Novel approach for treatment of cancer using immunomodulation

Abstract

To provide a novel approach for treating cancer using immune modulation.SOLUTION: The present disclosure provides a regimen for treating a subject afflicted with prostate cancer by administering Talabostat or a pharmaceutically acceptable salt thereof and Pembrolizumab. The present disclosure is based on the discovery that the combination of Talabostat mesylate or a pharmaceutically acceptable salt thereof and Pembrolizumab in a specific treatment regimen is very effective to treat subjects afflicted with prostate cancer.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present disclosure is in the field of immuno-oncology, and more particularly, to a therapeutic regimen comprising talabostat, or a pharmaceutically acceptable salt thereof, and pembrolizumab for treating prostate cancer.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application Nos. 62 / 777,352, filed December 10, 2018, and 62 / 924,429, filed October 22, 2019, the contents of each of which are incorporated by reference in their entirety for all purposes. [Background technology]

[0003] Cancer is a multi-step process that begins with subtle pre-neoplastic changes and can progress to tumorigenesis; this neoplastic damage can lead to increased capacities for invasion, proliferation, metastasis, and heterogeneity. Current therapies for cancer treatment include surgery, hormonal therapy, radiation therapy, chemotherapy, and immunotherapy. Immunotherapy for cancer treatment has evolved with an improved understanding of the immune system. Specifically, understanding the ability of cancer cells to undermine anti-tumor immune responses has provided a rationale for the development of novel immunotherapies that target immune checkpoints responsible for the immune system's detection and destruction of escaped tumor cells.

[0004] Such immune escape mechanisms are mediated directly by tumor cells or by the tumor microenvironment. Tumor cells are known to express membrane proteins, secreted products, enzymes, anti-inflammatory cytokines, and chemokines, and to generate alterations in their genome that aid in immune evasion and immune inhibition. At the same time, the tumor microenvironment plays an important role.

[0005] Immune checkpoint molecules, such as PD-1, PD-L1, and CTLA-4, are cell surface signaling receptors that play a key role in regulating T cell responses within the tumor microenvironment. Tumor cells have been shown to exploit these checkpoints for their own benefit by upregulating their expression and activity. Therefore, immune checkpoint inhibitors have been developed that can unleash the immune system's cancer-destroying properties. Recent discoveries have identified immune checkpoints or targets, such as PD-1, PD-L1, PD-L2, CTLA4, TIM3, LAG3, CCR4, OX40, OX40L, IDO, and A2AR, as proteins responsible for immune evasion, acting as "brakes" on the immune system. Specific immune checkpoint inhibitors, including those targeting CTLA-4 and PD-1 receptors and their ligand PD-L1, have produced impressive results in the clinic, leading to FDA approval of Yervoy® (ipilimumab; a CTLA-4 antagonist), Opdivo® (nivolumab; a PD-1 antagonist), and Keytruda® (pembrolizumab; a PD-1 antagonist) in multiple oncology indications, and many more in ongoing clinical trials.

[0006] Unfortunately, checkpoint inhibitors suffer from several limitations. Only a small fraction of patients treated with checkpoint inhibitors demonstrate robust antitumor responses, and most responses are partial and transient. In many cases, patients initially respond but subsequently relapse due to the development of resistance, primarily due to the generation by tumor cells of a non-immune permissive microenvironment.

[0007] Combining two checkpoint inhibitors, ipilimumab and nivolumab, has been shown to increase response rates in melanoma patients from 11% and 32% seen with the respective monotherapies to 60% with the combination. Unfortunately, this combination has the significant drawback of high toxicity associated with an excessive immune response, resulting in pneumonitis, hepatitis, colitis, and other immune-related disorders.

[0008] Talabostat, also known as PT-100 (Val-boroPro; L-valinyl-L-boroproline), was originally developed by Point Therapeutics between 2000 and 2007. It is an orally available synthetic selective inhibitor of dipeptidyl peptidases, including FAP and DPP8 and DPP9. Stereoisomers of the talabostat molecule are disclosed in U.S. Pat. No. 6,825,169, while oral formulations thereof, such as tablets, capsules, and lozenges, are disclosed in U.S. Pat. No. 7,265,118.

[0009] Talabostat plays an important role in immune evasion and modulates innate and / or adaptive immunity. However, talabostat has been reported to exhibit numerous side effects at therapeutically effective doses, with the most common adverse events being edema / peripheral swelling, hypotension, hypovolemia, and dizziness. These adverse events, as well as poor primary and secondary outcomes reported in certain cancer clinical trials, have limited the use of talabostat as an anticancer agent.

[0010] In our U.S. Patent Publication No. 2017 / 0266280A1 (incorporated herein by reference in its entirety), we disclose the novel discovery that combining a selective dipeptidyl peptidase (DPP) inhibitor, such as talabostat, with an immune checkpoint inhibitor is effective in cancer treatment. Surprisingly, the combination is effective without the side effects that limit combination therapy. This disclosure is based on the novel discovery that talabostat can be particularly effective in treating prostate cancer in combination with the PD-1 antagonist pembrolizumab when both are administered in a specific treatment regimen.

[0011] Therefore, a primary object of the present disclosure is to provide an improved therapeutic method for treating prostate cancer using a novel therapeutic regimen comprising talabostat or a pharmaceutically acceptable salt thereof and pembrolizumab, which may also be effective in treating one or more other solid tumors, such as advanced solid tumors, for which pembrolizumab has or is expected to have an effective anti-cancer effect. Summary of the Invention

[0012] The present disclosure is based on the discovery that the combination of talabostat, or a pharmaceutically acceptable salt thereof, and pembrolizumab in a specific treatment regimen is a highly effective therapy for treating subjects with prostate cancer. Specifically, the dosage of each active agent used and the selected administration schedule result in highly effective treatment of prostate cancer (e.g., small molecule neuroendocrine prostate cancer; SCNC).

[0013] Accordingly, in a primary aspect, the present disclosure provides a regimen for treating prostate cancer in a subject in need thereof, the regimen comprising administering to the subject an effective amount of talabostat, or a pharmaceutically acceptable salt thereof, and an effective amount of pembrolizumab, as separate pharmaceutical formulations.

[0014] Another aspect provides a method of treating prostate cancer, comprising administering to a subject in need thereof an effective amount of talabostat, or a pharmaceutically acceptable salt thereof, and an effective amount of pembrolizumab, as separate pharmaceutical formulations.

[0015] In certain embodiments, separate pharmaceutical formulations of talabostat, or a pharmaceutically acceptable salt thereof, and pembrolizumab are administered to a subject at comparable times and in suitable amounts during one or more treatment cycles of about 21 days to maximize the combined immunotherapeutic effect.

[0016] A further aspect provides a method of enhancing an immune response in a subject with prostate cancer, the method comprising administering to the subject a regimen comprising an effective amount of talabostat, or a pharmaceutically acceptable salt thereof, and an effective amount of pembrolizumab, as separate pharmaceutical formulations.

[0017] In some aspects, the present disclosure provides a first pharmaceutical formulation comprising talabostat or a pharmaceutically acceptable salt thereof for use in combination with a separate second pharmaceutical formulation of pembrolizumab to treat prostate cancer, wherein the first pharmaceutical formulation comprises talabostat or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers or adjuvants, and the second pharmaceutical formulation comprises pembrolizumab, together with one or more pharmaceutically acceptable carriers or adjuvants.

[0018] In another aspect, the disclosure provides a method of improving the innate immune response in a subject afflicted with prostate cancer, the method comprising administering to the subject an effective amount of talabostat, or a pharmaceutically acceptable salt thereof, and an effective amount of pembrolizumab, as separate pharmaceutical formulations, wherein the improved innate immune response is associated with increased activity of tumor-destructive natural killer cells and macrophages, as well as NK cells and CD8+ T cells.

[0019] In a further aspect, the present disclosure provides a method of improving the innate immune response in a subject with prostate cancer, the method comprising administering to the subject an effective amount of talabostat, or a pharmaceutically acceptable salt thereof, and an effective amount of pembrolizumab, as separate pharmaceutical formulations, wherein the improved innate immune response is associated with suppression of T regulatory cells.

[0020] In some aspects, the present disclosure provides a kit for use in treating prostate cancer, the kit comprising: (i) a first pharmaceutical formulation comprising talabostat or a pharmaceutically acceptable salt thereof; (ii) a second pharmaceutical formulation comprising pembrolizumab; and and (iii) instructions for using the first and second pharmaceutical formulations in accordance with the methods and regimens described herein.

[0021] Other features, objects, and advantages of the disclosure will be apparent from the description and drawings, and from the claims. [Brief explanation of the drawings]

[0022] [Figure 1] 1 shows a scheme for administering talabostat mesylate and pembrolizumab to subjects with SCNC during the lead-in and efficacy stages of treatment. [Figure 2] Prostate-specific antigen (PSA) levels in three subjects in Cohort 1 during the fourth or fifth treatment cycle are shown. [Figure 3] 1 shows a scheme for administering talabostat mesylate and pembrolizumab to subjects with advanced solid tumors during the lead-in and efficacy stages of treatment. DETAILED DESCRIPTION OF THE INVENTION

[0023] In the following sections, different aspects of the present disclosure are defined in more detail. Each aspect so defined may be combined with any one or more other aspects, unless expressly indicated otherwise. In particular, any feature indicated as preferred or advantageous may be combined with any other feature or features indicated as preferred or advantageous.

[0024] Shorthand: As used herein, the following abbreviations have the following meanings: A2AR: A2A adenosine receptor ADT: Androgen deprivation therapy ALK: anaplastic lymphoma kinase ALT: alanine aminotransferase ANC: absolute neutrophil count AR: androgen receptor AST: Aspartate aminotransferase AUC: Area under the plasma concentration-time curve AUC 0-last : Area under the plasma concentration-time curve for the final measurable concentration BS: Bone scintigraphy BUN: Blood urea nitrogen CAF: cancer-associated fibroblasts CLL: chronic lymphocytic leukemia CR: complete remission CRPC: Castration-resistant prostate cancer CT: Computed tomography CTC: circulating tumor cells ctDNA: circulating tumor DNA CTLA4: cytotoxic T-lymphocyte-associated protein 4 CPS: Combined Positive Score DPP: dipeptidyl peptidase DKA: diabetic ketoacidosis DLT: Dose-limiting toxicity DOR: duration of response DSRC: Data Security Review Committee EGFR: epidermal growth factor receptor ECOG: Eastern Cooperative Oncology Group eCRF: Electronic Case Report Form EOT: End of treatment FAP: fibroblast activation protein GM-CSF: Granulocyte-macrophage colony-stimulating factor G-CSF: Granulocyte colony stimulating factor GCP: Good Clinical Practice HER2: human epidermal growth factor receptor 2 HCC: hepatocellular carcinoma ICI: immune checkpoint inhibitor IC50: half maximal inhibitory concentration ICH: International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use IEC: Independent Ethics Committee IL: Interleukin IDO: indoleamine 2,3-dioxygenase IMT: Inflammatory myofibroblastic tumor IrCR: immune-related complete disease irPR: immune-related partial response irSD: immune-related stable disease IND: Investigational New Drug (Indication) IRB: Institutional Review Board iRECIST: Immune Response Evaluation Criteria in Solid Tumors ITT: Intention to Treat LAG3: lymphocyte activation gene 3 protein LDH: lactate dehydrogenase LHRH: Luteinizing hormone-releasing hormone MSI-H: Microsatellite instability-high MDSC: myeloid-derived suppressor cells MedDRA: Medical Regulatory Information MRI: Magnetic Resonance Imaging mRNA: messenger ribonucleic acid NK: Natural Killer NCI CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events NEPC: Neuroendocrine prostate cancer NHL: Non-Hodgkin's lymphoma NSCLC: Non-small cell lung cancer OS: Overall survival PCWG3: Prostate Cancer Working Group 3 PD: Progressive disease PD-1: Programmed cell death 1 PD-L1: programmed cell death ligand 1 PD-L2: Programmed cell death ligand 2 PFS: progression-free survival PR: Partial Response PD-1: Programmed cell death 1 QD: Daily QTcB: QT interval corrected for heart rate using Bazett's formula RECIST: Response Evaluation Criteria in Solid Tumors rPFS: Radiographic progression-free survival SD: stable disease SAE: Serious Adverse Event SAP: Statistical Analysis Plan SJS: Stevens-Johnson syndrome SCNC: small cell neuroendocrine prostate cancer sHASEGP: soluble neutral-active hyaluronidase glycoprotein TIM3: T-cell immunoglobulin and mucin-domain containing 3 Treg: Regulatory T cells or T regulatory cells TPS: Tumor Proportion Score TRAE: Treatment-related adverse events TEN: Toxic epidermal necrolysis T1DM: Type 1 diabetes Tmax: time of maximum observed concentration ULN: upper normal limit

[0025] The intended therapeutic agents talabostat and pembrolizumab for use in this disclosure are described below:

[0026] 1. Therapeutic drugs a) talabostat or a pharmaceutically acceptable salt thereof: Talabostat is interchangeably referred to as PT-100, talabostat (USAN), and [(2R)-II [(2S)-2-amino-3-methyl-1-oxobutyl]-2-pyrrolidinyl]boronic acid. The CAS Registry Number for talabostat is 149682-77-9. Talabostat, also known as Val-boro-pro (L-valinyl-L-boroproline), is disclosed in PCT Application Publication No. 1989 / 003223. The IUPAC name for talabostat is [(2R)-1-[(2S)-2-amino-3-methylbutanoyl]pyrrolidin-2-yl]boronic acid. Talabostat (PubChem ID: 6918572) or a pharmaceutically acceptable salt thereof, such as talabostat mesylate (PubChem CID: 1152248). In some embodiments, the free base may be used. In other embodiments, talabostat or a pharmaceutically acceptable salt thereof may be a solvate. In most clinical formulations, talabostat is provided as a salt form, e.g., talabostat mesylate. Talabostat has two chiral centers in the R,S configuration. Talabostat or a pharmaceutically acceptable salt thereof can exist in both linear and cyclic forms (RJ Snow et al., J. Am. Chem. Soc., 1994, 116(24), pp 10860-10869).

[0027] Talabostat or its pharmaceutically acceptable salts are effective in cancer treatment by modulating multiple intracellular and extracellular dipeptidyl peptidases. More specifically, intracellular and extracellular dipeptidyl peptidases include fibroblast activation proteins DPP8 / 9, CD26 / DPP4, and DPP2. Talabostat or its pharmaceutically acceptable salts have a dual mechanism of action, including stroma-targeting activity through FAP inhibition and targeted immune activation activity through DPP8 / 9 inhibition. Talabostat suppresses tumor growth by inhibiting FAP enzyme activity. Talabostat or its pharmaceutically acceptable salts also inhibit DPP8 / 9, thereby inducing an IL1β response (mediated by caspase-1) in the stroma of tumors and lymph nodes. Talabostat's dual mechanism of action combines both tumor-targeting and immune-stimulating activity in a single agent, introducing a novel approach to cancer treatment.

[0028] b) Pembrolizumab: Pembrolizumab (also known as MK-3475, lambrolitumab, Keytruda®, and SCH-900475) is a humanized antibody that targets the PD-1 receptor on lymphocytes, thereby blocking the inhibitory signaling of PD-1. Pembrolizumab is readily available on the market.

[0029] 2.How to use: The present disclosure is based, in part, on an improved regimen for treating prostate cancer (e.g., SCNC) using effective amounts of talabostat, or a pharmaceutically acceptable salt thereof, and pembrolizumab. The combination of talabostat, or a pharmaceutically acceptable salt thereof, and pembrolizumab disclosed herein can produce improved T cell priming, increased T cell stimulation, increased infiltration of neutrophils and macrophages in the tumor microenvironment, reduced tumor volume, increased activation of natural killer cells, improved dendritic cell activation, a synergistic increase in pro-inflammatory cytokines (IL1, IL2, IL18, IFNγ, IL6, IL12p40, IL15, IL7, G-CSF, and GM-CSF), an improved anti-tumor memory response, reduced metastasis, and reduced toxicity.

[0030] In one embodiment, the present disclosure provides a combination comprising an effective amount of talabostat, or a pharmaceutically acceptable salt thereof, and an effective amount of pembrolizumab, administered to a subject afflicted with prostate cancer (e.g., SCNC) in one or more treatment cycles, each cycle being about 21 days in duration.

[0031] An advantage of using certain regimens of talabostat or a pharmaceutically acceptable salt thereof and pembrolizumab disclosed herein is to reduce the progression of prostate cancer (e.g., SCNC), reduce tumor burden, reduce metastasis, and / or induce tumor regression in a subject.

[0032] Thus, in one aspect, the present disclosure relates to a combination of talabostat, or a pharmaceutically acceptable salt thereof, and pembrolizumab administered to a subject with prostate cancer (e.g., SCNC) in a particular treatment regimen to promote an effective anti-tumor response.

[0033] In one embodiment, provided herein is a method for delaying, or preventing or delaying, tumor recurrence, tumor growth, or progression of tumor expansion in a subject afflicted with prostate cancer (e.g., SCNC), the method comprising administering to the subject effective amounts of talabostat, or a pharmaceutically acceptable salt thereof, and pembrolizumab, as separate pharmaceutical formulations, for one or more treatment cycles, each cycle lasting about 21 days.

[0034] In another embodiment, provided herein is a method of improving immune function in a subject afflicted with prostate cancer (e.g., SCNC), the method comprising administering to the subject effective amounts of talabostat or a pharmaceutically acceptable salt thereof, and pembrolizumab, as separate pharmaceutical formulations, for one or more treatment cycles, each cycle lasting about 21 days.

[0035] In a further embodiment, provided herein is a method of initiating, maintaining, or enhancing an anti-tumor immune response in a subject afflicted with prostate cancer (e.g., SCNC), the method comprising administering to the subject effective amounts of talabostat, or a pharmaceutically acceptable salt thereof, and pembrolizumab, as separate pharmaceutical formulations, for one or more treatment cycles, each cycle lasting about 21 days.

[0036] In some embodiments, the treatment regimens described herein result in a sustained response in a subject after cessation of treatment.

[0037] In some embodiments, the subject has prostate cancer, which can be early or late stage. In certain embodiments, the cancer is a progressive malignant solid neoplasm. In another specific embodiment, the cancer is a recurrent malignant solid neoplasm.

[0038] In some embodiments, the prostate cancer is metastatic.

[0039] In some embodiments, the subject is a human.

[0040] In another embodiment, the present disclosure provides a method for reducing the toxicity of talabostat or a pharmaceutically acceptable salt thereof with a reduced effective dose of talabostat, the method comprising administering to a subject afflicted with prostate cancer (e.g., SCNC) talabostat or a pharmaceutically acceptable salt thereof, and pembrolizumab as separate pharmaceutical formulations in a treatment regimen described herein.

[0041] In a further embodiment, the therapeutic regimen of the present disclosure comprises using effective amounts of talabostat, or a pharmaceutically acceptable salt thereof, and pembrolizumab as separate pharmaceutical formulations to generate an increased innate immune response compared to the innate immune response when talabostat alone is administered to a subject. The innate immune response can be increased by infiltration of innate immune cells, particularly macrophages in the blood and NK cells in tumors. Furthermore, the therapeutic regimen comprising an effective amount of talabostat, or a pharmaceutically acceptable salt thereof, and pembrolizumab can generate greater suppression of Treg function than that obtained with talabostat alone.

[0042] The present treatment regimen comprising an effective amount of talabostat or a pharmaceutically acceptable salt thereof and pembrolizumab can also significantly increase tumor infiltration of immune subpopulations, such as NK cells and macrophages, compared to monotherapy with talabostat or a pharmaceutically acceptable salt thereof and pembrolizumab.

[0043] 3. Treatment regimen: In some embodiments, during each treatment cycle of about 21 days, talabostat or a pharmaceutically acceptable salt thereof may be administered in an effective amount on each of days 1 to 14, and pembrolizumab may be administered in an effective amount on day 1. The above regimen is effective for treating subjects with prostate cancer (e.g., SCNC). The regimens disclosed herein for treating prostate cancer (e.g., SCNC) can also be used more generally to treat subjects with solid tumors, such as advanced solid tumors.

[0044] Talabostat or a pharmaceutically acceptable salt thereof can be administered in the disclosed regimen as a single dose daily, or more specifically, as a multiple dosage form to achieve an effective total daily dose to treat a subject suffering from prostate cancer (e.g., SCNC). In an alternative embodiment, talabostat or a pharmaceutically acceptable salt thereof can be administered in the disclosed dosing regimen twice daily to achieve an effective total daily dose to treat a subject suffering from prostate cancer (e.g., SCNC).

[0045] Pembrolizumab can be conveniently administered as a single dose in the regimens disclosed herein to effectively treat subjects afflicted with prostate cancer (e.g., SCNC).

[0046] In certain embodiments, pembrolizumab may be conveniently administered by injection (e.g., intravenously), most preferably as a continuous infusion over 30 minutes, at a total dose of about 1 mg / kg to about 10 mg / kg per day. A suitable dose of pembrolizumab administered intravenously in the treatment regimens of the present disclosure may conveniently be about 100 mg to about 500 mg per day, for example, about 200 mg per day.

[0047] In some embodiments, pembrolizumab (MK-3475) is administered as a liquid formulation comprising 25 mg / mL MK-3475, 7% (w / v) sucrose, 0.02% (w / v) polysorbate 80 in 10 mM histidine buffer (pH 5.5), with the selected dose of the formulation administered by IV infusion over a period of about 30 minutes.

