200 mg once every three weeks [Q3W]). This second arm will be initiated only if at least two doses of SA of Compound No. 14 have been evaluated and deemed safe and tolerable. If there is no need for dose reduction to DL-1 in the SA arm, the starting dose of Compound No. 14 in this arm will be 0.2 mg (MABEL of Compound No. 14) administered on days 1, 8, and 15 of a 21-day dosing cycle in combination with 200 mg pembrolizumab administered on day 1. In Cycle 1 only, Compound No. 14 may be administered on day 1 and pembrolizumab on day 2 for better evaluation of safety. For the remaining dosing, beginning on Day 1 of Cycle 2, both drugs will be administered starting with Compound No. 14 on Day 1, followed by pembrolizumab with a 1-hour interval between the two drugs. If clinical safety and / or PK / pharmacodynamic data support it, less frequent dosing of Compound No. 14 in combination with pembrolizumab may be considered, such as dosing on Days 1 and 8 of a 21-day cycle. Alternate dosing schedules may also be considered if the collective safety, PK, and pharmacodynamic data support it.

[0283] The study design consists of a dose escalation portion followed by dose expansion cohorts for both the SA and combination arms of Compound #14. Dose escalation of Compound #14 as SA and in combination with pembrolizumab will follow an adaptive design using Bayesian logistic regression modeling (BLRM). BLRM with an overdose control will be used to inform dose escalation decisions and MTD estimation for the SA and combination arms, while a combination of PK and pharmacodynamic data will be used to estimate the PAD. Once the PAD for Compound #14 as SA or in combination with pembrolizumab is determined, either the SA or combination expansion cohorts of Compound #14 can be initiated without specifying the SA or combination MTD, respectively. In both the SA and combination arms, three patients will be enrolled in the initial DL, followed by a 3 + 3 + 3 dose escalation rule. Starting with a patient's second DL, BLRM with an overdose control will be used for all subsequent dose recommendations for both the SA and combination arms, along with consideration of other non-dose-limiting toxicity (DLT) safety and available PK data. The final decision regarding the next DL will be made jointly by the sponsor and participating investigators within the DL boundaries, taking into account the output of the BLRM and other available clinical or translational information.

[0284] Once the MTD and / or PAD are determined for Compound #14 as SA or in combination with pembrolizumab, an expansion cohort of approximately 15 patients treated with Compound #14 as SA or in combination with pembrolizumab may be initiated to better evaluate safety and tolerability at that dose. Expansion cohorts may be initiated after PADs are identified and do not need to await MTD determination. If the dose escalation phase does not resolve the MTD or PAD, the ability to expand to more than one dose may be agreed upon between the sponsor and the investigator. In principle, these cohorts will enroll the same patient population as the dose escalation phase; however, some enrichment strategies may be implemented for these expansion cohorts if supported by either literature / publications, nonclinical / validation work, or evidence of antitumor activity during the escalation phase. A formal sample size calculation will not be performed for expansion cohorts.

[0285] Toxicity was assessed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events. DLTs will be evaluated according to the International Institute Common Terminology Criteria for Adverse Events, version 5.0. A DLT will be defined as any treatment-emergent adverse event (TEAE), including but not limited to, a detailed description, that occurs during Cycle 1 and that the investigator considers to be at least possible associated with Compound No. 14 as a SA or in combination with pembrolizumab. TEAEs meeting the DLT definition occurring in subsequent cycles will be considered in determining the PAD and RP2D of Compound No. 14, both as a SA and in combination with pembrolizumab, which may be at or below the MTD.

[0286] Patients who tolerate Compound #14 treatment well at their initially assigned dose (i.e., complete at least Cycle 1 without a DLT) and who, based on the investigator's assessment, would benefit from the study treatment, may have their dose of Compound #14 increased in subsequent treatment cycles following discussion with the sponsor. This can only be considered if all patients in the next DL cohort have not experienced DLT-like toxicity or discontinued due to adverse events after three cycles of treatment, and it has been determined that this DL will not exceed the MTD. If any patient in the next DL cohort progresses during the first three cycles of treatment, this does not prohibit intrapatient dose escalation from the previous dose.

