Administration of STING agonists and checkpoint inhibitors

Abstract

The present disclosure provides methods, pharmaceutical compositions, and kits for treating cancer in a patient in need thereof. The methods comprise administering to a patient in need thereof a STING (Stimulating Factor of Interferon Gene) agonist, such as a number 14 compound as defined in the specification or a pharmaceutically acceptable salt thereof, in combination with one or more checkpoint inhibitors. Also provided are medicaments for treating cancer.

Description

[0001] This application is a divisional application of the Chinese invention patent application with application date of July 9, 2020, application number 202080049601.5, and invention name “Administration of STING agonists and checkpoint inhibitors”. Technical Field

[0002] The present disclosure relates to methods for treating cancer. Specifically, the present disclosure provides methods for treating a variety of cancers by administering a STING (stimulator of interferon genes) agonist in combination with one or more checkpoint inhibitors. Background Art

[0003] In 2012, there were an estimated 14 million diagnosed cases of cancer and approximately 8.2 million deaths worldwide. The global cancer burden is growing at an alarming rate; in 2030 alone, approximately 21.3 million new cancer cases and 13.1 million cancer deaths are expected to occur simply due to population growth and aging. Cancer is the second most common cause of death in the United States, second only to heart disease, accounting for nearly a quarter of all deaths. The National Cancer Institute estimates that approximately 14.5 million Americans alive in 2014 had a history of cancer. Some of these individuals do not have cancer, while others still have evidence of cancer and may already be undergoing treatment. Although medical advances have improved cancer survival rates, there is a constant need for new and more effective treatments.

[0004] Cancer treatment mainly relies on surgery, radiation therapy, cytotoxic chemotherapy and their combination. However, in the past decade, targeted cancer therapies have ushered in a new era in the field of oncology. Targeted cancer therapies are drugs 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).

[0005] STING is a transmembrane receptor located in the ER that recognizes and binds cyclic dinucleotides. Natural ligands recognized by STING include cyclic dinucleotides (CDNs) of bacterial / protist origin, 2', 3'-cGAMP synthesized by upstream cGAS (cyclic GMP-AMP synthase), etc. See Trends in Immunology 35:88-93 (2014). It is reported that 2', 3'-cGAMP, one of the natural ligands, is decomposed by pyrophosphatase / phosphodiesterase ENPP1 (exonucleotide pyrophosphatase / phosphodiesterase), and other CDNs are decomposed 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 TBK1 (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).

[0006] The effect of STING on the control of cancer cell growth was demonstrated using genetically modified mice. It is reported that STING-deficient and IRF3-deficient mice show uncontrolled tumor growth compared with wild-type mice. See Immunity 41:830-842 (2014). In addition, it is reported that cancer cell growth in tumor allogeneic mice is inhibited by radiotherapy, but the effect of radiotherapy is reduced in mice with STING and IFNAR1 (interferon (α and β) receptor 1, type I IFN receptor produced by downstream signals) genes. See Immunity 41:843-852 (2014). Combining the above evidence, STING is considered to play a key role in inhibiting cancer cell growth. Therefore, STING agonists can be used as anticancer agents. In addition, due to the ability of STING to activate innate immunity and adaptive immunity, the activation of STING can further enhance the immune effect of traditional vaccines. See Ther Adv Vaccines 1:131-143 (2013). Therefore, STING agonists can also be used as adjuvants for various vaccines.

[0007] In addition to small molecules, targeted therapies can also include monoclonal antibodies. For example, among the many known monoclonal antibody targeted therapies, there are monoclonal antibodies against PD-1 (e.g., nivolumab / and pembrolizumab / ), monoclonal antibodies against PD-L1 (e.g., atezolizumab / Durvalumab / and avelumab / ) and monoclonal antibodies against CTLA-4 (eg, ipilimumab / ). Therefore, some cancers can be PD-1 mediated disorders, PD-L1 mediated disorders, and CTLA-4 mediated disorders. Additional monoclonal antibody targeted therapies include, but are not limited to, monoclonal antibodies against CD20 (e.g., rituximab / ), monoclonal antibodies against CD52 (e.g., alemtuzumab / ), VEGF (eg, bevacizumab / ), monoclonal antibodies against HER2 (e.g., trastuzumab for the treatment of Her2+ breast cancer and gastric cancer) / ) and monoclonal antibodies against EGFR (e.g., cetuximab for the treatment of colorectal cancer / ).

[0008] In order to extend the life span of patients while maintaining a high quality of life, it is desirable to provide new combinations of therapeutic agents that have beneficial effects in cancer treatment. New combinations may provide increased benefits compared to each individual agent. Specifically, combination therapy regimens may help patients with the following disease conditions, including proliferative disorders, autoimmune diseases, inflammatory diseases, fibrotic diseases, and kidney diseases; and potentially even be able to reduce recurrence rates or overcome resistance to specific anticancer agents that are sometimes seen in these patients. This is especially true in cases where the cancer may be resistant or refractory to currently available treatment regimens.

[0009] Therefore, new cancer treatment options, including combination therapies, are needed. Summary of the invention

[0010] In one aspect, the disclosure relates to methods of treating cancer comprising administering a STING agonist in combination with a checkpoint inhibitor to a subject in need of such treatment.

[0011] In one aspect, the present disclosure relates to a method of treating a patient suffering from cancer, comprising administering to a subject in need of such treatment a compound No. 14 having the following structure:

[0012]

[0013] or a combination of a pharmaceutically acceptable salt thereof and a checkpoint inhibitor.

[0014] 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.

[0015] In some embodiments, the checkpoint inhibitor is an anti-PD-1 antibody.

[0016] In some embodiments, the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, lambrolizumab, pidilizumab, BMS-936559, and AMP-224.

[0017] In some embodiments, the checkpoint inhibitor is an anti-PD-L1 antibody.

[0018] 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.

[0019] In some embodiments, the checkpoint inhibitor is an anti-CTLA-4 antibody.

[0020] In some embodiments, the anti-CTLA-4 antibody is selected from the group consisting of ipilimumab and tremelimumab.

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

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

[0023] In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered by intravenous infusion.

[0024] In some embodiments, the checkpoint inhibitor is administered intravenously.

[0025] In some embodiments, the checkpoint inhibitor is administered by intravenous infusion.

[0026] In some embodiments, the checkpoint inhibitor is administered by subcutaneous injection.

[0027] In some embodiments, the checkpoint inhibitor is administered subcutaneously.

[0028] In some embodiments, Compound 14 and a checkpoint inhibitor are administered concurrently.

[0029] In some embodiments, Compound 14 and the checkpoint inhibitor are administered sequentially in separate pharmaceutical compositions.

[0030] In some embodiments, the cancer is a PD-1 positive cancer, a PD-L1 positive cancer, or a CTLA-4 positive cancer.

[0031] 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.

[0032] In some embodiments, the cancer is melanoma, lung cancer, kidney cancer, lymphoma, head and neck cancer, urothelial carcinoma, prostate cancer, bladder cancer, breast cancer, gastric cancer, colorectal cancer, leukemia, cervical cancer, microsatellite instability-high cancer, hepatocellular carcinoma, or Merkel cell carcinoma.

[0033] In some embodiments, the melanoma is metastatic melanoma, unresectable melanoma, or cutaneous melanoma.

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

[0035] 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.

[0036] In some embodiments, the renal cancer is renal cell carcinoma.

[0037] In some embodiments, the lymphoma is classical Hodgkin lymphoma or primary mediastinal large B-cell lymphoma.

[0038] In some embodiments, the head and neck cancer is head and neck squamous cell carcinoma.

[0039] In some embodiments, the urothelial cancer is urothelial carcinoma

[0040] In some embodiments, the prostate cancer is hormone-refractory prostate cancer.

[0041] In some embodiments, the gastric cancer is gastroesophageal junction adenocarcinoma.

[0042] In some embodiments, the cancer is a microsatellite instability-high cancer.

[0043] 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 every day.

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

[0045] In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered once a week.

[0046] 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.

[0047] In some embodiments, the checkpoint inhibitor is administered once every twelve weeks, once every four weeks, once every three weeks, once every two weeks, once a week, twice a week, three times a week, or every day.

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

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

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

[0051] In some embodiments, the checkpoint inhibitor is administered once every twelve weeks.

[0052] In some embodiments, the checkpoint inhibitor is administered on day 1 of a treatment cycle.

[0053] In some embodiments, the treatment cycle is 14 days, 21 days, 28 days, or 84 days.

[0054] In some embodiments, Compound 14 or a pharmaceutically acceptable salt thereof and the check point inhibitor are administered once every twelve weeks, once every four weeks, once every three weeks, once every two weeks, once a week, twice a week, three times a week, every day, or simultaneously on days 1, 4, 8, and 11 of a 21-day cycle.

[0055] In some embodiments, Compound 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 the check point inhibitor is administered once every twelve 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 alone.

[0056] In one aspect, the present disclosure relates to a kit comprising a medicament for treating cancer in a subject in need of such treatment. The kit comprises a medicament comprising a STING agonist and instructions for administering the STING agonist and the one or more check point inhibitors; or the kit comprises a medicament comprising the one or more check point inhibitors and instructions for administering the one or more check point inhibitors and the STING agonist. The kit may comprise a medicament comprising a STING agonist and a medicament comprising one or more check point inhibitors, as well as instructions for administering the STING agonist and the one or more check point inhibitors. The kit may also comprise one or more additional therapeutic agents.

[0057] In one aspect, the present disclosure relates to a medicament for treating cancer in a subject in need of such treatment. The medicament comprises a STING inhibitor and one or more checkpoint inhibitors. The medicament may also comprise one or more additional therapeutic agents. BRIEF DESCRIPTION OF THE DRAWINGS

[0058] Figure 1a Shown is a Kaplan-Meier plot of progression-free survival as a function of time following administration of Compound No. 14, anti-mouse PD-1 antibody ("anti-mPD-1"), a combination of Compound No. 14 and anti-mPD-1, and vehicle to mice in the mouse A20 syngeneic tumor model.

[0059] Figure 1b Shown is a graph of individual tumor volume as a function of time following administration of Compound No. 14, anti-mPD-1, a combination of Compound No. 14 and anti-mPD-1, and vehicle to mice in the mouse A20 syngeneic tumor model.

[0060] Figure 2a Shown is a Kaplan-Meier plot of progression-free survival as a function of time following administration of Compound No. 14, anti-mPD-1, a combination of Compound No. 14 and anti-mPD-1, and vehicle to mice in the mouse L5178-R syngeneic tumor model.

[0061] Figure 2b Shown is a graph of individual tumor volume as a function of time following administration of Compound No. 14, anti-mPD-1, a combination of Compound No. 14 and anti-mPD-1, and vehicle to mice in the mouse L5178-R syngeneic tumor model.

[0062] Figure 3a Shown is a Kaplan-Meier plot of progression-free survival as a function of time following administration of Compound No. 14, anti-mPD-1, a combination of Compound No. 14 and anti-mPD-1, and vehicle to mice in the mouse WEHI-3 syngeneic tumor model.

[0063] Figure 3b Shown is a graph of individual tumor volume as a function of time following administration of Compound No. 14, anti-mPD-1, a combination of Compound No. 14 and anti-mPD-1, and vehicle to mice in the mouse WEHI-3 syngeneic tumor model.

[0064] Figure 4a Shown is a Kaplan-Meier plot of progression-free survival as a function of time following administration of Compound No. 14, anti-mPD-1, a combination of Compound No. 14 and anti-mPD-1, and vehicle to mice in the mouse RM-1 syngeneic tumor model.

[0065] Figure 4b Shown is a graph of individual tumor volume as a function of time following administration of Compound No. 14, anti-mPD-1, a combination of Compound No. 14 and anti-mPD-1, and vehicle to mice in the mouse RM-1 syngeneic tumor model.

[0066] Figure 5a Shown is a Kaplan-Meier plot of progression-free survival as a function of time following administration of Compound No. 14, anti-mPD-1, a combination of Compound No. 14 and anti-mPD-1, and vehicle to mice in the mouse L1210 syngeneic tumor model.

[0067] Figure 5b Shown is a graph of individual tumor volume as a function of time following administration of Compound No. 14, anti-mPD-1, a combination of Compound No. 14 and anti-mPD-1, and vehicle to mice in the mouse L1210 syngeneic tumor model. DETAILED DESCRIPTION

[0068] Definitions and Abbreviations

[0069] To facilitate understanding of the present disclosure, a number of abbreviations, terms and phrases are defined below.

[0070]

[0071]

[0072] 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 the invention belongs. All patents and publications mentioned herein are incorporated herein by reference in their entirety.