[0048] In certain embodiments, talabostat or a pharmaceutically acceptable salt thereof may be conveniently administered orally (e.g., via tablets) at a total dose of about 0.001 mg / kg to about 0.1 mg / kg (e.g., about 0.001 mg / kg to about 0.035 mg / kg, or about 0.001 mg / kg to about 0.014 mg / kg). In the treatment regimen of the present disclosure, a suitable daily dose of talabostat or a pharmaceutically acceptable salt thereof, administered orally via one or more (e.g., two or three) tablets, may conveniently be about 0.1 mg to about 1 mg (e.g., about 0.05 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, or about 1 mg, preferably about 0.1 mg to about 0.6 mg, more preferably about 0.4 mg to about 0.6 mg). In certain embodiments, talabostat or a pharmaceutically acceptable salt thereof may be orally administered in divided doses twice daily at a dose of about 0.3 mg. In one particular embodiment, talabostat or a pharmaceutically acceptable salt thereof may be orally administered in divided doses three times daily at a dose of about 0.2 mg. In another particular embodiment, talabostat or a pharmaceutically acceptable salt thereof may be orally administered twice daily at a dose of about 0.4 mg in the morning and about 0.2 mg in the evening.

[0049] A suitable treatment regimen for treating a human patient with prostate cancer (e.g., SCNC) includes, for example, administering an effective amount of each of talabostat, or a pharmaceutically acceptable salt thereof, and pembrolizumab as separate pharmaceutical formulations, the regimen including at least one administration cycle (e.g., 1, 2, 3, 4, 5, 6, or more cycles), each cycle being about 21 days in duration, during which talabostat or a pharmaceutically acceptable salt thereof is administered orally (e.g., by tablet) on each of days 1-14, and pembrolizumab is administered intravenously on day 1.

[0050] In certain embodiments, during one or more treatment cycles of about 21 days, talabostat is administered on days 1-14 at a total daily dose of about 0.4 mg to about 0.6 mg, and pembrolizumab is administered on day 1 at a total dose of about 100 mg to about 500 mg per day, e.g., about 200 mg per day.

[0051] In another embodiment, the daily dose of talabostat or a pharmaceutically acceptable salt thereof may vary over time. For example, during the first cycle (including the lead-in stage), talabostat or a pharmaceutically acceptable salt thereof may be administered at a lower daily dose than during subsequent cycles (e.g., the efficacy stage). For example, talabostat or a pharmaceutically acceptable salt thereof may be conveniently administered at a daily dose of about 0.4 mg during the lead-in stage, and, in the absence of side effects or other criteria preventing further treatment, the subject may be entered into the efficacy stage, during which a daily dose of about 0.6 mg is administered. In another embodiment, talabostat or a pharmaceutically acceptable salt thereof may be administered at a daily dose of about 0.6 mg during the lead-in stage and at a daily dose of about 0.4 mg during the efficacy stage. In another embodiment, patients are treated directly during the efficacy stage with a daily dose of about 0.4 mg or about 0.6 mg.

[0052] In other embodiments, talabostat or a pharmaceutically acceptable salt thereof and pembrolizumab are administered to a subject with prostate cancer (e.g., SCNC) for any desired number of treatment cycles as long as a clinical response is observed or until there is a complete response, confirmed progressive disease, or unmanageable toxicity.

[0053] In further embodiments, the daily dose of talabostat, or a pharmaceutically acceptable salt thereof, and pembrolizumab used in accordance with the treatment regimens of the present disclosure may be less than the daily dose of one or both of talabostat, or a pharmaceutically acceptable salt thereof, and pembrolizumab administered as a single agent to treat a subject with prostate cancer (e.g., SCNC).

[0054] In some embodiments, the combination therapy is preferably administered for at least 12 weeks (three 4-week cycles, or four 3-week cycles), more preferably for at least 24 weeks, and even more preferably for at least 2-4 weeks after the patient achieves complete remission.

[0055] In some embodiments, a single administration cycle comprises 21 days (21-day cycle). In particular embodiments, talabostat mesylate is administered once daily (QD) on days 1-14 of a 21-day cycle, in addition to 200 mg of pembrolizumab administered intravenously (IV) on day 1 of each 21-day cycle.

[0056] In some embodiments, a single administration cycle comprises 21 days (a 21-day cycle). In a particular embodiment, talabostat mesylate is administered at a dose of 0.3 mg twice daily on days 1-14 of a 21-day cycle, in addition to 200 mg of pembrolizumab administered intravenously (IV) on day 1 of each of the 21 days. In another embodiment, talabostat mesylate is administered at a dose of about 0.2 mg three times daily on days 1-14 of a 21-day cycle, in addition to 200 mg of pembrolizumab administered intravenously (IV) on day 1 of each of the 21 days. In another embodiment, talabostat mesylate is administered at a dose of about 0.4 mg in the morning and about 0.2 mg in the evening on days 1-14 of a 21-day cycle, in addition to 200 mg of pembrolizumab administered intravenously (IV) on day 1 of each of the 21 days. In another embodiment, talabostat mesylate is administered at a dose of about 0.2 mg in the morning and about 0.4 mg in the evening on days 1-14 of a 21 day cycle, in addition to 200 mg of pembrolizumab administered intravenously (IV) on day 1 of each 21 day.

[0057] In some embodiments, the combination therapy of the present disclosure is administered to patients who have not been previously treated with a biological or chemotherapeutic agent, i.e., treatment-naive patients. In other embodiments, the combination therapy is administered to patients who have failed to achieve a durable response after previous treatment with a biological or chemotherapeutic agent, i.e., treatment-experienced patients.

[0058] In some embodiments of any of the methods or regimens described herein, prior to the period of time, the subject has been treated with talabostat mesylate as a monotherapy, and optionally, prior treatment with talabostat mesylate as a monotherapy has been unsuccessful. In some embodiments of any of the methods or regimens described herein, prior to the period of time, the patient has been treated with pembrolizumab, or a biologically similar substance, as a monotherapy, and optionally, treatment with pembrolizumab, or a biologically similar substance, has been unsuccessful.

[0059] A suitable period can be determined by one of ordinary skill in the art (e.g., a physician) based on one or more of the following: the stage of the patient's disease, the patient's weight and sex, clinical trial guidelines (e.g., those on the fda.gov website), and information in the approved drug label, as can be understood in the art.For example, suitable time periods may be, inclusively, 1 week to 2 years, 1 week to 22 months, 1 week to 20 months, 1 week to 18 months, 1 week to 16 months, 1 week to 14 months, 1 week to 12 months, 1 week to 10 months, 1 week to 8 months, 1 week to 6 months, 1 week to 4 months, 1 week to 2 months, 1 week to 1 month, 2 weeks to 2 years, 2 weeks to 22 months, 2 weeks to 20 months, 2 weeks to 18 months, 2 weeks to 16 months, 2 weeks to 14 months, 2 weeks to 12 months, 2 weeks to 10 months, 2 weeks to 8 months, 2 weeks to 6 months, 2 weeks to 4 months , 2 weeks to 2 months, 2 weeks to 1 month, 1 month to 2 years, 1 month to 22 months, 1 month to 20 months, 1 month to 18 months, 1 month to 16 months, 1 month to 14 months, 1 month to 12 months, 1 month to 10 months, 1 month to 8 months, 1 month to 6 months, 1 month to 4 months, 1 month to 2 months, 2 months to 2 years, 2 months to 22 months, 2 months to 20 months, 2 months to 18 months, 2 months to 16 months, 2 months to 14 months, 2 months to 12 months, 2 months to 10 months, 2 months to 8 months, 2 months to 6 months, 2 months to 4 months, 3 months to 2 years, 3 months to 22 months, 3 months to 20 months, 3 months to 18 months, 3 months to 16 months, 3 months to 14 months, 3 months to 12 months, 3 months to 10 months, 3 months to 8 months, 3 months to 6 months, 4 months to 2 years, 4 months to 22 months, 4 months to 20 months, 4 months to 18 months, 4 months to 16 months, 4 months to 14 months, 4 months to 12 months, 4 months to 10 months, 4 months to 8 months, 4 months to 6 months, 6 months to 2 years, 6 months to 22 months, 6 months to 20 months, 6 months to 18 months, 6 months to 16 months, 6 months to 14 months, 6 months to 12 months, 6 It can be months to 10 months, 6 months to 8 months, 8 months to 2 years, 8 months to 22 months, 8 months to 20 months, 8 months to 18 months, 8 months to 16 months, 8 months to 14 months, 8 months to 12 months, 8 months to 10 months, 10 months to 2 years, 10 months to 22 months, 10 months to 20 months, 10 months to 18 months, 10 months to 16 months, 10 months to 14 months, 10 months to 12 months, 12 months to 2 years, 12 months to 22 months, 12 months to 20 months, 12 months to 18 months, 12 months to 16 months, or 12 months to 14 months.

[0060] 4. Pharmaceutical Formulation In one embodiment, the present disclosure provides a pharmaceutical formulation comprising an effective amount of talabostat or a pharmaceutically acceptable salt thereof and an effective amount of pembrolizumab, together with one or more pharmaceutically acceptable carriers or adjuvants, for use in the treatment regimens described herein. Any pharmaceutically acceptable carrier or adjuvant described herein or known in the art may be used. As used herein, the term "pharmaceutical formulation" refers to a formulation comprising talabostat or a pharmaceutically acceptable salt thereof, or a formulation comprising pembrolizumab, each formulation also comprising one or more pharmaceutically acceptable carriers or adjuvants. Pharmaceutically acceptable carriers or adjuvants are well known to those skilled in the art and typically vary depending on the selected route of administration.

[0061] In some embodiments, a first formulation comprising talabostat or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or adjuvants, and a second formulation comprising pembrolizumab and one or more pharmaceutically acceptable carriers or adjuvants, when administered according to the treatment regimens disclosed herein, produce a synergistic effect in the treatment of a subject with prostate cancer (e.g., SCNC).

[0062] Pharmaceutical formulations can be formulated in a variety of ways, including, for example, liquid, semi-solid, and solid dosage forms, such as solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes, and suppositories. In some embodiments, the compositions can be formulated as injectable or infusible solutions. The formulations are in a form suitable for oral, intravenous, intraarterial, intramuscular, subcutaneous, parenteral, transmucosal, transdermal, or topical administration. The formulations can be formulated as immediate, controlled, sustained, or delayed release compositions.

[0063] In some embodiments, a formulation containing talabostat or a pharmaceutically acceptable salt thereof may be administered orally. In some embodiments, a formulation containing pembrolizumab may be administered parenterally. As used herein, the term "parenteral" includes subcutaneous, intravenous, intraarterial, intraperitoneal, intracardiac, intrathecal, and intramuscular injections, as well as infusion injections.

[0064] Liquid pharmaceutical formulations for parenteral administration can be formulated for administration by injection or continuous infusion. In some embodiments, parenteral formulations can include pre-filled syringes, vials, injectable powders for reconstitution, injectable concentrates that are diluted (ready to be diluted) prior to delivery, and ready-to-use solutions.

[0065] Injectable pharmaceutical formulations can be aqueous isotonic solutions or suspensions, and suppositories can be prepared from fatty emulsions or suspensions.

[0066] Pharmaceutical formulations formulated for parenteral administration (e.g., by intravenous injection) may conveniently include liquid carriers or may be reconstituted into liquid solutions or suspensions for parenteral administration.

[0067] In general, such formulations typically include a pharmaceutically acceptable carrier or adjuvant. As used herein, the term "pharmaceutically acceptable" means approved by a government regulatory agency or listed in the United States Pharmacopoeia or another generally recognized pharmacopeia for use in animals, especially humans.

[0068] Pharmaceutical formulations of pembrolizumab for intravenous administration can be commercially available or prepared using conventional pharmaceutical techniques. Pharmaceutically acceptable carriers are generally non-toxic to recipients at the dosages and concentrations used and include, but are not limited to, buffers of phosphate, citrate, and other organic acid salts; antioxidants including ascorbic acid and methionine; derivatives (such as octadecyldimethylbenzylammonium chloride; hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol, chlorobutanol, thimerosal, alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, and m-cresol); low molecular weight ( Examples of suitable pharmaceutically acceptable carriers include polypeptides (less than about 10 residues); proteins such as serum albumin, gelatin, or immunoglobulins; hydrophobic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; chelating agents such as EDTA; monosaccharides, disaccharides, and other carbohydrates, including sugars such as sucrose, mannitol, trehalose, or sorbitol, glucose, mannose, or dextrins; salt-forming counterions such as sodium; metal complexes (e.g., zinc-protein complexes); and / or non-ionic surfactants such as polyethylene glycol (PEG). Exemplary pharmaceutically acceptable carriers herein further include intercalating drug dispersants, such as soluble neutral active hyaluronidase glycoproteins (sHASEGPs), e.g., human soluble PH-20 hyaluronidase glycoproteins, such as rHuPH20 (HYLENEX®, Baxter International, Inc.). The carrier can be a solvent or reconstitution medium or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. More specifically, pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.In such cases, the composition must be sterile and must be fluid to the extent that easy syringability exists. The composition must be stable under the conditions of manufacture and storage and preferably preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. Suitable formulations for use in the therapeutic methods disclosed herein are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., 16th ed. (1980).

[0069] In some embodiments, the formulation contains an isotonic agent, such as a sugar, a polyalcohol such as mannitol, sorbitol, or sodium chloride. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL (BASF, Parsippany, NJ), or phosphate buffered saline (PBS). Absorption of injectable compositions can be delayed by including in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin.

[0070] Sterile injectable solutions can be prepared by incorporating the molecule, alone or in combination with other active agents, alone or in combination with the ingredients enumerated herein, in the required amount in a suitable solvent, followed by sterile filtration, as needed. Dispersions are usually prepared by incorporating the active compound into a sterile vehicle containing a basic dispersion medium and the other required ingredients enumerated above. In the case of sterile powders for preparing sterile injectable solutions, one method of preparation is vacuum drying and freeze-drying, which yields a powder of the active ingredient plus any additional desired ingredients from a previously sterile-filtered solution. Injectable preparations are processed and filled into containers such as ampoules, bags, bottles, syringes, or vials, and sealed under aseptic conditions according to methods known in the art. Such products preferably have a label or package insert indicating that the relevant composition is useful for treating subjects suffering from or susceptible to autoimmune or neoplastic diseases. Pharmaceutical formulations may be sterilized and / or contain adjuvants such as preservatives, stabilizers or emulsifiers, solution promoters, salts for adjusting the osmotic pressure and / or buffers, etc. In addition, they may also contain other therapeutically valuable substances.

[0071] Solution or suspension formulations used for subcutaneous application typically contain one or more of the following components: a sterile carrier such as water for injection, saline solution, fixed oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; an antibacterial agent such as benzyl alcohol or methylparaben; an antioxidant such as ascorbic acid or sodium bisulfite; a chelating agent such as ethylenediaminetetraacetic acid; a buffer such as acetate buffer, citrate buffer, or phosphate buffer; and a tonicity adjuster such as sodium chloride or dextrose. The pH can be adjusted with acids or bases such as hydrochloric acid or sodium hydroxide. Such preparations may be enclosed in glass or plastic ampoules, disposable syringes, or multiple-dose vials.

[0072] The pharmaceutical formulation of talabostat or its pharmaceutically acceptable salt for oral use herein may be administered in the form of, for example, tablets, capsules, powders, dispersible granules, sachets, etc., or as an aqueous solution or suspension, preferably as a tablet. Oral compositions generally include an inert carrier (e.g., a diluent) or an edible carrier. The formulation may be enclosed in a gelatin capsule or compressed into a tablet. Pharmaceutically compatible binders and / or adjuvants may be included as part of the formulation. The tablets, pills, capsules, granules, sachets, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, primogel, or corn starch; a lubricant such as magnesium stearate or stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0073] In some embodiments, the oral pharmaceutical formulations containing talabostat or a pharmaceutically acceptable salt thereof described herein may include one or more pharmaceutically acceptable carriers or adjuvants selected from the group including fillers, buffers, surfactants, and pH adjusters. The pharmaceutical formulation may be adjusted to a suitable pH.

[0074] In certain embodiments, talabostat or a pharmaceutically acceptable salt thereof is formulated as a tablet for oral administration according to the treatment regimen of the present disclosure. The pharmaceutical tablet may be an immediate release or modified release tablet. The tablet may be in a matrix form or a coated form.

[0075] Certain embodiments include various processes for making the above-described formulations or compositions, and such formulations can be manufactured by any of the processes known in the art.

[0076] Exemplary immediate-release tablets comprise an effective amount of talabostat or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers selected from diluents, binders, disintegrants, glidants, lubricants, pH modifiers, and combinations thereof.

[0077] Diluents: The one or more diluents include, but are not limited to, dibasic calcium phosphate, pullulan, maltodextrin, isomalt, sugar pellets, mannitol, spray-dried mannitol, microcrystalline cellulose, dibasic calcium phosphate dihydrate, lactose, sugars, sorbitol, a mixture of microcrystalline cellulose and guar gum (Avicel CE-15), a mixture of mannitol, polyplasdone, and syloid (Pharmaburst), a mixture of mannitol, crospovidone, and polyvinyl acetate (Ludiflash), isomalt, Panexcea, F-Melt, sucrose, calcium salts and similar inorganic salts, magnesium bicarbonate, and the like, and mixtures thereof. Preferably, the diluent is lactose or microcrystalline cellulose.

[0078] Binder: The one or more binders include, but are not limited to, low-substituted hydroxypropyl cellulose, xanthan gum, polyvinylpyrrolidone (povidone), gelatin, sugars, glucose, natural gum, rubber, synthetic cellulose, polymethacrylate, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, methylcellulose, and other cellulose derivatives, and mixtures thereof. Preferably, the binder is polyvinylpyrrolidone or hydroxypropylcellulose or hydroxypropylmethylcellulose.

[0079] Disintegrants: The one or more binders include, but are not limited to, at least one of sodium starch glycolate, croscarmellose sodium, crospovidone, sodium alginate, gum, starch, and magnesium aluminum silicate, or mixtures thereof. Preferably, the disintegrant is sodium starch glycolate.

[0080] Lubricants: One or more lubricants include, but are not limited to, sodium stearyl fumarate, sodium lauryl sulfate, magnesium stearate, polyethylene glycol, metal stearates, hydrogenated castor oil, and the like, and mixtures thereof. Preferably, the lubricant is magnesium stearate.

[0081] Lubricant: The one or more lubricants include, but are not limited to, stearic acid, colloidal silicon dioxide, talc, aluminum silicate, and the like, and mixtures thereof. Preferably, the lubricant is talc.

[0082] pH modifying agents: The one or more pH modifying agents include, but are not limited to, organic acids or salts thereof, such as phosphoric acid, citric acid, and the like.

[0083] In one embodiment, the relative proportions of the ingredients in a tablet formulation of talabostat are shown below in Table 1: [Table 1]

[0084] Exemplary talabostat mesylate immediate release tablets are shown below in Table 2: [Table 2]

[0085] In some embodiments, talabostat or a pharmaceutically acceptable salt thereof may be formulated as a modified-release matrix tablet. Exemplary extended-release tablets contain an effective amount of talabostat or a pharmaceutically acceptable salt thereof, and the pharmaceutically acceptable carrier or adjuvant is selected from diluents, binders, modified-release materials, glidants, lubricants, colorants, and combinations thereof. Alternatively, the modified-release tablet may contain an immediate-release core and a coating, wherein the coating contains a modified-release material and other pharmaceutical excipients.

[0086] Modified-release materials include, but are not limited to, polyvinylpyrrolidone (K90), hydroxypropyl methylcellulose (K4M, K10), hydroxypropyl cellulose (high-viscosity grade), carnauba wax, glyceryl behenate, castor wax, polyvinyl acetate, carboxymethylethylcellulose, ethylcellulose, cellulose phthalate or cellulose succinate, particularly cellulose acetate phthalate and hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose succinate, or hydroxypropyl methylcellulose acetate succinate; polymeric polyalkylene oxides such as polyethylene oxide and polypropylene oxide, and copolymers of ethylene oxide and propylene oxide, etc. Specific modified-release materials include polyvinylpyrrolidone (K90), hydroxypropyl methylcellulose (K4M, K10), hydroxypropyl cellulose (high-viscosity grade-HF), polyethylene oxide, etc. The modified-release material may conveniently be present in the range of 10-50% by weight of the tablet.

[0087] Exemplary modified-release tablets of talabostat or a pharmaceutically acceptable salt thereof are shown below in Table 3: [Table 3]

[0088] In some preferred embodiments, the amount of talabostat in a unit dose is about 50 micrograms, about 100 micrograms per tablet, about 200 micrograms per tablet, about 300 micrograms per tablet, about 400 micrograms per tablet, about 500 micrograms per tablet, about 600 micrograms per tablet, about 700 micrograms per tablet, or about 800 micrograms per tablet.

[0089] Various methods can be used to manufacture tablets of talabostat or its pharmaceutically acceptable salts for use in the therapeutic regimens of the present disclosure. One process involves dissolving talabostat in a suitable solvent (with or without a binder), and distributing this solution evenly over filler particles (which may contain other materials) to form agglomerated particles / granules. Wet granulation, coating, or spraying processes can also be used. Granules can be sized or further processed by dry granulation / slugging / roller compaction methods followed by a milling step to achieve suitable granules of a specific particle size distribution. The sized granules can be further blended with other ingredients and / or subsequently lubricated in a suitable blender and compressed into tablets of a specific size using appropriate tooling. Tablet coating, if appropriate, can be performed using conventional methods and standard equipment.

[0090] 5. Kit In some embodiments, the kit includes a formulation comprising talabostat or a pharmaceutically acceptable salt thereof and a formulation comprising pembrolizumab, with or without instructions for their use. The combination therapy can be manufactured and / or formulated by the same or different manufacturers. Thus, the combination therapy as a whole can be separate pharmaceutical dosage forms or compositions sold independently of each other. In several embodiments, the instructions for combination use are (i) provided prior to release to the physician (e.g., in the case of a "kit of parts" including a first therapeutic agent and another therapeutic agent), (ii) briefly provided prior to administration by the physician (or under the physician's guidance), or (iii) provided to the patient by the physician or medical staff.

