Dazostinag or conjugates thereof for treatment of neuroendocrine neoplasms

Abstract

The present disclosure provides a method of treating a neuroendocrine neoplasm in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, and optionally, an immune checkpoint inhibitor.

Description

STING AGONISTS FOR TREATMENT OF NEUROENDOCRINE NEOPLASMSCROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to U.S. Provisional Application No. 63 / 691,940, filed September 6, 2024, which is incorporated herein by reference in its entirety.REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY VIA EFS-WEB

[0002] The content of the electronically submitted sequence listing in .XML file (Name:3817_232PC01_Sequencelisting_ST26; Size: 3,876 bytes; Date of Creation: September 4, 2025) filed with the application is incorporated herein by reference in its entirety.FIELD

[0003] The present disclosure relates to methods of treating neuroendocrine neoplasms. In particular, the present disclosure provides method for treating neuroendocrine neoplasms by administering a STING (stimulator of interferon genes) agonist to a subject in need thereof, optionally in combination with an immune checkpoint inhibitor.BACKGROUND

[0004] Neuroendocrine neoplasms, which include both neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs), are rare abnormal growths that originate from widely distributed cells within the neuroendocrine system. Neuroendocrine neoplasms account for 2% of all malignancies in the United States. See, e.g., J. Clin. Med. 72(15):5138 (2023).

[0005] In general, cancer treatments have mainly relied on the surgery, radiotherapy, cytotoxic chemotherapies and combinations thereof. Within the last decade, however, targeted cancer therapies have opened a new era in the field of oncology. Targeted cancer therapies are drugs designed to interfere with specific molecules necessary for tumorgrowth and progression, and can include small molecules and larger chemical entities, such as monoclonal antibodies (mAbs).

[0006] However, neuroendocrine tumors often exhibit an immunologically “cold” tumor microenvironment. Despite the success of targeted immunotherapies in treating several types of solid tumors, durable responses in NET / NECs are rare.

[0007] Thus, remains a need to develop effective targeted therapies for neuroendocrine neoplasms.SUMMARY

[0008] In some embodiments, the present disclosure provides a method of treating a neuroendocrine neoplasm in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of dazostinag or ADC- B 17, or a pharmaceutically acceptable salt thereof.

[0009] In some embodiments, the method comprises administering to the subject a therapeutically effective amount of dazostinag, or the pharmaceutically acceptable salt thereof.

[0010] In some embodiments, from about 0.1 mg to about 18 mg of dazostinag, or the pharmaceutically acceptable salt thereof, is administered to the subject.

[0011] In some embodiments, about 2.5 mg of dazostinag, or the pharmaceutically acceptable salt thereof, is administered to the subject once per week.

[0012] In some embodiments, about 3.5 mg of dazostinag, or the pharmaceutically acceptable salt thereof, is administered to the subject once per week.

[0013] In some embodiments, about 5 mg of dazostinag, or the pharmaceutically acceptable salt thereof, is administered to the subject once per week.

[0014] In some embodiments, about 14 mg of dazostinag, or the pharmaceutically acceptable salt thereof, is administered to the subject once per week.

[0015] In some embodiments, the method comprises administering to the subject a therapeutically effective amount of ADC-B17, or the pharmaceutically acceptable salt thereof.

[0016] In some embodiments, ADC-B17 is administered to the subject in an amount equivalent to from about 1 pg / kg to about 100 pg / kg.

[0017] In some embodiments, ADC-B17 is administered to the subject in an amount equivalent to from about 4 pg / kg to about 40 qg / kg.

[0018] In some embodiments, ADC-B17 is administered to the subject in an amount equivalent to about 8 qg / kg once every three weeks.

[0019] In some embodiments, ADC-B17 is administered to the subject in an amount equivalent to about 16 qg / kg once every three weeks.

[0020] In some embodiments, an EZH2 inhibitor is not administered prior to, concurrently or after administration of dazostinag or ADC-B17, or the pharmaceutically acceptable salt thereof.

[0021] In some embodiments, the method further comprises administering to the subject an immune checkpoint inhibitor.

[0022] In some embodiments, the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-Ll antibody, or an anti-CTLA-4 antibody.

[0023] In some embodiments, the immune checkpoint inhibitor is an anti-PD-1 antibody.

[0024] In some embodiments, the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, cemiplimab, retifanlimab, toripalimab, dostarlimab , and AMP -224.

[0025] In some embodiments, the anti-PD-1 antibody is pembrolizumab.

[0026] In some embodiments, from about 100 mg to about 500 mg of pembrolizumab is administered to the subject.

[0027] In some embodiments, about 200 mg of pembrolizumab is administered to the subject every three weeks.

[0028] In some embodiments, about 400 mg of pembrolizumab is administered to the subject every six weeks.

[0029] In some embodiments, the anti-PD-1 antibody is nivolumab.

[0030] In some embodiments, about 240 mg of nivolumab is administered to the subject every two weeks.

[0031] In some embodiments, about 480 mg of nivolumab is administered to the subject every four weeks.

[0032] In some embodiments, the immune checkpoint inhibitor is an anti-PD-Ll antibody.

[0033] In some embodiments, the anti-PD-Ll antibody is selected from the group consisting of atezolizumab, durvalumab, avelumab, YW243.55.S70, LY3300054, and BMS-936559.

[0034] In some embodiments, the immune checkpoint inhibitor is an anti-CTLA-4 antibody.

[0035] In some embodiments, the anti-CTLA-4 antibody is selected from the group consisting of ipilimumab and tremelimumab.

[0036] In some embodiments, dazostinag or ADC-B17, or the pharmaceutically acceptable salt thereof, is administered intravenously.

[0037] In some embodiments, dazostinag or ADC-B17, or the pharmaceutically acceptable salt thereof, is administered by intravenous infusion.

[0038] In some embodiments, dazostinag or ADC-B17, or the pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor are administered simultaneously.

[0039] In some embodiments, dazostinag or ADC-B17, or the pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor are administered separately.

[0040] In some embodiments, the neuroendocrine neoplasm is a gynecologic neuroendocrine neoplasm, a pancreatic neuroendocrine neoplasm, a gastrointestinal neuroendocrine neoplasm, a genitourinary neuroendocrine neoplasm, a lung neuroendocrine neoplasm, a thoracic neuroendocrine neoplasm, or a head & neck neuroendocrine neoplasm.

[0041] In some embodiments, the neuroendocrine neoplasm is a pancreatic neuroendocrine neoplasm.

[0042] In some embodiments, the pancreatic neuroendocrine neoplasm is a gastrinoma, an insulinoma, a glucagonoma, a VIPoma, a PPoma, or a somatostatinoma.

[0043] In some embodiments, the neuroendocrine neoplasm is a genitourinary neuroendocrine neoplasm.

[0044] In some embodiments, the neuroendocrine neoplasm is poorly immunogenic.

[0045] In some embodiments, the neuroendocrine neoplasm is a neuroendocrine carcinoma.

[0046] In some embodiments, the neuroendocrine carcinoma is poorly differentiated.

[0047] In some embodiments, the neuroendocrine carcinoma is a small-cell neuroendocrine carcinoma.

[0048] In some embodiments, the neuroendocrine carcinoma is a large-cell neuroendocrine carcinoma.

[0049] In some embodiments, the neuroendocrine neoplasm or neuroendocrine carcinoma is a neuroendocrine tumor.

[0050] In some embodiments, the neuroendocrine tumor has a Ki67 labeling index of less than 3%.

[0051] In some embodiments, the neuroendocrine tumor has a Ki67 labeling index of from about 3% to about 20%.

[0052] In some embodiments, the neuroendocrine tumor has a Ki67 labeling index of above 20%.

[0053] In some embodiments, the subject exhibits symptoms selected from persistent cough, hemoptysis, fatigue, frequent chest infections, chest pain, shoulder pain, hoarseness, facial swelling, neck swelling, clubbing, fatigue, anorexia, weight loss, dyspnea, shortness of breath, diarrhea, flushing, hypoglycemia, hyperglycemia, constipation, skin flushing, palpitation, bronchospasm, frequent urination, increased thirst, dizziness, shakiness, rashes, abdominal pain, abdominal bloating, bowel obstruction, wheezing, indigestion, nausea, vomiting, and combinations thereof.

[0054] In some embodiments, the method further comprises administering to the subject chemotherapy, hormone deprivation, radiotherapy targeting hormone receptors, a tyrosine kinase inhibitor, a somatostatin analog, an mTOR inhibitor, an NTRK inhibitor, or radiotherapy.

[0055] In some embodiments, the neuroendocrine neoplasm is refractory to primary therapy.

[0056] In some embodiments, primary therapy comprised one or more of administration of an immune checkpoint inhibitor, chemotherapy, hormone deprivation, radiotherapy targeting hormone receptors, a tyrosine kinase inhibitor, a somatostatin analog, an mTOR inhibitor, an NTRK inhibitor, or radiotherapy.

[0057] In some embodiments, the subject has a tumor mutational burden of greater than10 muts / Mb.

[0058] In some embodiments, the present disclosure also provides a method of treating a neuroendocrine neoplasm and / or one or more symptoms associated with the neuroendocrine neoplasm in a subject in need thereof comprising: administering a therapeutically effective amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, to the subject weekly until the subject exhibits intolerance or progression of symptoms.

[0059] In some embodiments, the method further comprises administering to the subject an immune checkpoint inhibitor.

[0060] In some embodiments, the present disclosure also provides method of increasing immunogenicity in a subject having a neuroendocrine neoplasm comprising administering to the subject a pharmaceutically acceptable amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof.

[0061] In some embodiments, the method further comprises administering to the subject an immune checkpoint inhibitor.

[0062] In some embodiments, the present disclosure also provides a method of treating a neuroendocrine cold tumor in a subject in need thereof comprising administering to the subject a pharmaceutically acceptable amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof.

[0063] In some embodiments, the method further comprises administering to the subject an immune checkpoint inhibitor.BRIEF DESCRIPTION OF THE FIGURES

[0064] FIG. la depicts the result of Western Blot experiments. The figure shows low or a lack of expression of endogenous STING in SCLC NET cell lines. Furthermore, by measuring pIRF3, FIG. la shows there is no STING pathway activation following dazostinag treatment in SCLC NET and THP-1 STING KO cell lines.

[0065] FIG. lb shows that there is no significant modulation of the IFN pathway in SCLC NET cell lines following dazostinag treatment.

[0066] FIG. 2 shows no effect of dazostinag or cisplatin treatment at different concentrations on SCLC NET cell viability assays.

[0067] FIG. 3 shows an upregulation of MHC-I (HLA-A / B / C) and PDL-1 expression in SCLC NET cell lines following treatment of exogenous type VII IFN’s at varying concentrations.

[0068] FIG. 4a illustrates an upregulation of MHC-I and PD-L1 in myeloid cell Tumor cell co-cultures following dazostinag treatment in NET-H82 cell lines. Furthermore, FIG. 4a illustrates no effect on MHC-I and PD-L1 following dazostinag treatment on STING- KO myeloid cell Tumor cell co-cultures.

[0069] FIG. 4b illustrates an upregulation of MHC-I and PD-L1 in myeloid cell Tumor cell co-cultures following dazostinag treatment in SCLC cells. Furthermore, FIG. 4b illustrates no effect on MHC-I and PD-L1 following dazostinag treatment on STING-KO myeloid cell Tumor cell co-cultures.

[0070] FIG. 4c is a schematic that illustrates the myeloid cell Tumor cell co-culture assay.