[0073] The term "cancer" as used herein 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 at ectopic sites. The term "cancer" includes solid tumors and non-solid tumors, such as, for example, blood tumors. The term "cancer" encompasses diseases of the skin, tissues, organs, bones, cartilage, blood, and blood vessels. The term "cancer" also encompasses primary and metastatic cancers.

[0074] As used herein, the term "autoimmune disease" refers to a condition caused by an abnormal immune response to a normal body part. The term "autoimmune disease" encompasses conditions including, but not limited to, rheumatoid arthritis (RA), granulomatosis with polyangiitis (GPA) (Wegener's granulomatosis), and microscopic polyangiitis (MPA).

[0075] Unless otherwise indicated, the term "PD-1" (also known as programmed cell death protein 1, PDCD1, CD279, SLEB2 or SLE1) refers to any native PD-1. The term "PD-1" encompasses "full-length", unprocessed PD-1 and any form of PD-1 produced by intracellular processing. The term also encompasses naturally occurring variants of PD-1, e.g., splice variants, allelic variants, and isoforms.

[0076] Unless otherwise indicated, the term "PD-L1" (also known as programmed cell death 1 ligand) refers to any native PD-L1. The term "PD-L1" encompasses "full-length", unprocessed PD-L1 and any form of PD-L1 produced by intracellular processing. The term also encompasses naturally occurring variants of PD-L1, e.g., splice variants, allelic variants, and isoforms.

[0077] Unless otherwise indicated, the term "CTLA-4" (also known as cytotoxic T-lymphocyte-associated antigen 4) refers to any native CTLA-4. The term "CTLA-4" encompasses "full-length," unprocessed CTLA-4 and any form of CTLA-4 produced by intracellular processing. The term also encompasses naturally occurring variants of CTLA-4, e.g., splice variants, allelic variants, and isoforms.

[0078] The term "antibody" means an immunoglobulin molecule that recognizes and specifically binds to a target (such as a protein, polypeptide, peptide, carbohydrate, polynucleotide, lipid, or a combination of the foregoing) through at least one antigen recognition site in the variable region of the immunoglobulin molecule. As used herein, the term "antibody" encompasses complete polyclonal antibodies, complete monoclonal antibodies, antibody fragments (such as Fab, Fab', F(ab')2, and Fv fragments), single-chain Fv (scFv) mutants, multispecific antibodies (such as bispecific antibodies produced by at least two complete antibodies), chimeric antibodies, humanized antibodies, human antibodies, fusion proteins comprising antigenic determinants of antibodies, and any other modified immunoglobulin molecules comprising antigen recognition sites, as long as the antibody exhibits the desired biological activity. Based on the identity of their heavy chain constant domains, which are referred to as α, δ, ε, γ, and μ, respectively, antibodies can be any of the five major classes of immunoglobulins, IgA, IgD, IgE, IgG, and IgM, or their subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The different classes of immunoglobulins have different and well-known subunit structures and three-dimensional configurations. Antibodies can be naked or conjugated to other molecules, such as toxins, radioisotopes, etc.

[0079] A "blocking" antibody or "antagonist" antibody is an antibody that inhibits or reduces the biological activity of an antigen to which it binds (such as PD-1, PD-L1, or CTLA-4). In a certain embodiment, a blocking antibody 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%.

[0080] The term "anti-PD-1 antibody" or "antibody that binds to PD-1" refers to an antibody that is capable of binding to PD-1 with sufficient affinity so that the antibody can be used as a diagnostic and / or therapeutic agent 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, for example, as measured by radioimmunoassay (RIA). In certain embodiments, the antibody that binds to PD-1 has a dissociation constant (Kd) of ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, or ≤0.1 nM.

[0081] The term "anti-PD-L1 antibody" or "antibody that binds to PD-L1" refers to an antibody that is capable of binding to PD-L1 with sufficient affinity so that the antibody can be used as a diagnostic and / or therapeutic agent 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, for example, as measured by radioimmunoassay (RIA). In certain embodiments, the antibody that binds to PD-L1 has a dissociation constant (Kd) of ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, or ≤0.1 nM.

[0082] The term "anti-CTLA-4 antibody" or "antibody that binds to CTLA-4" refers to an antibody that binds to CTLA-4 with sufficient affinity so that the antibody can be used as a diagnostic and / or therapeutic agent 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, for example, as measured by radioimmunoassay (RIA). In certain embodiments, the antibody that binds to CTLA-4 has a dissociation constant (Kd) of ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, or ≤0.1 nM.

[0083] "Monoclonal antibody" refers to a homogeneous antibody population that participates in the highly specific recognition and binding of a single antigenic determinant or epitope. This is in contrast to polyclonal antibodies that typically contain different antibodies for different antigenic determinants. The term "monoclonal antibody" encompasses complete and full-length monoclonal antibodies as well as antibody fragments (such as Fab, Fab', F(ab')2, Fv), single-chain (scFv) mutants, fusion proteins comprising antibody portions, and any other modified immunoglobulin molecules comprising antigen recognition sites. In addition, "monoclonal antibody" refers to such antibodies made in a variety of ways including but not limited to hybridomas, phage selection, recombinant expression, and transgenic animals.

[0084] The term "chimeric antibody" refers to an antibody whose amino acid sequence of an immunoglobulin molecule is derived from two or more species. Typically, the variable regions of the light and heavy chains correspond to the variable regions of an antibody with the desired specificity, affinity and capacity derived from one mammalian species (e.g., mouse, rat, rabbit, etc.), while the constant regions are homologous to sequences of antibodies derived from another species (usually humans) to avoid causing an immune response in that species.

[0085] As used herein, the term "effective amount" or "therapeutically effective amount" refers to the amount of a compound or a combination of one or more compounds that causes a desired biological or medical response (e.g., destroying target cancer cells or slowing or preventing cancer progression in a patient) when administered (sequentially or simultaneously). The therapeutically effective amount may vary according to the intended application (in vitro or in vivo) or the patient and disease condition being treated, such as the patient's weight and age, the severity of the disease condition, the mode of administration, etc., which can be easily determined by a person skilled in the art. The term also applies to doses that will cause a specific response in target cells (e.g., reducing platelet adhesion and / or cell migration). For example, in some embodiments, as used herein, a "therapeutically effective amount" refers to the amount of compound No. 14 or a pharmaceutically acceptable salt thereof and the amount of a checkpoint inhibitor that have a beneficial effect when administered alone or in combination. In some embodiments, the combined effect is cumulative. In some embodiments, the combined effect is synergistic. In addition, those skilled in the art will appreciate that in the case of combination therapy, the amount of compound No. 14 or its pharmaceutically acceptable salt and / or the amount of the checkpoint inhibitor may be used in a "subtherapeutic amount", i.e., less than the therapeutically effective amount of compound No. 14 or its pharmaceutically acceptable salt or the checkpoint inhibitor alone.

[0086] In any form or composition, the dose or therapeutically effective (total) amount administered may be based on (i) BSA, for example in mg / m 2 form, or (ii) an amount, for example in mg, expressed as the amount of therapeutic substance per patient.

[0087] The term "about" means approximately, within the range of, roughly, or around. When the term "about" is used in conjunction with a number or a numerical range, it means that the number or numerical range mentioned is an approximation within the experimental variability (or within the statistical experimental error), and thus the number or numerical range may vary, for example, between 1% and 15% of the number or numerical range. Typically, the term "about" is used to modify a numerical value to the value being stated to vary up and down by ±10%.

[0088] As used herein, "patient" generally refers to a mammal (e.g., a human) who has been diagnosed with a disease, disorder, or condition (such as cancer), exhibits symptoms of a disease, disorder, or condition, or is otherwise believed to be afflicted with a disease, disorder, or condition.

[0089] As used herein, "body surface area" (BSA) is calculated using a standard nomogram, e.g. or

[0090] The terms "administered in combination", "administered in combination", and "administering a combination" refer to administering more than one pharmaceutically active ingredient (including but not limited to Compound No. 14 or a pharmaceutically acceptable salt thereof and a checkpoint inhibitor disclosed herein) to a patient. Administration in combination may refer to simultaneous administration or may refer to sequential administration of Compound No. 14 or a pharmaceutically acceptable salt thereof and a checkpoint inhibitor disclosed herein.

[0091] The terms "simultaneous" and "simultaneously" refer to administering Compound No. 14 or its pharmaceutically acceptable salt and the checkpoint inhibitor disclosed herein to the patient at the same time or at two different time points no more than 2 hours apart. The simultaneous administration of Compound No. 14 or its pharmaceutically acceptable salt and the checkpoint inhibitor can be in a single dosage form or in separate dosage forms.

[0092] The terms "sequentially" and "sequentially" refer to administering Compound 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 2 hours (e.g., about 3 hours, about 4 hours, about 5 hours, about 8 hours, about 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days or even longer).

[0093] The term "intermittent" refers to the period after which one or more specific pharmaceutically active ingredients are administered to a patient on an intermittent schedule. An intermittent refers to a rest period in which at least one day a specific pharmaceutically active ingredient is not administered.

[0094] The term "synergistic effect" refers to a situation where the combination of two or more agents produces an effect that is greater than the sum of the effects of each individual agent. The term encompasses not only alleviation of the symptoms of the condition to be treated, but also improved side effect profiles, improved drug tolerance, improved patient compliance, improved efficacy, or any other improved clinical outcome.

[0095] As used herein, unless otherwise specified, the exemplary terms "include," "such as," "for example," and the like (and variations thereof, e.g., "includes," "including," "examples") are intended to be non-limiting. That is, unless expressly stated otherwise, such terms are intended to imply "but not limited to," e.g., "include" means including but not limited to.

[0096] Unless otherwise indicated, structures depicted herein are intended to include chemical entities that differ only in the presence of one or more isotopically enriched atoms. For example, in addition to the replacement of a hydrogen atom by deuterium or tritium or a carbon atom by 13 C- or 14 Chemical entities having the present structures are within the scope of the present invention except for C-enriched carbon substitutions.

[0097] Unless the stereochemical configuration is indicated, structures depicted herein are intended to include all stereochemical forms of the structure, i.e., the R and S configurations for each asymmetric center. Therefore, unless otherwise indicated, single stereochemical isomers as well as enantiomeric, racemic and diastereomeric mixtures of the chemical entities of the invention are within the scope of the invention. When the stereochemical configuration of a compound is indicated, the diastereoisomer or enantiomeric excess of the compound is at least 99.0%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9%.

[0098] STING agonists

[0099] The present disclosure provides a combination therapy for patients suffering from cancer or autoimmune diseases. The combination therapy comprises, inter alia, administering to a subject in need thereof a therapeutically effective amount of at least one STING agonist.

[0100] In some embodiments, the STING agonist is a compound of Formula I having the following structure or a pharmaceutically acceptable salt thereof:

[0101]

[0102] Where R 1 and R 2 are each independently a hydroxyl group or a halogen atom;

[0103] B 1 yes:

[0104]

[0105] R 18 is hydrogen or C 1-6 alkyl;

[0106] R 19 is a halogen atom;

[0107] B 2 yes:

[0108] and

[0109] Q 2 and Q 4 are each independently an oxygen atom or a sulfur atom.

[0110] In some embodiments, the STING agonist is compound 14 having the following structure or a pharmaceutically acceptable salt thereof:

[0111] Compound No. 14.

[0112] In some embodiments, the STING agonist is Compound No. 14 or a pharmaceutically acceptable salt thereof.

[0113] In some embodiments, the STING agonist is Compound No. 14.

[0114] Specific STING agonists as disclosed herein are described, for example, in PCT Application Publication No. WO 2018 / 100558. They can be prepared by methods known to those skilled in the art and / or according to the methods described in WO 2018 / 100558 (which reference is hereby incorporated by reference in its entirety).

[0115] In some embodiments, the STING agonist is Compound No. 14 or a crystalline form thereof.

[0116] Checkpoint inhibitors

[0117] The present disclosure provides a combination therapy, which includes, among other things, 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.

[0118] PD-1 is a type I transmembrane protein that is one of the main immune checkpoint molecules (Blank et al., 2005, Cancer Immunotherapy, 54: 307-314). PD-1 is mainly expressed on activated T cells and interacts with ligands PD-L1 (B7-H1 or CD274) and PD-L2 (B7-DC or CD273) to induce inhibitory signals, leading to a decrease in T cell proliferation, cytokine production, and cytotoxic activity (Freeman et al., 2000, J. Exp. Med., 192: 1027-34).

[0119] 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.

[0120] 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.