[0091] In one example, a single bolus dose may be administered. In another example, multiple divided doses may be administered over time. In yet another example, the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. As used herein, dosage unit form refers to physically discrete units suited as unitary doses for treating mammalian subjects. Each unit may contain a predetermined amount of active compound calculated to produce the desired therapeutic effect. In some embodiments, the dosage unit forms of the present disclosure are dictated by and directly depend on the unique characteristics of the active compound and the specific therapeutic or prophylactic effect to be achieved.

[0092] In some embodiments, the kit comprises a package insert containing instructions for using talabostat or a pharmaceutically acceptable salt thereof and pembrolizumab to treat or delay the progression of cancer in a subject or to improve the immune function of a subject with cancer. In some embodiments, the kit comprises talabostat or a pharmaceutically acceptable salt thereof and pembrolizumab, and a package insert containing instructions for using the same to treat or delay the progression of cancer in a subject or to improve the immune function of a subject with cancer. In some embodiments, the kit comprises talabostat or a pharmaceutically acceptable salt thereof and pembrolizumab, and a package insert containing instructions for using the same to treat or delay the progression of cancer in a subject or to improve the immune function of a subject with cancer.

[0093] In some embodiments, the kit includes a container, including, but not limited to, a bottle, a vial (e.g., a dual-chamber vial), a syringe (single- or dual-chamber syringe), and a test tube. The container may be formed from a variety of materials, such as glass or plastic. In some embodiments, the kit may include a label (e.g., on or associated with the container) or package insert. The label or package insert may indicate that the compound contained in the kit may be, or may be intended to be, beneficial for treating or delaying the progression of cancer in a subject, or for improving immune function in a subject with cancer. The kit may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

[0094] 6.Results Patients with prostate cancer (e.g., SCNC) who are administered talabostat or a pharmaceutically acceptable salt thereof and pembrolizumab according to the treatment regimens disclosed herein preferably experience an improvement in at least one symptom of the cancer. In one embodiment, the improvement can be measured by a decrease in the amount and / or size of measurable tumor damage. In another embodiment, damage can be measured using x-rays, CT scans, or MRI scans. In another embodiment, cytology or histology can be used to assess responsiveness to therapy. In another embodiment, an extension of progression-free survival and / or overall survival can be achieved in patients with prostate cancer (e.g., SCNC). In another embodiment, an extension of progression-free survival and / or overall survival can be achieved in patients with advanced solid cancer.

[0095] In certain embodiments, the anti-tumor response is a tumor-specific response, a clinical response, a decrease in tumor size / volume, a decrease in tumor-specific biomarkers, an increase in anti-tumor cytokines, or a combination thereof.

[0096] In certain embodiments, the clinical response is a decrease in tumor growth and / or a decrease in tumor size. In certain embodiments, the initiation, maintenance, or enhancement of an anti-tumor immune response is for the treatment of cancer.

[0097] In a further aspect, the anti-tumor response is inhibition of tumor growth; induction of tumor cell death; tumor regression; tumor recurrence; prevention or delay of tumor growth, tumor spread; or elimination of the tumor.

[0098] In a further aspect, the anti-tumor response is a reduction in metastasis, a delay in metastasis, or a prevention of metastasis. In a preferred embodiment, the anti-tumor response is a prevention of metastasis.

[0099] In certain embodiments, the tumor response is a reduction in the number of tumor cells. In certain embodiments, the tumor response is a reduction in the rate of tumor growth. In certain embodiments, the tumor response is blockage of dipeptidyl peptidase enzyme activity. The tumor response is induction of an inflammatory cytokine response and a cytotoxic T cell response.

[0100] The treatment regimens described herein may be used to achieve a pulmonary respiration rate of greater than about 10%, greater than about 20%, greater than about 21%, greater than about 22%, greater than about 23%, greater than about 24%, greater than about 25%, greater than about 26%, greater than about 27%, greater than about 28%, greater than about 29%, greater than about 30%, greater than about 31%, greater than about 32%, greater than about 33%, greater than about 34%, greater than about 35%, greater than about 36%, greater than about 37%, greater than about 37%, greater than about 38%, greater than about 39%, greater than about 40%, greater than about 41%, greater than about 42%, greater than about 43%, greater than about 44%, greater than about 45%, greater than about 46%, greater than about 47%, greater than about 48%, greater than about 49%, greater than about 50%, greater than about 51%, greater than about 52%, greater than about 53%, greater than about 54%, greater than about 55%, greater than about 56% greater than about 57%, greater than about 58%, greater than about 59%, greater than about 60%, greater than about 61%, greater than about 62%, greater than about 63%, greater than about 64%, greater than about 65%, greater than about 66%, greater than 67%, greater than 68%, greater than 69%, greater than about 70%, greater than about 71%, greater than about 72%, greater than about 73%, greater than about 74%, greater than about 75%, greater than about 76%, greater than about 77%, greater than about 78%, greater than about 79%, greater than about 80%, greater than about 81%, greater than about 82%, greater than about 83%, greater than about 84%, greater than about 85%, greater than about 90%, greater than 91%, greater than 92%, greater than 93%, greater than 94%, greater than about 95%, greater than 96%, greater than 97%, greater than 98%, greater than 99%, and up to 100% inhibition of tumor size.

[0101] In some embodiments, the regimens and methods provided herein are for a period of 1 day to 2 years (e.g., 1 day to 22 months, 1 day to 20 months, 1 day to 18 months, 1 day to 16 months, 1 day to 14 months, 1 day to 12 months, 1 day to 10 months, 1 day to 9 months, 1 day to 8 months, 1 day to 7 months, 1 day to 6 months, 1 day to 5 months, 1 day to 4 months, 1 day to 3 months, 1 day to 2 months, 1 day to 1 month, 1 week to 2 years, 1 week to 22 months, 1 week to 20 months, 1 week to 18 months, 1 week to 16 months, 1 week to 14 months, 1 week to 12 months, 1 week to 10 months, 1 week to 9 months, 1 week to 8 months, months, 1 week to 7 months, 1 week to 6 months, 1 week to 5 months, 1 week to 4 months, 1 week to 3 months, 1 week to 2 months, 1 week to 1 month, 2 weeks to 2 years, 2 weeks to 22 months, 2 weeks to 20 months, 2 weeks to 18 months, 2 weeks to 16 months, 2 weeks to 14 months, 2 weeks to 12 months, 2 weeks to 10 months, 2 weeks to 9 months, 2 weeks to 8 months, 2 weeks to 7 months, 2 weeks to 6 months, 2 weeks to 5 months, 2 weeks to 4 months, 2 weeks to 3 months, 2 weeks to 2 months, 2 weeks to 1 month, 1 month to 2 years, 1 month to 22 months, 1 month to 20 months, 1 month to 18 months, 1 month to 16 months, 1 month 1 month to 14 months, 1 month to 12 months, 1 month to 10 months, 1 month to 9 months, 1 month to 8 months, 1 month to 7 months, 1 month to 6 months, 1 month to 6 months, 1 month to 5 months, 1 month to 4 months, 1 month to 3 months, 1 month to 2 months, 2 months to 2 years, 2 months to 22 months, 2 months to 20 months, 2 months to 18 months, 2 months to 16 months, 2 months to 14 months, 2 months to 12 months, 2 months to 10 months, 2 months to 9 months, 2 months to 8 months, 2 months to 7 months, 2 months to 6 months, or 2 months to 5 months, 2 months to 4 months, 3 months to 2 years, 3 months to 22 months, 3 months to 20 months, 3 months ~18 months, 3 months to 16 months, 3 months to 14 months, 3 months to 12 months, 3 months to 10 months, 3 months to 8 months, 3 months to 6 months, 4 months to 2 years, 4 months to 22 months, 4 months to 22 months, 4 months to 20 months, 4 months to 16 months, 4 months to 14 months, 4 months to 12 months, 4 months to 10 months, 4 months to 8 months, 4 months to 6 months, 6 months to 2 years, 6 months to 22 months, 6 months to 20 months, 6 months to 18 months, 6 months to 16 months, 6 months to 14 months, 6 months to 12 months, 6 months to 10 months, or 6 months to 8 months) after treatment with combination therapy.1% to 99% (e.g., 1% to 98%, 1% to 95%, 1% to 90%, 1% to 85%, 1% to 80%, 1% to 75%, 1% to 70%, 1% to 65%, 1% to 60%, 1% to 55%, 1% to 50%, 1% to 45%, 1% to 40%, 1% to 35%, 1% to 30%, 1% to 25%, 1% to 20%, 1% to 15%, 1% to 10%, 1% to 5%, 2% to 99%, 2% to 90%, 2% to 85%, 2% to 80%, 2% to 75%, 2% to 70%, 2% to 65%, 2% to 60%, 2% to 5 ... ~50%, 2%~45%, 2%~40%, 2%~35%, 2%~30%, 2%~25%, 2%~20%, 2%~15%, 2%~10%, 2%~5%, 4%~99%, 4%~95%, 4%~90%, 4%~85%, 4%~80%, 4%~75%, 4%~70%, 4%~6 ... %~60%, 4%~55%, 4%~50%, 4%~45%, 4%~40%, 4%~35%, 4%~30%, 4%~25%, 4%~20%, 4%~15%, 4%~10%, 6%~99%, 6%~95%, 6%~90%, 6%~85%, 6%~80%, 6%~75%, 6%~70%, 6%~65%, 6%~60%, 6%~55%, 6%~50%, 6%~45%, 6%~40%, 6%~35%, 6%~30%, 6%~25%, 6%~20%, 6%~15%, 6%~10%, 8%~99%, 8%~95%, 8%~90%, 8%~85%, 8%~80%, 8%~75 %, 8%~70%, 8%~65%, 8%~60%, 8%~55%, 8%~50%, 8%~45%, 8%~40%, 8%~35%, 8%~30%, 8%~25%, 8%~20%, 8%~15%, 10%~99%, 10%~95%, 10%~90%, 10%~85%, 10%~80% , 10%~75%, 10%~70%, 10%~65%, 10%~60%, 10%~55%, 10%~50%, 10%~45%, 10%~40%, 10%~35%, 10%~30%, 10%~25%, 10%~20%, 10%~15%, 15%~99%, 15%~95%, 15% ~90%, 15%~85%, 15%~80%, 15%~75%, 15%~70%, 15%~65%, 15%~60%, 15%~55%, 15%~50%, 15%~55%, 15%~50%, 15%~45%, 15%~40%, 15%~35%, 15%~30%, 15%~25%,15%~20%、20%~99%、20%~95%、20%~90%、20%~85%、20%~80%、20%~75%、20%~70%、20%~65%、20%~60%、20%~55%、20%~50%、20%~45%、20%~40%、20%~35%、20%~30%、20%~25%、25%~99%、25%~95%、25%~90%、25%~85%、25%~80%、25%~75%、25%~70%、25%~65%、25%~60%、25%~55%、25%~50%、25%~45%、25%~40%、25%~35%、25%~30%、30%~99%、30%~95%、30%~90%、30%~85%、30%~80%、30%~75%、30%~70%、30%~65%、30%~60%、30%~55%、30%~50%、30%~45%、30%~40%、30%~35%、35%~99%、35%~95%、35%~90%、35%~85%、35%~80%、35%~75%、35%~70%、35%~65%、35%~60%、35%~55%、35%~50%、35%~45%、35%~40%、40%~99%、40%~95%、40%~90%、40%~85%、40%~80%、40%~75%、40%~70%、40%~65%、40%~60%、40%~55%、40%~60%、40%~55%、40%~50%、40%~45%、45%~99%、45%~95%、45%~95%、45%~90%、45%~85%、45%~80%、45%~75%、45%~70%、45%~65%、45%~60%、45%~55%、45%~50%、50%~99%、50%~95%、50%~90%、50%~85%、50%~80%、50%~75%、50%~70%、50%~65%、50%~60%、50%~55%、50%~99%、55%~95%、55%~90%、55%~85%、55%~80%、55%~75%、55%~70%、55%~65%、55%~60%、60%~99%、60%~95%、60%~90%、60%~85%、60%~80%、60%~75%、60%~70%、60%~65%、65%~99%、60%~95%、60%~90%、60%~85%、60%~80%、60%~75%、60%~70%、60%~65%、70%~99%、70%~95%、70%~90%、70%~85%、70%~80%、The method can result in a reduction in the volume of one or more solid tumors in a patient by 70% to 75%, 75% to 99%, 75% to 95%, 75% to 90%, 75% to 85%, 75% to 80%, 80% to 99%, 80% to 95%, 80% to 90%, 80% to 85%, 85% to 99%, 85% to 95%, 85% to 90%, 90% to 99%, 90% to 95%, or 95% to 100%.

[0102] In some embodiments, the regimens or methods provided herein provide a therapeutic effect of 1% to 99% (e.g., 1% to 98%, 1% to 95%, 1% to 90%, 1% to 85%, 1% to 80%, 1% to 75%, 1% to 70%, 1% to 65%, 1% to 60%, 1% to 55%, 1% to 50%, 1% to 45%, 1% to 40%, 1% to 35%, 1% to 30%, 1% to 25%, 1% to 20%, 1% to 15%, 1% to 10%, 1% to 5%, 2% to 99%, 2% to 90%, 2% to 85%, 2% to 80%, 2% to 75%, 2% to 70%, 2% to 65%, 2% to 60%, 2% to 5 ... %~50%, 2%~45%, 2%~40%, 2%~35%, 2%~30%, 2%~25%, 2%~20%, 2%~15%, 2%~10%, 2%~5%, 4%~99%, 4%~95%, 4%~90%, 4%~85%, 4%~80%, 4%~75%, 4%~70%, 4%~65%, 4%~60%, 4%~55%, 4%~50%, 4%~45%, 4%~40%, 4%~35%, 4%~30%, 4%~25%, 4%~20%, 4%~15%, 4%~10%, 6%~99%, 6%~95%, 6%~90%, 6%~85%, 6%~80%, 6%~75%, 6%~70% , 6%~65%, 6%~60%, 6%~55%, 6%~50%, 6%~45%, 6%~40%, 6%~35%, 6%~30%, 6%~25%, 6%~20%, 6%~15%, 6%~10%, 8%~99%, 8%~95%, 8%~90%, 8%~85%, 8%~80%, 8%~7 5%, 8%~70%, 8%~65%, 8%~60%, 8%~55%, 8%~50%, 8%~45%, 8%~40%, 8%~35%, 8%~30%, 8%~25%, 8%~20%, 8%~15%, 10%~99%, 10%~95%, 10%~90%, 10%~85%, 10%~80 %, 10%~75%, 10%~70%, 10%~65%, 10%~60%, 10%~55%, 10%~50%, 10%~45%, 10%~40%, 10%~35%, 10%~30%, 10%~25%, 10%~20%, 10%~15%, 15%~99%, 15%~95%, 15% ~90%, 15%~85%, 15%~80%, 15%~75%, 15%~70%, 15%~65%, 15%~60%, 15%~55%, 15%~50%, 15%~55%, 15%~50%, 15%~45%, 15%~40%, 15%~35%, 15%~30%, 15%~25%,15%~20%、20%~99%、20%~95%、20%~90%、20%~85%、20%~80%、20%~75%、20%~70%、20%~65%、20%~60%、20%~55%、20%~50%、20%~45%、20%~40%、20%~35%、20%~30%、20%~25%、25%~99%、25%~95%、25%~90%、25%~85%、25%~80%、25%~75%、25%~70%、25%~65%、25%~60%、25%~55%、25%~50%、25%~45%、25%~40%、25%~35%、25%~30%、30%~99%、30%~95%、30%~90%、30%~85%、30%~80%、30%~75%、30%~70%、30%~65%、30%~60%、30%~55%、30%~50%、30%~45%、30%~40%、30%~35%、35%~99%、35%~95%、35%~90%、35%~85%、35%~80%、35%~75%、35%~70%、35%~65%、35%~60%、35%~55%、35%~50%、35%~45%、35%~40%、40%~99%、40%~95%、40%~90%、40%~85%、40%~80%、40%~75%、40%~70%、40%~65%、40%~60%、40%~55%、40%~60%、40%~55%、40%~50%、40%~45%、45%~99%、45%~95%、45%~95%、45%~90%、45%~85%、45%~80%、45%~75%、45%~70%、45%~65%、45%~60%、45%~55%、45%~50%、50%~99%、50%~95%、50%~90%、50%~85%、50%~80%、50%~75%、50%~70%、50%~65%、50%~60%、50%~55%、50%~99%、55%~95%、55%~90%、55%~85%、55%~80%、55%~75%、55%~70%、55%~65%、55%~60%、60%~99%、60%~95%、60%~90%、60%~85%、60%~80%、60%~75%、60%~70%、60%~65%、65%~99%、60%~95%、60%~90%、60%~85%、60%~80%、60%~75%、60%~70%、60%~65%、70%~99%、70%~95%、70%~90%、70%~85%、70%~80%、A reduction in the risk of progression of metastases, or the risk of progression of further metastases, in patients with prostate cancer of 70% to 75%, 75% to 99%, 75% to 95%, 75% to 90%, 75% to 85%, 75% to 80%, 80% to 99%, 80% to 95%, 80% to 90%, 80% to 85%, 85% to 99%, 85% to 95%, 85% to 90%, 90% to 99%, 90% to 95%, or 95% to 100%.

[0103] In some embodiments, the treatment regimens or methods described herein result in an increase in patient survival time (e.g., between 1% and 400%, between 1% and 380%, between 1% and 360%, between 1% and 340%, between 1% and 320%, between 1% and 300%, between 1% and 280%, between 1% and 260%, between 1% and 240%, between 1% and 220%, between 1% and 200%, between 1% and 180%, between 1% and 160%, between 1% and 140%, between 1% and 120%, between 1% and 100%, between 1% and 95%, between 1% and 90%, between 1% and 85%, between 1% and 80%, 1%~75%, 1%~70%, 1%~65%, 1%~60%, 1%~55%, 1%~50%, 1%~45%, 1%~40%, 1%~35%, 1%~30%, 1%~25%, 1%~20%, 1%~15%, 1%~10%, 1%~5%, 5%~400%, 5%~380%, 5%~3 60%, 5%~340%, 5%~320%, 5%~300%, 5%~280%, 5%~260%, 5%~240%, 5%~220%, 5%~200%, 5%~180%, 5%~160%, 5%~140%, 5%~120%, 5%~100%, 5%~90%, 5%~80%, 5%~ 70%, 5%~60%, 5%~50%, 5%~40%, 5%~30%, 5%~20%, 5%~10%, 10%~400%, 10%~380%, 10%~360%, 10%~340%, 10%~320%, 10%~300%, 10%~280%, 10%~260%, 10%~24 0%, 10%~220%, 10%~200%, 10%~180%, 10%~160%, 10%~140%, 10%~120%, 10%~100%, 10%~90%, 10%~80%, 10%~70%, 10%~60%, 10%~50%, 10%~40%, 10%~30%, 10% ~20%, 20%~400%, 20%~380%, 20%~360%, 20%~340%, 20%~320%, 20%~300%, 20%~280%, 20%~260%, 20%~240%, 20%~220%, 20%~200%, 20%~180%, 20%~160%, 20% ~140%, 20%~120%, 20%~100%, 20%~90%, 20%~80%, 20%~70%, 20%~60%, 20%~50%, 20%~40%, 20%~30%, 30%~400%, 30%~380%, 30%~360%, 30%~340%, 30%~320%,30%~300%、30%~280%、30%~260%、30%~240%、30%~220%、30%~200%、30%~180%、30%~160%、30%~140%、30%~120%、30%~100%、30%~90%、30%~80%、30%~70%、30%~60%、30%~50%、30%~40%、40%~400%、40%~380%、40%~360%、40%~340%、40%~320%、40%~300%、40%~280%、40%~260%、40%~240%、40%~220%、40%~200%、40%~180%、40%~160%、40%~140%、40%~120%、40%~100%、40%~90%、40%~80%、40%~70%、40%~60%、40%~50%、50%~400%、50%~380%、50%~360%、50%~340%、50%~320%、50%~300%、50%~280%、50%~260%、50%~240%、50%~220%、50%~200%、50%~180%、50%~160%、50%~140%、50%~140%、50%~120%、50%~100%、50%~90%、50%~80%、50%~70%、50%~60%、60%~400%、60%~380%、60%~360%、60%~340%、60%~320%、60%~300%、60%~280%、60%~260%、60%~240%、60%~220%、60%~200%、60%~180%、60%~160%、60%~140%、60%~120%、60%~100%、60%~90%、60%~80%、60%~70%、70%~400%、70%~380%、70%~360%、70%~340%、70%~320%、70%~300%、70%~280%、70%~260%、70%~240%、70%~220%、70%~200%、70%~180%、70%~160%、70%~140%、70%~120%,~100%、70%~90%、70%~80%、80%~400%、80%~380%、80%~360%、80%~340%、80%~320%、80%~300%、80%~280%、80%~260%、80%~240%、80%~220%、80%~200%、80%~180%、80%~160%、80%~140%、80%~120%、80%~100%、80%~90%、90%~400%、90%~380%、90%~360%、90%~340%、90%~320%、90%~300%、90%~280%、90%~260%、90%~240%、90%~220%、90%~200%、90%~180%、90%~160%、90%~140%、90%~120%、90%~100%、100%~400%、100%~380%、100%~360%、100%~340%、100%~320%、100%~300%、100%~280%、100%~260%、100%~240%、100%~220%、100%~200%、100%~180%、100%~160%、100%~140%、100%~120%、120%~400%、120%~380%、120%~360%、120%~340%、120%~320%、120%~300%、120%~280%、120%~260%、120%~240%、120%~220%、120%~200%、120%~180%、120%~160%、120%~140%、140%~400%、140%~380%、140%~360%、140%~340%、140%~320%、140%~300%、140%~280%、140%~260%、140%~240%、140%~220%、140%~200%、140%~180%、140%~160%、160%~400%、160%~380%、160%~360%、160%~340%、160%~320%、160%~300%、160%~280%、160%~260%、160%~240%、160%~220%、160%~200%、160%~180%、180%~400%、180%~380%、180%~360%、180%~340%、180%~320%、180%~300%、180%~280%、180%~260%、180%~240%、180%~220%、180%~200%、200%~400%、200%~380%、200%~360%、200%~340%、200%~320%、200%~300%、200%~280%、200%~260%、200%~240%、200%~220%、220%~400%、220%~380%、220%~360%、220%~340%、220%~320%、220%~300%、220%~280%、220%~260%、220%~240%、240%~400%、240%~380%, 240%~360%, 240%~340%, 240%~320%, 240%~300%, 240%~280%, 240%~260%, 260%~400%, 260%~380%, 260%~360%, 260%~340%, 260%~320%, 260%~300%, 260% to 280%, 280% to 400%, 280% to 380%, 280% to 360%, 280% to 340%, 280% to 320%, 280% to 300%, 300% to 400%, 300% to 380%, 300% to 360%, 300% to 340%, or 300% to 320%.