[0071] FIG. 5 illustrates an increase of MHC-I and PD-L1 expression in patient-derived lung NET samples following treatment with dazostinag, pembrolizumab, a combination of dazostinag and pembrolizumab, IFNa, or aCD3 / 28 / 2.

[0072] FIG. 6 shows an increase of MHC-I and PD-L1 expression in patient-derived lung NET samples following treatment of a combination of dazostinag and anti-mPD-1.

[0073] FIG. 7 illustrates the longitudinal effects of treatment with dazostinag, anti-mPD- 1, or dazostinag + anti-mPD-1 on the tumor volume of individual SCLC tumor-bearing mice.

[0074] FIG. 8 illustrates the longitudinal effects of treatment with dazostinag, anti-mPD- 1, or dazostinag + anti-mPD-1 on the average tumor volume of a murine SCLC tumorbearing mouse model.

[0075] FIG. 9 illustrates the longitudinal effects of treatment with dazostinag, anti-mPD- 1, or dazostinag + anti-mPD-1 on the average tumor volume of a murine SCLC tumorbearing mouse model that has been baseline corrected by body weight.

[0076] FIG. 10 illustrates the increase of average lymphocyte counts in immune cells following treatment of dazostinag + anti-mPD-1.

[0077] FIG. 11 illustrates the increase of myeloid PD-L1 expression in tumors following treatment of dazostinag + anti-mPD-1.

[0078] FIG. 12 is a set of CT scans of the cervix of a subject having a cervical small-cell neuroendocrine tumor before and after treatment with dazostinag and pemrolizumab.DETAILED DESCRIPTIONDefinitions and Abbreviations

[0079] To facilitate an understanding of the present disclosure, a number of abbreviations, terms, and phrases are defined below.

[0080] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

[0081] The term “neuroendocrine neoplasm” refers to an abnormal growth originating from cells within the neuroendocrine system. As used herein, the term “neuroendocrine neoplasm” encompasses neuroendocrine carcinomas (NECs) and neuroendocrine tumors (NETs).

[0082] The term “PD-1” (also known as programmed cell death protein 1, PDCD1, CD279, SLEB2, or SLE1) refers to any native PD-1, unless otherwise indicated. The term “PD-1” encompasses “full-length,” unprocessed PD-1 as well as any form of PD-1 that results from processing within the cell. The term also encompasses naturally occurring variants of PD-1, e.g., splice variants, allelic variants, and isoforms.

[0083] The term “PD-L1” (also known as programmed cell death 1 ligand) refers to any native PD-L1, unless otherwise indicated. The term “PD-L1” encompasses “full-length,” unprocessed PD-L1 as well as any form of PD-L1 that results from processing within the cell. The term also encompasses naturally occurring variants of PD-L1, e.g., splice variants, allelic variants, and isoforms.

[0084] The term “CTLA-4” (also known as cytotoxic T-lymphocyte-associated antigen 4) refers to any native CTLA-4, unless otherwise indicated. The term “CTLA-4” encompasses “full-length,” unprocessed CTLA-4 as well as any form of CTLA-4 that results from processing within the cell. The term also encompasses naturally occurring variants of CTLA-4, e.g., splice variants, allelic variants, and isoforms.

[0085] 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 combinations of the foregoing through at least one antigen recognition site within the variable region of the immunoglobulin molecule. As used herein, the term “antibody” encompasses intact polyclonal antibodies, intact monoclonalantibodies, antibody fragments (such as Fab, Fab', F(ab')2, and Fv fragments), single chain Fv (scFv) mutants, multispecific antibodies such as bispecific antibodies generated from at least two intact antibodies, chimeric antibodies, humanized antibodies, human antibodies, fusion proteins comprising an antigen determination portion of an antibody, and any other modified immunoglobulin molecule comprising an antigen recognition site so long as the antibodies exhibit the desired biological activity. An antibody can be of any of the five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, or subclasses (isotypes) thereof (e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2), based on the identity of their heavy-chain constant domains referred to as alpha, delta, epsilon, gamma, and mu, respectively. 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.

[0086] A “blocking” antibody or an “antagonist” antibody is one which inhibits or reduces biological activity of the antigen it binds, such as, e.g., PD-1, PD-L1, or CTLA-4. In a certain embodiment, blocking antibodies or antagonist antibodies substantially or completely inhibit the biological activity of the antigen. Desirably, the biological activity is reduced by 10%, 20%, 30%, 50%, 70%, 80%, 90%, 95%, or even 100%.

[0087] The term “anti -PD-1 antibody” or “an antibody that binds to PD-1” refers to an antibody that is capable of binding PD-1 with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent in targeting PD-1. The extent of binding of an anti-PD-1 antibody to an unrelated, non-PD-1 protein is less than about 10% of the binding of the antibody to PD-1 as measured, e.g., by a radioimmunoassay (RIA). In certain embodiments, an antibody that binds to PD-1 has a dissociation constant (Kd) of <1 pM, <100 nM, <10 nM, <1 nM, or <0.1 nM.

[0088] The term “anti-PD-Ll antibody” or “an antibody that binds to PD-L1” refers to an antibody that is capable of binding PD-L1 with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent in targeting PD-L1. The extent of binding of an anti-PD-Ll antibody to an unrelated, non-PD-Ll protein is less than about 10% of the binding of the antibody to PD-L1 as measured, e.g., by a radioimmunoassay (RIA). In certain embodiments, an antibody that binds to PD-L1 has a dissociation constant (Kd) of <1 pM, <100 nM, <10 nM, <1 nM, or <0.1 nM.

[0089] The term “anti-CTLA-4 antibody” or “an antibody that binds to CTLA-4” refers to an antibody that is capable of binding CTLA-4 with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent in targeting CTLA-4. The extent of binding of an anti-CTLA-4 antibody to an unrelated, non-CTLA-4 protein is less than about 10% of the binding of the antibody to CTLA-4 as measured, e.g., by a radioimmunoassay (RIA) In certain embodiments, an antibody that binds to CTLA-4 has a dissociation constant (Kd) of <1 pM, <100 nM, <10 nM, <1 nM, or <0.1 nM.

[0090] A “monoclonal antibody” refers to a homogeneous antibody population involved in the highly specific recognition and binding of a single antigenic determinant, or epitope. This is in contrast to polyclonal antibodies that typically include different antibodies directed against different antigenic determinants. The term “monoclonal antibody” encompasses both intact 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 an antibody portion, and any other modified immunoglobulin molecule comprising an antigen recognition site. Furthermore, “monoclonal antibody” refers to such antibodies made in any number of manners including but not limited to by hybridoma, phage selection, recombinant expression, and transgenic animals.

[0091] The term “chimeric antibodies” refers to antibodies wherein the amino acid sequence of the immunoglobulin molecule is derived from two or more species. Typically, the variable region of both light and heavy chains corresponds to the variable region of antibodies derived from one species of mammals (e.g., mouse, rat, rabbit, etc.) with the desired specificity, affinity, and capability while the constant regions are homologous to the sequences in antibodies derived from another (usually human) to avoid eliciting an immune response in that species.

[0092] As used herein, the term “effective amount” or “therapeutically effective amount” refers to an amount of a compound, or combination of one or more compounds that, when administered (either sequentially or simultaneously) elicits the desired biological or medicinal response, e.g., either destroys the target cancer cells or slows or arrests the progression of the cancer in a patient. The therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the patient and disease condition being treated, e.g., the weight and age of the patient, the severity of the disease condition, the manner of administration and the like, which may readily be determined byone skilled in the art. The term also applies to a dose that will induce a particular response in target cells, e.g., reduction of platelet adhesion and / or cell migration. For example, in some embodiments, the “therapeutically effective amount” as used herein refers to the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, and, optionally, the amount of immune checkpoint inhibitor that, when administered separately or in combination, have a beneficial effect. In some embodiments, when both the dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, and, the immune checkpoint inhibitor are administered, the combined effect is additive. In some embodiments, the combined effect is synergistic. Further, it will be recognized by one skilled in the art that in the case of combination therapy, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, and / or the amount of the immune checkpoint inhibitor may be used in a “sub-therapeutic amount,” i.e., less than the therapeutically effective amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, or the immune checkpoint inhibitor alone.

[0093] The term “about” refers to approximately, in the region 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 referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary from, for example, between 1% and 15% of the stated number or numerical range. In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of ±10%.

[0094] As used herein, a “subject” or “patient” generally means a mammal (e.g., human) who has been diagnosed with, exhibits symptoms of, or is otherwise believed to be afflicted with a disease, disorder, or condition (such as cancer, e.g., a neuroendocrine neoplasm).

[0095] The terms “simultaneous” and “simultaneously” refer to the administration of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor as disclosed herein, to a subject at the same time, or at two different time points that are separated by no more than 2 hours. The simultaneous administration of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor may be in a single dosage form or in separate dosage forms.

[0096] The terms “sequential” and “sequentially” refer to the administration of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor as disclosed herein, to a subject at two different time points that are 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.

[0097] The term “intermission” refers to a period that is subsequent to the administration of one or more particular pharmaceutically active ingredients to a patient in an intermittent regimen. Intermission refers to a rest period wherein a particular pharmaceutically active ingredient is not administered for at least one day.

[0098] The term “synergistic effect” refers to a situation where the combination of two or more agents produces a greater effect than the sum of the effects of each of the individual agents. The term encompasses not only a reduction in symptoms of the disorder to be treated, but also an improved side effect profile, improved tolerability, improved patient compliance, improved efficacy, or any other improved clinical outcome.

[0099] As used herein, the illustrative terms “include,” “such as,” “for example” and the like (and variations thereof, e.g., “includes” and ‘including,” “examples”), unless otherwise specified, are intended to be non-limiting. That is, unless explicitly stated otherwise, such terms are intended to imply “but not limited to,” e.g., “including” means “including but not limited to.”

[0100] Unless otherwise stated, structures depicted herein are meant to include chemical entities which differ only in the presence of one or more isotopically enriched atoms. For example, chemical entities having the present structure except for the replacement of a hydrogen atom by a deuterium or tritium, or the replacement of a carbon atom by a 13C- or14C-enriched carbon are within the scope of the invention.

[0101] Unless stereochemical configuration is denoted, structures depicted herein are meant 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 present chemical entities are within the scope of the invention. When a stereochemical configuration is denoted for a compound, the diastereoisomeric or enantiomeric excess of the compound is at least 99.0%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9%.STING Agonist

[0102] Neuroendocrine neoplasms, which include neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs), are a collection of rare malignancies that generally exhibit an immunologically “cold” tumor microenvironment. Despite the success of immunotherapies in treating several types of solid tumors, durable responses in NET / NECs are rare, potentially attributable to low MHC class I and / or STING expression. In the field, it has recently been suggested that EZH2 inhibitors could help prime neuroendocrine tumor cells for immune rejection via de-repression of MHC-I and STING expression, providing rationale for their use as a combination partner for STING agonists (Cancer Di scov 2021;11 : 1952-69). This hypothesis implies that tumor cell intrinsic factors (ex. EZH2) need to be targeted to increase immunogenicity and sensitivity to immunotherapy.

[0103] However, as disclosed herein, treatment with dazostinag, when combined with an immune checkpoint inhibitor, surprisingly demonstrated durable responses in some patients with neuroendocrine neoplasms without administration of an EZH2 inhibitor. Without wishing to be bound by theory, it is believed that STING agonism increases immune trafficking and infiltration into the neuroendocrine neoplasm microenvironment, and enhancing antigenicity and immune recognition leading to sensitization to immunotherapy.