[0121] 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, attachment to cellular ligands or other proteins. In some embodiments, the derivatized anti-PD-1 antibody may comprise one or more unnatural amino acids, for example, using ambrx technology (see, e.g., Wolfson, 2006, Chem. Biol. 13(10): 1011-2).

[0122] In some embodiments, the anti-PD-1 antibody is nivolumab.

[0123] Nivolumab is a human monoclonal antibody that blocks the interaction between PD-1 and its ligands PD-L1 and PD-L2. Nivolumab is an IgG4κ immunoglobulin with a calculated molecular mass 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 used as Commercially available.

[0124] In some embodiments, the anti-PD-1 antibody is pembrolizumab.

[0125] Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands PD-L1 and PD-L2. Pembrolizumab is an IgG4κ immunoglobulin with a molecular mass of approximately 149 kDa. Pembrolizumab is produced in recombinant Chinese hamster ovary (CHO) cells. Pembrolizumab is approved by the FDA for the treatment of melanoma, non-small cell lung cancer, head and neck cancer, classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, urothelial carcinoma, microsatellite instability-high cancer, gastric cancer, and cervical cancer. Commercially available.

[0126] In some embodiments, the anti-PD-1 antibody is cemiplimab.

[0127] Cimiprizumab is a human monoclonal antibody that binds to PD-1 and blocks its interaction with PD-L1 and PD-L2. Cimiprizumab is an IgG4 immunoglobulin with a molecular mass of approximately 146 kDa. Cimiprizumab is produced in Chinese hamster ovary (CHO) cell suspension by recombinant DNA technology. Cimiprizumab is approved by the FDA for the treatment of metastatic cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC who are not candidates for curative surgery or curative radiation. Cimiprizumab is used as Commercially available.

[0128] Additional anti-PD-1 antibodies include, for example, pidilizumab (Medivation), BMS-936559 (Bristol-Myers Squibb), and AMP-224.

[0129] 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.

[0130] 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.

[0131] PD-L1 is a type I transmembrane protein that includes an extracellular Ig-V-like domain, an Ig-C-like domain, a transmembrane domain, and an intracellular C-terminal domain. PD-L1 is expressed at high frequencies in a wide range of cancers (including tumor cells and / or tumor-infiltrating immune cells) and can contribute to the suppression of anti-tumor immune responses in the microenvironment. In some cancers, the expression of PD-L1 is associated with reduced survival and unfavorable prognosis. PD-L1 is expressed on many cell types (including T cells, B cells, endothelial, epithelial, and antigen-presenting cells), on cells of lung, liver, and heart tissues, and on several types of tumor cells. It has also been shown that the expression of PD-L1 on the cell surface is upregulated by IFN-y stimulation. At least 4 PD-1 variants 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 to 4. Nielsen et al., Cell. Immunol. 235: 109-16 (2005). The amino acid sequence of human PD-L1 is shown in GenBank Accession No. NP 054862.1.

[0132] In some embodiments, the anti-PD-L1 antibody is a full-length (intact) antibody. In some embodiments, the anti-PD-L1 antibody consists of an anti-PD-L1 binding fragment, including but not limited to Fab, Fab', F(ab')2, Fd, Fv and dAb fragments, single-chain Fv fragments and PD-L1 binding domain immunoglobulin fusion proteins.

[0133] In some embodiments, the anti-PD-L1 antibody is atezolizumab.

[0134] Atezolizumab is a programmed cell death ligand 1 (PD-L1) blocking antibody. Atezolizumab is an Fc-engineered, humanized, aglycosylated IgG1κ immunoglobulin with a calculated molecular mass 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. Commercially available.

[0135] In some embodiments, the anti-PD-L1 antibody is durvalumab.

[0136] Durvalumab is a programmed cell death ligand 1 (PD-L1) blocking antibody. Durvalumab is a human immunoglobulin G1κ (IgG1κ) monoclonal antibody produced in Chinese hamster ovary (CHO) cell suspension culture by recombinant DNA technology. Durvalumab is approved by the FDA for the treatment of urothelial carcinoma and non-small cell lung cancer. Commercially available.

[0137] In some embodiments, the anti-PD-L1 antibody is avelumab.

[0138] Avelumab is a programmed death ligand-1 (PD-L1) blocking antibody. Avelumab is a human IgG1λ monoclonal antibody with a molecular weight of approximately 147 kDa. Avelumab is approved by the FDA for the treatment of metastatic Merkel cell carcinoma and locally advanced or metastatic urothelial carcinoma. Commercially available.

[0139] Additional anti-PD-L1 antibodies include, for example, YW243.55.S70 (U.S. Pat. No. 8,217,149), MEDI-4736, MSB-0010718C, LY3300054 (Eli Lilly and Co.), BMS-936559 (Bristol-Meyers Squibb), MPDL3280A, and MDX-1105.

[0140] 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. In some embodiments, the anti-PD-L1 antibody is atezolizumab.

[0141] 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.

[0142] 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.

[0143] CTLA-4 is a type I transmembrane protein encoded by the CTLA-4 gene in humans. It has been found that CTLA-4 is associated with cancer growth and development due to its negative role in immune response. 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 intrinsic and extrinsic mechanisms (Grosso and Kunkel, Cancer Immunity (2013) 13: 5). It has been shown that inhibition of CTLA-4 negative regulation promotes stimulation of adaptive immune response and T cell activation. The representative amino acid sequence of human CTLA-4 can be found in GenBank Accession No.: AAL07473.1, and the representative mRNA nucleic acid sequence encoding human CTLA-4 can be found in GenBank Accession No.: AF414120.1.

[0144] 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')2, Fv and single-chain fragments, diabodies, disulfide-stabilized Fv fragments (dsFv), (dsFv)2, bispecific dsFv (dsFv-dsFv'), disulfide-stabilized diabodies (dsdiabodies), single-chain antibody molecules (scFv), scFv dimers (bivalent diabodies), multispecific antibodies, camelized single domain antibodies, nanobodies, domain antibodies, and bivalent domain antibodies.

[0145] In some embodiments, the anti-CTLA-4 antibody is ipilimumab.

[0146] Ipilimumab is a recombinant human monoclonal antibody that binds to cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). Ipilimumab is an IgG1κ immunoglobulin with a molecular mass 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 used as Commercially available.

[0147] Additional anti-CTLA-4 antibodies include, for example, Tremelimumab.

[0148] 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. In some embodiments, the anti-CTLA-4 antibody is ipilimumab.

[0149] Methods for treating cancer

[0150] In some embodiments, the present disclosure relates to a method of treating cancer in a patient by administering to the patient in need of such treatment a combination of a STING agonist, or a pharmaceutically acceptable salt thereof, and one or more checkpoint inhibitors.

[0151] In some embodiments, the disclosure relates to a method of treating cancer by administering a combination of a STING agonist and a checkpoint inhibitor to a patient in need of such treatment.

[0152] In some embodiments, the disclosure relates to the use of a STING agonist in combination with a checkpoint inhibitor for treating cancer in a patient.

[0153] In some embodiments, the present disclosure relates to a composition comprising a STING agonist for 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 treating cancer in a patient, wherein the STING agonist is combined with the checkpoint inhibitor. In some embodiments, the STING agonist can be administered simultaneously or sequentially with the checkpoint inhibitor.

[0154] In some embodiments, the disclosure relates to methods of treating cancer comprising administering a therapeutically effective amount of a combination of a STING agonist and a checkpoint inhibitor to a patient in need of such treatment.

[0155] In some embodiments, the present disclosure relates to a method of treating cancer by administering to a patient a combination of Compound No. 14 or a pharmaceutically acceptable salt thereof and a checkpoint inhibitor.

[0156] In another aspect, the present invention relates to the use of compound No. 14 or a pharmaceutically acceptable salt thereof in combination with a checkpoint inhibitor for treating cancer.

[0157] In some embodiments, the method for treating cancer as described herein may 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 may be chemotherapeutic agents. In some embodiments, the one or more additional therapeutic agents may include but are not limited to fludarabine, cyclophosphamide, doxorubicin, vincristine, methotrexate, anthracycline-based chemotherapeutic agents, prednisone, methylprednisolone, glucocorticoids, Ibritumomab tiuxetan, acetaminophen, antihistamines, and combinations thereof. In another embodiment, checkpoint inhibitors are co-administered with human hyaluronidase.

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

[0159] In some embodiments, cancer is a solid tumor. In some embodiments, cancer is a metastatic solid tumor. In some embodiments, cancer is an advanced solid tumor. Non-limiting examples of solid tumors include pancreatic cancer; bladder cancer, including invasive bladder cancer; colorectal cancer, including high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR) metastatic colorectal cancer; thyroid cancer; gastric cancer; breast cancer, including metastatic breast cancer; prostate cancer, including androgen-dependent and androgen-independent prostate cancer; kidney cancer, including, for example, metastatic renal cell carcinoma and advanced renal cell carcinoma; urothelial carcinoma, including locally advanced or metastatic urothelial carcinoma; high microsatellite instability cancer; liver cancer, including, for example, hepatocellular carcinoma and intrahepatic bile duct carcinoma; lung and bronchial cancer, including non-small cell lung cancer (NSCLC), squamous lung cancer, bronchioalveolar carcinoma (BAC), lung adenocarcinoma and small cell lung cancer (SCLC); ovarian cancer, including, for example, progressive epithelial cancer and primary peritoneal cancer; cervical cancer; uterine cancer, including, for example, uterine corpus cancer and cervical cancer; endometrial cancer; esophageal cancer; head and neck cancer, including, for example, head and neck squamous cell carcinoma, nasopharyngeal carcinoma, oral cavity and pharyngeal cancer; melanoma, including unresectable or metastatic melanoma, and adjuvant therapy for melanoma; metastatic Merkel cell carcinoma; neuroendocrine cancer, including metastatic neuroendocrine tumors; brain cancer, including, for example, glioma / glioblastoma, anaplastic oligodendroglial carcinoma, adult glioblastoma multiforme, and adult anaplastic astrocytoma; neuroendocrine cancer, including metastatic neuroendocrine tumors; bone cancer; gastroesophageal junction cancer and soft tissue sarcoma.

[0160] In some embodiments, the cancer is a blood cancer. Non-limiting examples of hematologic malignancies include acute myeloid leukemia (AML); chronic myeloid leukemia (CML), including accelerated CML and blast crisis CML (CML-BP); acute lymphocytic leukemia (ALL); chronic lymphocytic leukemia (CLL); Hodgkin lymphoma (HL), including classical Hodgkin lymphoma; non-Hodgkin lymphoma (NHL), including B-cell lymphoma, T-cell lymphoma, follicular lymphoma (FL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), diffuse Large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma and Burkitt's lymphoma; multiple myeloma (MM); amyloidosis; Waldenstrom's macroglobulinemia; myelodysplastic syndrome (MDS), including refractory anemia (RA), refractory anemia with ring sideroblasts (RARS), refractory anemia with immature cells (RAEB) and RAEB-T in transformation (RAEB-T); and myeloproliferative syndrome. In some embodiments, the cancer is chronic lymphocytic leukemia (CLL); Hodgkin's 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's lymphoma.

[0161] In some embodiments, the cancer is melanoma, lung cancer, kidney cancer, lymphoma, head and neck cancer, urothelial carcinoma, prostate cancer, bladder cancer, breast cancer, gastric cancer, colorectal cancer, leukemia, cervical cancer, microsatellite instability-high cancer, hepatocellular carcinoma, or Merkel cell carcinoma.

[0162] In some embodiments, the melanoma is metastatic melanoma, unresectable melanoma, or cutaneous melanoma.

[0163] In some embodiments, the lung cancer is non-small cell lung cancer or small cell lung cancer.

[0164] 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.

[0165] In some embodiments, the kidney cancer is renal cell carcinoma.

[0166] In some embodiments, the lymphoma is classical Hodgkin lymphoma or primary mediastinal large B-cell lymphoma.

[0167] In some embodiments, the head and neck cancer is head and neck squamous cell carcinoma.

[0168] In some embodiments, the urothelial cancer is urothelial carcinoma.

[0169] In some embodiments, the prostate cancer is hormone-refractory prostate cancer.

[0170] In some embodiments, the gastric cancer is gastroesophageal junction adenocarcinoma.

[0171] In some embodiments, the cancer is a microsatellite instability-high cancer.

[0172] In some embodiments, the cancer is recurrent. In some embodiments, a recurrent cancer is a cancer that strikes again after a period of time in which the cancer could not be detected.