[0104] In one embodiment, patients suffering from prostate cancer (e.g., SCNC) who are administered talabostat or a pharmaceutically acceptable salt thereof and pembrolizumab according to the treatment regimen disclosed herein may exhibit complete response (CR), partial response (PR), stable disease (SD), immune-mediated complete disease (irCR), immune-mediated partial response (irPR), or immune-mediated stable disease (irSD). In another embodiment, patients suffering from advanced solid cancer who are administered talabostat or a pharmaceutically acceptable salt thereof and pembrolizumab according to the treatment regimen disclosed herein may exhibit complete response (CR), partial response (PR), stable disease (SD), immune-mediated complete disease (irCR), immune-mediated partial response (irPR), or immune-mediated stable disease (irSD).

[0105] In another embodiment, a patient suffering from prostate cancer (e.g., SCNC) who is administered talabostat or a pharmaceutically acceptable salt thereof and pembrolizumab according to the treatment regimen disclosed herein may experience tumor shrinkage and / or a reduction in the rate of growth, i.e., suppression of tumor growth. In another embodiment, unwanted cell proliferation may be reduced or inhibited.

[0106] In still other embodiments, one or more of the following may occur in a patient afflicted with prostate cancer (e.g., SCNC) who is administered talabostat, or a pharmaceutically acceptable salt thereof, and pembrolizumab in accordance with the treatment regimens disclosed herein: the number of cancer cells may be reduced; tumor size may be reduced; infiltration of cancer cells into peripheral organs may be inhibited, delayed, slowed, or stopped; tumor metastasis may be slowed or inhibited; tumor growth may be inhibited; tumor recurrence may be prevented or delayed; or one or more symptoms associated with cancer may be alleviated.

[0107] In other embodiments, patients suffering from prostate cancer (e.g., SCNC) who are administered talabostat or a pharmaceutically acceptable salt thereof and pembrolizumab according to the treatment regimens disclosed herein may exhibit at least one therapeutic effect selected from the group consisting of a decrease in tumor size, a reduction in the number of metastatic lesions appearing over time, a complete remission, a partial remission, or stable disease.

[0108] In yet other embodiments, the treatment regimens herein may produce comparable clinical response rates (CBR=CR+PR+SD≧6 months) that are better than those achieved with talabostat or a pharmaceutically acceptable salt thereof, or pembrolizumab alone.

[0109] In other embodiments, the improvement in clinical benefit rate achieved with the treatment regimens of the present disclosure may be about 20%, 30%, 40%, 50%, 60%, 70%, 80% or more compared to treatment with talabostat or pembrolizumab alone.

[0110] In some embodiments, the therapeutic regimens of the present disclosure may result in CD8+ T cells in a subject with improved priming, activation, proliferation, and / or cytolytic activity compared to administration of talabostat or a pharmaceutically acceptable salt thereof, or pembrolizumab alone.

[0111] In some embodiments, the number of CD4+ and / or CD8+ T cells is increased compared to before administration of the combination.

[0112] In some embodiments, the activated CD4+ and / or CD8+ T cells are characterized by y-IFN+-producing CD4+ and / or CD8+ T cells and / or enhanced cytolytic activity compared to before administration of the combination.

[0113] In some embodiments, the CD4+ and / or CD8+ T cells exhibit increased release of cytokines selected from the group consisting of G-CSF, MCP-1, eotaxin, IFN-γ, KC, TNF-α, and interleukins (IL-5, IL-6, IL-1β, IL-12p70, IL-18).

[0114] In some embodiments, the CD4+ and / or CD8+ T cells are effector memory T cells. In some embodiments, the CD4+ and / or CD8+ effector memory T cells are characterized by γ-IFN+-producing CD4+ and / or CD8+ T cells and / or enhanced cytolytic activity.

[0115] In some embodiments, the serum concentration of the cytokine IL-18 and / or the chemokines GM-CSF, G-CSF in a subject is increased in the presence of a combination of talabostat, or a pharmaceutically acceptable salt thereof, and pembrolizumab compared to administration of the agents alone.

[0116] In some embodiments, the cancer has increased T cell infiltration when the combination of talabostat, or a pharmaceutically acceptable salt thereof, and pembrolizumab is used in accordance with the treatment regimens described herein, compared to administration of talabostat or pembrolizumab alone.

[0117] In some embodiments, when cancers are used according to the treatment regimens described herein, the concentration of T regulatory cells is suppressed / decreased in the presence of the combination of talabostat or a pharmaceutically acceptable salt thereof and pembrolizumab compared to administration of talabostat or a pharmaceutically acceptable salt thereof, or pembrolizumab alone. In some embodiments, when cancers are used according to the treatment regimens described herein, the concentration of NK cells and macrophages is increased in the presence of the combination of talabostat or a pharmaceutically acceptable salt thereof, and pembrolizumab compared to administration of talabostat or a pharmaceutically acceptable salt thereof, or pembrolizumab alone.

[0118] With respect to the target lesion, responses to the treatment regimens described herein may include complete remission (CR), partial remission (PR), progressive disease (PD), stable disease (SD), immune-related complete remission (irCR), immune-related partial remission (irPR), immune-related progressive disease (irPD), and immune-related stable disease (irSD).

[0119] For non-target lesions, responses to the treatment regimens described herein may include complete remission (CR), progressive disease (PD), immune-related complete remission (irCR), and immune-related progressive disease (irPD).

[0120] In one embodiment, the treated patient exhibits a complete response (CR), partial response (PR), stable disease (SD), immune-related complete disease (irCR), immune-related partial response (irPR), or immune-related stable disease (irSD). In another embodiment, the treated patient experiences tumor shrinkage and / or a slowed growth rate, i.e., suppression of tumor growth. In another embodiment, unwanted cell proliferation is reduced or inhibited. In yet other embodiments, one or more of the following may occur: the number of cancer cells may be reduced; tumor size may be reduced; cancer cell invasion of peripheral organs may be inhibited, delayed, slowed, or halted; tumor metastasis may be slowed or inhibited; tumor growth may be inhibited; tumor recurrence may be prevented or delayed; or one or more symptoms associated with cancer may be alleviated to some extent.

[0121] 7. Specific Embodiments of the Disclosure Embodiment 1: A regimen for treating prostate cancer in a subject in need thereof, comprising administering to the subject an effective amount of talabostat, or a pharmaceutically acceptable salt thereof, and an effective amount of pembrolizumab, in separate pharmaceutical formulations.

[0122] Embodiment 2: A method of treating prostate cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of talabostat, or a pharmaceutically acceptable salt thereof, and an effective amount of pembrolizumab, in separate pharmaceutical formulations.

[0123] Embodiment 3: A method of enhancing an immune response in a subject suffering from prostate cancer, the method comprising administering to the subject a regimen comprising an effective amount of talabostat, or a pharmaceutically acceptable salt thereof, and an effective amount of pembrolizumab, as separate pharmaceutical formulations.

[0124] Embodiment 4: A method of improving the innate immune response in a subject afflicted with prostate cancer, the method comprising administering to the subject an effective amount of talabostat or a pharmaceutically acceptable salt thereof, and an effective amount of pembrolizumab, as separate pharmaceutical formulations, wherein the improved innate immune response is associated with increased activity of tumor-destructive natural killer cells and macrophages, as well as NK cells and CD8+ T cells.

[0125] Embodiment 5: A method of enhancing the innate immune response in a subject with prostate cancer, the method comprising administering to the subject an effective amount of talabostat, or a pharmaceutically acceptable salt thereof, and an effective amount of pembrolizumab, in separate pharmaceutical formulations, wherein the enhanced innate immune response is associated with suppression of T regulatory cells.

[0126] Embodiment 6: A method for treating, delaying the progression of, or preventing or delaying tumor recurrence, tumor growth, or tumor expansion in a subject afflicted with prostate cancer (e.g., SCNC), the method comprising administering to the subject effective amounts of talabostat, or a pharmaceutically acceptable salt thereof, and pembrolizumab, in separate pharmaceutical formulations.

[0127] Embodiment 7: A method of improving immune function in a subject afflicted with prostate cancer (e.g., SCNC), the method comprising administering to the subject effective amounts of talabostat or a pharmaceutically acceptable salt thereof, and pembrolizumab, in separate pharmaceutical formulations.

[0128] Embodiment 8: A method of initiating, maintaining, or improving an anti-tumor immune response in a subject afflicted with prostate cancer (e.g., SCNC), the method comprising administering to the subject effective amounts of talabostat, or a pharmaceutically acceptable salt thereof, and pembrolizumab, in separate pharmaceutical formulations.

[0129] Embodiment 9: A method of reducing the toxicity of talabostat with a lower effective dose of talabostat, the method comprising administering to a subject with prostate cancer (e.g., SCNC) effective amounts of talabostat or a pharmaceutically acceptable salt thereof, and pembrolizumab, as separate pharmaceutical formulations.

[0130] Embodiment 10: The treatment regimen or method of any one of embodiments 1-9, wherein the talabostat, or a pharmaceutically acceptable salt thereof, and pembrolizumab are administered to the subject in one or more (e.g., 1, 2, 3, 4, 5, 6 or more) treatment cycles, each treatment cycle being about 21 days in duration.

[0131] Embodiment 11: The treatment regimen or method of any one of embodiments 1 to 10, wherein the subject maintains a sustained response against the progression of prostate cancer after treatment has ended.

[0132] Embodiment 12: The treatment regimen or method of embodiment 10 or 11, wherein, for each treatment cycle, talabostat or a pharmaceutically acceptable salt thereof is administered on each of days 1 to 14, and pembrolizumab is administered on day 1.

[0133] Embodiment 13: A treatment regimen or method according to any one of embodiments 1 to 12, wherein talabostat or a pharmaceutically acceptable salt thereof is administered orally (e.g., in a tablet formulation).

[0134] Embodiment 14: The treatment regimen or method of any one of embodiments 1 to 12, wherein pembrolizumab is administered by injection (e.g., intravenously).

[0135] Embodiment 15: The treatment regimen or method of any one of embodiments 1 to 14, wherein talabostat or a pharmaceutically acceptable salt thereof is administered at a total daily dose of about 0.001 mg / kg to about 0.1 mg / kg (e.g., about 0.001 mg / kg to about 0.035 mg / kg, or about 0.001 mg / kg to about 0.014 mg / kg).

[0136] Embodiment 16: The treatment regimen or method of any one of embodiments 1 to 15, wherein pembrolizumab is administered at a dose of about 1 mg / kg to about 10 mg / kg per day.

[0137] Embodiment 17: A treatment regimen or method according to any one of embodiments 1 to 16, wherein talabostat or a pharmaceutically acceptable salt thereof is administered at a total daily dose of about 0.4 mg to about 0.6 mg (e.g., orally administered twice daily, such as a dose of about 0.4 mg in the morning and a dose of about 0.2 mg in the evening).

[0138] Embodiment 18: A treatment regimen or method according to any one of embodiments 1 to 17, wherein pembrolizumab is administered at a total dose of about 100 mg to about 500 mg per day (e.g., about 200 mg per day).

[0139] Embodiment 19: A treatment regimen or method according to any one of embodiments 1 to 18, wherein the total daily dose of talabostat or a pharmaceutically acceptable salt thereof in cycle 1 is less than the total daily dose of talabostat or a pharmaceutically acceptable salt thereof in one or more subsequent cycles.

[0140] Embodiment 20: A therapeutic regimen or method according to any one of embodiments 1 to 19, comprising administering talabostat mesylate.

[0141] Embodiment 21: A therapeutic regimen for the treatment of prostate cancer in a subject in need thereof, the regimen comprising administering to the subject one or more treatment cycles of talabostat mesylate and pembrolizumab, each treatment cycle being about 21 days in duration, and wherein, for each treatment cycle, talabostat is administered on each of days 1-14, pembrolizumab is administered on day 1, talabostat mesylate is administered as one or more tablets to provide a total daily dose of talabostat of about 0.4 mg to about 0.6 mg, and pembrolizumab is administered as a single intravenous injection to provide a dose of about 100 mg to about 500 mg per day. [Example]

[0142] Example 1: Treatment regimen for Phase 1b / 2 study This Phase 1b / 2 study is designed to measure the composite response rate of a daily oral formulation of talabostat mesylate in combination with a formulation of pembrolizumab (more specifically, Keytruda®) in patients with SCNC. The study will also evaluate other efficacy parameters, such as rPFS, PSA, PFS, OS, and DOR, as well as the safety of the combination treatment. The study consists of two phases: Lead-in Phase - This study evaluated the safety and tolerability of talabostat mesylate administered once daily (QD) on days 1–14 of a 21-day cycle in combination with pembrolizumab 200 mg administered intravenously (IV) on day 1 of each 21-day cycle. During the lead-in phase, the pembrolizumab dose was fixed (200 mg IV qday 21), and the talabostat mesylate dose was escalated (0.4 mg–0.6 mg orally QD on days 1–14 of a 21-day cycle) using a 3 × 3 design in patients with SCNC. In cycle 1, the initial dose of talabostat mesylate administered was 0.4 mg. Following no safety concerns after treatment, the dose was increased to 0.6 mg. There was a 7-day rest period after the final (14th) dose of talabostat mesylate and day 1 of subsequent cycles. The key endpoints were safety and the recommended phase 2 dose (RP2D) for the combination. Composite response (RECIST, PSA, CTC) was also assessed. If there are no safety concerns at 0.6 mg, this will then be the RP2D used in the efficacy stage. If safety concerns exist, the 0.6 mg cohort will be expanded to enroll additional patients. The dosing schedule may also be adjusted.

[0143] During the lead-in stage, no patients were observed to have dose-limiting toxicities (DLTs) during cycle 1. Three patients were initially treated with 0.4 mg talabostat mesylate plus pembrolizumab (200 mg IV). - Because no DLTs were observed in Cycle 1, the dose of talabostat mesylate was increased to 0.6 mg in the next cohort of 3 patients. - If one or more of the three original patients had a DLT in Cycle 1, after discussion with the sponsor and investigator, either three patients (if one patient experienced a DLT) or six to nine patients (if two or three patients experienced a DLT) were added at the 0.4 mg talabostat mesylate dose level. For this expanded 0.4 mg cohort, If less than one-third of patients experience DLTs, consider dose escalation to 0.6 mg talabostat mesylate plus pembrolizumab ○ If one-third of patients experience DLT, the efficacy stage can begin If more than one-third of patients experience DLTs, discussions will be held between the investigator and sponsor regarding how to proceed.

[0144] After dose escalation to 0.6 mg talabostat mesylate plus pembrolizumab in 3 patients, - At this dose level, if there are no DLTs or 1 / 3 of patients have DLTs, the efficacy stage can begin. -If more than one-third of patients had DLT in cycle 1, after discussion with the sponsor and investigator, 6 to 9 patients were added at the 0.4 mg talabostat mesylate dose level. If 1 / 3 or less patients have DLT, the efficacy stage may be initiated at the 0.6 mg talabostat mesylate dose plus pembrolizumab. - If more than one-third of patients experience DLTs, consider using 0.4 mg talabostat mesylate plus pembrolizumab during the efficacy stage.

[0145] Figure 1 presents an overview of the study.

[0146] During the lead-in stage, patients who do not meet the discontinuation criteria will be allowed to continue treatment at their originally assigned dose.

[0147] All safety data from all patients enrolled in each cohort will be reviewed to identify any DLTs experienced and determine enrollment in the next cohort and the talabostat mesylate dose to be used in the efficacy stage. Patients must receive >70% of the talabostat mesylate dose in Cycle 1 (i.e., ≥10 of the planned 14 doses) plus pembrolizumab administered on Day 1 of Cycle 1 to be eligible for DLT assessment, unless the dose is maintained due to an AE.

[0148] Toxicity will be assessed by the investigator using the Common Terminology Criteria for Adverse Events (NCI CTCAE) (Version 5). The relationship of AEs to concomitant therapy (i.e., attribution to talabostat mesylate and / or pembrolizumab) must be assessed by the investigator using the criteria in the protocol.

[0149] A DLT is defined as any of the following AEs occurring during Cycle 1, regardless of the investigator's attribution to study treatment, unless the AE can clearly and indisputably be attributed to an unrelated cause (e.g., disease progression): - Any Grade 4 laboratory-based anomaly, regardless of duration - Any Grade 3 non-hematologic AE (except Grade 3 nausea, vomiting, diarrhea, constipation, fever, fatigue, skin rash, or nonclinical significant laboratory abnormalities that resolve to Grade 2 or less with optimal medical management within 72 hours). - Grade 3 thrombocytopenia greater than Grade 1, with requirement for blood sampling or platelet transfusion. - Grade 3 febrile neutropenia. - Grade 3 fever. - Grade 3 skin rash. - Laboratory abnormalities meeting Hy's law criteria (aspartate aminotransferase [AST] or alanine aminotransferase [ALT] > 3 × upper limit of normal [ULN] with concomitant total bilirubin > 2 × ULN). - Grade 3 transaminase (AST / ALT) elevation. - Any toxicity resulting in ≥30% held / skipped doses of talabostat mesylate during Cycle 1. - Delay of Cycle 2 by 14 days or more due to toxicity. Any other significant toxicity deemed by the investigator and sponsor's medical representative to be dose limiting.

[0150] Efficacy Stage: Following safety assessment and confirmation of the talabostat mesylate / pembrolizumab dose schedule (i.e., talabostat mesylate at a total daily dose of either 0.6 mg or 0.4 mg) to be used in later stages, the efficacy stage will begin. Eligible SCNC patients will receive talabostat mesylate QD on days 1-14 of a 21-day cycle, plus pembrolizumab 200 mg administered IV on day 1 of each 21-day cycle.

[0151] Study design characteristics (both stages): During the lead-in stage, patients were screened for the study after providing written informed consent and within 28 days prior to their first study drug administration. Patients who were determined to be eligible based on the screening assessment were enrolled in the study on Day 1 of Cycle 1 (baseline, prior to the first dose of talabostat mesylate). Similarly, during the efficacy stage, patients were screened as per the process described above.

[0152] All study visits will be conducted on an outpatient basis but, at the investigator's discretion, may be conducted on an inpatient basis.All study visits will be conducted on an outpatient basis but, at the investigator's discretion, may be conducted on an inpatient basis.

[0153] All patients must undergo pretreatment (before study treatment administration) imaging (chest / abdominal / pelvic computed tomography [CT] scan or magnetic resonance imaging [MRI] for baseline tumor measurement, and bone scintigraphy [BS]). Patients with cutaneous, subcutaneous, or lymph node metastases may also have tumor assessment (including ruler measurement) via physical examination. Patients with a history of central nervous system (CNS) malignant infiltration or CNS symptoms must undergo either CT or MRI imaging of the brain to evaluate for active CNS malignancy.

[0154] Tumor measurements and disease response assessments (CT or MRI; BS) should also be performed at the end of Cycle 3 (approximately 9 weeks after the first study treatment administration), and then approximately every 9 weeks thereafter until progression to progressive disease (PD). For patients with evidence of disease control (stable disease or better) at Week 27, tumor and disease response assessments can be performed less frequently thereafter (approximately every 12 weeks). Tumor measurements and disease response assessments can also be performed at the end of treatment (EOT) visit.

[0155] In addition, serum PSA measurements will be performed on day 1 of each treatment cycle. See Figure 2.

[0156] CTC counts by Veridex assay will be performed on Day 1 of Cycle 1, Day 1 of Cycle 2, Day 1 of Cycle 4, and every 3 cycles thereafter until the EOT visit.

[0157] The population pharmacokinetics of talabostat mesylate will be assessed using diffuse pharmacokinetic sampling.

[0158] Patients may continue to receive treatment until radiographic progression by RECIST 1.1 / Prostate Cancer Working Group 3 (PCWG3) criteria, overt clinical progression, unacceptable toxicity, another discontinuation criterion, or the end of the study; no maximum duration of treatment has been established. Patients with PSA progression in the absence of radiographic or clinical progression must continue to receive protocol therapy.

[0159] Study population Approximately 6-12 patients with SCNC who meet the protocol eligibility criteria will be enrolled during the lead-in stage. Approximately 15-28 patients who meet the protocol eligibility criteria will be enrolled during the efficacy stage.

[0160] Eligibility Criteria All patients must meet the following inclusion and exclusion criteria to be eligible for enrollment in the clinical trial: Patients with histologic evidence of SCNC on archival tissue analysis may proceed with enrollment without fresh biopsy confirmation.