[0104] The present disclosure provides a method of treating a neuroendocrine neoplasm in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of dazostinag or ADC-B17.

[0105] In some embodiments, the STING agonist is dazostinag, or a pharmaceutically acceptable salt thereof. Dazostinag has the following structure:

[0106] Dazostinag and other STING agonists are described, for example, in WO 2018 / 100558. They may be prepared by methods known to one skilled in the art and / or according to the methods described in WO 2018 / 100558, which is hereby incorporated by reference in its entirety.

[0107] In some embodiments, the STING agonist is dazostinag or a crystalline form thereof.

[0108] In some embodiments, the STING agonist is an antibody drug conjugate (ADC).In some embodiments, the ADC comprises dazostinag as the payload. In some embodiments, the ADC is ADC-B17, which comprises the following structure:wherein: a is an integer from 1 to 6; andAb is an anti-human CCR2 monoclonal antibody composed of the humanized variable domains of the heavy and the light chains of the 1D9 mouse monoclonal antibody and the constant domains of human IgGl heavy chain and human kappa light chain (humanized 1D9, also called TAK-202, may also be referred to as the hlgGl isotype), which is described in US 7,473,421 B2, which is incorporated by reference herein in its entirety.Sequence of humanized 1D9Heavy chain:EVQLVESGGG LVKPGGSLRL SCAASGFTFS AYAMNWVRQA PGKGLEWVGRIRTKNNNYAT YYADSVKDRF TISRDDSKNT LYLQMNSLKT EDTAVYYCTTFYGNGVWGQG TLVTVSSAST KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF PEPVTVSWNS GALTSGVHTF PAVLQSSGLY SLSSVVTVPS SSLGTQTYIC NVNHKPSNTK VDKKVEPKSC DKTHTCPPCP APELAGAPSV FLFPPKPKDT LMISRTPEVT CVVVDVSHED PEVKFNWYVD GVEVHNAKTK PREEQ YNSTY RVVSVLTVLH QDWLNGKEYK CKVSNKALPA PIEKTISKAK GQPREPQVYT LPPSRDELTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS DGSFFLYSKL TVDKSRWQQGNVFSCSVMHE ALHNHYTQKS LSLSPGK (SEQ IDNO: 1)Light chain:DVVMTQSPLS LPVTLGQPAS ISCKSSQSLL DSDGKTFLNW FQQRPGQSPR RLIYLVSKLD SGVPDRFSGS GSGTDFTLKI SRVEAEDVGV YYCWQGTHFP YTFGQGTRLE IKRTVAAPSV FIFPPSDEQL KSGTASVVCL LNNFYPREAK VQWKVDNALQ SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE VTHQGLSSPV TKSFNRGEC (SEQ ID NO: 2)

[0109] ADC-B17 and other STING agonist ADCs are described, for example, in WO 2022 / 097117. They may be prepared by methods known to one skilled in the art and / or according to the methods described in WO 2022 / 097117, which is hereby incorporated by reference in its entirety.Immune Checkpoint Inhibitors

[0110] The present disclosure provides a method of treating neuroendocrine neoplasms that includes, inter alia, administering to a subject in need thereof a therapeutically effective amount of at least one immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor is an anti-PD-1 antibody. In some embodiments, the immune checkpoint inhibitor is an anti-PD-Ll antibody. In some embodiments, the immune checkpoint inhibitor is an anti-CTLA-4 antibody.[OHl] PD-1 is a type I transmembrane protein that is one of the major immune checkpoint molecules (Blank et al., 2005, Cancer Immunotherapy, 54:307-314). PD-1 is primarily expressed on activated T cells, and it interacts with the ligands PD-L1 (B7-H1 or CD274) and PD-L2 (B7-DC or CD273) to induce an inhibitory signal resulting inreduced T cell proliferation, cytokine production, and cytotoxic activity (Freeman et al., 2000, J. Exp. Med., 192:1027-34).

[0112] 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.

[0113] In some embodiments, the anti-PD-1 antibody is a full length (intact) antibody. In some embodiments, the anti-PD-1 antibody consists of anti-PD-1 binding fragments, including, but not limited to, Fab, Fab', F(ab')2, and Fv fragments, single chain Fv fragments, and single chain domain fragments.

[0114] 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, linkage to a cellular ligand or other protein. In some embodiments, the derivatized anti- PD-1 antibody can contain one or more non-natural amino acids, e.g., using ambrx technology (See, e.g., Wolfson, 2006, Chem. Biol. 13(10): 1011-2).

[0115] In some embodiments, the anti-PD-1 antibody is nivolumab.

[0116] Nivolumab is a human monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Nivolumab is an IgG4 kappa immunoglobulin that has 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 treating unresectable or metastatic melanoma, melanoma, metastatic non-small cell lung cancer, advanced renal cell carcinoma, classical Hodgkin lymphoma, squamous cell carcinoma of the head and neck, urothelial carcinoma, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer, and hepatocellular carcinoma. Nivolumab is commercially available as Opdivo®.

[0117] In some embodiments, the anti-PD-1 antibody is pembrolizumab.

[0118] Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Pembrolizumab is an IgG4 kappa immunoglobulin with an approximate molecular mass of 149 kDa. Pembrolizumab is produced in recombinant Chinese hamster ovary (CHO) cells. Pembrolizumab is approved by the FDA for treating melanoma, non-small cell lung cancer, head and neckcancer, classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, urothelial carcinoma, microsatellite instability-high cancer, gastric cancer, and cervical cancer. Pembrolizumab is commercially available as Keytruda®.

[0119] In some embodiments, the anti-PD-1 antibody is cemiplimab.

[0120] Cemiplimab is a human monoclonal antibody that binds to PD-1 and blocks its interaction with PD-L1 and PD-L2. Cemiplimab is an IgG4 immunoglobulin with an approximate molecular mass of 146 kDa. Cemiplimab is produced by recombinant DNA technology in Chinese hamster ovary (CHO) cell suspension. Cemiplimab is approved by the FDA for treating metastatic cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC who are not candidates for curative surgery or curative radiation. Cemiplimab is commercially available as Libtayo®.

[0121] Additional anti-PD-1 antibodies include, for example, retifanlimab, toripalimab, and AMP -224.

[0122] 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.

[0123] 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.

[0124] PD-L1 is a type I transmembrane protein that comprises an extracellular Ig-V like domain, an Ig-C like domain, a transmembrane domain and an intracellular C-terminus domain. PD-L1 is expressed in a broad range of cancers with a high frequency, including tumor cells and / or tumor infiltrating immune cells and can contribute to the inhibition of the anti-tumor immune response in the tumor microenvironment. In some cancers, expression of PD-L1 has been 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. Expression of PD-L1 on the cell surface has also been shown to be upregulated through IFN-y stimulation. There are at least 4 variants of PD-1 that 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 through 4. Nielsen et al., Cell. Immunol.235: 109-16 (2005). The amino acid sequence of a human PD-L1 is represented in GenBank Accession No. NP 054862.1.

[0125] In some embodiments, the anti-PD-Ll antibody is a full length (intact) antibody. In some embodiments, the anti-PD-Ll antibody consists of anti-PD-Ll binding fragments, including, but not limited to, Fab, F(ab')2, Fd, Fv, and dAb fragments, single chain Fv fragments, and PD-L1 -binding domain immunoglobulin fusion proteins.

[0126] In some embodiments, the anti-PD-Ll antibody is atezolizumab.

[0127] Atezolizumab is a programmed cell death ligand 1 (PD-L1) blocking antibody.Atezolizumab is an Fc-engineered, humanized, non-glycosylated IgGl kappa immunoglobulin that has a calculated molecular mass of 145 kDa. Atezolizumab is approved by the FDA for treating locally advanced or metastatic urothelial carcinoma and metastatic non-small cell lung cancer. Atezolizumab is commercially available as Tecentriq®.

[0128] In some embodiments, the anti-PD-Ll antibody is durvalumab.

[0129] Durvalumab is a programmed cell death ligand 1 (PD-L1) blocking antibody.Durvalumab is a human immunoglobulin G1 kappa (IgGlK) monoclonal antibody that is produced by recombinant DNA technology in Chinese Hamster Ovary (CHO) cell suspension culture. Durvalumab is approved by the FDA for treating urothelial carcinoma and non-small cell lung cancer. Durvalumab is commercially available as Imfinzi®.

[0130] In some embodiments, the anti-PD-Ll antibody is avelumab.

[0131] Avelumab is a programmed death ligand-1 (PD-L1) blocking antibody.Avelumab is a human IgGl lambda monoclonal antibody that has a molecular weight of approximately 147 kDa. Avelumab is approved by the FDA for treating metastatic Merkel cell carcinoma and locally advanced or metastatic urothelial carcinoma.Avelumab is commercially available as Bavencio®.

[0132] Additional anti-PD-Ll antibodies include, for example, YW243.55.S70 (U.S.Patent No. 8,217,149), LY3300054 (Eli Lilly and Co.), and BMS-936559 (Bristol-Meyers Squibb).

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

[0134] In some embodiments, the anti-PD-Ll antibody used in the methods (and kits) described herein is durvalumab or an anti-PD-Ll antibody that binds to the same epitope as durvalumab. In some embodiments, the anti-PD-Ll antibody is durvalumab.

[0135] In some embodiments, the anti-PD-Ll antibody used in the methods (and kits) described herein is avelumab or an anti-PD-Ll antibody that binds to the same epitope as avelumab. In some embodiments, the anti-PD-Ll antibody is avelumab.

[0136] CTLA-4 is a Type I transmembrane protein encoded in humans by the CTLA-4 gene. CTLA-4 has been found to have a correlation with cancer growth and development due to its negative role in immune response. CTLA-4 is expressed at the cell surface of activated CD4+ and CD8+ T cells, and is an important negative regulator of T cells function. CTLA-4 has been shown to negatively regulate immune activation through both intrinsic and extrinsic mechanisms (Grosso and Kunkel, Cancer Immunity (2013) 13: 5). Inhibition of negative regulation by CTLA-4 has been shown to promote stimulation of adaptive immune response and T cell activation. A representative amino acid sequence of human CTLA-4 can be found under GenBank accession number: AAL07473.1, and a representative mRNA nucleic acid sequence encoding human CTLA-4 can be found under GenBank accession number: AF414120.1.

[0137] In some embodiments, the anti-CTLA-4 antibody is a full length (intact) antibody. In some embodiments, the anti-CTLA-4 antibody consists of anti-CTLA-4 binding fragments, including, but not limited to, Fab, Fab', F(ab')2, Fv, and single chain fragments, a diabody, a disulfide stabilized Fv fragment (dsFv), a (dsFv)2, a bispecific dsFv (dsFv- dsFv'), a disulfide stabilized diabody (ds diabody), a single-chain antibody molecule (scFv), an scFv dimer (bivalent diabody), a multispecific antibody, a camelized single domain antibody, a nanobody, a domain antibody, and a bivalent domain antibody.

[0138] In some embodiments, the anti-CTLA-4 antibody is ipilimumab.

[0139] Ipilimumab is a recombinant, human monoclonal antibody that binds to the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). Ipilimumab is an IgGl kappa immunoglobulin with an approximate molecular mass of 148 kDa. Ipilimumab is produced in mammalian (Chinese hamster ovary) cell culture. Ipilimumab is approved by the FDA for treating unresectable or metastatic melanoma, adjuvant treatment of melanoma, and advanced renal cell carcinoma. Ipilimumab is commercially available as Yervoy®.