[0173] In some embodiments, cancer is refractory. In some embodiments, refractory cancer is unresponsive to cancer treatment; it is also called resistant cancer. In some embodiments, cancer is resistant to rituximab. In some embodiments, cancer is unresponsive to rituximab treatment. In some embodiments, cancer is rituximab-resistant recurrent cancer. In some embodiments, the patient has become refractory to a regimen containing rituximab. 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 treated previously. In some embodiments, the cancer is locally advanced. In some embodiments, "locally advanced" refers to cancer that is slightly extensive but still confined to one area. In some cases, "locally advanced" may refer to a small tumor that has not yet spread but has invaded nearby organs or tissues, making it difficult to remove with surgery alone. In some embodiments, cancer is metastatic. In some embodiments, metastatic cancer is a cancer that has spread from the part of the body (primary site) where it started to other parts of the body.

[0174] In some embodiments, the present disclosure relates to a method of treating a disorder, wherein the disorder is an autoimmune disease.

[0175] In some embodiments, the disorder is a STING-mediated disorder.

[0176] In some embodiments, the disorder is a PD-1 positive cancer. PD-1 positive cancers include cancers in which PD-1 is expressed on cancer cells.

[0177] In some embodiments, the disorder is a PD-L1 positive cancer. PD-L1 positive cancers include cancers in which PD-L1 is expressed on cancer cells.

[0178] In some embodiments, the disorder is a CTLA-4 positive cancer. CTLA-4 positive cancers include cancers in which CTLA-4 is expressed on cancer cells.

[0179] drug

[0180] In some embodiments, the present disclosure relates to a medicament for treating cancer in a patient in need of such treatment. The medicament comprises a STING agonist and a checkpoint inhibitor and is in a single dosage form or in separate dosage forms.

[0181] In some embodiments, a medicament as described herein may include a combination of a STING agonist, a checkpoint inhibitor, and optionally one or more additional therapeutic agents.

[0182] In some embodiments, the disclosure relates to the use of a STING agonist in the manufacture of a medicament for treating cancer, wherein the STING agonist is administered with a checkpoint inhibitor and wherein the medicament is in a single dosage form or in separate dosage forms. In some embodiments, the STING agonist is administered with a checkpoint inhibitor and one or more additional therapeutic agents.

[0183] In some embodiments, the present disclosure relates to the use of a STING agonist for the manufacture of a medicament for treating a cancer 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 may be administered simultaneously or sequentially with a checkpoint inhibitor. In some aspects, the present disclosure relates to the use of a STING agonist for the manufacture of a medicament for treating a cancer 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 and the checkpoint inhibitor are in the same composition. In some embodiments, the STING agonist and the checkpoint inhibitor are in a separate composition. In some embodiments, the STING agonist and one or more additional therapeutic agents are in the same composition. In some embodiments, the STING agonist and the checkpoint inhibitor and optionally one or more additional therapeutic agents are in the same composition. In some embodiments, the STING agonist and the checkpoint inhibitor and optionally one or more additional therapeutic agents are in a separate composition. In some embodiments, the STING agonist and the checkpoint inhibitor and optionally one or more additional therapeutic agents are in a separate composition. In some embodiments, the STING agonist and the checkpoint inhibitor and optionally one or more additional therapeutic agents are in a separate composition.

[0184] 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 manufacture of a medicament for treating cancer. In some embodiments, the present 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 for the manufacture of a medicament for treating cancer.

[0185] In another aspect, the present disclosure relates to the use of Compound No. 14 or a pharmaceutically acceptable salt thereof for 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.

[0186] In some embodiments, the one or more additional therapeutic agents may be chemotherapeutic agents. In some embodiments, the one or more additional therapeutic agents may include but are not limited to fludarabine, cyclophosphamide, doxorubicin, vincristine, methotrexate, anthracycline-based chemotherapeutic agents, prednisone, methylprednisolone, glucocorticoids, ibritumomab tiuxetan, acetaminophen, antihistamines, and combinations thereof. In another embodiment, checkpoint inhibitors are co-administered with human hyaluronidase.

[0187] Combined administration

[0188] 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 a separate dosage form. In some embodiments, when administered as a separate dosage form, the checkpoint inhibitor may be administered before, simultaneously with, or after the 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 the administration of Compound No. 14 or a pharmaceutically acceptable salt thereof. As understood by those skilled in the art, as used herein, the "combination" administration of Compound No. 14 or a pharmaceutically acceptable salt thereof, a checkpoint inhibitor, and optionally one or more additional therapeutic agents refers not only to the simultaneous or sequential administration of the agents, but also to the administration of the agents in a single treatment cycle. 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.

[0189] STING agonists can be administered by any method known to those skilled in the art. For example, in some embodiments, STING agonists can be administered in the form of a pharmaceutical composition of a 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 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 also contain one or more additional therapeutic agents.

[0190] Check point inhibitors can be administered by any method known to those skilled in the art. In some embodiments, check point inhibitors are administered intravenously (iv). In some embodiments, check point inhibitors are administered subcutaneously (sc). In some embodiments, check point inhibitors are administered orally. For example, check point inhibitors can be administered in the form of a second composition, in some embodiments, in the form of a pharmaceutical composition of a check point inhibitor and a pharmaceutically acceptable carrier (such as those described herein). In some aspects, 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 embodiments, the pharmaceutical composition is a liquid dosage form suitable for oral administration. In some embodiments, these compositions optionally also include one or more additional therapeutic agents.

[0191] In some embodiments, the checkpoint inhibitor may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, orally, vaginally, or via an implantable drug box. As used herein, the term "parenteral" includes subcutaneous, intravenous, intraperitoneal, intramuscular, intraarticular, 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, the intravenous administration may 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 and then by subcutaneous injection. In another embodiment, the checkpoint inhibitor is co-administered with human hyaluronidase subcutaneously. These administration methods may be designed to be short-acting, rapid-release, or long-acting. Furthermore, checkpoint inhibitors can be administered locally rather than systemically, such as at the site of a tumor (e.g., by injection).

[0192] In some embodiments, the checkpoint inhibitors can also be administered by nasal aerosol or inhalation. The checkpoint inhibitors can be prepared according to techniques well known in the art and can be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0193] The amount or suitable dosage of the method of the present disclosure depends on many factors, including the nature of the severity of the condition to be treated, the specific inhibitor, the route of administration, and the age, weight, overall health status, and response of the individual patient. In some embodiments, the suitable dosage level is a dosage level that achieves a therapeutic response, which is measured by other standard measures of tumor regression or disease progression, progression-free survival, or overall survival. In some embodiments, a suitable dosage level is a dosage level that achieves this therapeutic response and minimizes any side effects associated with the administration of the therapeutic agent. A suitable dosage level can be a dosage level that prolongs the therapeutic response and / or prolongs life.

[0194] It should be understood that suitable doses of a STING agonist, a checkpoint inhibitor, and optionally one or more additional therapeutic agents can be taken at any time of the day or night. In some embodiments, each dose of a suitable dose is taken in the morning. In some embodiments, each dose of a suitable dose is taken in the evening. In some embodiments, each dose of a suitable dose is taken in the morning and evening. It should be understood that each dose of a suitable dose may or may not be taken with food. In some embodiments, a dose of a suitable dose is taken with a meal. In some embodiments, a dose of a suitable dose is taken on an empty stomach.

[0195] 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 once every three days for a total of three doses. In some embodiments, compound No. 14 or a pharmaceutically acceptable salt thereof is administered on a twice-weekly schedule. In some embodiments, compound No. 14 or a pharmaceutically acceptable salt thereof is administered on a three-weekly schedule. In some embodiments, compound No. 14 or a pharmaceutically acceptable salt thereof is administered on a weekly schedule. In some embodiments, compound No. 14 or a pharmaceutically acceptable salt thereof is administered on a biweekly schedule.

[0196] In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered once a day. In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered twice a day. In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered three times a day.

[0197] In some embodiments, compound No. 14 or a pharmaceutically acceptable salt thereof is administered at least 3 times every other day within a 7-day cycle. In some embodiments, compound No. 14 or a pharmaceutically acceptable salt thereof is administered on days 1 and 4 of a 7-day cycle. In some embodiments, compound No. 14 or a pharmaceutically acceptable salt thereof is administered on consecutive days in a 7-day cycle, followed by discontinuation. In some embodiments, compound No. 14 or a pharmaceutically acceptable salt thereof is administered for 2 consecutive days, followed by discontinuation for 5 consecutive days, for at least one 7-day cycle. In some embodiments, compound No. 14 or a pharmaceutically acceptable salt thereof is administered for 3 consecutive days, followed by discontinuation for 4 consecutive days, for at least one 7-day cycle. In some embodiments, compound No. 14 or a pharmaceutically acceptable salt thereof is administered for 4 consecutive days, followed by discontinuation for 3 consecutive days, for at least one 7-day cycle. In some embodiments, compound No. 14 or a pharmaceutically acceptable salt thereof is administered for 5 consecutive days, followed by discontinuation for 2 consecutive days, for at least one 7-day cycle. In some embodiments, there will be a rest period between one or more 7-day treatment cycles. In some embodiments, there will be a 7-day rest period between one or more 7-day treatment cycles.

[0198] 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, a treatment cycle is from about 7 days to about 56 days or more. In some embodiments, a treatment cycle is 7 days, 14 days, 21 days, 28 days, 35 days, 42 days, 49 days, or 56 days. In some embodiments, a treatment cycle is 21 days or 28 days. In some embodiments, there will be a rest period between one or more treatment cycles. For example, in some embodiments, there will be a rest period at the end of a treatment cycle. In some embodiments, there will be a rest period between a second treatment cycle and a third treatment cycle, but not between a first treatment cycle and a second treatment cycle. In another embodiment, there may be a rest period between a first treatment cycle and a second treatment cycle, but not between a second treatment cycle and a third treatment cycle. Dosing schedules include, for example, administering a STING agonist once during a treatment schedule, e.g., on day 1 of a 21 day cycle; twice during a treatment cycle, 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 a treatment cycle, 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 a treatment cycle, 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 contemplated by the present invention.

[0199] 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 of a 21-day cycle. In some embodiments, compound No. 14 or a pharmaceutically acceptable salt thereof is administered on day 4 of a 21-day cycle. In some embodiments, compound No. 14 or a pharmaceutically acceptable salt thereof is administered on day 8 of a 21-day cycle. In some embodiments, compound No. 14 or a pharmaceutically acceptable salt thereof is administered on day 11 of 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 of a 21-day cycle.

[0200] 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 of a 21-day cycle. In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered on Day 8 of a 21-day cycle. In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered on Days 1 and 8 of a 21-day cycle.

[0201] In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered for a duration of 1 year or less. In some embodiments, Compound No. 14 or a pharmaceutically acceptable salt thereof is administered for a duration of 1 year or more.

[0202] In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is from about 0.5 mg to about 1000 mg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is from about 0.5 mg to about 300 mg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is from about 1 mg to about 300 mg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is from about 3 mg to about 300 mg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is from about 0.5 mg to about 200 mg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is from about 1 mg to about 200 mg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is from about 10 mg to about 200 mg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is from about 0.5 mg to about 100 mg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is from about 0.5 mg to about 50 mg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is from about 0.5 mg to about 10 mg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is from about 0.5 mg to about 5 mg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is from about 1 mg to about 3 mg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is from about 2 mg to about 5 mg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is from about 5 mg to about 10 mg. In some embodiments, the amount of Compound No. 14 or its pharmaceutically acceptable salt 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 its pharmaceutically acceptable salt administered on each day of administration is from about 10 mg to about 20 mg. In some embodiments, the amount of Compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is from about 15 mg to about 25 mg. In some embodiments, the amount of Compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is from about 20 mg to about 30 mg. In some embodiments, the amount of Compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is from about 25 mg to about 35 mg.In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 30 mg to about 40 mg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 35 mg to about 45 mg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 40 mg to about 50 mg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 55 mg to about 65 mg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 50 mg to about 100 mg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 90 mg to about 150 mg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 140 mg to about 200 mg. In some embodiments, the amount of Compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is from about 190 mg to about 250 mg. In some embodiments, the amount of Compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is from about 240 mg to about 300 mg. In some embodiments, the amount of Compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is from about 290 mg to about 350 mg. In some embodiments, the amount of Compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is from about 340 mg to about 400 mg. In some embodiments, the amount of Compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is from about 390 mg to about 450 mg. In some embodiments, the amount of Compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is from about 440 mg to about 500 mg.