[0161] Inclusion criteria for patients 1. Patients have evidence of progressive, metastatic, castration-resistant disease as defined by PCWG3 criteria. a. Patients with de novo small cell prostate cancer do not need to undergo androgen deprivation therapy (ADT). 2. Progression during or after completion of at least one prior line of systemic therapy for locally advanced or metastatic prostate cancer. 3. Efficacy stage only: a. Patients have histologic evidence of SCNC at central pathology confirmation on archival tissue analysis. Patients without evaluable archival metastatic tumor tissue may undergo a fresh tumor biopsy during screening. b. Must be willing to undergo a metastatic tumor biopsy during screening. The requirement may be waived in patients without safely accessible lesions or for patients with evaluable archival metastatic tumor tissue. c. Patients have received at least one prior course of cytotoxic chemotherapy. Patients who either refuse chemotherapy or are considered unsuitable for chemotherapy may be eligible after discussion with the sponsor. 4. Except for patients with de novo small cell prostate cancer, patients have a serum testosterone of <50 ng / dL during screening. a. Patients with treatment-emergent SCNC without a history of bilateral orchiectomy should be maintained on luteinizing hormone-releasing hormone (LHRH) analogs during the course of protocol therapy, except for patients with de novo small cell prostate cancer. 5. Patients have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. 6. The patient is 18 years of age or older. 7. The patient's acute toxic effects from previous anticancer therapy have resolved to grade 1 or less, with the exception of grade 2-3 peripheral neuritis or alopecia of any grade. 8. Patient has adequate baseline organ function as shown below: a. Serum creatinine ≤ 1.5 times the institutional ULN, calculated creatinine clearance > 50 mL / min; b. Serum albumin ≥ 2.5 g / dL; c.Total bilirubin ≤ 1.5 × ULN; d. AST and ALT ≤ 2.5 × institutional ULN (patients with liver metastases must have AST / ALT ≤ 5 × ULN); 9. Patient has adequate baseline hematological function as follows: a. Absolute neutrophil count (ANC) of ≥ 1.5 × 109 / L. b. Hemoglobin ≥ 8 g / dL and zero red blood cell transfusions in the previous 14 days. c. Platelet count ≥ 100 x 109 / L and zero platelet transfusions in the previous 14 days. 10. Patient agrees to use acceptable contraception for the duration of the study and to continue using acceptable contraception for 6 months after the last treatment dose. 11. The patient signed an informed consent form before beginning any study-specific procedures or treatments. 12. Patient is able to adhere to the study visit schedule and other protocol requirements, including follow-up for OS.

[0162] Exclusion criteria 1. Patients have been treated with more than two cytotoxic chemotherapy regimens for CRPC. Chemotherapy in the hormone-sensitive setting will not be considered in this study if the last dose was more than 6 months prior to study entry. 2. Prior to study treatment, the patient received external beam radiation or another systemic anticancer therapy within 14 days or 5 half-lives, whichever is shorter. 3. Patients received treatment with an investigational systemic anti-cancer agent within 14 days prior to study drug administration. 4. Prior to treatment, the patient received an anti-PD-1, anti-PD-L1, anti-programmed death-ligand 2 (PD-L2) agent, or another concurrent inhibitory T-cell receptor-directed agent (e.g., cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4], OX-40, CD137, sipuleucel-T). 5. The patient has an additional active malignancy that may confound the assessment of study endpoints. If the patient has a past cancer history (active malignancy within 2 years prior to study entry) with the potential for potential recurrence, the matter must be discussed with the sponsor prior to study entry. Patients with the following concomitant tumor diagnoses are eligible: non-melanoma skin cancer, and carcinoma in situ (including transitional cell carcinoma in situ, anal cancer, and melanoma). 6. Patients have clinically significant cardiovascular disease (e.g., uncontrolled or New York Heart Association (NYHA) class 3 or 4 congestive heart failure, uncontrolled angina, history of myocardial infarction, unstable angina or stroke within 6 months prior to study entry, uncontrolled hypertension not controlled by medication, or clinically significant arrhythmias). 7. QT interval corrected for heart rate using Bazett's formula (QTcB) > 440 msec at screening 8. The patient has uncontrolled, clinically significant pulmonary disease (e.g., chronic obstructive pulmonary disease, pulmonary hypertension) that, in the opinion of the investigator, puts the patient at significant risk for pulmonary complications during the study. 9. Patients have symptomatic and progressive brain or leptomeningeal metastases on imaging. Patients with a history of CNS metastases must be receiving appropriate treatment. CNS imaging is not required prior to study entry unless there is a history of or clinical suspicion of CNS involvement. Imaging of patients with a prior history of CNS metastases should be compared with previous imaging to identify disease progression. 10. The patient has an active autoimmune disease or grade 3 or greater pneumonia that has required systemic treatment (i.e., using disease-modifying agents, corticosteroids, or immunosuppressants) within the past two years. Replacement therapy that acts to reduce thyroid hormone production due to hyperfunctioning of the thyroid gland (e.g., in Graves' disease) (e.g., thyroxine, insulin, or physiological corticosteroid replacement therapy for adrenal or pituitary insufficiency) or treatment with medications (e.g., neomethimazole, carbimazole, etc.) is not considered a form of systemic treatment for autoimmune disease. 11. Patient has a diagnosis of immunodeficiency or is receiving systemic steroid therapy at a prednisone equivalent dose greater than 10 mg / day for at least 1 week, or other forms of immunosuppressive therapy within 7 days prior to C1D1. 12. Patient has uncontrolled intercurrent illnesses, including but not limited to uncontrolled infection, disseminated intravascular coagulation, or psychiatric / social conditions that limit compliance with study requirements. 13. Patient has known positive status for human immunodeficiency virus activity, or chronic hepatitis B, or hepatitis C. Screening is not required. 14. The patient has any medical condition that, in the opinion of the investigator, places the patient at an unacceptably high risk of toxicity.

[0163] Research Methodology Approximately 6 to 12 patients with SCNC were enrolled in the lead-in stage of the study.

[0164] Approximately 15 to 28 patients with SCNC were enrolled in the efficacy stage of the study. In the first stage, 15 patients were accrued. If there were two or fewer complicated responses among these 15 patients, accrual to the study group was stopped. Otherwise, 13 more patients were accrued for a total of 28 patients. A complicated response was defined as one or more of the following: - Objective response according to RECIST 1.1 criteria - CTC conversion of >5 / 7.5mL to <5 / 7.5mL per Veridex assay upon completion of 12 weeks of protocol therapy - A PSA reduction of more than 50% from baseline upon completion of 12 weeks of protocol therapy

[0165] A tabular study schedule of assessments is found in Appendix A. A detailed description of study procedures by visit is found in Appendix B.

[0166] During the screening period, patients who sign consent forms are evaluated every other day to ensure they meet the inclusion and exclusion criteria. Patient demographics, performance status, and disease staging are collected. Vital signs (both sitting and standing blood pressure, heart rate, temperature, and respiratory rate), physical examination, electrocardiogram (ECG), and clinical laboratory assessments (complete blood count and specific serum chemistries, liver function tests, and analysis) are performed at screening and baseline and monitored throughout the treatment period. Patients who meet the entry criteria will begin study treatment during the 4-week screening visit. At the investigator's discretion, patients with out-of-range clinical laboratory assessments at screening will be retested during the screening period and included in the study if the investigator believes the retest values ​​will be within range.

[0167] Patients will undergo tumor assessment, which should include cross-sectional imaging of the chest / abdomen / pelvis (MRI or CT scanning with IV contrast when possible), plus a whole-body bone scan. Other body regions (e.g., neck) should be included as clinically indicated. Tumor assessments will be performed at screening, C4D1 (±7 days), C7D1 (±7 days), C10D1 (±7 days), and on day 1 of each third cycle thereafter (±7 days).

[0168] The same imaging method used to measure the index lesion size at baseline should be used to follow the lesion size throughout the study. Assessments will be performed throughout the treatment phase as shown in Appendix A and Appendix B.

[0169] AEs, clinical laboratories, PSA, and concomitant medications will be monitored and recorded throughout the entire study period.

[0170] Patients may continue receiving study treatment until radiographic or clinical progression, unacceptable toxicity, another discontinuation criterion, or termination of the study by the sponsor; there is no maximum duration of treatment.

[0171] After discontinuation of study treatment, patients will complete an EOT visit within 21 days after the last dose of study medication. If drug-related AEs have not resolved at that time, safety follow-up will be conducted for 30 days (± 7 days) after the last dose of study medication and for an additional subsequent time. Patients will also be contacted by telephone approximately every 90 days for clinical evidence of disease progression, and for assessment of survival status in settings where discontinuation of study therapy was for reasons other than PD (protocol-specified tumor measurements are not required after the EOT visit). This extended follow-up for disease status and survival after discontinuation of study treatment will continue for up to 12 months after the start of study treatment.

[0172] Concomitant medications Permitted medications / treatments: All medications taken within 3 months of study initiation and used throughout the study must be recorded in the appropriate section of the patient's electronic case report form (eCRF).

[0173] Patients who have not previously undergone bilateral orchiectomy should continue LHRH-like therapy to maintain castrate levels of testosterone throughout the course of study treatment (except for patients with de novo small cell prostate cancer).

[0174] The use of bone-altering agents (e.g., zoledronic acid, denosumab) is permitted as clinically indicated.

[0175] Use of growth factors (e.g., granulocyte colony-stimulating factor [G-CSF]) is permitted as clinically indicated for the treatment of grade 3 or greater cytopenias.

[0176] The use of any other systemic anti-cancer therapy other than that outlined in the protocol is prohibited during the course of study treatment.

[0177] Suggested supportive care measures for the management of AEs with a potential immune etiology are outlined below. When appropriate, these guidelines include oral or IV treatment with corticosteroids and the use of additional anti-inflammatory agents if symptoms do not improve with corticosteroid administration. Note that several courses of steroid tapering may be necessary if symptoms may worsen as the steroid dose is reduced. For each AE, an attempt must be made to rule out other causes, such as metastatic disease or bacterial or viral infection, and additional supportive care may be required. It is intended that treatment guidelines be applied when the investigator determines that the event should be related to pembrolizumab.

[0178] As part of the evaluation of an event, it may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin photography.

[0179] - Pneumonitis: For grade 2 events, treat with systemic corticosteroids (e.g., oral prednisone 1 mg / kg or equivalent). When symptoms improve to grade 1 or less, a steroid taper should be initiated and continued for at least 4 weeks. For grade 3-4 events, treat immediately with IV steroids (e.g., solumedulol 1-2 mg / kg every 6-8 hours). Administer additional anti-inflammatory measures as needed. When symptoms improve to grade 1 or less, a steroid taper should be initiated and continued for at least 4 weeks. If steroid administration is extended, add prophylactic antibiotics for opportunistic infections. - Diarrhea / Colitis: Patients should be closely monitored for signs and symptoms of enterocolitis (e.g., diarrhea with or without fever, abdominal pain, blood or mucus in the stool) and of intestinal perforation (e.g., peritoneal signs and ileus). All patients experiencing diarrhea / colitis should be encouraged to consume clear fluids ad libitum. If adequate oral fluid intake is not feasible, fluids and electrolytes should be administered via IV infusion. For grade 2 or greater diarrhea, consider a gastroenterological diagnosis and endoscopy to confirm or rule out colitis. For grade 2 diarrhea / colitis, administer oral corticosteroids (e.g., oral prednisone 1 mg / kg or equivalent). When symptoms improve to grade 1 or less, a steroid taper should be initiated and continued for at least 4 weeks. For grade 3 or 4 diarrhea / colitis, treat with IV steroids (e.g., solumedulol 1-2 mg / kg every 6-8 hours), followed by high-dose oral steroids. When symptoms improve to grade 1 or less, a steroid taper should be initiated and continued for at least 4 weeks. Type 1 diabetes mellitus (T1DM) (new onset including diabetic ketoacidosis [DKA] or grade 3 or higher hyperglycemia if associated with ketosis (ketonuria) or metabolic acidosis (DKA)) ○ Regarding T1DM or grade 3-4 hyperglycemia ■Insulin replacement therapy is recommended for T1DM and for grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria. ■ Evaluate patients with serum glucose and metabolic panel, urine ketones, glycosylated hemoglobin, and C-peptide. - Hypophysitis: For grade 2 events, treat with corticosteroids (e.g., oral prednisone 1 mg / kg / day). When symptoms improve to grade 1 or less, a steroid taper should be initiated and continued for at least 4 weeks. As the steroid dose is tapered, appropriate hormone replacement may be required. For grade 3-4 events, treat with an initial dose of IV corticosteroids (e.g., solumedulol 1-2 mg / kg every 6-8 hours) for 24-48 hours, followed by high-dose oral corticosteroids. When symptoms improve to grade 1 or less, a steroid taper should be initiated and continued for at least 4 weeks. As the steroid dose is tapered, appropriate hormone replacement may be required. Hyperthyroidism or hypothyroidism: Thyroid dysfunction may occur at any time during treatment. Monitor patients (at the initiation of treatment, periodically during treatment, and as indicated based on clinical evaluation) for changes in thyroid function and for clinical signs and symptoms of thyroid dysfunction. Grade 2 hyperthyroidism events and grades 2-4 hypothyroidism: In hyperthyroidism, nonselective beta-blockers (e.g., propranolol) are suggested as initial therapy. · In hypothyroidism, thyroid hormone replacement therapy with levothyroxine or liothyronine is indicated by standard of care. Grade 3-4 hyperthyroidism Treatment with an initial dose of IV corticosteroids, followed by oral corticosteroids. When symptoms improve to Grade 1 or less, a steroid taper should be initiated and continued for at least 4 weeks. As the steroid dose is tapered, appropriate hormone replacement may be required. - Liver: For grade 2 events, monitor liver function tests more frequently (consider weekly) until return to baseline values. · Treatment with IV or oral corticosteroids (e.g., prednisone 1 mg / kg / day or equivalent). For grade 3-4 events, treat with IV corticosteroids for 24-48 hours (e.g., solumedulol 1-2 mg / kg every 6-8 hours), then transition to oral high-dose steroids (e.g., prednisone 1 mg / kg / day or equivalent). When symptoms improve to Grade 1 or less, a steroid taper should be initiated and continued for at least 4 weeks. - Renal failure or nephritis: For grade 2 events, treat with oral corticosteroids (e.g., prednisone 1 mg / kg / day). For grade 3-4 events, treat with IV corticosteroids (e.g., solumedulol 1-2 mg / kg every 6-8 hours) for 24-48 hours, then transition to oral high-dose steroids (e.g., prednisone 1 mg / kg / day or equivalent). When symptoms improve to Grade 1 or less, a steroid taper should be initiated and continued for at least 4 weeks. - Management of infusion reactions: Signs and symptoms usually develop during or shortly after the drug infusion and generally resolve completely within 24 hours of completing the infusion.

[0180] Table 4 provides treatment guidelines for patients experiencing an infusion reaction associated with the administration of pembrolizumab. [Table 4-1] [Table 4-2]

[0181] Prohibited Medications / Therapies Patients enrolled cannot receive investigational or approved anti-cancer drugs, including cytotoxic chemotherapy agents, anti-cancer tyrosine kinase inhibitors, or therapeutic monoclonal antibodies.

[0182] Palliative radiation therapy is not permitted during study enrollment unless it is performed for existing non-progressing metastases / symptoms and involves a small radiation field (eg, isolated bone lesions).

[0183] Preclinical studies have demonstrated that talabostat mesylate has a low potential to inhibit the following major human hepatic CYP isoenzymes: CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Furthermore, relevant concentrations of talabostat mesylate did not inhibit CYP3A4 or CYP1A2. Therefore, there are no prohibited medications based on CYP isoenzymes.

[0184] Efficacy evaluation Primary efficacy parameter - The primary efficacy parameter is the composite response rate, defined as achieving one or more of the following: Objective response according to RECIST 1.1 criteria Circulating tumor cell (CTC) conversion of >5 / 7.5mL to <5 / 7.5mL per Veridex assay upon completion of 12 weeks of protocol therapy A prostate-specific antigen (PSA) reduction of more than 50% from baseline upon completion of 12 weeks of protocol therapy Secondary efficacy parameters: - Median radiographic progression-free survival (rPFS) when treated with the combination - Median progression-free survival (PFS) when treated with the combination - Median overall survival (OS) when treated with the combination - Median duration of response (DOR) when treated with the combination - Characterize the safety profile of the combination - To evaluate the population pharmacokinetics of talabostat mesylate using pharmacokinetic sampling. - Evaluate the pharmacodynamic profile of the combination by measuring relevant effects on cytokines previously shown to be controlled by talabostat in humans.

[0185] Explanatory validity analysis: - To measure the response rate by iRECIST with talabostat mesylate in combination with pembrolizumab. - To evaluate the quantitative and qualitative effects of talabostat mesylate in combination with pembrolizumab on relevant immune effector cytokines and various immune effector cells, including neutrophils, MDSCs, dendritic cells, CAFs, and T cells, in the blood and, where feasible, in tumor tissues. - To discover the predictive value of baseline PD-L1 tumor expression in metastatic tumor tissue and CTCs with subsequent clinical outcomes. - To discover the relationship between baseline and treatment-associated circulating tumor neoantigens and T cell repertoires and clinical outcomes (assessed in a central laboratory). -To discover the relationship between baseline tumor mRNA immune profiling panels and clinical outcomes.

[0186] Safety evaluation Non-serious adverse events Investigators must assess AEs at each visit. Any AE, including observed or spontaneous problems, complaints, or symptoms, must be recorded on the eCRF. Each AE must be evaluated for duration, intensity, and causal relationship to study treatment or other factors.

[0187] Any AEs occurring during the treatment period and / or within 30 days of the last dose of talabostat mesylate will be followed until the end of the study or until resolved. AEs will be graded according to the revised NCI CTCAE, version 5.0 (see http: / / ctep.cancer.gov / reporting / ctc.html). AEs occurring within 30 days after the last dose of talabostat mesylate do not need to be reported unless the investigator considers the event to be related to talabostat mesylate.

[0188] Investigators must report to the sponsor, or the sponsor's representative, any AEs experienced during active treatment in the clinical trial and within 30 days after the last dose of talabostat mesylate. Any AE, whether serious or non-serious, that leads to permanent discontinuation of study medication must be reported to the sponsor.

[0189] Clinical laboratory data must be collected in this study, and toxicity trends will be analyzed using objective toxicity criteria.

[0190] Associated and possibly associated cause criteria are considered "related" to the study drug(s) for purposes of controllability reporting requirements.

[0191] Reporting of serious adverse events Any SAE or death occurring during the treatment period and / or within 30 days after the last dose of study medication must be reported to the sponsor or the sponsor's representative within 24 hours of first noticing it. If any SAE occurs, study treatment should be interrupted or discontinued at the discretion of the physician-investigator.

[0192] Adverse Event Tracking Patients will be monitored for AEs throughout the treatment period and for a minimum of 30 days after the last dose of talabostat mesylate.

[0193] Pharmacokinetic evaluation Disseminated pharmacokinetic sampling will be performed to analyze talabostat mesylate concentrations at the time points listed in Appendix A. Samples will also be collected immediately prior to the final dose on Day 14 of Cycles 1, 2, and 3, and up to 168 hours after C3D14 administration (with the final sample collected immediately prior to C4D1 administration). Pharmacokinetic data will be analyzed using a population pharmacokinetic approach.

[0194] Pharmacodynamic evaluation Whole blood samples will be collected at the time points described in the appendix for analysis of relevant immune effector cytokines and various immune effector cells, including neutrophils, MDSCs, dendritic cells, CAFs, and T cells.

[0195] disease progression Worsening of signs and symptoms of prostate cancer must be considered by the investigator as a disease assessment. PD is being evaluated as an efficacy outcome in this study and should not be reported as an AE. However, death solely due to PD occurring within 30 days of the last dose of talabostat mesylate must be reported as an AE outcome, with the AE duration reported as "progressive disease."

[0196] Exclusion of patients from the study Patients may be discontinued from the study for any of the following reasons: - The researcher recommends discontinuation and provides a written reason(s) for the discontinuation - Requires any treatment not permitted by the protocol - The patient withdraws consent or decides to discontinue for any reason. - Presence of an intolerable AE considered related to study medication - Sponsorship Request All patients who discontinue during the treatment period will be required to return and complete safety and disease assessments (see Appendix A and Appendix B).

[0197] Completing the research The study will be considered complete when all patients have completed all post-study treatment procedures according to disease progression; lost follow-up, died, or been excluded due to toxicity; according to patient request; at the investigator's discretion.

[0198] Study medication Study medication was administered in 21-day cycles.

[0199] Talabostat mesylate dosage and administration Talabostat mesylate tablets contain valine-proline boronic acid formulated as the methanesulfonate salt. Current dosage strengths include 0.05 mg and 0.2 mg tablets for oral administration.

[0200] The starting dose regimen of talabostat mesylate (i.e., the dose regimen in Cohort 1) was 0.4 mg QD on days 1-14 of each 21-day period. The talabostat mesylate dose regimen for any given patient depended on the cohort into which the patient was enrolled during the lead-in stage. Additional dosing schedules (e.g., 0.6 mg QD) were also evaluated during the lead-in stage.

[0201] Talabostat mesylate was administered orally as 0.2 mg tablets. Patients took two or three tablets daily, for a total daily dose of 0.4 or 0.6 mg, once daily (two or three tablets, twice daily (one plus one or one plus two tablets taken in the morning and afternoon) or three times daily (one plus one plus one tablets given at different times during the day) on days 1-14 of each cycle. Talabostat mesylate was continued until disease progression or unacceptable toxicity occurred.