[0140] Additional anti-CTLA-4 antibodies include, for example, tremelimumab (Imjudo®).

[0141] 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.Methods of Treating Cancer

[0142] In some embodiments, the present disclosure relates to a method of treating a neuroendocrine neoplasm in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of dazostinag or ADC- B 17, or a pharmaceutically acceptable salt thereof.

[0143] In some embodiments, the present disclosure relates to a method of treating a neuroendocrine neoplasm in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of dazostinag, or a pharmaceutically acceptable salt thereof.

[0144] In some embodiments, the present disclosure relates to a method of treating a neuroendocrine neoplasm in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of ADC-B17, or a pharmaceutically acceptable salt thereof.

[0145] In some embodiments, the present disclosure relates to a method of treating a neuroendocrine neoplasm in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of dazostinag or ADC- B 17, or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor.

[0146] In some embodiments, the present disclosure relates to a method of treating a neuroendocrine neoplasm in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of dazostinag, or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor.

[0147] In some embodiments, the present disclosure relates to a method of treating a neuroendocrine neoplasm in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of ADC-B17, or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor.

[0148] The neuroendocrine neoplasm can be any type of neuroendocrine neoplasm. In some embodiments, the neuroendocrine neoplasm is a gynecologic neuroendocrineneoplasm, a pancreatic neuroendocrine neoplasm, a gastrointestinal neuroendocrine neoplasm, a genitourinary neuroendocrine neoplasm, a lung neuroendocrine neoplasm, a thoracic neuroendocrine neoplasm, or a head & neck neuroendocrine neoplasm.

[0149] In some embodiments, the neuroendocrine neoplasm is a pancreatic neuroendocrine neoplasm. Non-limiting examples of pancreatic neuroendocrine neoplasms include gastrinomas, insulinomas, glucagonomas, VIPomas, PPomas, and somatostatinomas.

[0150] In some embodiments, the neuroendocrine neoplasm is poorly immunogenic. In some embodiments, the term “poorly immunogenic” refers to a neoplasm that does not respond to immunotherapy, e.g., administration of an immune checkpoint inhibitor.

[0151] In some embodiments, the neuroendocrine neoplasm is a neuroendocrine carcinoma. In some embodiments, the neuroendocrine carcinoma is poorly differentiated. In some embodiments, the term “poorly differentiated” indicates that the cells of the carcinoma do not resemble normal cells and / or cannot be readily identified. In some embodiments, the neuroendocrine carcinoma is a small-cell neuroendocrine carcinoma. In some embodiments, the neuroendocrine carcinoma is a large-cell neuroendocrine carcinoma.

[0152] In some embodiments, the neuroendocrine neoplasm or neuroendocrine carcinoma is a neuroendocrine tumor. In some embodiments, the neuroendocrine tumor has a Ki67 labeling index of less than 3%, i.e. the tumor is a grade 1 neuroendocrine tumor. In some embodiments, the neuroendocrine tumor has a Ki67 labeling index of from about 3% to about 20%, i.e. the tumor is a grade 2 neuroendocrine tumor. In some embodiments, the neuroendocrine tumor has a Ki67 labeling index of above 20%, i.e. the tumor is a grade 3 neuroendocrine tumor.

[0153] In some embodiments, the subject exhibits one or more symptoms resulting from the neuroendocrine neoplasm. In some embodiments, the symptoms are selected from persistent cough, hemoptysis, fatigue, frequent chest infections, chest pain, shoulder pain, hoarseness, facial swelling, neck swelling, clubbing, fatigue, anorexia, weight loss, dyspnea, shortness of breath, diarrhea, flushing, hypoglycemia, hyperglycemia, constipation, skin flushing, palpitation, bronchospasm, frequent urination, increased thirst, dizziness, shakiness, rashes, abdominal pain, abdominal bloating, bowel obstruction, wheezing, indigestion, nausea, vomiting, and combinations thereof.

[0154] In some embodiments, the neuroendocrine neoplasm is refractory to primary therapy. In some embodiments, primary therapy comprised one or more of administration of an immune checkpoint inhibitor, e.g., the immune checkpoint inhibitors discussed above; chemotherapy, e.g., capecitabine, temozolomide, streptozotocin, 5-fluorouracil, cisplatin, carboplatin, etoposide, doxorubicin, or a combination thereof; hormone deprivation; radiotherapy targeting hormone receptors; a somatostatin analog, e.g., lanreotide or octreotide; a tyrosine kinase inhibitor, e.g., sunitinib; an mTOR inhibitor, e.g., everolimus; an NTRK inhibitor, e.g., larotrectinib or entrectinib; or radiotherapy.

[0155] In some embodiments, the subject has a tumor mutational burden of greater than 10 muts / Mb. In some embodiments, the subject has a tumor mutational burden of greater than 20 muts / Mb.Medicament

[0156] In some embodiments, the present disclosure relates to a medicament for use in treating a neuroendocrine neoplasm in a subject in need thereof. In some embodiments, the medicament comprises a STING agonist, e.g., dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof. In some embodiments, the medicament comprises a STING agonist, e.g., dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor.

[0157] In some embodiments, the present disclosure relates to the use of a STING agonist, e.g., dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a neuroendocrine neoplasm in a subject.

[0158] In some embodiments, the present disclosure relates to the use of dazostinag, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a neuroendocrine neoplasm in a subject.

[0159] In some embodiments, the present disclosure relates to the use of ADC-B17, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a neuroendocrine neoplasm in a subject.

[0160] In some embodiments, the present disclosure relates to the use of a STING agonist, e.g., dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a neuroendocrine neoplasm in a subject, wherein the subject is also treated with an immune checkpoint inhibitor. In some embodiments, the STING agonist may be administered simultaneously or sequentiallywith the immune checkpoint inhibitor. In some embodiments, the STING agonist is in the same composition as the immune checkpoint inhibitor. In some embodiments, the STING agonist is in a separate composition as the immune checkpoint inhibitor.

[0161] In some embodiments, the present disclosure relates to the use of dazostinag, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a neuroendocrine neoplasm in a subject, wherein the subject is also treated with an immune checkpoint inhibitor.

[0162] In some embodiments, the present disclosure relates to the use of ADC-B17, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a neuroendocrine neoplasm in a subject, wherein the subject is also treated with an immune checkpoint inhibitor.Administration of the STING Agonist and, Optionally, Immune Checkpoint Inhibitor

[0163] In some embodiments, the methods disclosed herein comprise administering to a subject a therapeutically effective amount of dazostinag, or a pharmaceutically acceptable salt thereof.

[0164] In some embodiments, from about 0.1 mg to about 18 mg of dazostinag, or the pharmaceutically acceptable salt thereof, is administered to the subject. In some embodiments, from about 0.1 mg to about 0.5 mg, from about 0.1 mg to about 1 mg, from about 0.1 mg to about 3 mg, from about 0.1 mg to about 5 mg, from about 0.1 mg to about 7 mg, from about 0.1 mg to about 9 mg, from about 0.1 mg to about 11 mg, from about 0.1 mg to about 14 mg, from about 0.1 mg to about 18 mg, from about 0.5 mg to about 1 mg, from about 0.5 mg to about 3 mg, from about 0.5 mg to about 5 mg, from about 0.5 mg to about 7 mg, from about 0.5 mg to about 9 mg, from about 0.5 mg to about 11 mg, from about 0.5 mg to about 14 mg, from about 0.5 mg to about 18 mg, from about 1 mg to about 3 mg, from about 1 mg to about 5 mg, from about 1 mg to about 7 mg, from about 1 mg to about 9 mg, from about 1 mg to about 11 mg, from about 1 mg to about 14 mg, from about 1 mg to about 18 mg, from about 3 mg to about 5 mg, from about 3 mg to about 7 mg, from about 3 mg to about 9 mg, from about 3 mg to about 11 mg, from about 3 mg to about 14 mg, from about 3 mg to about 18 mg, from about 5 mg to about 7 mg, from about 5 mg to about 9 mg, from about 5 mg to about 11 mg, from about 5 mg to about 14 mg, from about 5 mg to about 18 mg, from about 7 mg to about 9mg, from about 7 mg to about 11 mg, from about 7 mg to about 14 mg, from about 7 mg to about 18 mg, from about 11 mg to about 14 mg, from about 11 mg to about 18 mg, or from about 14 mg to about 18 mg of dazostinag, or the pharmaceutically acceptable salt thereof, is administered to the subject.

[0165] In some embodiments, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg, about 13.5 mg, about 14 mg, about 14.5 mg, or about 15 mg, of dazostinag, or the pharmaceutically acceptable salt thereof, is administered to the subject.

[0166] In some embodiments, dazostinag, or the pharmaceutically acceptable salt thereof, is administered to the subject once per week. In some embodiments, dazostinag, or the pharmaceutically acceptable salt thereof, is administered to the subject 2, 3, 4, 5, 6, or 7 times per week.

[0167] In some embodiments, the methods disclosed herein comprise administering to a subject a therapeutically effective amount of ADC- 17, or a pharmaceutically acceptable salt thereof.

[0168] In some embodiments, ADC-B17, or the pharmaceutically acceptable salt thereof, is administered to the subject in an amount equivalent to from about 1 pg / kg to about 100 pg / kg of the subject’s body weight. In some embodiments, ADC-B17, or the pharmaceutically acceptable salt thereof, is administered to the subject in an amount equivalent to from about 1 pg / kg to about 10 pg / kg, from about 1 pg / kg to about 20 pg / kg, from about 1 pg / kg to about 30 pg / kg, from about 1 pg / kg to about 40 pg / kg, from about 1 pg / kg to about 50 pg / kg, from about 1 pg / kg to about 60 pg / kg, from about 1 pg / kg to about 70 pg / kg, from about 1 pg / kg to about 80 pg / kg, from about 1 pg / kg to about 90 pg / kg, from about 1 pg / kg to about 100 pg / kg, from about 4 pg / kg to about 6 pg / kg, from about 4 pg / kg to about 8 pg / kg, from about 4 pg / kg to about 10 pg / kg, from about 4 pg / kg to about 12 pg / kg, from about 4 pg / kg to about 14 pg / kg, from about 4 pg / kg to about 16 pg / kg, from about 4 pg / kg to about 18 pg / kg, from about 4 pg / kg to about 20 pg / kg, from about 6 pg / kg to about 8 pg / kg, from about 6 pg / kg to about 10 pg / kg, from about 6 pg / kg to about 12 pg / kg, from about 6 pg / kg to about 14 pg / kg, fromabout 6 .g / kg to about 16 gg / kg, from about 6 gg / kg to about 18 gg / kg, from about 6 pg / kg to about 20 pg / kg, from about 8 pg / kg to about 10 pg / kg, from about 8 pg / kg to about 12 pg / kg, from about 8 pg / kg to about 14 pg / kg, from about 8 pg / kg to about 16 pg / kg, from about 8 pg / kg to about 18 pg / kg, from about 8 pg / kg to about 20 pg / kg, from about 10 pg / kg to about 12 pg / kg, from about 10 pg / kg to about 14 pg / kg, from about 10 pg / kg to about 16 pg / kg, from about 10 pg / kg to about 18 pg / kg, from about 10 pg / kg to about 20 pg / kg, from about 12 pg / kg to about 14 pg / kg, from about 12 pg / kg to about 16 pg / kg, from about 12 pg / kg to about 18 pg / kg, from about 12 pg / kg to about 20 pg / kg, from about 14 pg / kg to about 16 pg / kg, from about 14 pg / kg to about 18 pg / kg, from about 14 pg / kg to about 20 pg / kg, from about 16 pg / kg to about 18 pg / kg, from about 16 pg / kg to about 20 pg / kg, or from about 18 pg / kg to about 20 pg / kg of the subject’s body weight.