[0203] In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 0.5 mg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 1 mg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 2 mg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 3 mg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 4 mg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 6 mg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 8 mg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 10 mg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 12 mg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 16 mg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 20 mg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 30 mg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 40 mg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 50 mg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 60 mg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 70 mg. In some embodiments, the amount of Compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 80 mg. In some embodiments, the amount of Compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 90 mg. In some embodiments, the amount of Compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 100 mg. In some embodiments, the amount of Compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 150 mg. In some embodiments, the amount of Compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 200 mg. In some embodiments, the amount of Compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 250 mg.In some embodiments, the amount of Compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 300 mg. In some embodiments, the amount of Compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 350 mg. In some embodiments, the amount of Compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 400 mg. In some embodiments, the amount of Compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 450 mg. In some embodiments, the amount of Compound No. 14 or its pharmaceutically acceptable salt 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 of any pharmaceutically acceptable salt.

[0204] In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt 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 its pharmaceutically acceptable salt 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 its pharmaceutically acceptable salt administered on each day of administration is about 0.1 mg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 0.2 mg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 0.4 mg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 0.8 mg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 1.2 mg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt 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.

[0205] In some embodiments, the amount of Compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is from about 0.01 mg / kg to about 100 mg / kg. In some embodiments, the amount of Compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is from about 0.01 mg / kg to about 50 mg / kg. In some embodiments, the amount of Compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is from about 0.01 mg / kg to about 20 mg / kg.

[0206] In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 0.01 mg / kg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 0.05 mg / kg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 0.1 mg / kg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 1 mg / kg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 2 mg / kg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 4 mg / kg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 6 mg / kg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 8 mg / kg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 10 mg / kg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 12 mg / kg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 14 mg / kg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 16 mg / kg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 18 mg / kg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 20 mg / kg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt administered on each day of administration is about 30 mg / kg. In some embodiments, the amount of compound No. 14 or its pharmaceutically acceptable salt 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.

[0207] 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 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-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-week schedule. In some embodiments, the checkpoint inhibitor is administered on a once-every-three-week schedule. In some embodiments, the checkpoint inhibitor is administered on a once-every-four-week schedule. In some embodiments, the checkpoint inhibitor is administered on a once-every-eight-week schedule. In some embodiments, the checkpoint inhibitor is administered on a once-every-twelve-week schedule.

[0208] In some embodiments, the checkpoint inhibitor is administered at least 3 times every other day within a 7-day cycle. In some embodiments, the checkpoint inhibitor is administered on day 1 of the treatment cycle. In some embodiments, the checkpoint inhibitor is administered on day 1 and day 4 of a 7-day cycle. In some embodiments, the checkpoint inhibitor is administered on consecutive days in a 7-day cycle, followed by an intermittent period. In some embodiments, the checkpoint inhibitor is administered for 2 consecutive days, followed by an intermittent period of 5 consecutive days, for at least one 7-day cycle. In some embodiments, the checkpoint inhibitor is administered for 3 consecutive days, followed by an intermittent period of 4 consecutive days, for at least one 7-day cycle. In some embodiments, the checkpoint inhibitor is administered for 4 consecutive days, followed by an intermittent period of 3 consecutive days, for at least one 7-day cycle. In some embodiments, the checkpoint inhibitor is administered for 5 consecutive days, followed by an intermittent period of 2 consecutive days, for at least one 7-day cycle.

[0209] 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 subsequent 21 day treatment cycle.

[0210] This description contemplates the 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 from about 7 days to about 84 days or more. In some embodiments, the treatment cycle is 7 days, 14 days, 21 days, 28 days, 35 days, 42 days, 49 days, 56 days, or 84 days. In some embodiments, the treatment cycle is 21 days or 28 days. In some embodiments, there will be a rest period between one or more treatment cycles. For example, in some embodiments, there will be a rest period at the end of the treatment cycle. In some embodiments, there will be a rest period between the second treatment cycle and the third treatment cycle, but not between the first treatment cycle and the second treatment cycle. In another embodiment, there may be a rest period between the first treatment cycle and the second treatment cycle, but not between the second treatment cycle and the third treatment cycle. Dosing schedules include, for example, administering a checkpoint inhibitor once during a treatment schedule, e.g., on day 1 of a 21-day cycle; twice during a treatment cycle, 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 a treatment cycle, 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 a treatment cycle, 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 dosage schedules are contemplated by the present invention.

[0211] 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.

[0212] In some embodiments, both Compound 14 and the checkpoint inhibitor are administered on day 1 of a 21-day treatment cycle. In some embodiments, Compound 14 is administered first on day 1 of a 21-day treatment cycle, followed by the checkpoint inhibitor. In some embodiments, Compound 14 is administered on day 1 of a 21-day treatment cycle, and the checkpoint inhibitor is administered 1 hour after Compound 14 is administered on day 1 of a 21-day treatment cycle.

[0213] In some embodiments, Compound No. 14 is administered as an intravenous infusion over 60±10 minutes.

[0214] In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is from 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 from 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 from 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 from 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 from 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 from 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 from about 1 mg to about 500 mg. In some embodiments, the amount of anti-PD-1 antibody administered on each day of administration is from 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 dosing is from about 200 mg to about 300 mg.

[0215] 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.

[0216] In some embodiments, the amount of anti-PD-1 antibody administered on each day of dosing is about 200 mg.

[0217] 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.

[0218] 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 cemiplizumab or a pharmaceutically acceptable salt thereof.

[0219] In some embodiments, administration of nivolumab, pembrolizumab, and cemiplimab is in accordance with their prescribing information approved by health authorities, such as those published by the FDA or EMA, the entire contents of which are incorporated herein by reference.

[0220] 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.

[0221] 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 No. 14 is administered 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 No. 14 is administered in an amount of 0.1 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 No. 14 is administered in an amount of 0.2 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 No. 14 is administered in an amount of 0.2 mg or more 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 No. 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 No. 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 No. 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 No. 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 No. 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.

[0222] In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is from 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 from 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 from 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 from 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 from 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 from 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 from about 1 mg to about 2000 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is from about 10 mg to about 2000 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is from about 100 mg to about 2000 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is from about 200 mg to about 2000 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is from about 400 mg to about 2000 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is from about 600 mg to about 2000 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is from about 800 mg to about 2000 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is from about 1000 mg to about 2000 mg. In some embodiments, the amount of anti-PD-L1 antibody administered on each day of administration is from 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 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.

[0223] 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.

[0224] 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 14 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 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.

[0225] 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.

[0226] In some embodiments, administration of atezolizumab, durvalumab, and avelumab is in accordance with their prescribing information approved by health authorities, such as those issued by the FDA or EMA, the entire contents of which are incorporated herein by reference.

[0227] 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 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 dosing is about 2000 mg.

[0228] 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.

[0229] In some embodiments, the anti-CTLA-4 antibody is ipilimumab or a pharmaceutically acceptable salt thereof.

[0230] In some embodiments, administration of ipilimumab is in accordance with its prescribing information approved by health authorities, such as those issued by the FDA or EMA, the entire contents of which are incorporated herein by reference.

[0231] Pharmaceutical composition

[0232] The STING agonists and checkpoint inhibitors used in the methods and kits described herein can be formulated as pharmaceutical compositions suitable for administration. The pharmaceutical composition may include a pharmaceutically acceptable excipient. As used herein, pharmaceutically acceptable excipients include, but are not limited to, any and all solvents, dispersion media or other liquid vehicles, dispersion or suspension aids, diluents, granulation and / or dispersants, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, adhesives, lubricants or oils, coloring, sweetening or flavoring agents, stabilizers, antioxidants, antimicrobial or antifungal agents, osmotic pressure regulators, pH regulators, buffers, chelating agents, cryoprotectants and / or bulking agents, as long as they are suitable for the desired specific dosage form. A variety of excipients for preparing pharmaceutical compositions and techniques for preparing the compositions are known to those skilled in the art (see Remington: The Science and Practice of Pharmacy, 21st edition, ARGennaro (Lippincott, Williams and Wilkins, Baltimore, MD), 2006; incorporated herein by reference in its entirety)

[0233] Any therapeutic agent described herein can be in the form of a pharmaceutically acceptable salt. In some embodiments, such salts are derived from inorganic or organic acids or bases. For a review of suitable salts, see, e.g., Berge et al., J. Pharm. Sci., 1977, 66, 1-19 and Remington: The Science and Practice of Pharmacy, 20th edition, A. Gennaro (ed.), Lippincott Williams and Wilkins (2000).

[0234] Examples of suitable acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, lucoheptanoate, 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, toluenesulfonate and undecanoate.

[0235] 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; salts with organic bases such as dicyclohexylamine salts; N-methyl-D-glucamine salts; and salts with amino acids such as arginine, lysine, and the like.

[0236] For example, Berge lists the following FDA-approved commercially available salts: anionic acetate, besylate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, glucoheptonate, gluconate, glutamate, glycolylarsanilate, glycolylamidophenylarsonate e)), hexylresorcinol salt, hydrabamine (N,N'-di(dehydroabietyl)ethylenediamine), hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate (2-hydroxyethanesulfonate), lactate, lactobionate, malate, maleate, mandelate, mesylate (methanesulfonate), methylbromide, methylnitrate, methylsulfate, mucate, naphthylsulfonate (2-naphthylsulfonate), nitrate, pamoate (enbolate), pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate (8-chlorotheophyllina te) and triethyl iodide; the organic cations benzathine (N,N'-dibenzylethylenediamine), chloroprocaine, choline, diethanolamine, ethylenediamine, meg lumine (N-methylglucamine) and procaine; and the metal cations aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.

[0237] Berge additionally lists the following non-FDA approved commercially available (outside the United States) salts: anionic adipic acid, alginate, aminosalicylate, dehydromethylene citrate, arecoline, aspartate, bisulfate, butyl bromide, camphorate, digluconate, dihydrobromide, disuccinate, glycerophosphate, hemisulfate, hydrofluoride, hydroiodide, methylenebis(salicylate), naphthalene disulfonate (1,5-naphthalene disulfonate), oxalate, pectinate, persulfate, phenethylbarbiturate, picrate, propionate, thiocyanate, toluenesulfonate, and undecanoate salts; organic cations benethamine (N-benzylphenethylamine), clemizole (1-p-chlorobenzyl-2-pyrrolidin-1'-ylmethylbenzimidazole), diethylamine, piperazine, and tromethamine (tris(hydroxymethyl)aminomethane); and metal cations barium and bismuth.

[0238] 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. The toxicity or adverse effects associated with the carrier (if any) are preferably commensurate with the reasonable risk / benefit ratio of the intended use of the active agent.

[0239] Pharmaceutically acceptable carriers that can 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, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and lanolin.

[0240] The pharmaceutical compositions used in the methods of the present disclosure can be manufactured by methods well known to those skilled in the art, such as conventional granulation, mixing, dissolution, encapsulation or emulsification processes, etc. The compositions can be produced in various forms, including granules, precipitates or microparticles; powders, including freeze-dried, rotary-dried or spray-dried powders, amorphous powders; tablets, capsules, syrups, suppositories, injections, emulsions, elixirs, suspensions or solutions. The formulations may include stabilizers, pH regulators, surfactants, solubilizers, bioavailability regulators and combinations of these. These pharmaceutical compositions are formulated for drug administration to humans. Such compositions can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, orally, vaginally or via an implantable drug box. As used herein, the term "parenteral" includes subcutaneous, intravenous, intraperitoneal, intramuscular, intraarticular, 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, the 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 and then by subcutaneous injection. In another embodiment, the checkpoint inhibitor is co-administered with human hyaluronidase subcutaneously. These preparations can be designed to be short-acting, rapid-release or long-acting. In addition, the composition can be administered locally rather than systemically, such as (e.g., by injection) at the tumor site.

[0241] Liquids such as oil, water, alcohol and combinations of these can be used to prepare pharmaceutical preparations in liquid suspensions or solutions. Solubilizers such as cyclodextrins may be included. Pharmaceutically suitable surfactants, suspending agents or emulsifiers may be added for oral or parenteral administration. The suspension may contain oils such as peanut oil, sesame oil, cottonseed oil, corn oil and olive oil. Suspension formulations may also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides. Suspension formulations may contain alcohols such as ethanol, isopropanol, hexadecanol, glycerol and propylene glycol; ethers such as polyethylene glycol; petroleum hydrocarbons such as mineral oil and vaseline; and water.