[0202] On days when pharmacodynamic studies are being conducted, talabostat mesylate should be administered at the center of the study and should be administered at (approximately) the same time of day on each treatment day in the cycle. In cycles in which pharmacodynamics are not being evaluated, talabostat mesylate should also be administered at (approximately) the same time of day, preferably at 8:00 PM, on each treatment day in the cycle.

[0203] Dose adjustment of talabostat mesylate secondary to toxicity Dose modifications of talabostat mesylate during a treatment cycle are not permitted in Cycle 1 in the absence of a DLT. From Cycle 2 onwards, dose modifications during a treatment cycle are made at the investigator's discretion. A dose that is maintained due to an AE may not be made up later during or after a cycle. A dose forgotten for reasons other than an AE (i.e., the patient forgets to take the dose) may be administered on a day after the scheduled dose. Any such adjustments must be discussed with the medical monitor or designee. Under no circumstances may a forgotten dose be made up on a day when the patient is already taking the scheduled dose (i.e., no "doubling up" to account for the forgotten dose).

[0204] If an SAE considered to be related to talabostat mesylate occurs during the treatment period, administration of talabostat mesylate must be discontinued in that patient until the SAE resolves. If the investigator wishes to continue talabostat mesylate in a patient, the sponsor must be contacted to discuss continuing talabostat mesylate at the same or reduced dose.

[0205] The most frequently observed AEs considered characteristic of talabostat mesylate are edema / peripheral swelling, hypotension, dizziness, and hypovolemia. These events, including edema, tend to be manageable and reversible and usually resolve after maintenance drug administration. Talabostat mesylate should be maintained for the occurrence of Grade 2 or higher AEs until these AEs resolve. Talabostat mesylate may be resumed at the full dose after resolution of these AEs, including edema. For other Grade 2 or higher AEs considered related to talabostat mesylate or for edema not responding to maintenance drug administration, the dose of talabostat mesylate may be reduced in 0.2 mg increments at the investigator's discretion.

[0206] Discontinuation of talabostat mesylate should occur for any life-threatening AE or for any Grade 2 or greater treatment-related AE that does not respond to dose reduction to 0.2 mg. If talabostat mesylate is discontinued due to an AE, all treatment procedures and evaluations should be stopped.

[0207] Monitoring patient compliance with study administration of talabostat mesylate All talabostat mesylate dose containers must be returned to the clinic at each visit. Patients must be questioned about adherence to the dosing regimen, and medication containers must be inspected at each visit to determine whether any talabostat mesylate doses have been missed and whether any missed doses have been documented. Patients must be at least 75% compliant with talabostat mesylate intake in Cycles 1 and 2 to be included in per-protocol efficacy analyses.

[0208] Description and storage of talabostat mesylate Talabostat mesylate was supplied as 0.05 mg and 0.2 mg tablets in high-density polyethylene bottles with desiccant and child-resistant caps. 30 tablets were contained in each bottle. Talabostat mesylate supplies were appropriately labeled for clinical investigational substances. Talabostat mesylate should be stored under refrigerated conditions between 2°C and 8°C (33°F and 46°F).

[0209] Pembrolizumab dose modification Pembrolizumab dose modifications should be in accordance with the current package insert for AEs considered related to pembrolizumab, as discussed herein.

[0210] Pembrolizumab should be withheld in any of the following: - Grade 2 pneumonia (see US Package Insert - Warnings and Precautions section 5.1) - Grade 2 or 3 colitis (see Warnings and Precautions [5.2]) - Grade 3 or 4 endocrinopathy (see Warnings and Precautions [5.4]) - Grade 2 nephritis (see Warnings and Precautions [5.5]) - Grade 3 severe skin reaction or suspected Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TN) (see Warnings and Precautions [5.6]) - AST or ALT >3-5xULN or total bilirubin >1.5-3xULN - Any other Grade 2 or 3 treatment-related adverse reaction based on severity and type of reaction (see Warnings and Precautions [5.7]).

[0211] In patients whose adverse reactions resolve to grade 0 or 1, clinical investigators are advised to restart pembrolizumab.

[0212] For AEs with unclear causality, discussion of dose modification with medical monitoring is recommended.

[0213] Discontinuation of pembrolizumab Pembrolizumab dose modifications, including discontinuation, must be in accordance with the current labeling.

[0214] Permanently discontinue pembrolizumab for any of the following: - Any life-threatening adverse reaction (excluding endocrine disorders controlled by hormone replacement therapy). - Grade 3 or 4 pneumonitis or recurrent pneumonitis of Grade 2 severity (see Warnings and Precautions [5.1]) - Grade 3 or 4 nephritis (see Warnings and Precautions [5.5]) - Grade 4 severe skin reaction or confirmed SJS or TEN (see Warnings and Precautions [5.6]) - AST or ALT > 5 x ULN or total bilirubin > 3 x ULN - Initiate treatment for grade 2 AST or ALT if AST or ALT increases by 50% or more from baseline and persists for at least 1 week, for patients with liver metastases - Grade 3 or 4 myocarditis, encephalitis, or Guillain-Barré syndrome (see Warnings and Precautions [5.7]) - Grade 3 or 4 infusion-related reaction (see Warnings and Precautions [5.8]) - Failure to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent daily within 12 weeks - Persistent Grade 2 or 3 adverse reactions that do not resolve to Grade 0 or 1 within 12 weeks after the last dose of pembrolizumab (excluding secretory diseases controlled with hormone replacement therapy).

[0215] Data analysis and statistical considerations A statistical analysis plan (SAP) will be written to accommodate the analysis of data recorded in the clinical database, as well as laboratory, pharmacodynamic, and other data transferred to Novella Clinical. Analysis of safety lead-in data to determine the talabostat mesylate dose for use in the efficacy stage of the study will initially use data management listings. These lead-in data will be combined with data from the efficacy stage of the study and presented in the clinical study report.

[0216] Continuous variables, including baseline characteristics, will be summarized by reporting the number of observations, mean, standard deviation, median, minimum and maximum values.

[0217] Categorical / discrete variables will be summarized using frequency tables showing the number and percentage of patients in the category. Time-to-event data will be summarized using the Kaplan-Meier method.

[0218] Summary statistics are reported for observed data only unless otherwise specified. Missing data are not imputed. If baseline values ​​are missing, change from baseline will not be calculated. Baseline is defined as the last available observation prior to the first dose of study medication at C1D1.

[0219] In addition to the methods to be used for reporting endpoints, the SAP will specify the handling of missing data.

[0220] Statistical analysis will be performed by Novella Clinical using SAS (version 9.4 or higher). Any deviations from SAP will be reported in the clinical study report.

[0221] Analysis population The intention-to-treat (ITT) analysis population consisted of patients who met the eligibility criteria.

[0222] The response-evaluable patient population consists of patients who have completed at least two cycles of treatment with the combination of talabostat mesylate and pembrolizumab and have at least one post-baseline response assessment performed by the investigator(s).

[0223] The safety analysis population consisted of all patients who received any dose of talabostat mesylate / pembrolizumab during either the lead-in or efficacy stages of the study.

[0224] The pharmacodynamic analysis population consisted of all patients who received any dose of talabostat mesylate / pembrolizumab and had at least one measurement of DPP activity or cytokine concentrations.

[0225] Analysis of demographic and baseline characteristics Demographic and baseline disease characteristics will be summarized and tabulated for the ITT analysis population. If the number of patients in the ITT analysis population differs substantially from the number of patients in the measurable response or safety analysis populations, the demographic and baseline characteristics for these analysis populations will be presented.

[0226] Analysis of efficacy data Primary and secondary efficacy parameters are defined herein. Objective response rate is defined as the number of patients with CR or PR among all measurable patients. Responses are measured according to RECIST 1.1 criteria. Duration of response is defined as the time interval measured between the first date on which objective response criteria are met and the first date on which objective progression is documented. Patients who do not experience disease progression during the treatment and follow-up period and do not die during the treatment period have an event time that is tested for evidence of lack of disease progression by objective tumor assessment on the last day of study. One day is added to each calculation to account for indications on the first day of treatment, such as study day 1. Patients who achieve PR and then CR have their time calculated using the date of PR. Radiographic PFS is defined as the time from the start of protocol treatment to the date on which the criterion for PD is first met, according to RECIST 1.1 / PCWG3 criteria, or death from any cause, whichever occurs first. Patients who lack assessment of tumor response are tested for event time on day 1. Patients who do not experience disease progression during treatment and during the extended disease assessment period and who do not die during the treatment period have an event time at the last day tested for evidence of lack of disease progression by objective tumor assessment. Patient data are tested at the time the patient receives new cancer treatment in the absence of documented disease progression. One day is added to each calculation to account for indications at the first day of treatment, such as study day 1. Progression-free survival (PFS) is defined by PCWG3 criteria as the time from the start of protocol treatment to the date a metric for PSA progression is first met. Patients who do not meet the final criterion for progression are tested at the latest date of evaluation. Overall survival: Survival time is the difference in days between the date of death and the first day of study treatment (+1 day). Patients who do not die have their survival time tested at the last known date of contact documented as the patient being alive. Treated patients with missing data beyond the start of treatment have their survival time tested at day 1.

[0227] Analysis of the primary efficacy parameter Stage 1 Analysis When 15 patients have completed approximately six cycles of treatment and have two post-baseline tumor assessments and PSA or CTC measurements, the number of patients who meet the composite response criteria of achieving one or more of the following: 1) an objective response by RECIST 1.1 criteria, 2) a 50% or greater reduction from baseline in serum PSA by 12 weeks of treatment, or 3) a CTC conversion of >5 / 7.5 mL to <5 / 7.5 mL per Veridex assay by completion of 12 weeks of protocol therapy will be assessed.

[0228] Using a minimax two-stage Simon design, enrollment will be stopped if two or fewer of the 15 Stage 1 patients meet at least one of the composite response criteria. This indicates that the data to date are consistent with the null hypothesis that the composite response rate is 15% or less, and therefore the alternative hypothesis of a 35% composite response rate will be abandoned. If three or more of the 15 patients meet at least one of the composite response criteria, 13 more patients will be enrolled and treated to progress to Stage 2, for a total of 28 patients in both stages.

[0229] Stage 2 Analysis When an additional 13 enrolled and treated stage 2 patients complete approximately six cycles of treatment, two post-baseline tumor assessments, and PSA and CTC measurements, the number of patients meeting at least one of the three criteria for the composite endpoint will be evaluated. If the total number of patients meeting the composite endpoint among 28 patients in both stages is seven or fewer, the data is consistent with the null hypothesis of a composite endpoint rate of 15% or less, with a nominal one-sided significance level of 0.05. If the number of patients meeting the composite endpoint is eight or more, the data is consistent with a composite endpoint rate of at least 35%. The composite endpoint rate across the two stages and its exact 95% confidence interval (CI) are calculated as if the data were collected in a single stage. This approach, which ignores sequential statistical testing, may result in biased estimates of the composite endpoint rate, and the CI may not result in the stated inclusion probability, but is generally acceptable when the event rate is relatively small.

[0230] Sensitivity analysis Composite endpoint rates are also calculated for the ITT analysis population. Patients in the ITT population with missing composite endpoints are considered non-responders (i.e., one of the three criteria for the composite endpoint was not met).

[0231] Analysis of secondary parameter(s): time-to-event response The distributions of time-to-event responses, including rPFS, PSA, PFS, DOR, and OS, will be estimated using Kaplan-Meier methodology. When available, the median values ​​of these time-to-event efficacy responses and their two-sided 95% CIs will be reported. Additionally, the proportion of patients with an event at selected time points will be presented along with their two-sided 95% CIs. Calculations will be based on a fixed-sample, single-stage design.

[0232] The primary analysis will be performed using the ITT analysis population. A secondary time-to-event analysis will be performed using the response-evaluable analysis population.

[0233] Analysis of overall duration of objective response is performed on the ITT analysis population of all patients achieving confirmed PR or CR, thus limiting the use of the Kaplan-Meier method to provide reliable information. In this case, descriptive statistics or listings are provided.

[0234] After discontinuation of study medication, patients may be treated with additional therapy. Data collected after patients are treated with additional therapy will not be used to assess the duration of objective response.

[0235] Analysis of secondary endpoints: DPP activity and cytokine concentrations Analyses of secondary efficacy endpoints, including DPP activity and cytokine concentrations, are reported for the PD analysis population. The proportion of patients showing DPP activity is reported, and descriptive statistics are reported for concentrations of cytokines previously shown to be controlled by talabostat mesylate in humans.

[0236] Analysis of Examination Endpoints Exploratory endpoints will be analyzed using the response-evaluable analysis population.

[0237] The percentage of patients meeting iRECIST criteria will be presented.

[0238] At a minimum, the proportion of subjects experiencing a clinical response (PR, CR) and OS will be reported.

[0239] Whenever feasible, cross-tabulations of clinical outcomes according to the presence / absence of relevant immune effector cytokines and various immune effector cells, including neutrophils, MDSCs, dendritic cells, CAFs, and T cells, in the blood and tumor tissue will be presented.

[0240] Baseline PD-L1 tumor expression in metastatic tumor tissue and CTCs will be cross-tabulated with subsequent clinical outcomes. Similarly, baseline and on-treatment circulating tumor neoantigen and T-cell repertoires, as well as baseline tumor mRNA immune profiling panels, will be cross-tabulated with clinical outcomes related to response and safety.

[0241] Analysis of treatment exposure Descriptive summary statistics are provided for the total number of cycles, dose, mean dose, and duration of treatment.

[0242] Analysis of patient research predispositions The number of patients enrolled in the ITT analysis population, the number of patients safe, the evaluable response, and the pharmacodynamic population will be reported.

[0243] The number of patients who discontinue the study over time will be tabulated for the ITT population.

[0244] Power and sample size considerations The sample size is calculated to reflect a Simon two-stage design for the efficacy stage. In a Simon two-stage design, an initial number of patients are enrolled and evaluated for discontinuation due to futility. That is, the consistency of the data is tested with the null hypothesis using a one-sided test. If the analysis shows that the data is consistent with the null hypothesis, the study is stopped due to futility. Alternatively, the study proceeds to a second stage, in which an additional number of patients are enrolled if the data supports either the null hypothesis or the alternative hypothesis. The Simon two-stage design only considers discontinuation due to futility in stage 1, and an acceptable sample size that meets the previously specified power and type 1 error is considered for both study stages.

[0245] A total sample size of 28 patients, 15 in stage 1 and 13 in stage 2, were treated with a combination of talabostat mesylate and pembrolizumab to detect, with 80% power, a composite endpoint of 35% and an alternative hypothesis proportion of patients meeting the null hypothesis of a 15% rate, with early discontinuation due to futility in stage 1 in a one-sided test at a significance level of 0.05 (actual value 0.0461). Two or fewer patients meeting the composite endpoint in stage 1 would trigger early discontinuation. Of the 28 patients in both stages, seven or fewer patients would trigger abandonment of the alternative hypothesis that the composite endpoint rate was at least 35%.

[0246] Safety analysis All patients in the safety analysis population, apart from the lead-in patients who will be stratified into two dose cohorts (0.4 and 0.6 mg), will be included in the final listing and listing of safety data. A listing of AEs and other safety parameters will be provided as appropriate. The emphasis in the analysis of AEs will be on treatment-emergent events within 30 days after the last dose of talabostat mesylate / pembrolizumab.

[0247] The frequency of patients experiencing at least one AE is indicated by body system and preferred term according to the Medical Dictionary for Regulatory Affairs (MedDRA) terminology. Details collected for each AE include a description of the event, duration, whether the AE is serious, the nature of the event (single vs. multiple occurrences), intensity (i.e., NCI CTCAE grade), relationship to study drug, action taken, clinical outcome, and whether the AE results in surgery or an alternative procedure. The intensity (severity) of the AE will be graded according to the NCI CTCAE. The latest versions of MedDRA and NCI CTCAE will be used.

[0248] Tables will be prepared showing the number of patients reporting an AE, the frequency of patient reports, and the corresponding proportions. Proportions will be calculated using the number of patients in the safety analysis set as the denominator. Within each table, AEs will be categorized by MedDRA body system and preferred term. Further subcategories will be based on the intensity and relationship of the event to study drug. AE data will span all cycles and be presented for each cycle. The denominator for each cycle is the patients available at the start of the cycle who received the dose of talabostat mesylate for that cycle.

[0249] To the extent possible, identify the relationship of AEs to either talabostat mesylate or pembrolizumab.

[0250] Individual patient listings will be prepared for all AE data.

[0251] ECG, vital signs, and ECOG performance status will be summarized by visit / cycle, with descriptive statistics applicable to continuous or categorical measures of these additional safety data. Summary tables for the lead-in and efficacy stages are presented.

[0252] Patient rotation Patients will be assigned a patient number and will be replaced if they do not receive at least two cycles of talabostat mesylate.

[0253] result: Stage 1 - Lead-in Stage - Preliminary Data Three patients were treated with the initial dose concentration for at least four cycles. All patients remain on active treatment. No DLTs or SAEs were reported. Grade 3 treatment-related adverse events (TRAEs) were limited to thrombocytopenia requiring transfusion in one patient. The only TRAE reported in more than one patient was hypocalcemia (two patients). Safety evaluation of talabostat mesylate plus pembrolizumab is ongoing in the final dose-escalation cohort.

[0254] Conclusion: The combination of talabostat mesylate (0.4 mg QD on days 1-14 of a 21-day cycle) and pembrolizumab (200 mg IV on day 1 of each 21-day cycle) is safe in patients with CRPC. [Table 5] [Table 6] [Table 7] [Table 8]

[0255] The talabostat mesylate formulation herein is consistent with previously reported results from point treatment (healthy volunteer study CA168-002) based on initial plasma concentration data from two patients in the current study. [Table 9]

[0256] overview: In subjects with CRPC, in the Phase 1b safety lead-in portion of this study: The safety of talabostat mesylate plus pembrolizumab has been demonstrated in the initial cohort with no SAEs or DLTs and a low rate of treatment-related grade 3 or higher events. Safety evaluation of the talabostat mesylate + pembrolizumab combination is ongoing in the final dose-escalation cohort Preliminary pharmacokinetics of talabostat mesylate are within expectations based on previous data All subjects are continuing treatment

[0257] The phase 2 portion of the study will be restricted to subjects with SCNC, an aggressive form of prostate cancer, and will evaluate the antitumor activity of the talabostat mesylate plus pembrolizumab combination in a setting where checkpoint inhibitor monotherapy has shown limited clinical benefit.

[0258] Evaluation research schedule [Table 10-1] [Table 10-2]

[0259] Research Tracking After discontinuation of study medication, patients will complete an EOT visit within 21 days after the last dose of study medication. b. Safety follow-up visits may be conducted for 30 days (± 7 days) after the last dose of study drug, and thereafter, if the drug-related AE has not resolved at that time. Thereafter, patients without documented disease progression (PD) will be followed every 90 days for disease assessments until documentation of PD. After documentation of PD, patients will be followed for vital status every 90 days. Such follow-up will likely be conducted by telephone. c. Day 1 of Cycle 2 and all subsequent cycles will occur 21 days (± 3 days) after the previous study medication has been administered. d. Tumor assessments must include cross-sectional imaging of the chest / abdomen / pelvis (MRI or CT scanning with intravenous contrast when possible), plus a whole-body bone scan. Other body regions (e.g., neck) should be included as clinically indicated. Tumor assessments will be performed at screening, C4D1 (±7 days), C7D1 (±7 days), C10D1 (±7 days), and on Day 1 (±7 days) of each third cycle thereafter. e. Tumor biopsy is optional in the lead-in stage and mandatory in the efficacy stage. The requirement may be waived if a safely accessible injury OR patient does not have available archival metastatic tumor tissue. f. ECG must be performed in triplicate prior to collection of blood samples. At screening only, the QT interval corrected for heart rate will be measured using Bazett's formula (QTcB). g. Serum chemistries include sodium (Na), potassium (K), chloride (Cl), bicarbonate, calcium (Ca), magnesium (Mg), phosphate, blood urea nitrogen (BUN) / creatinine (Cr), and lactate dehydrogenase (LDH). h. Liver function tests include aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin, and albumin. i. Whole blood for immune parameters will be collected pre-dose and 6 and 24 hours after dosing of C1D1, C1D14, C2D1, and C2D14. The 24 hour sample on day 1 will be collected pre-dose on day 2. j. CTC enumeration will be performed at C1D1, C2D1, and C4D1, then at D1 of every third cycle thereafter, and at the EOT visit. k. Samples collected immediately prior to the final dose will be administered on Day 14 (patient diaries should be kept to record the number of doses the patient has taken during the cycle). l. Cycle 3 only; samples collected immediately prior to the final dose will be administered on Day 14, and at 2, 6, 12, 24, 72, 120, and 168 hours after the final dose, with the 168 hour sample collected immediately prior to the C4D1 dose (patient diaries should be kept to record the number of doses the patient received during the cycle).

[0260] Detailed study procedures by visit screening period (Day -28 to Day -1) Informed consent will be obtained before any procedures are completed.

[0261] All clinical laboratories are analyzed by institutional laboratories or other local laboratories.

[0262] Within 28 days prior to the first scheduled dose of talabostat mesylate, patients must have the following evaluations performed: - Informed consent - Review of inclusion and exclusion criteria to determine whether patients are eligible to participate in the study - Collecting demographic data - Evaluation for AE - Documentation of any concomitant medications - History of prostate cancer treatment - Archived Tumor Collection - Core pathology confirmation of primary or metastatic prostate cancer tissue - Tumor assessment should include cross-sectional imaging of the chest / abdomen / pelvis (MRI or CT scanning with IV contrast when possible), plus a whole-body bone scan. Other body regions (e.g., neck) should be included as clinically indicated. - Metastatic tumor biopsy (optional in lead-in stage). This may be withdrawn if the patient does not have available archival metastatic tumor tissue and there is no safely accessible trauma OR. - Physical examination (including vital signs [sitting and standing blood pressure, heart rate, respiratory rate, and temperature] and physical measurements [height, weight, and body frame check]) - Complete medical history - ECOG performance status - Obtain a 12-lead ECG (including QTcB assessment) - Clinical Laboratory Evaluation: - Hematology (Complete Blood Count [CBC] + Differential) - Serum chemistry (sodium [Na], potassium [K], chloride [Cl], bicarbonate, calcium [Ca], magnesium [Mg], phosphate, blood urea nitrogen [BUN] / creatinine [Cr], and lactate dehydrogenase [LDH]) - Liver function tests (AST, ALT, alkaline phosphatase, total bilirubin, albumin) - Serum PSA - Urine test - Once a patient is deemed eligible for the study, a consecutive patient number will be assigned at each site.