[0169] In some embodiments, ADC-B17, or the pharmaceutically acceptable salt thereof, is administered to the subject in an amount equivalent to about 1 pg / kg, about 2 pg / kg, about 3 pg / kg, about 4 pg / kg, about 5 pg / kg, about 6 pg / kg, about 7 pg / kg, about 8 pg / kg, about 9 pg / kg, about 10 pg / kg, about 11 pg / kg, about 12 pg / kg, about 13 pg / kg, about 14 pg / kg, about 15 pg / kg, about 16 pg / kg, about 17 pg / kg, about 18 pg / kg, about 19 pg / kg, about 20 pg / kg, about 25 pg / kg, about 30 pg / kg, about 35 pg / kg, about 40 pg / kg, about 45 pg / kg, about 50 pg / kg, about 55 pg / kg, about 60 pg / kg, about 65 pg / kg, about 70 pg / kg, about 75 pg / kg, about 80 pg / kg, about 85 pg / kg, about 90 pg / kg, about 95 pg / kg, or about 100 pg / kg of the subject’s body weight.

[0170] In some embodiments, ADC-B17, or the pharmaceutically acceptable salt thereof, is administered to the subject once every three weeks. In some embodiments, ADC-B17, or the pharmaceutically acceptable salt thereof, is administered to the subject once every 1, 2, 4, 5, or 6 weeks.

[0171] In some embodiments, dazostinag or ADC-B17, or the pharmaceutically acceptable salt thereof, is administered intravenously. In some embodiments, dazostinag or ADC-B17, or the pharmaceutically acceptable salt thereof, is administered by intravenous infusion.

[0172] In some embodiments, an EZH2 inhibitor is not administered prior to, concurrently or after administration of dazostinag or ADC-B17, or the pharmaceutically acceptable salt thereof.

[0173] In some embodiments, dazostinag or ADC-B17, or the pharmaceutically acceptable salt thereof, is administered in combination with an immune checkpoint inhibitor. The immune checkpoint inhibitor can be administered before, simultaneously with, or after administration of dazostinag or ADC-B17, or the pharmaceutically acceptable salt thereof.

[0174] As used herein, the administration of dazostinag or ADC-B17, or the pharmaceutically acceptable salt thereof, “in combination” with an immune checkpoint inhibitor refers not only to simultaneous or sequential administration of the agents, but also to the administration of the agents during a single treatment cycle, as understood by one skilled in the art. When dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, is administered in combination with the immune checkpoint inhibitor, a therapeutically effective amount of the combination is administered.

[0175] In some embodiments, from about 100 mg to about 200 mg, from about 100 mg to about 300 mg, from about 100 mg to about 400 mg, from about 100 mg to about 500 mg, from about 200 mg to about 300 mg, from about 200 mg to about 400 mg, from about 200 mg to about 500 mg, from about 300 mg to about 400 mg, from about 300 mg to about 500 mg, or from about 400 mg to about 500 mg of the immune checkpoint inhibitor is administered to the subject. In some embodiments, from about 100 mg to about 500 mg of the immune checkpoint inhibitor is administered to the subject.

[0176] In some embodiments, the immune checkpoint inhibitor is administered to the subject every 1, 2, 3, 4, 5, 6, 7, or 8 weeks. In some embodiments, the immune checkpoint inhibitor is administered to the subject every 2 weeks. In some embodiments, the immune checkpoint inhibitor is administered to the subject every 3 weeks. In some embodiments, the immune checkpoint inhibitor is administered to the subject every 4 weeks. In some embodiments, the immune checkpoint inhibitor is administered to the subject every 6 weeks.

[0177] In some embodiments, dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, is administered on a daily schedule. In some embodiments, dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, is administered every other day. In some embodiments, dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, is administered once every three days. In some embodiments, dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, is administered once every threedays for three doses. In some embodiments, dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, is administered on a twice-weekly schedule. In some embodiments, dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, is administered on a three times a week schedule. In some embodiments, dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, is administered on a weekly schedule. In some embodiments, dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, is administered on a once every two weeks schedule.

[0178] In some embodiments, dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, is administered once per day. In some embodiments, dazostinag or ADC- B 17, or a pharmaceutically acceptable salt thereof, is administered twice per day. In some embodiments, dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, is administered three times per day.

[0179] In some embodiments, dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, is administered at least 3 times on alternate days within a 7-day cycle. In some embodiments, dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, is administered on day 1 and day 4 of a 7-day cycle. In some embodiments, dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, is administered on consecutive days in a 7-day cycle followed by an intermission. In some embodiments, dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, is administered for 2 consecutive days followed by an intermission of 5 consecutive days for at least one 7- day cycle. In some embodiments, dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, is administered for 3 consecutive days followed by an intermission of 4 consecutive days for at least one 7-day cycle. In some embodiments, dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, is administered for 4 consecutive days followed by an intermission of 3 consecutive days for at least one 7- day cycle. In some embodiments, dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, is administered for 5 consecutive days followed by an intermission of 2 consecutive days for at least one 7-day cycle. In some embodiments, there will be periods of rest between one or more of the 7-day treatment cycles. In some embodiments, there will be a 7-day rest between one or more of the 7-day treatment cycles.

[0180] The present description contemplates administration of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, for one or more treatment cycles, for example, 1, 2, 3, 4, 5, 6, or more, treatment cycles. In some embodiments, a treatment cycle is 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 periods of rest within or between one or more of the treatment cycles. For example, in some embodiments, there will be a period of rest at the end of the treatment cycle. In some embodiments, there will be a period of rest between the second and third treatment cycle but not the first and second treatment cycle. In another embodiment, there might be a period of rest between the first and second treatment cycle but not the second and third treatment cycle. Dosing schedules include, for example, administering dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, 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 of on days 1, 4, 8, and 11 of a 28 day cycle. Other dosage schedules are encompassed by the present invention.

[0181] In some embodiments, dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, is administered within a 21 -day cycle. In some embodiments, dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, is administered at least four times within a 21 -day cycle. In some embodiments, dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, is administered on day 1 within a 21 -day cycle. In some embodiments, dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, is administered on day 4 within a 21 -day cycle. In some embodiments, dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, is administered on day 8 within a 21 -day cycle. In some embodiments, dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, is administered on day 11 within a 21 -day cycle. In some embodiments, dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, is administered on days 1, 4, 8, and 11 within a 21 -day cycle.

[0182] In some embodiments, dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, is administered within a 21 -day cycle. In some embodiments, dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, is administered at least two times within a 21 -day cycle. In some embodiments, dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, is administered on day 1 within a 21 -day cycle. In some embodiments, dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, is administered on day 8 within a 21 -day cycle. In some embodiments, dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, is administered on days 1 and 8 within a 21 -day cycle.

[0183] In some embodiments, dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, is administered for a duration of 1 year or less. In some embodiments, dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, is administered for a duration of 1 year or more.

[0184] In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 0.5 mg to about 1000 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 0.5 mg to about 300 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 1 mg to about 300 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 3 mg to about 300 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 0.5 mg to about 200 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 1 mg to about 200 mg. In some embodiments, the amount of dazostinag or ADC- B 17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 10 mg to about 200 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 0.5 mg to about 100 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that isadministered on each day of dosing is about 0.5 mg to about 50 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 0.5 mg to about 10 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 0.5 mg to about 5 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 1 mg to about 3 mg. In some embodiments, the amount of dazostinag or ADC- B 17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 2 mg to about 5 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 5 mg to about 10 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 5 mg to about 15 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 10 mg to about 20 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 15 mg to about 25 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is between about 20 mg to about 30 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is between about 25 mg to about 35 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is between about 30 mg to about 40 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is between about 35 mg to about 45 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is between about 40 mg to about 50 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is between about 55 mg to about 65 mg. In some embodiments, the amount of dazostinag orADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is between about 50 mg to about 100 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is between about 90 mg to about 150 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is between about 140 mg to about 200 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is between about 190 mg to about 250 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is between about 240 mg to about 300 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is between about 290 mg to about 350 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is between about 340 mg to about 400 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is between about 390 mg to about 450 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is between about 440 mg to about 500 mg.

[0185] In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 0.5 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 1 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 2 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 3 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 4 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing isabout 6 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 8 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 10 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 12 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 16 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 20 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 30 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 40 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 50 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 60 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 70 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 80 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 90 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 100 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 150 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 200 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing isabout 250 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 300 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 350 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 400 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 450 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 500 mg. All dosing amounts refer to the amount of dazostinag or ADC-B17 administered, and do not include the weight amount of any pharmaceutically acceptable salt.

[0186] In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is from about 0.1 mg to about 3.5 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is from about 0.2 mg to about 3.5 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 0.1 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 0.2 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 0.4 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 0.8 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 1.2 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 1.8 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 2.25 mg. In some embodiments, the amountof dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 2.8 mg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 3.5 mg.

[0187] In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 0.01 mg / kg to about 100 mg / kg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 0.01 mg / kg to about 50 mg / kg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 0.01 mg / kg to about 20 mg / kg.

[0188] In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 0.01 mg / kg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 0.05 mg / kg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 0.1 mg / kg. In some embodiments, the amount of dazostinag or ADC-B 17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 1 mg / kg. In some embodiments, the amount of dazostinag or ADC-B 17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 2 mg / kg. In some embodiments, the amount of dazostinag or ADC-B 17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 4 mg / kg. In some embodiments, the amount of dazostinag or ADC-B 17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 6 mg / kg. In some embodiments, the amount of dazostinag or ADC-B 17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 8 mg / kg. In some embodiments, the amount of dazostinag or ADC-B 17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 10 mg / kg. In some embodiments, the amount of dazostinag or ADC-B 17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 12 mg / kg. In some embodiments, the amount of dazostinag or ADC-B 17, or apharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 14 mg / kg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 16 mg / kg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 18 mg / kg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 20 mg / kg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 30 mg / kg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 40 mg / kg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 50 mg / kg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 60 mg / kg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 70 mg / kg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 80 mg / kg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 90 mg / kg. In some embodiments, the amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, that is administered on each day of dosing is about 100 mg / kg.

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

[0190] In some embodiments, the immune checkpoint inhibitor is administered at least 3 times on alternate days within a 7-day cycle. In some embodiments, the immune checkpoint inhibitor is administered on day 1 of a treatment cycle. In some embodiments, the immune checkpoint inhibitor is administered on day 1 and day 4 of a 7-day cycle. In some embodiments, the immune checkpoint inhibitor is administered on consecutive days in a 7-day cycle followed by an intermission. In some embodiments, the immune checkpoint inhibitor is administered for 2 consecutive days followed by an intermission of 5 consecutive days for at least one 7-day cycle. In some embodiments, the immune checkpoint inhibitor is administered for 3 consecutive days followed by an intermission of 4 consecutive days for at least one 7-day cycle. In some embodiments, the immune checkpoint inhibitor is administered for 4 consecutive days followed by an intermission of 3 consecutive days for at least one 7-day cycle. In some embodiments, the immune checkpoint inhibitor is administered for 5 consecutive days followed by an intermission of 2 consecutive days for at least one 7-day cycle.