[0287] During dose escalation, patients who do not receive their scheduled dose in Cycle 1 for reasons other than a DLT will be replaced.

[0288] The study will enroll up to approximately 100 subjects.

[0289] Primary endpoint Primary endpoints for this Phase 1 trial may include the frequency and severity of TEAEs, the number of patients with DLTs, the number / proportion of patients with one or more serious adverse events, and the number / proportion of patients with one or more TEAEs leading to dose modification and treatment discontinuation.

[0290] The trial will be conducted in accordance with good clinical practice standards.

[0291] While certain particular embodiments have been illustrated and described, it is to be understood that changes and modifications can be made in accordance with the skills of those skilled in the art without departing from the technology in its broader aspects as defined in the following claims.

[0292] The present disclosure is not limited with respect to the specific embodiments described in this application. As will be apparent to those skilled in the art, modifications and variations can be made without departing from its spirit and scope. Functionally equivalent methods and compositions within the scope of the present disclosure, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing description. Such modifications and variations are intended to fall within the scope of the appended claims. The present disclosure is limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled. It is to be understood that the present disclosure is not limited to particular methods, reagents, compounds, compositions, or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0293] All publications, patent applications, issued patents, and other documents mentioned herein are incorporated by reference herein to the same extent as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions contained in text incorporated by reference are excluded to the extent they conflict with definitions in this disclosure.

Claims

1. 1. A method for treating a cancer patient, comprising: administering to a patient in need of said treatment Compound No. 14, having the following structure: 【Chemical 1】 or a pharmaceutically acceptable salt thereof; and a checkpoint inhibitor.

2. 2. The method of claim 1, wherein the checkpoint inhibitor is an anti-PD-1 antibody.

3. 3. The method of claim 2, wherein the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, lambrolizumab, pidilizumab, BMS-936559, and AMP-224.

4. The method of claim 1, wherein the checkpoint inhibitor is an anti-PD-L1 antibody.

5. 5. The method of claim 4, wherein the anti-PD-L1 antibody is selected from the group consisting of atezolizumab, durvalumab, avelumab, YW243.55.S70, MEDI-4736, MSB-0010718C, LY3300054, BMS-936559, MPDL3280A, and MDX-1105.

6. The method of claim 1, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody.

7. 7. The method of claim 6, wherein the anti-CTLA-4 antibody is selected from the group consisting of ipilimumab and tremelimumab.

8. 8. The method of any one of claims 1 to 7, wherein Compound No. 14, or a pharmaceutically acceptable salt thereof, is administered orally.

9. 8. The method of any one of claims 1 to 7, wherein Compound No. 14, or a pharmaceutically acceptable salt thereof, is administered intravenously.

10. 8. The method of any one of claims 1 to 7, wherein Compound No. 14, or a pharmaceutically acceptable salt thereof, is administered by intravenous infusion.

11. 11. The method of any one of claims 1 to 10, wherein compound No. 14 and the checkpoint inhibitor are administered simultaneously.

12. Compound No. 14 and the checkpoint inhibitor are administered sequentially in separate pharmaceutical compositions. The method according to any one of claims 1 to 10, wherein

13. The method of any one of claims 1 to 12, wherein the cancer is a PD-1 positive cancer, a PD-L1 positive cancer, or a CTLA-4 positive cancer.

14. 13. The method of any one of claims 1 to 12, wherein the cancer is melanoma, lung cancer, kidney cancer, lymphoma, head and neck cancer, urothelial cancer, prostate cancer, bladder cancer, breast cancer, gastric cancer, colorectal cancer, leukemia, cervical cancer, microsatellite instability-high cancer, hepatocellular carcinoma, or Merkel cell carcinoma.

15. 15. The method of claim 14, wherein the melanoma is metastatic melanoma, unresectable melanoma, or cutaneous melanoma.