[0263] Evaluations during treatment Cycle 1, Day 1 The following tests and procedures are performed: - Review inclusion and exclusion criteria to ensure patients remain eligible to continue in the study - Evaluation for AE - Questions about concomitant medications - Dispense talabostat mesylate for administration on Days 1-14 of Cycle 1 - Administer pembrolizumab - Physical examination (including vital signs [sitting and standing blood pressure, heart rate, respiratory rate, and temperature], and weight) - ECOG performance status - Obtain a 12-lead ECG - Clinical Laboratory Evaluation: - Hematology (CBC + differential) - Serum chemistry (Na, K, Cl, bicarbonate, Ca, Mg, phosphate, BUN / Cr, and LDH). - Liver function tests (AST, ALT, alkaline phosphatase, total bilirubin, albumin) - Serum PSA - Urine test - Whole blood for immune parameters (pre-dose, and 6 and 24 hours post-dose; 24 hour post-dose samples will be collected pre-dose on Day 2) - Collection of blood samples in CellSave storage tubes for CTC enumeration

[0264] Cycle 1, Day 8 The following tests and procedures are performed: - Evaluation for AE - Questions about concomitant medications - Physical examination (including vital signs [blood pressure, heart rate, respiratory rate, and temperature]) - ECOG performance status - Clinical Laboratory Evaluation: - Hematology (CBC + differential) - Serum chemistry (Na, K, Cl, bicarbonate, Ca, Mg, phosphate, BUN / Cr, and LDH). - Liver function tests (AST, ALT, alkaline phosphatase, total bilirubin, albumin)

[0265] Cycle 1, Day 14 The following tests and procedures are performed: - Whole blood for immune parameters (pre-dose, and 6 and 24 hours post-dose; 24 hour post-dose samples will be collected pre-dose on Day 15) - Collection of blood samples for pharmacokinetic analysis immediately before the final dose

[0266] Cycle 1, Day 15 The following tests and procedures are performed: - Evaluation for AE - Questions about concomitant medications - Physical examination (including vital signs [blood pressure, heart rate, respiratory rate, and temperature]) - ECOG performance status - Clinical Laboratory Evaluation: - Hematology (CBC + differential) - Serum chemistry (Na, K, Cl, bicarbonate, Ca, Mg, phosphate, BUN / Cr, and LDH). - Liver function tests (AST, ALT, alkaline phosphatase, total bilirubin, albumin)

[0267] Cycle 2, Day 1 The following tests and procedures are performed: - Evaluation for AE - Questions about concomitant medications - Dispense talabostat mesylate for administration on Days 1-14 of Cycle 2 - Administer pembrolizumab - Physical examination (including vital signs [blood pressure, heart rate, respiratory rate, and temperature] and weight) - ECOG performance status - Obtain a 12-lead ECG - Clinical Laboratory Evaluation: - Hematology (CBC + differential) - Serum chemistry (Na, K, Cl, bicarbonate, Ca, Mg, phosphate, BUN / Cr, and LDH). - Liver function tests (AST, ALT, alkaline phosphatase, total bilirubin, albumin) - Serum PSA - Urine test - Whole blood for immune parameters (pre-dose, and 6 and 24 hours post-dose; 24 hour post-dose samples will be collected pre-dose on Day 2) - Collection of blood samples in CellSave storage tubes for CTC enumeration

[0268] Cycle 2, Day 8 The following tests and procedures are performed: - Evaluation for AE - Questions about concomitant medications - Physical examination - ECOG performance status - Clinical Laboratory Evaluation: - Hematology (CBC + differential) - Serum chemistry (Na, K, Cl, bicarbonate, Ca, Mg, phosphate, BUN / Cr, and LDH). - Liver function tests (AST, ALT, alkaline phosphatase, total bilirubin, albumin)

[0269] Cycle 2, Day 14 The following tests and procedures are performed: - Whole blood for immune parameters (pre-dose, and 6 and 24 hours post-dose; 24 hour post-dose samples will be collected pre-dose on Day 15) - Collection of blood samples for pharmacokinetic analysis immediately before the final dose

[0270] Cycle 2, Day 15 The following tests and procedures are performed: - Evaluation for AE - Questions about concomitant medications - Physical examination (including vital signs [blood pressure, heart rate, respiratory rate, and temperature]) - ECOG performance status - Clinical Laboratory Evaluation: - Hematology (CBC + differential) - Serum chemistry (Na, K, Cl, bicarbonate, Ca, Mg, phosphate, BUN / Cr, and LDH). - Liver function tests (AST, ALT, alkaline phosphatase, total bilirubin, albumin)

[0271] Cycle 3 and subsequent cycles, day 1 The following tests and procedures are performed: - Evaluation for AE - Questions about concomitant medications - Dispense talabostat mesylate for administration on days 1-14 of the cycle - Administer pembrolizumab - Physical examination (including vital signs [blood pressure, heart rate, respiratory rate, and temperature] and weight) - ECOG performance status - Obtain a 12-lead ECG - Clinical Laboratory Evaluation: - Hematology (CBC + differential) - Serum chemistry (Na, K, Cl, bicarbonate, Ca, Mg, phosphate, BUN / Cr, and LDH). - Liver function tests (AST, ALT, alkaline phosphatase, total bilirubin, albumin) - Serum PSA - Urine test - Tumor assessments must include cross-sectional imaging of the chest / abdomen / pelvis (MRI or CT scanning with intravenous contrast when possible), plus a whole-body bone scan. Other body regions (e.g., neck) should be included as clinically indicated. Tumor assessments will be performed on C4D1 (± 7 days), C7D1 (± 7 days), C10D1 (± 7 days), and on Day 1 (± 7 days) of each third cycle thereafter. - Collection of blood samples in CellSave storage tubes for CTC enumeration on C4D1 and on the first day of every third cycle thereafter

[0272] Cycle 3 and subsequent cycles, days 8 and 15 The following tests and procedures are performed: - Evaluation for AE - Questions about concomitant medications - Clinical Laboratory Evaluation: - Hematology (CBC + differential) - Serum chemistry (Na, K, Cl, bicarbonate, Ca, Mg, phosphate, BUN / Cr, and LDH). - Liver function tests (AST, ALT, alkaline phosphatase, total bilirubin, albumin)

[0273] Cycle 3 only, days 14-21 The following tests and procedures are performed: - Collection of blood samples for pharmacokinetic analysis immediately prior to the final dose on Day 14, and at 2, 6, 12, 24 (Day 15), 72 (Day 17), 120 (Day 19), and 168 (Day 21) hours after the dose on Day 14.

[0274] End of treatment visit (within 21 days after last study medication administration) The following tests and procedures are performed: - Evaluation for AE - Questions about concomitant medications - Physical examination including weight - ECOG performance status - Obtain a 12-lead ECG - Clinical Laboratory Evaluation: - Hematology (CBC + differential) - Serum chemistry (Na, K, Cl, bicarbonate, Ca, Mg, phosphate, BUN / Cr, and LDH). - Liver function tests (AST, ALT, alkaline phosphatase, total bilirubin, albumin) - Urine test - Tumor assessment should include cross-sectional imaging of the chest / abdomen / pelvis (MRI or CT scanning with intravenous contrast when possible), plus a whole-body bone scan. Other body regions (e.g., neck) should be included as clinically indicated. - Collection of blood samples in CellSave storage tubes for CTC enumeration - Revisit (Safety follow-up visits may be conducted for 30 days [± 7 days] after the last dose of study drug and thereafter if the drug-related AE has not resolved at that time)

[0275] The following tests and procedures are performed: - Evaluation for AE - Questions about concomitant medications

[0276] Example 2: This is a phase 2 basket study of talabostat mesylate, a small molecule inhibitor of dipeptidyl peptidase (DPP), administered in combination with pembrolizumab in patients with advanced solid cancer.

[0277] Research purpose(s) Main purpose The main objectives of the study are: To assess response rates according to response evaluation criteria in solid tumors (RECIST) and immune-iRECIST in patients treated in Cohort A and in patients treated in Cohort B. To evaluate dose-limiting toxicities (DLTs) in the first six patients enrolled in the study.

[0278] Secondary Objectives Secondary objectives of the study for Cohort A and Cohort B include: To assess progression-free survival (PFS) To assess duration of response (DOR) To assess overall survival (OS) To assess overall safety and tolerability

[0279] Examination purpose To evaluate the quantitative and qualitative effects of talabostat mesylate in combination with pembrolizumab on relevant immune effector cytokines in the blood. To evaluate the quantitative and qualitative effects of talabostat mesylate in combination with pembrolizumab on various immune effector cells, including neutrophils, myeloid-derived suppressor cells (MDSCs), dendritic cells, cancer-associated fibroblasts (CAFs), T cells, and macrophage densities in pre-treatment primary biopsies and, where feasible, post-treatment tumor tissue. To discover the predictive value of baseline PD-L1 tumor expression and tumor mutational burden (TMB) with clinical outcome To assess changes in serially collected blood circular tumor DNA (ctDNA) to assess tumor response and clonal evolution To evaluate pre- and post-treatment PD-L1 PET / CT as a predictive tool for treatment response.

[0280] research design This is an open-label, single-center, Phase 2 study to measure the response rate of daily oral talabostat mesylate in combination with pembrolizumab in patients with advanced solid cancer. The study will also evaluate other efficacy parameters, such as PFS, OS, and DOR, as well as the safety of the combination treatment. A Bayesian optimal Phase 2 (BOP2) design will be adopted to monitor efficacy. The study consists of two stages: 1) Lead-in Stage (first 6 patients enrolled) - This study will evaluate and confirm the safety and tolerability of talabostat mesylate, administered orally daily on days 1-14 of a 21-day cycle, in combination with pembrolizumab 200 mg administered intravenously (IV) on day 1 of each 21-day cycle in patients with advanced solid cancer. The dose of talabostat mesylate is 0.6 mg. 2) Efficacy Stage (BOP2 Stage) - Here, patients with advanced solid cancer are treated with talabostat mesylate in combination with pembrolizumab. Patients enrolled in the lead-in stage are also evaluated in the efficacy stage.

[0281] During the lead-in stage, patients will be observed for dose-limiting toxicities (DLTs) during Cycle 1. Six patients will initially receive 0.6 mg talabostat mesylate daily (days 1-14) and 200 mg pembrolizumab: If two or more of the six original patients have DLTs in cycle 1, the dose will be considered above the maximum tolerated dose (MTD) and an additional six patients will be treated with talabostat mesylate 0.4 mg daily at the dose level on days 1-14. o The efficacy stage can begin if 1 or fewer patients experience a DLT If two or more patients experience DLT, discussions will be held between the investigator and sponsor regarding how to proceed.

[0282] Figure 3 presents an overview of the study.

[0283] All safety data for all patients who received at least one dose of study drug will be included in the safety analysis. Patients must have received >70% of talabostat mesylate in Cycle 1 (i.e., ≥30 of the planned 42 doses) plus pembrolizumab administered on Day 1 of Cycle 1 to be eligible for DLT assessment, unless the dose was held off by a DLT.

[0284] Toxicity will be assessed by the investigator using the Common Terminology Criteria for Adverse Events (NCI CTCAE) (Version 5). The relationship of AEs to concomitant therapy (i.e., attribution to talabostat mesylate and / or pembrolizumab) must be assessed by the investigator using the criteria in the protocol.

[0285] A DLT is defined as any of the following AEs occurring during Cycle 1, regardless of the investigator's attribution to study treatment, unless the AE can clearly and indisputably be attributed to an unrelated cause (e.g., disease progression) by the principal investigator: - Any Grade 4 laboratory-based anomaly, regardless of duration - Any Grade 3 non-hematologic AE (except Grade 3 nausea, vomiting, diarrhea, constipation, fever, fatigue, skin rash, or nonclinical significant laboratory abnormalities that resolve to Grade 2 or less with optimal medical management within 72 hours). - Grade 3 thrombocytopenia greater than Grade 1, with requirement for blood sampling or platelet transfusion. - Grade 3 febrile neutropenia. - Grade 3 fever. - Grade 3 skin rash. - Laboratory abnormalities meeting Hy's law criteria (aspartate aminotransferase [AST] or alanine aminotransferase [ALT] > 3 × upper limit of normal [ULN] with concomitant total bilirubin > 2 × ULN). - Grade 3 transaminase (AST / ALT) elevation. - Any toxicity resulting in ≥30% held / skipped doses of talabostat mesylate during Cycle 1. - Delay of Cycle 2 by 14 days or more due to toxicity. Any other significant toxicity deemed by the investigator and sponsor's medical representative to be dose limiting.

[0286] Efficacy Stage: Following safety evaluation and confirmation of the talabostat mesylate / pembrolizumab dose schedule to be used in later stages, the efficacy stage will begin. Eligible patients will receive oral talabostat mesylate daily on days 1-14 of a 21-day cycle, plus pembrolizumab 200 mg administered intravenously on day 1 of each 21-day cycle.

[0287] Study design characteristics (both stages): During both the lead-in and efficacy stages, patients will be screened for the study after providing written informed consent and within 28 days prior to their first study drug administration. Patients who are deemed eligible based on the screening assessment will be enrolled in the study on Day 1 (D) of Cycle (C) 1 (baseline, prior to the first dose of talabostat mesylate).

[0288] During treatment, patients will participate in study center visits and have study assessments performed as detailed in the assessment schedule (Appendix A). All study visits will be conducted on an outpatient basis, but may be conducted on an inpatient basis at the investigator's discretion.

[0289] All patients must undergo pretreatment (before study treatment administration) imaging (chest / abdominal / pelvic computed tomography [CT] scan or magnetic resonance imaging [MRI] for baseline tumor measurement, and bone scintigraphy [BS]). Patients with cutaneous, subcutaneous, or lymph node metastases may also have tumor assessment (including ruler measurement) via physical examination. Patients with a history of central nervous system (CNS) malignant infiltration or CNS symptoms must undergo either CT or MRI imaging of the brain to evaluate for active CNS malignancy.

[0290] Tumor measurements and disease response assessments (CT or MRI; BS) should also be performed at the end of Cycle 3 (approximately 9 weeks after the first study treatment administration), and then approximately every 9 weeks thereafter until progression to progressive disease (PD). For patients with evidence of disease control (stable disease or better) at Week 27, tumor and disease response assessments can be performed less frequently thereafter (approximately every 12 weeks). Tumor measurements and disease response assessments can also be performed at the end of treatment (EOT) visit.

[0291] Study procedures are listed in Appendix A.

[0292] Study population Approximately 6-12 and 24-48 patients who meet the protocol's eligibility criteria will be enrolled during the lead-in and efficacy stages of the protocol, respectively. Patients enrolled in the lead-in stage will be evaluated and used in the efficacy stage.

[0293] Eligibility Criteria All patients must meet the following inclusion and exclusion criteria to be eligible for enrollment in the trial.

[0294] Inclusion criteria for patients 1.Patients with histologically or cytologically proven advanced solid cancer who have failed or are intolerant to standard therapies known to confer a survival benefit, unless the standard of care includes PD1 or PD-L1 antibodies. Lead-in stage: Patients with advanced cancer meeting the above criteria, with or without prior treatment with PD1 / PDL1 antibodies. Patients who have received prior treatment with PD1 / PDL1 antibodies should relapse. b. Efficacy Stage Cohort A: Patients with advanced cancer not previously treated with a PD1 / PDL1 antibody. c. Efficacy stage cohort B: Patients with advanced cancer that has recurred or progressed after treatment with PD1 / PDL1 antibody 2. Patients with a life expectancy of greater than 3 months in the investigator's opinion. 3. Patients have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. 4. Patients must be 12 years of age or older. Patients under 18 years of age must weigh 40 kg or more. 5. Patients will have measurable disease by RECIST 1.1 and iRECIST. Biopsy-amenable disease is not required. 6. The patient's acute toxic effects from previous anticancer therapy have resolved to Grade 1 or less, with the exception of Grade 2 peripheral neuritis or any grade of alopecia. 7. Patient has adequate baseline organ function as shown below: a. Serum creatinine ≤ 1.5 times the institutional upper limit of normal (ULN) or calculated creatinine clearance > 40 mL / min; b. Serum albumin ≥ 2.5 g / dL; c. Total bilirubin ≤ 1.5 × ULN (< 3 × ULN for patients with known Gilbert's syndrome); d. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x institutional ULN (patients with liver metastases must have AST / ALT ≤ 5 x ULN). 8. Patient has adequate baseline hematological function as follows: a.≥ 1.0 × 10 9 Absolute neutrophil count (ANC) in / L. b. Hemoglobin ≥ 8 g / dL and zero red blood cell transfusions in the previous 7 days. C. Platelet count ≥ 75 x 10 9 / L. 9. Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU / L or equivalent units of human chorionic gonadotropin [HCG]) within 14 days of treatment initiation, and / or postmenopausal women must be amenorrheic for at least 12 months during which they are considered non-fertile. Women of childbearing potential must agree to and commit to using two highly effective birth control methods throughout the study, including at least 4 months after the last dose of study medication. Acceptable methods are defined as those that, when used consistently and correctly, result in a low failure rate (i.e., less than 1% per year), either alone or in combination, such as surgical sterilization, intrauterine devices, or hormonal contraception combined with barrier methods. It is currently unknown whether talabostat mesylate or pembrolizumab can reduce the effectiveness of systemically acting hormonal contraceptives. Therefore, women using systemically acting hormonal contraceptives must also use a barrier method. In certain countries (where permitted by law), WOCBP may agree to observe sexual abstinence from the opposite sex for the duration of their participation in the study. 10. Male patients and their female partners of childbearing potential must agree and commit to using barrier contraception (e.g., condoms with spermicidal foam / gel / film / cream / suppositories) throughout the study period until at least 60 days after the last dose of study medication, in addition to the female partner using either an intrauterine device or hormonal contraception and continuing this until at least 4 months after the last dose of study medication. This criterion may be waived for male patients who have had a vasectomy more than 6 months prior to signing the ICF. 11. The patient signed an informed consent form before beginning any study-specific procedures or treatments. 12. Patient is able to adhere to the study visit schedule and other protocol requirements.

[0295] Exclusion criteria 1. The patient is unable to swallow oral medications. 2. Patients have active central nervous system (CNS) metastases that have not been controlled by previous surgery or radiation therapy (patients should be steroid resistant). Patients with signs or symptoms suggestive of brain metastases are not eligible unless brain metastases are excluded by brain MRI / CT. 3. Prior to study treatment, the patient received external beam radiation or another systemic anticancer therapy within 14 days or 5 half-lives, whichever is shorter. 4. Patient received treatment with an investigational systemic anti-cancer agent within 14 days prior to study drug administration. 5. Patients have additional active malignancies that may confound the assessment of study endpoints. Patients with the following concomitant tumor diagnoses are eligible: non-melanoma skin cancer and carcinoma in situ (including transitional cell carcinoma in situ, anal cancer, and melanoma). Patients with synchronous cancers that are not active and do not require treatment may be eligible, depending on discussion with the PI and advocate. 6. Patients have clinically significant cardiovascular disease (e.g., uncontrolled or New York Heart Association (NYHA) class 3 or 4 congestive heart failure, uncontrolled angina, history of myocardial infarction, unstable angina or stroke within 6 months prior to study entry, uncontrolled hypertension not controlled by medication, or clinically significant arrhythmias). 7. Patient has a diagnosis of immunodeficiency or is receiving systemic steroid therapy at a prednisone equivalent dose greater than 10 mg / day for at least 1 week, or other forms of immunosuppressive therapy within 7 days prior to Cycle 1 Day 1 (C1D1). 8. Patient has uncontrolled intercurrent illnesses, including but not limited to uncontrolled infection, disseminated intravascular coagulation, or psychiatric / social conditions that limit compliance with study requirements. 9. Patient has known positive status for human immunodeficiency virus activity or chronic hepatitis B or C. Patients with a history of hepatitis B or C and an undetectable viral load are eligible. Screening is not required. 10. Have clinically significant upper gastrointestinal disorders, abnormal physiologic function, or malabsorption syndromes that may affect the absorption of study medication. 11. The patient has any medical condition that, in the opinion of the investigator, places the patient at an unacceptably high risk of toxicity. 12. The patient is pregnant or breastfeeding

[0296] Research Methodology Concomitant medications Permitted medications / treatments Use of growth factors (e.g., granulocyte colony-stimulating factor [G-CSF]) is permitted as clinically indicated for the treatment of grade 3 or greater cytopenias.

[0297] Suggested supportive care measures for the management of AEs with a potential immune etiology are outlined below. When appropriate, these guidelines include oral or IV treatment with corticosteroids and the use of additional anti-inflammatory agents if symptoms do not improve with corticosteroid administration. Note that several courses of steroid tapering may be necessary if symptoms may worsen as the steroid dose is reduced. For each AE, an attempt should be made to rule out other causes, such as metastatic disease or bacterial or viral infection, and further supportive care may be required.

[0298] Prohibited Medications / Therapies Patients enrolled cannot receive investigational or approved anti-cancer drugs, including cytotoxic chemotherapy agents, anti-cancer tyrosine kinase inhibitors, or therapeutic monoclonal antibodies.