[0242] The sterile injectable forms of these pharmaceutical compositions can be aqueous or oily suspensions. These suspensions can be prepared using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Among acceptable vehicles and solvents, water, Ringer's solution, and isotonic sodium chloride solution can be used. In addition, sterile non-volatile oils are routinely used as solvents or suspension media. For this purpose, any mild non-volatile oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are suitable for the preparation of injections, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated forms. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants commonly used to prepare pharmaceutically acceptable dosage forms (including emulsions and 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 may also be used for formulation purposes. The compound may be formulated for parenteral administration by injection, such as by bolus injection or continuous infusion. Unit dosage forms for injection may be in ampoules or multidose containers.

[0243] These pharmaceutical compositions can be orally administered in any oral acceptable dosage form, including capsules, tablets, aqueous suspensions or solutions. When oral use requires an aqueous suspension, the active ingredient is combined with an emulsifier and a suspending agent. If desired, certain sweeteners, flavorings or coloring agents may also be added. For oral administration in the form of capsules, available diluents include lactose and dry corn starch. For tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are also usually added. Coatings may be used for a variety of purposes, for example, to mask taste, to affect the site of dissolution or absorption or to prolong the drug action. Coatings may be applied to tablets or to the granular particles used in capsules.

[0244] Alternatively, these pharmaceutical compositions can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycol.

[0245] These pharmaceutical compositions may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0246] Topical application of the lower intestinal tract can be achieved with rectal suppository formulations (see above) or with suitable enema formulations. Topical transdermal patches can also be used. For topical application, the pharmaceutical composition can be formulated into a suitable ointment containing an active component suspended or dissolved in one or more carriers. Carriers for topical application of the disclosed compounds include mineral oil, liquid vaseline, white vaseline, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated into a suitable lotion or cream containing an active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0247] For ophthalmic use, the pharmaceutical composition can be formulated as a micronized suspension in isotonic, pH-adjusted sterile saline, or preferably, as a solution in isotonic, pH-adjusted sterile saline, with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition can be formulated as an ointment such as petrolatum.

[0248] The pharmaceutical compositions may also be administered by nasal aerosol or inhalation. Such compositions may be prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline utilizing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0249] In one embodiment, Compound No. 14 is formulated as a solution for intravenous infusion. In some embodiments, Compound No. 14 is formulated as a solution containing 3 mg / 3 mL of Compound No. 14 as a free base. In one embodiment, the solution of Compound No. 14 can be diluted prior to infusion.

[0250] Reagent test kit

[0251] In some embodiments, the STING agonists or checkpoint inhibitors described herein may be manufactured to be included in a kit. A "kit" is any article (e.g., a package or container) comprising at least one reagent or chemotherapeutic agent. The kit used in the methods herein may include a STING agonist, such as compound No. 14 or a pharmaceutically acceptable salt thereof. In some embodiments, the kit may also include a checkpoint inhibitor and optionally one or more additional therapeutic agents. In some embodiments, the kit may 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 may include one or more STING agonists or pharmaceutically acceptable salts thereof. In some embodiments, the kit may include one or more checkpoint inhibitors.

[0252] In some embodiments, the present disclosure relates to a kit comprising a drug for treating cancer in a patient in need of such treatment. The kit comprises a drug containing a STING agonist and instructions for administering the STING agonist and a checkpoint inhibitor; or the kit comprises a drug containing a checkpoint inhibitor and instructions for administering the checkpoint inhibitor and a STING agonist. The kit may comprise a drug containing a STING agonist and a checkpoint inhibitor and instructions for administering the STING agonist and the checkpoint inhibitor, wherein the drug is in a single dosage form or in separate dosage forms. In some embodiments, the kit optionally comprises one or more additional therapeutic agents.

[0253] In some embodiments, the kit comprising a STING agonist and a checkpoint inhibitor may further comprise another component or reagent. In some embodiments, the reagent in the kit may be a diluent for preparing the STING agonist for administration. In some embodiments, the reagent in the kit may be a diluent for preparing the checkpoint inhibitor for administration. In some embodiments, the component in the kit may be a container for mixing the combination of the STING agonist and the checkpoint inhibitor.

[0254] In another aspect, the present disclosure relates to a kit for treating cancer, comprising at least one drug containing at least one dose of Compound No. 14 or a pharmaceutically acceptable salt thereof, and at least one drug containing at least one dose of a checkpoint inhibitor, the kit for treating cancer also comprising instructions for administering the drug to treat a patient in recognized need thereof.

[0255] In order to more fully understand the present disclosure, the following examples are listed. These examples are merely illustrative and are not intended to limit the scope of the present disclosure in any way.

[0256] Example

[0257] abbreviation

[0258] H Hour

[0259] Min Minutes

[0260] HPLC High Pressure Liquid Chromatography

[0261] UPLC Ultra-High Pressure Liquid Chromatography

[0262] NMR Nuclear Magnetic Resonance

[0263] THF Tetrahydrofuran

[0264] WFI Water for Injection

[0265] TGI Tumor Growth Inhibition

[0266] Mg mg

[0267] mm 3 Cubic millimeters

[0268] HPbCD 2-Hydroxypropyl-β-cyclodextrin

[0269] CMC Carboxymethyl Cellulose

[0270] PO Oral

[0271] SC Subcutaneous

[0272] SD Start Date

[0273] SA single dose

[0274] Q3W Once every 3 weeks

[0275] BLRM Bayesian Logistic Regression Model

[0276] MTD maximum tolerated dose

[0277] PAD pharmacologically active dose

[0278] IV

[0279] DLT Dose-limiting toxicity

[0280] PK Pharmacokinetics

[0281] TEAE Treatment-emergent adverse events

[0282] DL dose level

[0283] RP2D Recommended Phase 2 Dose

[0284] MABEL Minimum anticipated biological effect level

[0285] Example 1: In vivo tumor efficacy

[0286] General analytical methods

[0287] Unless otherwise noted, Varian 300MHz was used to obtain 1 H NMR spectra. Unless otherwise indicated, HPLC was obtained on an Agilent 1100 Series and UPLC was obtained from Water Acuity Systems.

[0288] Compound No. 14 as used in the following examples can be synthesized according to the procedure described in Example 14 of PCT Publication No. WO 2018 / 100558.

[0289] General Experimental Conditions for Antitumor Efficacy in Mouse Tumor Models

[0290] Mouse syngeneic tumor models

[0291] As specified below, the following homology models were utilized in each of Studies 1-5.

[0292] A20 study 1: A20 is a mouse B-cell lymphoma cell line. Female BALB / c mice (Beijing Weitonglihua Laboratory Animal Technology Co., Ltd., China) were inoculated subcutaneously in the flank with 0.4 x 10 6 A20 cells (cell suspension) were used to generate the A20 mouse syngeneic tumor model. When the average tumor volume reached approximately 55 mm 3 At 1:10, the animals were randomly divided into a vehicle control group and three treatment groups (n=10 / group). The mice were then given PBS or compound No. 14 or anti-mouse PD-1 antibody or compound No. 14 plus anti-mouse PD-1 antibody over a period of 31 days. Tumor growth and body weight were measured twice a week during and after the treatment period, and once the mice reached the humane endpoint, they were humanely euthanized.

[0293] L5178-R Study 2: L5178-R is a mouse lymphoma cell line. Female DBA / 2 mice (Beijing Weitonglihua Laboratory Animal Technology Co., Ltd., China) were inoculated subcutaneously in the flank with 0.2 x 10 6 L5178-R cells (cell suspension) were used to generate the L5178-R mouse syngeneic tumor model. When the average tumor volume reached approximately 65 mm 3At , the animals were randomly divided into a vehicle control group and four treatment groups (n = 10 / group). The mice were then given PBS or compound No. 14 or anti-mouse PD-1 antibody or compound No. 14 plus 10 mg / kg anti-mouse PD-1 antibody (Q3D x 3 and QW x3) over a 10-day period. Tumor growth and body weight were measured twice a week during and after the treatment period, and once the mice reached the humane endpoint, they were humanely euthanized.

[0294] WEHI-3 Study 3: WEHI-3 is a mouse myelomonocytic leukemia cell line. Female BALB / c mice (Beijing Weitonglihua Laboratory Animal Technology Co., Ltd., China) were inoculated subcutaneously in the flank with 0.1 x 10 6 WEHI-3 cells (cell suspension) were used to generate the WEHI-3 mouse syngeneic tumor model. When the average tumor volume reached approximately 60 mm 3 At 1:10, the animals were randomly divided into a vehicle control group and four treatment groups (n=10 / group). The mice were then given PBS or compound No. 14 or anti-mouse PD-1 antibody or compound No. 14 plus anti-mouse PD-1 antibody over a 21-day period. Tumor growth and body weight were measured twice a week during and after the treatment period, and once the mice reached the humane endpoint, they were humanely euthanized.

[0295] RM-1 study 4: RM-1 is a mouse prostate cancer cell line. 10-week-old female C57BL / 6 mice (Beijing Weitonglihua Laboratory Animal Technology Co., Ltd., China) were inoculated subcutaneously with 0.8 x 10 6 RM-1 cells (cell suspension) were used to generate the RM-1 mouse syngeneic tumor model. When the average tumor volume reached approximately 60 mm 3 At 14:1, animals were randomly divided into a vehicle control group and four treatment groups (n=10 / group). Mice were then given PBS or compound No. 14 or anti-mouse PD-1 antibody or compound No. 14 plus anti-mouse PD-1 antibody over a 19-day period. Tumor growth and body weight were measured twice a week during and after the treatment period, and once the mice reached the humane endpoint, they were humanely euthanized.

[0296] L1210 study 5: L1210 is a mouse leukemia cell line. Female DBA / 2 mice (Beijing Weitonglihua Laboratory Animal Technology Co., Ltd., China) were inoculated subcutaneously in the flank of approximately 11 weeks old. 6 L1210 cells (cell suspension) were used to generate the L1210 mouse syngeneic tumor model. When the average tumor volume reached approximately 50 mm 3At 14:1, animals were randomly divided into a vehicle control group and four treatment groups (n=10 / group). Mice were then given PBS or compound No. 14 or anti-mouse PD-1 antibody or compound No. 14 plus anti-mouse PD-1 antibody over a 15-day period. Tumor growth and body weight were measured twice a week during and after the treatment period, and once the mice reached the humane endpoint, they were humanely euthanized.

[0297] Reagent

[0298] The following reagents were utilized in each of Studies 1-5 as specified below.

[0299] A20 Study 1: A 0.025 mg / mL stock solution of Compound No. 14 was prepared in phosphate buffered saline (PBS) and administered intravenously (IV) based on the exact animal weight on each day of treatment, using a dosing volume of 10 mL / kg body weight. The final dose received was 0.25 mg / kg. The dosing volume of Compound No. 14 was 0.2 mL. Anti-mouse PD1 antibody (anti-mPD-1) (BioXCell, 10 Technology Drive, Suite 2B, West Lebanon, NH 03784) was prepared at 2 mg / mL in phosphate buffered saline (PBS) before each injection and administered intraperitoneally (IP) based on the exact animal weight on each day of treatment, using a dosing volume of 5 mL / kg, resulting in a dose of 10 mg / kg. The dosing volume of anti-mPD-1 was 0.1 mL. Compound No. 14 was administered according to the Q3D schedule for 3 cycles until Day 6 (Days 0, 3, and 6) in both the single-agent treatment group and the combination treatment group, and anti-mPD-1 was administered according to the Q3D schedule for 3 cycles until Day 6 and according to the QW schedule for 3 weeks until Day 27 (Days 0, 3, 6, 13, 20, and 27) in both the single-agent treatment group and the combination treatment group.

[0300] L5178-R Study 2: A 0.025 mg / mL stock solution of Compound No. 14 was prepared in phosphate buffered saline (PBS) and administered intravenously (IV) based on the exact animal weight on each day of treatment, using a dosing volume of 10 mL / kg body weight. The final dose received was 0.25 mg / kg. The dosing 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 prepared at 2 mg / mL in phosphate buffered saline (PBS) before each injection and administered intraperitoneally (IP) based on the exact animal weight on each day of treatment, using a dosing volume of 5 mL / kg, resulting in a dose of 10 mg / kg. The dosing volume of anti-mPD-1 was 0.1 mL. Compound No. 14 was administered according to the Q3D schedule for 3 cycles until Day 6 (Days 0, 3, and 6) in both the single-agent treatment group and the combination treatment group, and anti-mPD-1 was administered according to the Q3D schedule for 3 cycles until Day 6 (Days 0, 3, and 6) in both the single-agent treatment group and the combination treatment group.