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

[0192] The present description contemplates administration of the immune checkpoint inhibitor for one or more treatment cycles, for example, 1, 2, 3, 4, 5, 6, or more, treatment cycles. In some embodiments, a treatment cycle is about 7 days to about 84 days, or more. In some embodiments, a 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, a treatment cycle is 21 days or 28 days. In some embodiments, there will be periods of rest within or between one or more of the treatment cycles. For example, in some embodiments, there will be aperiod of rest at the end of the treatment cycle. In some embodiments, there will be a period of rest between the second and third treatment cycle but not the first and second treatment cycle. In another embodiment, there might be a period of rest between the first and second treatment cycle but not the second and third treatment cycle. Dosing schedules include, for example, administering the immune 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 of on days 1, 4, 8, and 11 of a 28 day cycle. Other dosage schedules are encompassed by the present invention.

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

[0194] In some embodiments, both dazostinag or ADC-B17 and the immune checkpoint inhibitor are administered on day 1 of a 21 -day treatment cycle. In some embodiments, dazostinag or ADC-B17 is administered first on day 1 of a 21 -day treatment cycle followed by the immune checkpoint inhibitor. In some embodiments, dazostinag or ADC-B17 is administered on day 1 of a 21 -day treatment cycle and the immune checkpoint inhibitor is administered on day 1 of a 21 -day treatment cycle 1 hour after administration dazostinag or ADC-B17.

[0195] In some embodiments, dazostinag or ADC-B17 is administered as a 60 ±10- minute intravenous infusion.

[0196] In some embodiments, dazostinag or ADC-B17 is administered in combination with an additional therapeutic agent. In some embodiments, the additional therapeutic agent is one or more of an immune checkpoint inhibitor, e.g., the immune checkpoint inhibitors discussed above; chemotherapy, e.g., capecitabine, temozolomide, streptozotocin, 5-fluorouracil, cisplatin, carboplatin, etoposide, doxorubicin, or a combination thereof; hormone deprivation; radiotherapy targeting hormone receptors; asomatostatin analog, e.g., lanreotide or octreotide; a tyrosine kinase inhibitor, e.g., sunitinib; an mTOR inhibitor, e.g., everolimus; an NTRK inhibitor, e.g., larotrectinib or entrectinib; or radiotherapy.Pharmaceutical Compositions

[0197] The STING agonists and the immune checkpoint inhibitors used in the methods and kits described herein can be formulated into pharmaceutical compositions suitable for administration. The pharmaceutical compositions may comprise pharmaceutically acceptable excipients. A pharmaceutically acceptable excipient, as used herein, includes, but are not limited to, any and all solvents, dispersion media, or other liquid vehicles, dispersion or suspension aids, diluents, granulating and / or dispersing agents, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, binders, lubricants or oil, coloring, sweetening or flavoring agents, stabilizers, antioxidants, antimicrobial or antifungal agents, osmolality adjusting agents, pH adjusting agents, buffers, chelants, cyoprotectants, and / or bulking agents, as suited to the particular dosage form desired. Various excipients for formulating pharmaceutical compositions and techniques for preparing the composition are known in the art (see Remington: The Science and Practice of Pharmacy, 21stEd., A. R. Gennaro (Lippincott, Williams & Wilkins, Baltimore, MD), 2006; incorporated by reference in its entirety)

[0198] Any of the therapeutic agents described herein may be in the form of a pharmaceutically acceptable salt. In some embodiments, such salts are derived from inorganic or organic acids or bases. For reviews of suitable salts, see, e.g., Berge et al., J. Pharm. Sci., 1977, 66, 1-19 and Remington: The Science and Practice of Pharmacy, 20th Ed., A. Gennaro (ed.), Lippincott Williams & Wilkins (2000).

[0199] Examples of suitable acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, lucoheptanoate, glycerophosphate, hemi sulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3 -phenyl -propionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate.

[0200] 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, A-methyl-D-glucamine; and salts with amino acids such as arginine, lysine, and the like.

[0201] For example, Berge lists the following FDA-approved commercially marketed salts: anions acetate, besylate (benzenesulfonate), benzoate, bicarbonate, bitartrate, bromide, calcium edetate (ethylenediaminetetraacetate), camsylate (camphorsulfonate), carbonate, chloride, citrate, dihydrochloride, edetate (ethylenediaminetetraacetate), edisylate (1,2-ethanedi sulfonate), estolate (lauryl sulfate), esylate (ethanesulfonate), fumarate, gluceptate (glucoheptonate), gluconate, glutamate, glycollylarsanilate (glycollamidophenylarsonate), hexylresorcinate, hydrabamine (A,A'-di(dehydroabietyl)- ethylenediamine), hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate (2-hydroxyethanesulfonate), lactate, lactobionate, malate, maleate, mandelate, mesylate (methanesulfonate), methylbromide, methylnitrate, methyl sulfate, mucate, napsylate (2- naphthalenesulfonate), nitrate, pamoate (embonate), pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate (8-chlorotheophyllinate) and triethiodide; organic cations benzathine (M-V'-dibenzylethylenediamine), chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (A-methylglucamine) and procaine; and metallic cations aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.

[0202] Berge additionally lists the following non-FDA-approved commercially marketed (outside the United States) salts: anions adipate, alginate, aminosalicylate, anhydromethylenecitrate, arecoline, aspartate, bisulfate, butylbromide, camphorate, digluconate, dihydrobromide, disuccinate, glycerophosphate, hemisulfate, hydrofluoride, hydroiodide, methylenebis(salicylate), napadisylate (1,5-naphthalenedisulfonate), oxalate, pectinate, persulfate, phenylethylbarbiturate, picrate, propionate, thiocyanate, tosylate and undecanoate; organic cations benethamine (A-benzylphenethylamine), clemizole (l- / ?-chlorobenzyl-2-pyrrolildine-l'-ylmethylbenzimidazole), di ethylamine, piperazine and tromethamine (tris(hydroxymethyl)aminomethane); and metallic cations barium and bismuth.

[0203] The pharmaceutical compositions may comprise pharmaceutically acceptable carriers. As used herein, “pharmaceutically acceptable carrier” refers to a material that iscompatible with a recipient subject (a human) and is suitable for delivering an active agent to the target site without terminating the activity of the agent. The toxicity or adverse effects, if any, associated with the carrier preferably are commensurate with a reasonable risk / benefit ratio for the intended use of the active agent.

[0204] Pharmaceutically acceptable carriers that may be used in these compositions include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates or carbonates, 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, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0205] The pharmaceutical compositions for use in the methods of the present disclosure may be manufactured by methods well known in the art such as conventional granulating, mixing, dissolving, encapsulating, lyophilizing, or emulsifying processes, among others. Compositions may be produced in various forms, including granules, precipitates, or particulates, powders, including freeze dried, rotary dried or spray dried powders, amorphous powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions. Formulations may contain stabilizers, pH modifiers, surfactants, solubilizing agents, bioavailability modifiers and combinations of these. These pharmaceutical compositions are formulated for pharmaceutical administration to a human being. Such compositions may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intravenous, intraperitoneal, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In some embodiments, the compositions are administered orally, intravenously or subcutaneously. In some embodiments, the compositions are administered orally. In some embodiments, the compositions are administered intravenously. In some embodiments, the intravenous administration can be intravenous infusion or intravenous injection. In some embodiments, the compositions are administered by an intravenous infusion. In someembodiments, the compositions are administered by an intravenous injection. In some embodiments, the compositions are administered by subcutaneous injection. In some embodiments, the compositions are administered by intravenous infusion and then subsequently administered by subcutaneous injection. In another embodiment, the checkpoint inhibitor is coadministered with human hyaluronidase subcutaneously. These formulations may be designed to be short-acting, fast-releasing, or long-acting. Furthermore, the compositions may be administered in a local rather than systemic means, such as administration (e.g., by injection) at a tumor site.

[0206] Pharmaceutical formulations may be prepared as liquid suspensions or solutions using a liquid, such as an oil, water, an alcohol, and combinations of these. Solubilizing agents such as cyclodextrins may be included. Pharmaceutically suitable surfactants, suspending agents, or emulsifying agents, may be added for oral or parenteral administration. Suspensions may include oils, such as peanut oil, sesame oil, cottonseed oil, com oil and olive oil. Suspension preparations may also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides. Suspension formulations may include alcohols, such as ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol; ethers, such as poly(ethyleneglycol); petroleum hydrocarbons such as mineral oil and petrolatum; and water.

[0207] Sterile injectable forms of these pharmaceutical compositions may be aqueous or oleaginous suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their poly oxy ethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose orsimilar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as sorbitan alkyl esters, such as Tweens or Spans, and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation. Compounds may be formulated for parenteral administration by injection such as by bolus injection or continuous infusion. A unit dosage form for injection may be in ampoules or in multi-dose containers.

[0208] These pharmaceutical compositions may be orally administered in any orally acceptable dosage form including capsules, tablets, aqueous suspensions or solutions. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. In the case of tablets for oral use, carriers that are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. Coatings may be used for a variety of purposes, e.g., to mask taste, to affect the site of dissolution or absorption, or to prolong drug action. Coatings may be applied to a tablet or to granulated particles for use in a capsule.

[0209] Alternatively, these pharmaceutical compositions may be administered in the form of suppositories for rectal administration. These may be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[0210] 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.

[0211] Topical application for the lower intestinal tract may be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used. For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing theactive component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present disclosure include mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions may be formulated in a suitable lotion or cream containing the active component(s) suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0212] For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with our without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum.

[0213] The pharmaceutical compositions may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0214] In one embodiment, dazostinag is formulated as a solution for intravenous infusion. In some embodiments, dazostinag is formulated in a solution containing 3 mg / 3 mL dazostinag as free base. In one embodiment, the solution of dazostinag can be diluted prior to infusion.

[0215] In one embodiment, ADC-B17 is formulated as a solution for intravenous infusion. In one embodiment, the solution of ADC-B17 can be diluted prior to infusion.Kits

[0216] In some embodiments, the STING agonist and / or the immune checkpoint inhibitor described herein may be manufactured for inclusion in a kit. A “kit” is any article of manufacture (e.g., a package or container) comprising at least one reagent or chemotherapeutic agent. A kit for use in the methods herein may comprise a STING agonist, such as dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof.In some embodiments, the kit may further include an immune checkpoint inhibitor, and optionally one or more additional therapeutic agents. In some embodiments, the kit mayinclude dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, an immune 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 immune checkpoint inhibitors.

[0217] In some embodiments, the present disclosure relates to a kit comprising a medicament for use in treating cancer in a patient in need of such treatment. The kit comprises a medicament comprising a STING agonist, and instructions for administering the STING agonist and an immune checkpoint inhibitor; or the kit comprises a medicament comprising an immune checkpoint inhibitor, and instructions for administering the immune checkpoint inhibitor and a STING agonist. The kit may contain a medicament comprising a STING agonist and an immune checkpoint inhibitor, and instructions for administering the STING agonist and the immune checkpoint inhibitor, wherein the medicament is in single dosage form or in separate dosage forms. In some embodiments, the kit optionally comprises one or more additional therapeutic agents.

[0218] In some embodiments, a kit comprising a STING agonist and an immune checkpoint inhibitor may further include another component or reagent. In some embodiments, a reagent in the kit may be a diluent for preparing the STING agonist for administration. In some embodiments, a reagent in the kit may be a diluent for preparing the checkpoint inhibitor for administration. In some embodiments, a component in the kit may be a vessel for mixing the combination of the STING agonist and the immune checkpoint inhibitor.