16. 15. The method of claim 14, wherein the lung cancer is non-small cell lung cancer or small cell lung cancer.

17. 17. The method of claim 16, wherein the non-small cell lung cancer is metastatic non-small cell lung cancer, metastatic squamous non-small cell lung cancer, or metastatic non-squamous non-small cell lung cancer.

18. 15. The method of claim 14, wherein the renal cancer is renal cell carcinoma.

19. 15. The method of claim 14, wherein the lymphoma is classical Hodgkin's lymphoma or primary mediastinal large B-cell lymphoma.

20. 15. The method of claim 14, wherein the head and neck cancer is head and neck squamous cell carcinoma.

21. 15. The method of claim 14, wherein the urothelial cancer is urothelial carcinoma.

22. 15. The method of claim 14, wherein the prostate cancer is hormone-refractory prostate cancer.

23. 15. The method of claim 14, wherein the gastric cancer is gastroesophageal junction adenocarcinoma.

24. 15. The method of claim 14, wherein the cancer is a microsatellite instability-high cancer.

25. The method of any one of claims 1 to 12, wherein the cancer is a metastatic solid tumor.

26. 26. The method of any one of claims 1-25, wherein the checkpoint inhibitor is administered once every 12 weeks, once every 4 weeks, once every 3 weeks, once every 2 weeks, once a week, twice a week, three times a week, or daily.

27. 27. The method of claim 26, wherein the checkpoint inhibitor is administered once every two weeks.

28. 27. The method of claim 26, wherein the checkpoint inhibitor is administered once every three weeks.

29. 27. The method of claim 26, wherein the checkpoint inhibitor is administered once every four weeks.

30. 27. The method of claim 26, wherein the checkpoint inhibitor is administered once every 12 weeks.

31. 10. The method of claim 1, wherein the checkpoint inhibitor is administered on day 1 or day 2 of a treatment cycle.

26. The method according to any one of claims 1 to 25.

32. 32. The method of claim 31, wherein the treatment cycle is 14 days, 21 days, 28 days, or 84 days.

33. 26. The method of any one of claims 1-25, wherein compound no. 14 is administered on days 1, 4, 8, and 11 of a treatment cycle.

34. 26. The method of any one of claims 1-25, wherein compound no. 14 is administered on days 1 and 8 of a treatment cycle.

35. 35. The method of claim 33 or claim 34, wherein the treatment cycle is 14 days, 21 days, 28 days, or 84 days.

36. 32. The method of claim 31 , wherein the checkpoint inhibitor is administered on day 1 of a treatment cycle.

37. 26. The method of any one of claims 1-25, wherein compound no. 14 is administered on days 1, 8, and 15 of a treatment cycle.

38. 26. The method of any one of claims 1-25, wherein compound no. 14 is administered on days 1, 8, and 15 of a treatment cycle, and the checkpoint inhibitor is administered on day 1 of a treatment cycle.

39. 39. The method of any one of claims 31 to 38, wherein the treatment cycle is 21 days.

40. 40. The method of any one of claims 1-39, wherein the checkpoint inhibitor is administered in an amount of 200 mg.

41. 40. The method of any one of claims 1-39, wherein Compound No. 14 is administered in an amount of 0.1 mg, 0.2 mg, or greater than 0.2 mg.

42. 40. The method of any one of claims 1-39, wherein Compound No. 14 is administered in an amount of 0.1 mg to 3.5 mg, or in an amount of 0.2 mg to 3.5 mg, or in an amount of 0.1 mg to 1.2 mg, or in an amount of 0.2 mg to 1.2 mg.

43. 40. The method of any one of claims 1-39, wherein the checkpoint inhibitor is administered in an amount of 200 mg, and Compound No. 14 is administered in an amount of 0.1 mg to 3.5 mg, or in an amount of 0.2 mg to 3.5 mg, or in an amount of 0.1 mg to 1.2 mg, or in an amount of 0.2 mg to 1.2 mg.

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