[0301] WEHI-3 Study 3: A 0.025 mg / mL stock solution of Compound No. 14 was prepared in phosphate buffered saline (PBS) and administered intravenously (IV) based on the exact animal weight on each day of treatment, using a dosing volume of 10 mL / kg body weight. The final dose received was 0.25 mg / kg. The dosing 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 prepared at 2 mg / mL in phosphate buffered saline (PBS) before each injection and administered intraperitoneally (IP) based on the exact animal weight on each day of treatment, using a dosing volume of 5 mL / kg, resulting in a dose of 10 mg / kg. The dosing volume of anti-mPD-1 was 0.1 mL. Compound No. 14 was administered according to the Q3D schedule for 3 cycles until Day 6 (Days 0, 3, and 6) in both the single-agent treatment group and the combination treatment group, and anti-mPD-1 was administered according to the Q3D schedule for 3 cycles until Day 6 and according to the QW schedule for 1 week until Day 13 (Days 0, 3, 6, and 13) in both the single-agent treatment group and the combination treatment group.

[0302] RM-1 Study 4: A 0.025 mg / mL stock solution of Compound No. 14 was prepared in phosphate buffered saline (PBS) and administered intravenously (IV) based on the exact animal weight on each day of treatment, using a dosing volume of 10 mL / kg body weight. The final dose received was 0.25 mg / kg. The dosing 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 prepared at 2 mg / mL in phosphate buffered saline (PBS) before each injection and administered intraperitoneally (IP) based on the exact animal weight on each day of treatment, using a dosing volume of 5 mL / kg, resulting in a dose of 10 mg / kg. The dosing volume of anti-mPD-1 was 0.1 mL. Compound No. 14 was administered according to the Q3D schedule for 3 cycles until Day 6 (Days 0, 3, and 6) in both the single-agent treatment group and the combination treatment group, and anti-mPD-1 was administered according to the Q3D schedule for 3 cycles until Day 6 and according to the QW schedule for 1 week until Day 13 (Days 0, 3, 6, and 13) in both the single-agent treatment group and the combination treatment group.

[0303] L1210 Study 5: A 0.025 mg / mL stock solution of Compound No. 14 was prepared in phosphate buffered saline (PBS) and administered intravenously (IV) based on the exact animal weight on each day of treatment, using a dosing volume of 10 mL / kg body weight. The final dose received was 0.25 mg / kg. The dosing 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 prepared at 2 mg / mL in phosphate buffered saline (PBS) before each injection and administered intraperitoneally (IP) based on the exact animal weight on each day of treatment, using a dosing volume of 5 mL / kg, resulting in a dose of 10 mg / kg. The dosing volume of anti-mPD-1 was 0.1 mL. Compound No. 14 was administered according to the Q3D schedule for 3 cycles until Day 6 (Days 0, 3, and 6) in both the single-agent treatment group and the combination treatment group, and anti-mPD-1 was administered according to the Q3D schedule for 3 cycles until Day 6 and according to the QW schedule for 1 week until Day 13 (Days 0, 3, 6, and 13) in both the single-agent treatment group and the combination treatment group.

[0304] Tumor measurements:

[0305] Tumors were measured twice weekly using a vernier caliper. Tumor volume was calculated using the standard equation: V = W 2x L / 2, where V = tumor volume, W = width and L = length. When the mean tumor volume for Study 1 reached approximately 55 mm 3 , for Study 2, approximately 65 mm 3 , for Study 3, approximately 60 mm 3 , for Study 4, approximately 60 mm 3 , for Study 5, approximately 50 mm 3 In studies 1-5, mice were randomly divided into 4 groups (n=10 / group) and given vehicle (PBS), compound No. 14, anti-mPD-1, or a combination of compound No. 14 plus anti-mPD-1 at various doses and schedules. Tumor size and body weight were measured twice a week for the duration of the study. When the tumor volume of the mouse reached greater than 10% of the animal's body weight or when the size of a single tumor volume exceeded the humane endpoint (tumor length exceeded 2 cm), the mouse was euthanized.

[0306] Statistical analysis comparing different treatments in mouse syngeneic tumor models

[0307] The following statistical analysis methods were used in Studies 1-5.

[0308] Prior to logarithmic transformation, all values ​​of tumor volume were increased by 5. After transformation, linear interpolation was used to estimate the tumor volume of each mouse since randomization to 1000 mm 3 Time (in days) for mice with tumors reaching 1000mm 3 Events that did not reach 1000 mm at the end of the study were considered “tumor progression” events, and the above estimated time was called the time to progression (TTP). 3 , the last day of the study of mice was recorded and right censored. For each pair of treatments of interest, a parametric survival model assuming a Weibull distribution of TTP was used to estimate the hazard ratio (HR) between the two treatment groups. HR reflects the hazard ratio of mice in the two treatment groups experiencing progression events at any time point throughout the study. The HR between treatment A and treatment B is less than 1, indicating that the efficacy of treatment A is better than treatment B. Standard error (SE) and 95% confidence interval (CI) were also calculated to describe the uncertainty of the estimated HR. Finally, two types of tests were used to calculate P values ​​to assess the statistical significance of the differences between the following two treatments: 1) Wald test P value from the Weibull survival model; 2) non-parametric log-rank test.

[0309] result

[0310] A20 Study 1: The combination group of Compound 14 and anti-mouse PD-1 antibody produced a combined benefit during the 31-day treatment phase of the A20 study compared to the Compound 14 group or the anti-mouse PD-1 antibody group alone. The anti-mouse PD-1 antibody group alone achieved one complete response that was maintained throughout the 31 days, and the Compound 14 group also achieved one complete response. In contrast, four complete responses were observed in the combination group of Compound 14 and anti-mouse PD-1 antibody. The Weibull regression hazard ratio was significant relative to both control groups, although Compound 14 and anti-mouse PD-1 antibody were not significantly different from Compound 14 alone when assessed by the log-rank test (p=0.067).

[0311] The treatment groups from Study 1 are shown in Table 1a. The combined effects of treatment periods are also shown in Table 1a. Figure 1a Kaplan–Meier curves for progression-free survival during treatment are shown. Figure 1b Tumor growth curves during treatment are shown.

[0312] L5178-R Study 2: The combination of Compound 14 and anti-mouse PD-1 antibody produced a combination benefit during the 6-day treatment phase of the L5178-R study compared to the anti-mouse PD-1 antibody alone group, but not the Compound 14 group. No complete responses were seen in this study. The Weibull regression hazard ratio was significant relative to the anti-mouse PD-1 antibody control group.

[0313] The treatment groups from Study 2 are shown in Table 1a. The combined effects of treatment period are also shown in Table 1a. Figure 2a Kaplan–Meier curves for progression-free survival during treatment are shown. Figure 2b Tumor growth curves during treatment are shown.

[0314] WEHI-3 Study 3: The combination of Compound 14 and anti-mouse PD-1 antibody produced a combination benefit during the 14-day treatment phase of the WEHI-3 study compared to the anti-mouse PD-1 antibody alone group, but not the Compound 14 group. No complete responses were seen in this study. The Weibull regression hazard ratio was significant relative to the anti-mouse PD-1 antibody control group.

[0315] The treatment groups from Study 3 are shown in Table 1a. The combined effects of treatment periods are also shown in Table 1a. Figure 3a Kaplan–Meier curves for progression-free survival during treatment are shown. Figure 3b Tumor growth curves during treatment are shown.

[0316] RM-1 Study 4: The combination of Compound 14 and anti-mouse PD-1 antibody produced a combination benefit during the 14-day treatment phase of the RM-1 study compared with the anti-mouse PD-1 antibody alone group, but not with Compound 14. No complete responses were seen in this study. The Weibull regression hazard ratio was significant relative to the anti-mouse PD-1 antibody control group.

[0317] The treatment groups from Study 4 are shown in Table 1a. The combined effects of treatment periods are also shown in Table 1a. Figure 4a Kaplan–Meier curves for progression-free survival during treatment are shown. Figure 4b Tumor growth curves during treatment are shown.

[0318] L1210 Study 5: The combination of Compound 14 and anti-mouse PD-1 antibody produced a combination benefit during the 11-day treatment phase of the L1210 study compared to Compound 14 or anti-mouse PD-1 antibody alone. No complete responses were seen in this study. The Weibull regression hazard ratio was significant relative to both control groups.

[0319] The treatment groups from Study 5 are shown in Table 1a. The combined effects of treatment period are also shown in Table 1a. Figure 5a Kaplan–Meier curves for progression-free survival during treatment are shown. Figure 5b Tumor growth curves during treatment are shown.

[0320] Table 1a

[0321]

[0322]

[0323]

[0324] *Statistically significant hazard ratio based on log-rank test.

[0325] Additional mouse syngeneic studies

[0326] Unlike the A20, L5178-R, WEHI-3, RM-1, and L1210 syngeneic models, no combination benefit of Compound 14 plus anti-mouse PD-1 antibody was observed in the mouse mammary cancer 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 cancer EMT6, mouse hepatocarcinoma H22, mouse plasmacytoma J558, mouse mammary cancer JC, mouse lung cancer KLN205, mouse Lewis lung cancer LLC1, mouse Lewis lung cancer LLC-1luc, mouse colon cancer MC38, mouse lymphoma P388D1, mouse pancreatic duct adenocarcinoma PANC02, and mouse renal cancer RENCA models under similar experimental conditions and procedures in Studies 1-5.

[0327] Example 2: Clinical study evaluating the combination of compound 14 and anti-PD-1 antibody in the treatment of patients with metastatic solid tumors

[0328] A Phase 1, open-label, parallel-assignment, 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 estimate the maximum tolerated dose (MTD) of the pharmacologically active dose (PAD) to determine the recommended Phase 2 dose (RP2D) for SA and in combination with pembrolizumab. Dose escalation may be stopped after the PAD is determined but before the MTD is determined, based on the discussion of the safety data between the investigator and the sponsor.

[0329] Approximately 100 patients will be enrolled in this study. Once enrolled, patients will be administered Compound No. 14 intravenously (IV) on days 1, 4, 8, and 11 of each 21-day dosing cycle in the Compound No. 14 SA group and in the combination group with pembrolizumab. All patients will be hospitalized for treatment and monitoring for at least the first cycle on day 9. If there are no clinical issues (i.e., fever, hypotension, or other clinical safety issues), patients can be discharged 24 hours after the infusion on day 8. If clinical safety, PK, and pharmacodynamics are supportive, the dosing schedule can be modified to evaluate low-intensity administration of Compound No. 14 on days 1 and 8 of a 21-day cycle without modifying the regimen. Alternative dosing schedules may also be considered if supported by collective data on safety, PK, and pharmacodynamics. In addition, patients with clinical benefit may be switched to this less frequent schedule after cycle 6 if the investigator agrees with the patient that continuing the intensive schedule will have a negative impact on the patient's health.

[0330] Single dose of compound 14 group

[0331] The recommended initial explorable dose range is 0.2 mg to 3.5 mg (if the starting dose of 0.2 mg is not tolerated, a dose level [DL]-1 of 0.1 mg is specified). The starting dose is calculated using a combined minimum anticipated biological effect level (MABEL) and nonclinical toxicology approach. Doses greater than 3.5 mg may be explored if the final DL is deemed safe and tolerable. The upper DL of 3.5 mg corresponds approximately to a human equivalent dose that is slightly higher than the MTD in monkeys. For the first 3 patients at a given DL, patient enrollment will be staggered with a planned 4-day waiting period between each patient. If more than 3 patients are to be enrolled at the DL, or if taper is indicated, this waiting period may not be required if there are no clinically significant safety findings suggestive of infusion reactions or cytokine release syndrome. This 4-day waiting period may be reconsidered during the study in discussions with the study investigators and sponsor.

[0332] Compound 14 combined with pembrolizumab

[0333] The second group will evaluate the safety, tolerability, PK, and pharmacodynamics of compound 14 in combination with the approved dose and schedule of pembrolizumab (200 mg once every 3 weeks [Q3W]). The second group will be initiated only if at least 2 DLs of SA compound 14 have been evaluated and deemed safe and tolerable. If the SA group does not require a dose reduction of DL-1, the starting dose of compound 14 in this group will be 0.2 mg (compound 14 MABEL) administered on a dosing schedule of days 1, 4, 8, and 11, in combination with 200 mg pembrolizumab administered once every 3 weeks. For cycle 1 only, compound 14 will be administered on day 1 and pembrolizumab will be administered on day 2 to better assess safety. For the remaining administrations starting on day 1 of cycle 2, both drugs will be administered on day 1, starting with compound 14, followed by pembrolizumab, with an interval of 1 hour between the 2 drugs. If supported by clinical safety and / or PK / pharmacodynamics data, less frequent administration of Compound 14 in combination with pembrolizumab, such as administration on Days 1 and 8 of a 21-day cycle, may be considered. Alternative dosing schedules may also be considered if supported by the collective data on safety, PK, and pharmacodynamics.