[0219] In another aspect, the present disclosure relates to a kit for treating cancer comprising at least one medicament comprising at least one dose of dazostinag or ADC- B 17, or a pharmaceutically acceptable salt thereof, and at least one medicament comprising at least one dose of an immune checkpoint inhibitor, said kit for treating cancer further comprising dosing instructions for administering the medicaments for treatment of the patient in recognized need thereof.

[0220] In order that this present disclosure be more fully understood, the following examples are set forth. These examples are illustrative only and are not intended to limit the scope of the present disclosure in any way.EXAMPLESExample 1: SCLC Neuroendocrine Cells Do Not Respond to Dazostinag in a Tumor Intrinsic Manner

[0221] Indicated cell lines were seeded at a density of 3xl06cells / well in 3 mL total volume of RPMI-1640 + 10% heat-inactivated FBS in tissue culture-treated 6-well plates. Cells were incubated overnight in a 37 °C, 5% CO2 incubator. The following day, cells were treated with dazostinag (or an equal volume of PBS for untreated samples) at a final concentration of 10 pM and incubated for 3 hours in a 37 °C, 5% CO2 incubator. Following incubation, cells were harvested, centrifuged at 350xg at 4 °C and pellets were resuspended in 150 pL RIPA lysis buffer (supplemented 1 : 100 with protease inhibitors). Lysates were vortexed then clarified by centrifugation at 10,000 xg for 20 mins at 4 °C prior to total protein quantification using Pierce BCA Protein Assay Kit (Thermo Fisher). Lysates were normalized to a protein concentration of 0.4 mg / mL and run on ProteinSimple Jess for detection of STING, phospho-IRF3 and tubulin.

[0222] FIG. la shows low or a lack of expression of endogenous STING in SCLC NET cell lines. Furthermore, by measuring pIRF3, FIG. la shows there is no STING pathway activation following dazostinag treatment in SCLC NET and THP-1 STING KO cell lines. FIG lb shows that there is no significant modulation of the IFN pathway in SCLC NET cell lines following dazostinag treatment.Example 2: SCLC Neuroendocrine cells are insensitive to dazostinag treatment in cell viability assays

[0223] Indicated cell lines were seeded at a density of 5,000 cells / well in a total volume of 90 pL RPMI-1640 + 10% heat-inactivated FBS in opaque tissue-culture treated 96- well plates, dazostinag or cisplatin dilutions were prepared at 10X final concentration, then 10 pL of each dilution was added to cells to achieve final assay concentrations of 10 pM, 1 pM, or 0.1 pM (or an equivalent volume of media for untreated samples) and incubated overnight in a 37 °C, 5% CO2 incubator. Following 48 hours of incubation, 100 pL of CellTiter-Glo was added to each well and plate was read for luminescence. Percent viability was calculated relative to untreated controls respective of each cell line. FIG. 2 shows no effect of dazostinag or cisplatin treatment at different concentrations on SCLC NET cell viability assays.Example 3: Neuroendocrine cells upregulate MHC-I & PD-L1 in response to type I / II IFN

[0224] Indicated cell lines were seeded at a density of 100,000 cells / well in a total volume of 50 pL of RPMI-1640 + 10% heat-inactivated FBS in tissue-culture treated 96- well plates. Lyophilized human recombinant cytokines (IFN-beta, IFN-gamma, TNF- alpha, IL-6 and IL- 17: Peprotech) were solubilized in sterile water. Recombinant human IFN-alpha (Abeam) was supplied in liquid form. Cytokine dilutions were prepared at 2X final concentration in media, then 50 pL of each cytokine was added to cells for final assay concentrations of 1000 ng / mL or 10 ng / mL (or an equivalent volume of media for untreated samples). Cells were incubated for 24 h in a 37 °C, 5% CO2 incubator. Following incubation, cells were pelleted by centrifugation, resuspended in 50 pL of Human TruStain FcX (Biolegend) and incubated at room temperature for 5 mins to Fc block. A 50 pL master mix of antibody cocktails was added to each well such that each sample received 1 pL Alexa Fluor 647-conjugated anti-human HLA-A / B / C + 1 pL Alexa-Fluor 488-conjugated anti-human HLA-DR + 1 pL BV711 -conjugated anti-human PD-L1 + 47 pL FACS buffer (PBS + 3% FBS + 1 mM EDTA). Cells were incubated at 4 °C in the dark for 45 mins. Following incubation, cells were pelleted by centrifugation, resuspended in 150 pL / well FACS buffer to wash. Washes were repeated for a total of 2 washes. After last wash, cells were resuspended in 120 pL / well of FACS buffer supplemented with 7-AAD (BD Biosciences) at a 1 :200 dilution. Data was acquired by flow cytometry on LSRFortessa and analyzed using FlowJo.

[0225] FIG 3 shows an upregulation of MHC-I (HLA-A / B / C) and PDL-1 expression in SCLC NET cell lines following treatment of exogenous type Eli IFN’s at varying concentrations.Example 4: MHC-I / PD-L1 upregulation on NETs requires STING activation in innate immune cells

[0226] THP-1 Dual and THP-1 Dual STING KO cell lines (Invivogen) were pelleted by centrifugation, washed with DPBS and labeled with Cell Trace Violet (Thermo Fisher) in a 37 °C 5% CO2 incubator for 20 mins. Following incubation, THP-1 cells were washed with FBS to quench and plated in round-bottom tissue-culture treated 96-well plates at a density of 50,000 cells / well. H82 and SCLC-21H NET cell lines were added to wells at final cell densities of either 200,000, 100,000, 50,000, 25,000 or 12,500 cells / well toachieve effector-to-target (E:T) ratios of 1 :4, 1:2, 1 : 1, 2: 1 or 4: 1, respectively. Co-cultures were treated with dazostinag at a final assay concentration of 5 pM and placed in a 37 °C, 5% CO2 incubator for 24 hours. Following incubation, cells were pelleted by centrifugation, resuspended in 50 pL of Human TruStain FcX (Biolegend) and incubated at room temperature for 5 mins to Fc block. A 100 pL master mix of antibody cocktails was added to each well such that each sample received 1 pL APC-Cy7-conjugated antihuman CD45 + 1 pL Alexa-Fluor 488-conjugated anti-human HLA-A / B / C+ 1 pL BV785 -conjugated anti-human PD-L1 + 87 pL FACS buffer (PBS + 3% FBS + ImM EDTA). Cells were incubated at 4 °C in the dark for 60 mins. Following incubation, cells were pelleted by centrifugation, resuspended in 150 pL / well FACS buffer to wash.Washes were repeated for a total of 2 washes. After last wash, cells were resuspended in 120 pL / well of FACS buffer supplemented with 7-AAD (BD Biosciences) at a 1 :200 dilution. Data was acquired by flow cytometry on LSRFortessa and analyzed using FlowJo.

[0227] FIG 4a illustrates an upregulation of MHC-I and PD-L1 in myeloid cell Tumor cell co-cultures following dazostinag treatment in NET-H82 cell lines. Furthermore, FIG 4a illustrates no effect on MHC-I and PD-L1 following dazostinag treatment on STING-KO myeloid celktumor cell co-cultures.

[0228] FIG 4b illustrates an upregulation of MHC-I and PD-L1 in myeloid cell Tumor cell co-cultures following dazostinag treatment in SCLC cells. Furthermore, FIG 4b illustrates no effect on MHC-I and PD-L1 following dazostinag treatment on STING-KO myeloid cell Tumor cell co-cultures.Example 5: Dazostinag Mediates Upregulation of MHC-I and PD-L1 on Patient- Derived Lung Neuroendocrine Tumor Cells

[0229] Frozen, patient-derived lung neuroendocrine dissociated tumor cells (Discovery Life Sciences) were thawed in a 37 °C water bath, transferred to culture media (RPMI- 1640 + 10% heat-inactivated FBS + 2 mM L-glutamine + 1 mM sodium pyruvate + IX NEAA + HEPES + B-Me + rhIL-2) and pelleted by centrifugation. DTCs were plated in round-bottom, tissue-culture treated 96-well plates at a cell density of 200,000 cells / well in culture media and treated with dazostinag (1 pM) and / or pembrolizumab (10 pg / mL), recombinant human IFN-alpha (300 U / mL) or Immunocult aCD3 / aCD28 / aCD2 (5 pL / mL) for 24 hours in a 37 °C, 5% CO2 incubator. Following incubation, mediacontaining GolgiPlug (BD Biosciences) was added to each well at a 1000X dilution and cells were incubated for 4 additional hours. For extracellular staining, after live / dead staining with Zombie Aqua Fixable Viability Kit (Biolegend) per manufacturer’s instructions, single-cell suspensions were stained with fluorophore-conjugated primary antibodies in FACS buffer. For intracellular staining, after live / dead and extracellular staining, cells were fixed and permeabilized using Biolegend True Nuclear Transcription Factor Buffer Set, per manufacturer’s instructions. After washing, cells were incubated with fluorophore-conjugated primary antibodies. After washing, cells were resuspended in FACS buffer and analyzed on LSRFortessa flow cytometer. Data analyses performed in FlowJo. FIG 5 illustrates an increase of MHC-I and PD-L1 expression in patient- derived lung NET samples following treatment of dazostinag, pembrolizumab, a combination of dazostinag and pembrolizumab, IFNa, or aCD3 / 28 / 2. FIG 6 shows an increase of MHC-I and PD-L1 expression in patient-derived lung NET samples following treatment of a combination of dazostinag and anti-mPD-1.Example 6: Dazostinag Treatment Results in Antitumor Efficacy in RPP SCLC Tumor-Bearing Mice Which Is Enhanced In Combination With aPD-1

[0230] Experiments were performed using the methods described in: Mahadevan et al, Cancer Discovery. 2021 Aug; 11(8): 1952-1969. (DOI: 10.1158 / 2159-8290.CD-20-0913). Briefly, RPP cells (8 x 106) in 1 : 1 PBS / Matrigel (Corning #354234) were subcutaneously injected into the flank of 8-week-old syngeneic C57BL / 6 mice (Charles River Laboratories) anesthetized with isoflurane. Tumor volume was determined from caliper measurements of tumor length (L) and width (W) according to the formula (L x W)2 / 2. Both tumor size and body weight were measured three times per week. Once RPP tumors reached an appropriate volume, animals were injected IV with vehicle, dazostinag (1 mg / kg QW) plus Isotype control (10 mg Q3D), anti-mPD-1 (10 mg Q3D), or dazostinag (1 mg / kg QW) plus anti-mPD-1 treatments (10 mg Q3D) (n = 8 mice per group) (QW = once weekly; Q3D = once every three days). Mice were euthanized at preset or humane endpoints. All experiments were conducted in accordance with a DFCI Institutional Animal Care and Use-approved protocol. FIG 7 illustrates the longitudinal effects of treatment with dazostinag, anti-mPD-1, or dazostinag + anti-mPD-1 on the tumor volume of individual SCLC tumor-bearing mice.

[0231] FIG. 7 illustrates the longitudinal effects of treatment with dazostinag, anti-mPD- 1, or dazostinag + anti-mPD-1 on the tumor volume of individual SCLC tumor-bearing mice.

[0232] FIG. 8 illustrates the longitudinal effects of treatment with dazostinag, anti-mPD- 1, or dazostinag + anti-mPD-1 on the average tumor volume of a murine SCLC tumorbearing mouse model.