[0299] Palliative radiation therapy is not permitted during study enrollment unless it is performed for existing non-progressing metastases / symptoms and involves a small radiation field (eg, isolated bone lesions).

[0300] Preclinical studies have demonstrated that talabostat mesylate has a low potential to inhibit the following major human hepatic CYP isoenzymes: CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Furthermore, relevant concentrations of talabostat mesylate did not inhibit CYP3A4 or CYP1A2. Therefore, there are no prohibited medications based on CYP isoenzymes.

[0301] Efficacy evaluation Efficacy will be assessed during treatment using RECIST 1.1 and iRECIST every 9 weeks (every 3 cycles). Details of RECIST and iRECIST are provided in Appendix B and C.

[0302] Safety evaluation Non-serious adverse events Investigators must assess AEs at each visit. Any AEs, including observed or spontaneous problems, complaints, or symptoms, must be recorded in the eCRF. Each AE must be evaluated for duration, intensity, and causal relationship to study treatment or other factors. MOCLIA will be used for the eCRF in this study. The Research Department (Investigational Cancer Drugs) database team will create the CRF based on protocol requirements, and once ready, the IND Monitor will review and approve it.

[0303] The investigator will be responsible for monitoring the safety of patients entering the study. Any AEs that occur during the treatment period and / or within 30 days of the last dose of talabostat mesylate and / or pembrolizumab (investigational product, IP) will be followed until the end of the study or until resolved. AEs will be graded according to the revised NCI CTCAE, version 5.0 (see http: / / ctep.cancer.gov / reporting / ctc.html). AEs that occur within 30 days after the last dose of IP do not need to be reported unless the investigator considers the event to be IP-related.

[0304] [Table A]

[0305] Reporting of serious adverse events From the investigator's perspective, an adverse event or suspected rejection is considered "serious" if it results in any of the following outcomes: ·death Life-threatening adverse drug experience - any adverse experience occurring in a patient that, in the opinion of the initial reporter, carries a moderate risk of death from the adverse experience that occurred. Does not include adverse experiences that, if occurring in a more severe form, could result in death. · Inpatient hospitalization or extension of an existing hospitalization · Persistent or severe inability or substantial impairment of the ability to perform normal life functions. · Congenital malformations / abnormalities.

[0306] Significant medical events that may not result in death, may be life-threatening, or may require hospitalization may be considered serious adverse drug experiences when, based on sound medical judgment, they may endanger the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.

[0307] Any significant medical event, as described above, may also be considered a serious adverse event. Any significant medical event can and must be reported as an SAE if deemed appropriate by the Principal Investigator or IND Supporter, IND Office.

[0308] Any event that occurs during the implementation of the protocol and meets the definition of an SAE must be reported to the IRB according to the timeframes and procedures outlined in "The University of Texas MD Anderson Cancer Center Institutional Review Board Policy for Investigators on Reporting Serious Unanticipated Adverse Events for Drugs and Devices." Unless otherwise stated in the protocol, all SAEs, expected or unexpected, regardless of attribution, must be reported to the IND office (within five business days of becoming aware of the event).

[0309] Any unexpected, life-threatening, or fatal event related to the investigational drug must be reported to the IND Office Safety Project Manager within 24 hours (next business day) of becoming aware of the event.

[0310] Unless otherwise noted, the electronic SAE application (eSAE) will be used for secure reporting to the IND office and MDACC IRB.

[0311] Serious adverse events will be captured from the time of the first protocol-specific intervention until 90 days after the last dose of medication, or earlier if the participant waives consent or begins a new anticancer therapy. Serious adverse events must be followed until clinical recovery is complete, laboratory tests return to baseline, the progression of the event stabilizes, or there is acceptable resolution of the event.

[0312] Additionally, any serious adverse events occurring after the 90-day period related to the investigational treatment must be reported to the IND office, which may include the development of a second malignancy.

[0313] Adverse Event Tracking Patients will be monitored for AEs throughout the treatment period and for a minimum of 30 days after the last dose of talabostat mesylate.

[0314] Further reporting of new AEs is not required after the initiation of any subsequent chemotherapy or more than 30 days after the last dose of study medication, unless the study medication is deemed to have contributed to the new AE.

[0315] Pharmacokinetic / pharmacodynamic evaluation Whole blood samples and optimal tumor biopsies will be collected at the time points listed in Appendix A (section "Error! Reference source not found."). Example analyses will include testing of relevant immune effector cytokines, target engagement, and circulating tumor DNA (ctDNA).

[0316] disease progression Exclusion of patients from the study Within the bounds of safety and patient preference, every effort must be made for each patient to complete the study treatment period. Patients discontinued due to PD may be treated with any additional therapy deemed appropriate by the investigator.

[0317] Patients may be discontinued from the study for any of the following reasons: The researcher recommends discontinuation and provides a written reason(s) for the discontinuation -Needs some kind of treatment that is not permitted by the protocol · Patient's decision to waive consent or discontinue for any reason Presence of an intolerable AE considered related to study medication

[0318] All patients who discontinue during the treatment period will be required to return and complete safety and disease assessments (see Appendix A).

[0319] Completing the research The study will be considered complete when all patients have completed all post-study treatment procedures according to disease progression; lost follow-up, died, or been excluded due to toxicity; according to patient request; at the investigator's discretion.

[0320] Study medication Study medications will be administered in 21-day cycles. Either talabostat mesylate or pembrolizumab may be administered first. However, on Day 1 of Cycle 1, it is recommended that pembrolizumab be administered first, with at least one hour between administrations of talabostat mesylate. This will facilitate determining the relationship of any AEs to study medication.

[0321] Talabostat mesylate dosage and administration Talabostat mesylate tablets contain valine-proline boronic acid formulated as the methanesulfonate salt. Current dosage strengths include 0.05 mg and 0.2 mg tablets for oral administration.

[0322] Talabostat mesylate is administered orally as 0.2 mg tablets. Patients take three tablets daily on days 1–14 of each cycle for a total daily dose of 0.6 mg. Talabostat mesylate is continued until disease progression or unacceptable toxicity occurs.

[0323] On days when pharmacodynamic studies are being conducted, talabostat mesylate must be administered at the research center and must be administered at (approximately) the same time of day on each treatment day in the cycle. In cycles in which pharmacodynamics are not being evaluated, talabostat mesylate must also be administered at (approximately) the same time of day, preferably at 8:00 AM, on each treatment day in the cycle. If a patient forgets to take a study dose, that dose will be skipped.

[0324] Dose adjustment of talabostat mesylate secondary to toxicity No dose modifications of talabostat mesylate during a treatment cycle will be made in Cycle 1 unless required by AEs and / or DLTs. From Cycle 2 onwards, dose modifications during a treatment cycle will be made at the investigator's discretion. A dose that is maintained due to an AE may not be made up later during or after a cycle. A dose that is forgotten for reasons other than an AE (i.e., the patient forgets to take the dose) may be administered on a day after the scheduled dose. Any such adjustments must be discussed with the investigator. Under no circumstances should a forgotten dose be made up on a day when the patient is already taking the scheduled dose (i.e., no "doubling up" to account for the forgotten dose).

[0325] Dose modifications of talabostat mesylate are recommended for the following: Grade 2 or greater AEs of edema / peripheral swelling, hypotension, dizziness, and hypovolemia: Maintain talabostat mesylate until these AEs are ≤ Grade 1 or have resolved to baseline: Once these AEs have resolved to Grade 1 or less, including Grade 2 edema, or to baseline, resume talabostat mesylate at the full dose. After edema has returned to Grade 1 or below or to baseline, resume talabostat mesylate at a 0.2 mg reduced dose (one dose level decrement). If Grade 2 or higher edema does not recur during the next dosing period (2 weeks on / 1 week off), the talabostat mesylate dose may be increased again at the investigator's discretion. For other grade 2 or higher AEs considered to be related to talabostat mesylate: Maintain talabostat mesylate until these AEs are ≤ Grade 1 or have resolved to baseline: At the investigator's discretion, resume talabostat mesylate at the full dose or at a 0.2 mg reduced dose (1 dose level reduction). A maximum of two dose reductions per participant will be permitted for talabostat mesylate-related AEs, followed by permanent discontinuation of study drug. Any adverse event deemed related to talabostat mesylate that is Grade 1 or less or does not resolve to baseline within 6 weeks of initiation requires permanent discontinuation of talabostat mesylate.

[0326] If an SAE considered to be related to talabostat mesylate occurs during the treatment period, administration of talabostat mesylate should be discontinued in that patient until the SAE resolves. If the investigator wishes to continue talabostat mesylate in a patient, the sponsor should be contacted to discuss continuing talabostat mesylate at the same or reduced dose.

[0327] If talabostat mesylate is discontinued due to an AE, all treatment procedures and evaluations must be discontinued.

[0328] Monitoring patient compliance with study administration of talabostat mesylate All talabostat mesylate dose containers must be returned to the clinic at each visit. Patients must be questioned about adherence to the dosing regimen, and medication containers must be inspected at each visit to determine whether any talabostat mesylate doses have been missed and whether any missed doses have been documented. Patients must be at least 70% compliant with talabostat mesylate intake in Cycles 1 and 2 to be included in per-protocol efficacy analyses.

[0329] Description and storage of talabostat mesylate Talabostat mesylate is supplied as 0.05 mg and 0.2 mg tablets in high-density polyethylene bottles equipped with desiccant and child-resistant caps. 30 tablets are contained in each bottle. Talabostat mesylate supplies are appropriately labeled for clinical investigational substances. Talabostat mesylate should be stored under refrigerated conditions between 2°C and 8°C (36°F and 46°F).

[0330] Pembrolizumab administration, dose modification, and discontinuation Pembrolizumab is prepared, stored, and administered according to the current full prescribing information. Pembrolizumab is obtained from a commercial supply and administered intravenously at 200 mg over 30 minutes through a 0.2-5 micron sterile, nonpyrogenic, low-protein-binding online or add-on filter. No other medications are infused through the infusion line. The infusion will be interrupted and slowed for Grade 1 or 2 infusion-related reactions and permanently discontinued for Grade 3 or 4 infusion-related reactions. Pembrolizumab will be administered until disease progression, unacceptable toxicity, or consent is waived.

[0331] AEs associated with pembrolizumab exposure may be immune-mediated. Immune-related AEs can occur any time after pembrolizumab administration and can affect multiple body systems. Early recognition and treatment are important to reduce complications. Most immune-related AEs are reversible and can be managed by discontinuing pembrolizumab and initiating steroids. Refer to the current local pembrolizumab full prescribing information for recommended dose modifications for the management of toxicities (including immune-mediated and infusion-related reactions) considered related to pembrolizumab. Patients requiring pembrolizumab dose maintenance for 42 days or more will be discontinued from the study.

[0332] Pembrolizumab should not be used with other immunosuppressants, other than corticosteroids, given to control immune reactions thought to be associated with pembrolizumab. See the current topical pembrolizumab full prescribing information for further details.

[0333] Data analysis and statistical considerations This is a phase 2, single-center basket study of oral talabostat mesylate daily on days 1-14 in combination with an intravenous PD1 / PDL1 antibody on day 1 of 21 in subjects with advanced and refractory malignancies. Six patients will be enrolled in the lead-in cohort. Only six patients treated at the selected dose during the safety lead-in will be appropriately assigned to cohort A or B. That is, if there is a dose reduction during the safety lead-in, those six patients treated at the higher dose will not be assigned to the phase II cohort. Nine to 17 patients will be enrolled in cohorts A and B. Response assessment by CT and / or MRI will be performed every nine weeks (three cycles) according to RECIST and iRECIST criteria. The study follows a BOP2 design with the following operational characteristics: Force: 0.80 Type I error: 0.05 P0:0.05 P1: 0.25

[0334] Each cohort will enroll nine patients. If none of the first nine patients achieve a complete or partial response (CR), enrollment into that cohort will be stopped. If at least one PR or CR occurs among the first nine patients, enrollment will continue, for a total of 17 patients. If three or more CRs or PRs are observed among the 17 patients, the treatment will be considered promising for further investigation. Expected sample sizes range from 9 (if completed after a safety lead-in) to 34 patients. Considering that approximately 20% of patients will not be evaluated for efficacy, the actual number of patients expected to be recruited into the trial ranges from 11 to 42. [Table B]

[0335] The investigator is responsible for completing the Toxicity / Efficacy Summary Reports and submitting them to the IND Office Medical Affairs and Safety Group for review. These must be submitted as follows: Lead-in stage After the first 6 measurable patients complete study treatment in Cycle 1, IND Office approval must be obtained before proceeding to the efficacy stage. Validity Stage: After the first 9 measurable patients per cohort, 9 weeks of study treatment will be completed, for a total of 17 patients per cohort. A copy of the cohort summary must be placed in the investigator's control binder under "Communication with Sponsor." Toxicity monitoring will also be performed at this stage. If the empirical DLT rate exceeds 35%, escalation will be halted for safety reasons and discussions will be held for next steps.

[0336] Safety analysis All patients in the safety analysis set will be included in the final list and listing of safety data for lead-in patients.

[0337] The frequency of patients experiencing at least one AE is indicated by body system and preferred term according to the Medical Dictionary for Regulatory Affairs (MedDRA) terminology. Details collected for each AE include a description of the event, duration, whether the AE is serious, the nature of the event (single vs. multiple occurrences), intensity (i.e., NCI CTCAE Version 5 grade), relationship to study drug, action taken, clinical outcome, and whether the AE results in surgery or an alternative procedure. The intensity (severity) of the AE will be graded according to the NCI CTCAE. The latest versions of MedDRA and NCI CTCAE will be used.

[0338] Tables will be prepared showing the number of patients reporting an AE, the frequency of patient reports, and the corresponding proportions. Proportions will be calculated using the number of patients in the safety analysis set as the denominator. Within each table, AEs will be categorized by MedDRA body system and preferred term. Further subcategories will be based on the intensity and relationship of the event to study drug. AE data will span all cycles and be presented for each cycle. The denominator for each cycle is the patients available at the start of the cycle who received the dose of talabostat mesylate for that cycle.

[0339] To the extent possible, identify the relationship of AEs to either pembrolizumab or pembrolizumab.

[0340] Individual patient listings will be prepared for all AE data. Talabostat mesylate vital signs and ECOG performance status will be summarized by visit / cycle, with descriptive statistics applicable to continuous or categorical measures of these additional safety data. Listings will be presented for lead-in and efficacy stages.

[0341] Clinical Laboratory Analysis All clinical laboratory values ​​are individually enumerated and tabulated in a manner that identifies safety concerns on a patient-by-patient basis. Enumeration tables are prepared for each laboratory parameter and are structured to allow review of patient data as treatment progresses. The tables list treatment cycles, talabostat mesylate doses relative to lead-in data, and associated NCI CTCAE grades. Descriptive tabulation statistics are generated for each laboratory parameter.

[0342] Tables will be prepared to examine the distribution of these toxicities by cycle.

[0343] Graphic displays and shift tables can be prepared to show results over time in the study. Cumulative toxicity assessments can be made.

[0344] Researcher Requirements Adherence to protocols Each Investigator must agree to adhere to the protocol detailed herein and that any intended deviations from the protocol must be approved by the Principal Investigator or his / her designee before seeking approval by the IRB. Each Investigator is responsible for enrolling only patients who meet the protocol eligibility criteria.

[0345] Research Monitoring Requirements Site visits will be conducted by the sponsor or a representative of the sponsor to inspect study data, patient medical records, and other documentation in accordance with current U.S. Food and Drug Administration (FDA), Good Clinical Practice (GCP), and International Conference on Harmonization (ICH) guidelines, as well as local and national government regulations and guidelines. The investigator will allow the sponsor and / or its regulatory representative, the FDA, and local or national health authorities to inspect site facilities and records related to the study.

[0346] Drug Accountability Inventory control of all talabostat mesylate must be maintained throughout the duration of the study. Any discrepancies noted between medication dispensing records and medication inventory must be reported. Medication dispensing records will be provided to the study site. All study medication used during the study must be configured in the appropriate form. All unused study medication must be returned by the patient to the site for completion of their medication accountability record. All unused study medication will be disposed of by site personnel in a biohazard container in accordance with facility policy.

[0347] Record-keeping Records and documentation related to the conduct of this study, including screening logs, source documentation, consent forms, laboratory test results, medication inventory records, and other documentation, must be retained in accordance with local standard operating procedures and institutional and / or IRB policies.

[0348] Study discontinuation 1 Ethical considerations This study will be conducted in accordance with current FDA regulations, GCP, ICH guidelines, the ethical code originating from the Declaration of Helsinki, and local ethical and legal requirements.

Claims

1. 1. A therapeutic regimen for treating prostate cancer in a subject in need thereof, the regimen comprising administering to the subject an effective amount of talabostat or a pharmaceutically acceptable salt thereof, and an effective amount of pembrolizumab, as separate pharmaceutical formulations, wherein the talabostat or a pharmaceutically acceptable salt thereof, and the pembrolizumab are administered in one or more treatment cycles, each treatment cycle being about 21 days in duration.

2. 1. A method of treating prostate cancer in a subject in need of treatment, the method comprising administering to the subject an effective amount of talabostat or a pharmaceutically acceptable salt thereof, and an effective amount of pembrolizumab, as separate pharmaceutical formulations, wherein the talabostat or a pharmaceutically acceptable salt thereof, and pembrolizumab are administered to the subject in one, two, or three treatment cycles, each treatment cycle being about 21 days in duration.

3. 1. A method for improving immune function in a subject suffering from prostate cancer, said method comprising administering to said subject effective amounts of talabostat or a pharmaceutically acceptable salt thereof, and pembrolizumab as separate pharmaceutical formulations.

4. 1. A method of treating a subject suffering from prostate cancer with a therapeutically effective amount of talabostat without inducing treatment-limiting side effects, said method comprising administering to said subject effective amounts of talabostat or a pharmaceutically acceptable salt thereof, and pembrolizumab as separate pharmaceutical formulations.

5. The treatment regimen of claim 1 or the method of any one of claims 2 to 4, wherein the prostate cancer is small cell neuroendocrine prostate cancer (SCNC).

6. 10. The treatment regimen of claim 1 or the method of any one of claims 2-4, wherein the subject maintains a sustained response against the progression of the prostate cancer after treatment has ended.

7. 2. The treatment regimen of claim 1, wherein for each treatment cycle, talabostat or a pharmaceutically acceptable salt thereof is administered on each of days 1 to 14, and pembrolizumab is administered on day 1.

8. 5. The method of any one of claims 2-4, wherein for each treatment cycle, talabostat or a pharmaceutically acceptable salt thereof is administered on each of days 1 to 14, and pembrolizumab is administered on day 1.

9. 5. The therapeutic regimen of claim 1, or the method of any one of claims 2 to 4, wherein talabostat or a pharmaceutically acceptable salt thereof is administered orally in one or more tablets.

10. 10. The treatment regimen of claim 1, or the method of any one of claims 2-4, wherein pembrolizumab is administered by intravenous injection.

11. 5. The therapeutic regimen of claim 1, or the method of any one of claims 2-4, wherein talabostat or a pharmaceutically acceptable salt thereof is administered in a total daily dose of about 0.001 mg / kg to about 0.1 mg / kg.

12. 5. The treatment regimen of claim 1, or the method of any one of claims 2-4, wherein pembrolizumab is administered at a total dose of about 1 mg / kg to about 10 mg / kg per day.

13. 5. The therapeutic regimen of claim 1, or the method of any one of claims 2-4, wherein talabostat or a pharmaceutically acceptable salt thereof is administered in a total daily dose of about 0.4 mg / kg to about 0.6 mg / kg.

14. 5. The treatment regimen of claim 1, or the method of any one of claims 2-4, wherein pembrolizumab is administered at a total dose of about 100 mg to about 500 mg per day.

15. 5. The treatment regimen of claim 1, or the method of any one of claims 2-4, wherein pembrolizumab is administered at a total dose of about 200 mg per day.

16. 5. The treatment regimen of claim 1, or the method of any one of claims 2 to 4, wherein the total daily dose of talabostat in cycle 1 is less than the total daily dose of talabostat or a pharmaceutically acceptable salt thereof in one or more subsequent cycles.

17. 5. The treatment regimen of claim 1, or the method of any one of claims 2-4, wherein talabostat or a pharmaceutically acceptable salt thereof, and pembrolizumab are administered to the subject in one or more treatment cycles, each treatment cycle being about 21 days in duration, and wherein, for each treatment cycle, talabostat or a pharmaceutically acceptable salt thereof is administered on each of days 1 to 14, and pembrolizumab is administered on day 1.

18. 18. The therapeutic regimen or method of claim 17, wherein talabostat or a pharmaceutically acceptable salt thereof is administered in a total daily dose of about 0.4 mg to about 0.6 mg.

19. 20. The treatment regimen or method of claim 18, wherein the total daily dose of talabostat or a pharmaceutically acceptable salt thereof in cycle 1 is less than the total daily dose of talabostat in one or more subsequent cycles.

20. 5. The therapeutic regimen of claim 1, or the method of any one of claims 2 to 4, wherein the talabostat or a pharmaceutically acceptable salt thereof is talabostat mesylate.

21. 1. A therapeutic regimen for treating prostate cancer in a subject in need thereof, said regimen comprising administering to said subject one or more treatment cycles of talabostat mesylate and pembrolizumab, each treatment cycle being about 21 days in duration, and wherein, for each treatment cycle, talabostat is administered on each of days 1-14, pembrolizumab is administered on day 1, talabostat mesylate is administered as one or more tablets to provide a total daily dose of talabostat of about 0.4 mg to about 0.6 mg, and pembrolizumab is administered as a single intravenous infusion to provide a dose of about 100 mg to about 500 mg per day.

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