[0334] The study design consists of a dose escalation portion followed by dose expansion cohorts for compound 14 SA and combination arms. Dose escalation for compound 14 as SA and in combination with pembrolizumab will follow an adaptive design using a Bayesian logistic regression model (BLRM). The BLRM with excess controls will be used to inform dose escalation decisions and MTD estimates for the SA and combination arms, but a combination of PK and pharmacodynamic data will be used for PAD estimates. Once the PAD for compound 14 as SA or in combination with pembrolizumab is determined, compound 14 SA or combination expansion cohorts can be initiated without determining the SA or combination MTD, respectively. For both SA and combination arms, 3 patients will initially be enrolled at the starting DL, followed by a 3+3+3 dose escalation rule. Starting with the second DL of the patient, all subsequent dose recommendations will use the BLRM with excess controls for both SA and combination arms, taking into account other non-dose limiting toxicities (DLTs) safety and available PK data. The final decision on the next DL will be made jointly by the sponsor and participating investigators, taking into account the BLRM output and any other available clinical or translational information, and within the scope of the DL.

[0335] Once the MTD and / or PAD for Compound 14 as SA or in combination with pembrolizumab is determined, expansion cohorts of approximately 15 patients treated with Compound 14 SA or Compound 14 in combination with pembrolizumab may be initiated to better assess safety and tolerability at that dose. Expansion cohorts may be initiated once the PAD is identified and without waiting for determination of the MTD. The ability to expand to more than 1 dose may be agreed upon between the sponsor and investigator if the MTD or PAD is not elucidated from the dose escalation phase. 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 literature / publications, nonclinical / translational work, or evidence of antitumor activity from the escalation phase. No formal sample size calculation was performed for the expansion cohorts.

[0336] Toxicity will be assessed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 5.0. A DLT will be defined as any treatment-emergent adverse event (TEAE) that is described in detail, but not limited to, that occurs during Cycle 1 and is considered by the investigator to be at least possibly related to Compound 14 as a SA or in combination with pembrolizumab. TEAEs meeting the definition of a DLT occurring in subsequent cycles will be considered in determining the PAD and RP2D for Compound 14 as a SA and in combination with pembrolizumab that are likely to be equal to or below the MTD.

[0337] Patients who tolerated Compound 14 treatment well at the initially assigned dose (i.e., had at least a complete cycle 1 without DLT) and who benefited from study treatment based on the investigator's assessment may be allowed to have the dose of Compound 14 escalated in subsequent treatment cycles after discussion with the sponsor. This may only be considered if all patients in the next DL cohort have not experienced DLT-like toxicity or discontinued due to adverse events after 3 treatment cycles, and it has been decided that this DL does not exceed the MTD. If any patient in the next DL cohort progresses within the first 3 treatment cycles, this will not prevent intra-patient dose escalation from the previous dose.

[0338] During dose escalation, patients who did not receive the scheduled dose in Cycle 1 for reasons other than DLT will be replaced.

[0339] This study will enroll approximately 100 subjects.

[0340] Primary End Point

[0341] Primary endpoints for this Phase 1 trial may include the frequency and severity of TEAEs; the number of patients with DLTs; the number / percentage of patients experiencing 1 or more serious adverse events; and the number / percentage of patients experiencing 1 or more TEAEs leading to dose modifications and treatment interruptions.

[0342] The trial will be conducted in accordance with Good Clinical Practices.

[0343] Example 3: Clinical study evaluating the combination of compound 14 and anti-PD-1 antibody in the treatment of patients with metastatic solid tumors

[0344] A Phase 1, open-label, parallel-assignment, 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 estimate the maximum tolerated dose (MTD) of the pharmacologically active dose (PAD) to determine the recommended Phase 2 dose (RP2D) for SA and in combination with pembrolizumab. Dose escalation may be stopped after the PAD is determined but before the MTD is determined, based on the discussion of the safety data between the investigator and the sponsor.

[0345] Approximately 100 patients will be enrolled in this study. Once enrolled, patients will be administered Compound No. 14 as an intravenous (IV) infusion on days 1, 8, and 15 of each 21-day dosing cycle in the Compound No. 14 SA group and in the combination group with pembrolizumab. All patients will be hospitalized for treatment and monitoring for at least the first cycle on day 9. If there are no clinical issues (i.e., fever, hypotension, or other clinical safety issues), patients can be discharged 24 hours after the infusion on day 8. If clinical safety, PK, and pharmacodynamics are supportive, the dosing schedule can be modified to evaluate the low-intensity administration of Compound No. 14 on days 1 and 8 of a 21-day cycle without modifying the regimen. Alternative dosing schedules may also be considered if supported by the collective data on safety, PK, and pharmacodynamics. In addition, if the investigator agrees with the patient that continuing the intensive schedule will have a negative impact on the patient's health, patients with clinical benefit can be switched to this less frequent schedule after cycle 6.

[0346] Single dose of compound 14 group

[0347] The recommended initial explorable dose range is 0.2 mg to 3.5 mg (if the starting dose of 0.2 mg is not tolerated, a dose level [DL]-1 of 0.1 mg is specified). The starting dose is calculated using a combined minimum anticipated biological effect level (MABEL) and nonclinical toxicology approach. Doses greater than 3.5 mg may be explored if the final DL is deemed safe and tolerable. The upper DL of 3.5 mg corresponds approximately to a human equivalent dose that is slightly higher than the MTD in monkeys. For the first 3 patients at a given DL, patient enrollment will be staggered with a planned 4-day waiting period between each patient. If more than 3 patients are to be enrolled at the DL, or if taper is indicated, this waiting period may not be required if there are no clinically significant safety findings suggestive of infusion reactions or cytokine release syndrome. This 4-day waiting period may be reconsidered during the study in discussions with the study investigators and sponsor.

[0348] Compound 14 combined with pembrolizumab

[0349] The second arm will evaluate the safety, tolerability, PK, and pharmacodynamics of compound 14 in combination with the approved dose and schedule of pembrolizumab (200 mg once every 3 weeks [Q3W]). The second arm will be initiated only if at least 2 DLs of SA compound 14 have been evaluated and deemed safe and tolerable. If the SA arm does not require a dose reduction of DL-1, the starting dose of compound 14 in this arm will be 0.2 mg (compound 14 MABEL) administered on a dosing schedule of days 1, 8, and 15, in combination with 200 mg pembrolizumab administered on day 1 of a 21-day dosing cycle. For cycle 1 only, compound 14 may be administered on day 1 and pembrolizumab may be administered on day 2 to better assess safety. For the remainder of administrations starting on day 1 of cycle 2, both drugs will be administered on day 1, starting with compound 14 followed by pembrolizumab, with a 1-hour interval between the 2 drugs. If supported by clinical safety and / or PK / pharmacodynamics data, less frequent administration of Compound 14 in combination with pembrolizumab, such as administration on Days 1 and 8 of a 21-day cycle, may be considered. Alternative dosing schedules may also be considered if supported by the collective data on safety, PK, and pharmacodynamics.

[0350] The study design consists of a dose escalation portion followed by dose expansion cohorts for compound 14 SA and combination arms. Dose escalation for compound 14 as SA and in combination with pembrolizumab will follow an adaptive design using a Bayesian logistic regression model (BLRM). The BLRM with excess controls will be used to inform dose escalation decisions and MTD estimates for the SA and combination arms, but a combination of PK and pharmacodynamic data will be used for PAD estimates. Once the PAD for compound 14 as SA or in combination with pembrolizumab is determined, compound 14 SA or combination expansion cohorts can be initiated without determining the SA or combination MTD, respectively. For both SA and combination arms, 3 patients will initially be enrolled at the starting DL, followed by a 3+3+3 dose escalation rule. Starting with the second DL of the patient, all subsequent dose recommendations will use the BLRM with excess controls for both SA and combination arms, taking into account other non-dose limiting toxicities (DLTs) safety and available PK data. The final decision on the next DL will be made jointly by the sponsor and participating investigators, taking into account the BLRM output and any other available clinical or translational information, and within the scope of the DL.

[0351] Once the MTD and / or PAD for Compound 14 as SA or in combination with pembrolizumab is determined, expansion cohorts of approximately 15 patients treated with Compound 14 SA or Compound 14 in combination with pembrolizumab may be initiated to better assess safety and tolerability at that dose. Expansion cohorts may be initiated once the PAD is identified and without waiting for determination of the MTD. The ability to expand to more than 1 dose may be agreed upon between the sponsor and investigator if the MTD or PAD is not elucidated from the dose escalation phase. 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 literature / publications, nonclinical / translational work, or evidence of antitumor activity from the escalation phase. No formal sample size calculation was performed for the expansion cohorts.

[0352] Toxicity will be assessed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 5.0. A DLT will be defined as any treatment-emergent adverse event (TEAE) that is described in detail, but not limited to, that occurs during Cycle 1 and is considered by the investigator to be at least possibly related to Compound 14 as a SA or in combination with pembrolizumab. TEAEs meeting the definition of a DLT occurring in subsequent cycles will be considered in determining the PAD and RP2D for Compound 14 as a SA and in combination with pembrolizumab that are likely to be equal to or below the MTD.

[0353] Patients who tolerated Compound 14 treatment well at the initially assigned dose (i.e., had at least a complete cycle 1 without DLT) and who benefited from study treatment based on the investigator's assessment may be allowed to have the dose of Compound 14 escalated in subsequent treatment cycles after discussion with the sponsor. This may only be considered if all patients in the next DL cohort have not experienced DLT-like toxicity or discontinued due to adverse events after 3 treatment cycles, and it has been decided that this DL does not exceed the MTD. If any patient in the next DL cohort progresses within the first 3 treatment cycles, this will not prevent intra-patient dose escalation from the previous dose.

[0354] During dose escalation, patients who did not receive the scheduled dose in Cycle 1 for reasons other than DLT will be replaced.

[0355] This study will enroll approximately 100 subjects.

[0356] Primary End Point

[0357] Primary endpoints for this Phase 1 trial may include the frequency and severity of TEAEs; the number of patients with DLTs; the number / percentage of patients experiencing 1 or more serious adverse events; and the number / percentage of patients experiencing 1 or more TEAEs leading to dose modifications and treatment interruptions.

[0358] The trial will be conducted in accordance with Good Clinical Practice.

[0359] While certain embodiments have been illustrated and described, it will be appreciated that changes and modifications may be made thereto in accordance with one skilled in the art without departing from the broader aspects of the technology as defined in the following claims.

[0360] The present disclosure is not limited to the specific embodiments described in this application. Modifications and changes can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. In addition to the methods and compositions listed herein, functionally equivalent methods and compositions within the scope of the present disclosure will be apparent to those skilled in the art from the foregoing description. Such modifications and changes are intended to fall within the scope of the appended claims. The present disclosure is limited only by the terms of the appended claims together with the full scope of equivalents granted by such claims. It should be understood that the present disclosure is not limited to specific methods, reagents, compound compositions or biological systems, which may of course vary. It should also be understood that the terms used herein are only for the purpose of describing specific embodiments and are not intended to be limiting.

[0361] All publications, patent applications, issued patents, and other documents mentioned in this specification are hereby incorporated by reference 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. A method of treating a patient suffering from cancer, comprising: Compound No. 14 having the following structure is administered to a patient in need of the treatment: or a pharmaceutically acceptable salt thereof, and Checkpoint inhibitors.

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

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

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

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

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

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

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

11. The method of any one of claims 1-10, wherein compound 14 and the checkpoint inhibitor are administered concurrently.

12. The method of any one of claims 1-10, wherein compound 14 and the checkpoint inhibitor are administered sequentially in separate pharmaceutical compositions.

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

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

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

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

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

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

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

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

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

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

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

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

26. The method of any one of claims 1-25, wherein the checkpoint inhibitor is administered once every twelve weeks, once every four weeks, once every three weeks, once every two weeks, once a week, twice a week, three times a week, or every day.

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

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

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

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

31. The method of any one of claims 1-25, wherein the checkpoint inhibitor is administered on day 1 or day 2 of a treatment cycle.

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

33. 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. The method of any one of claims 1-25, wherein Compound No. 14 is administered on Day 1 and Day 8 of a treatment cycle.

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

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

37. 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. The method of any one of claims 1-25, wherein compound 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. The method of any one of claims 31-38, wherein the treatment cycle is 21 days.

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

41. 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 0.2 mg or more.

42. 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. 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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