[0233] FIG. 9 illustrates the longitudinal effects of treatment with dazostinag, anti-mPD- 1, or dazostinag + anti-mPD-1 on the average tumor volume of a murine SCLC tumorbearing mouse model that has been baseline corrected by body weight.Example 7: Enhanced Efficacy with Dazostinag + aPD-1 Combination Treatment Coincides with Increased Myeloid PD-L1 and T / NK Cell Infiltration in SCLC Tumors

[0234] Experiments were performed using the methods described in: Mahadevan et al, Cancer Discovery. 2021 Aug; 11(8): 1952-1969. (DOI: 10.1158 / 2159-8290.CD-20-0913). Briefly, mice were inoculated and treated as described above for efficacy evaluation. Mice were euthanized at preset endpoints and tumors collected and processed with gentleMACS C tubes (Miltenyi 130-093-237) per the manufacturer's protocol prior to flow cytometry. All experiments were conducted in accordance with a DFCI Institutional Animal Care and Use-approved protocol. Following tumor harvest, single mouse tumor cell suspensions were generated using the mouse Tumor Disassociation Kit (cat. 130-096- 730; Miltenyi Biotec) per the manufacturer's protocol using the gentleMACS Octo Disassociator with heaters using the 37C_m_TDKl protocol. After red blood cell lysis and filtration, cell suspensions were subjected to flow cytometry. For extracellular staining, after live / dead staining with Zombie NIR Fixable Viability Kit (cat. 423106; Biolegend) per the manufacturer's instructions, single-cell suspensions were stained with fluorophore-conjugated primary antibodies in PBS containing 2% FBS at 2 pg / mL. For intracellular staining, after live / dead and extracellular staining, cells were fixed in fresh 4% paraformaldehyde and permeabilized in 100% ice-cold methanol for 30 minutes. After washing, cells were incubated with fluorophore-conjugated primary antibodies. After washing, cells were resuspended in PBS containing 2% FBS and analyzed on a LSRFortessa flow cytometer (Becton Dickinson). Levels were compared with isotype control antibodies. Cell cycle analysis was performed using the BD Cycletest Plus Kit(cat. 340242; BD Biosciences) per the manufacturer's protocol. The data analyses were performed with FlowJo software (TreeStar).

[0235] FIG. 10 illustrates the increase of average lymphocyte counts in immune cells following treatment of dazostinag + anti-mPD-1. FIG. 11 illustrates the increase of myeloid PD-L1 expression in tumors following treatment of dazostinag + anti-mPD-1.Example 8: Partial Response in Subject Having Cervical Small-Cell Neuroendocrine Tumor After Treatment with Dazostinag and Pembrolizumab

[0236] Portions of the clinical trial described in Example 3 of International Appl. No. PCT / IB2020 / 056440, which is incorporated herein by reference in its entirety, were performed.

[0237] One study subject having a cervical small-cell neuroendocrine tumor, who had received atezolizumab prior to treatment, exhibited a partial response after treatment with 5 mg dazostinag in combination with pembrolizumab. As shown in FIG. 12, a -60% lesion reduction was observed after six treatment cycles. The subject exhibited progressive disease after fifteen treatment cycles.

[0238] While certain embodiments have been illustrated and described, it should be understood that changes and modifications can be made therein in accordance with ordinary skill in the art without departing from the technology in its broader aspects as defined in the following claims.

[0239] The present disclosure is not to be limited in terms of the particular embodiments described in this application. Modifications and variations can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and compositions within the scope of the disclosure, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. The present disclosure is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled. It is to be understood that this disclosure is not limited to particular methods, reagents, compounds compositions or biological systems, which can of course vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0240] All publications, patent applications, issued patents, and other documents referred to in this specification are herein incorporated by reference 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 that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure.

Claims

WHAT IS CLAIMED IS:

1. A method of treating a neuroendocrine neoplasm in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, comprising administering to the subject a therapeutically effective amount of dazostinag, or the pharmaceutically acceptable salt thereof.

3. The method of claim 2, wherein from about 0.1 mg to about 18 mg of dazostinag, or the pharmaceutically acceptable salt thereof, is administered to the subject.

4. The method of claim 3, wherein about 2.5 mg of dazostinag, or the pharmaceutically acceptable salt thereof, is administered to the subject once per week.

5. The method of claim 3, wherein about 3.5 mg of dazostinag, or the pharmaceutically acceptable salt thereof, is administered to the subject once per week.

6. The method of claim 3, wherein about 5 mg of dazostinag, or the pharmaceutically acceptable salt thereof, is administered to the subject once per week.

7. The method of claim 3, wherein about 14 mg of dazostinag, or the pharmaceutically acceptable salt thereof, is administered to the subject once per week.

8. The method of claim 1, comprising administering to the subject a therapeutically effective amount of ADC-B17, or the pharmaceutically acceptable salt thereof.

9. The method of claim 8, wherein ADC-B17 is administered to the subject in an amount equivalent to from about 1 pg / kg to about 100 pg / kg.

10. The method of claim 9, wherein ADC-B17 is administered to the subject in an amount equivalent to from about 4 pg / kg to about 40 pg / kg.

11. The method of claim 10, wherein ADC-B17 is administered to the subject in an amount equivalent to about 8 pg / kg once every three weeks.

12. The method of claim 10, wherein ADC-B17 is administered to the subject in an amount equivalent to about 16 pg / kg once every three weeks.

13. The method of any one of claims 1-12, wherein an EZH2 inhibitor is not administered prior to, concurrently or after administration of dazostinag or ADC-B17, or the pharmaceutically acceptable salt thereof.

14. The method of any one of claims 1-13, further comprising administering to the subject an immune checkpoint inhibitor.

15. The method of claim 14, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-Ll antibody, or an anti-CTLA-4 antibody.

16. The method of claim 15, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody.

17. The method of claim 16, wherein the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, retifanlimab, toripalimab, dostarlimab, and AMP -224.

18. The method of claim 17, wherein the anti-PD-1 antibody is pembrolizumab.

19. The method of claim 18, wherein from about 100 mg to about 500 mg of pembrolizumab is administered to the subject.

20. The method of claim 19, wherein about 200 mg of pembrolizumab is administered to the subject every three weeks.

21. The method of claim 19, wherein about 400 mg of pembrolizumab is administered to the subject every six weeks.

22. The method of claim 17, wherein the anti-PD-1 antibody is nivolumab.

23. The method of claim 22, wherein about 240 mg of nivolumab is administered to the subject every two weeks.

24. The method of claim 22, wherein about 480 mg of nivolumab is administered to the subject every four weeks.

25. The method of claim 15, wherein the immune checkpoint inhibitor is an anti-PD-Ll antibody.

26. The method of claim 25, wherein the anti-PD-Ll antibody is selected from the group consisting of atezolizumab, durvalumab, avelumab, YW243.55.S70, LY3300054, and BMS-936559.

27. The method of claim 15, wherein the immune checkpoint inhibitor is an anti-CTLA-4 antibody.

28. The method of claim 27, wherein the anti-CTLA-4 antibody is selected from the group consisting of ipilimumab and tremelimumab.

29. The method of any one of claims 1-28, wherein dazostinag or ADC-B17, or the pharmaceutically acceptable salt thereof, is administered intravenously.

30. The method of any one of claims 1-28, wherein dazostinag or ADC-B17, or the pharmaceutically acceptable salt thereof, is administered by intravenous infusion.

31. The method of any one of claims 1-30, wherein dazostinag or ADC-B 17, or the pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor are administered simultaneously.

32. The method of any one of claims 1-27, wherein dazostinag or ADC-B 17, or the pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor are administered separately.

33. The method of any one of claims 1-32, wherein the neuroendocrine neoplasm is a gynecologic neuroendocrine neoplasm, a pancreatic neuroendocrine neoplasm, a gastrointestinal neuroendocrine neoplasm, a genitourinary neuroendocrine neoplasm, a lung neuroendocrine neoplasm, a thoracic neuroendocrine neoplasm, or a head & neck neuroendocrine neoplasm.

34. The method of claim 33, wherein the neuroendocrine neoplasm is a pancreatic neuroendocrine neoplasm.

35. The method of claim 34, wherein the pancreatic neuroendocrine neoplasm is a gastrinoma, an insulinoma, a glucagonoma, a VIPoma, a PPoma, or a somatostatinoma.

36. The method of claim 33, wherein the neuroendocrine neoplasm is a genitourinary neuroendocrine neoplasm.

37. The method of any one of claims 1-36, wherein the neuroendocrine neoplasm is poorly immunogenic.

38. The method of any one of claims 1-37, wherein the neuroendocrine neoplasm is a neuroendocrine carcinoma.

39. The method of claim 38, wherein the neuroendocrine carcinoma is poorly differentiated.

40. The method of claim 38, wherein the neuroendocrine carcinoma is a small-cell neuroendocrine carcinoma.41 . The method of claim 38, wherein the neuroendocrine carcinoma is a large-cell neuroendocrine carcinoma.

42. The method of any one of claims 1-41, wherein the neuroendocrine neoplasm or neuroendocrine carcinoma is a neuroendocrine tumor.

43. The method of claim 42, wherein the neuroendocrine tumor has a Ki67 labeling index of less than 3%.

44. The method of claim 42, wherein the neuroendocrine tumor has a Ki67 labeling index of from about 3% to about 20%.

45. The method of claim 42, wherein the neuroendocrine tumor has a Ki67 labeling index of above 20%.

46. The method of any one of claims 1-45, wherein the subject exhibits symptoms selected from persistent cough, hemoptysis, fatigue, frequent chest infections, chest pain, shoulder pain, hoarseness, facial swelling, neck swelling, clubbing, fatigue, anorexia, weight loss, dyspnea, shortness of breath, diarrhea, flushing, hypoglycemia, hyperglycemia, constipation, skin flushing, palpitation, bronchospasm, frequent urination, increasedthirst, dizziness, shakiness, rashes, abdominal pain, abdominal bloating, bowel obstruction, wheezing, indigestion, nausea, vomiting, and combinations thereof.

47. The method of any one of claims 1-46, further comprising administering to the subject chemotherapy, hormone deprivation, radiotherapy targeting hormone receptors, a tyrosine kinase inhibitor, a somatostatin analog, an mTOR inhibitor, an NTRK inhibitor, or radiotherapy.

48. The method of any one of claims 1-47, wherein the neuroendocrine neoplasm is refractory to primary therapy.

49. The method of claim 48, wherein primary therapy comprised one or more of administration of an immune checkpoint inhibitor, chemotherapy, hormone deprivation, radiotherapy targeting hormone receptors, a somatostatin analog, a tyrosine kinase inhibitor, an mTOR inhibitor, an NTRK inhibitor, or radiotherapy.

50. The method of any one of claims 1-49, wherein the subject has a tumor mutational burden of greater than 10 muts / Mb.

51. A method of treating a neuroendocrine neoplasm and / or one or more symptoms associated with the neuroendocrine neoplasm in a subject in need thereof comprising: administering a therapeutically effective amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof, to the subject weekly until the subject exhibits intolerance or progression of symptoms.

52. The method of claim 51, further comprising administering to the subject an immune checkpoint inhibitor.

53. A method of increasing immunogenicity in a subject having a neuroendocrine neoplasm comprising administering to the subject a pharmaceutically acceptable amount of dazostinag or ADC-B17, or a pharmaceutically acceptable salt thereof.

54. The method of claim 53, further comprising administering to the subject an immune checkpoint inhibitor.

55. A method of treating a neuroendocrine cold tumor in a subject in need thereof comprising administering to the subject a pharmaceutically acceptable amount of dazostinag or ADC- B 17, or a pharmaceutically acceptable salt thereof.

56. The method of claim 55, further comprising administering to the subject an immune checkpoint inhibitor.

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