Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/69—Boron compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K40/00—Cellular immunotherapy
  • A61K40/40—Cellular immunotherapy characterised by antigens that are targeted or presented by cells of the immune system
  • A61K40/41—Vertebrate antigens
  • A61K40/42—Cancer antigens
  • A61K40/4202—Receptors, cell surface antigens or cell surface determinants
  • A61K40/421—Immunoglobulin superfamily
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
  • C07K16/2818—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
  • A61K2039/541—Mucosal route
  • A61K2039/542—Mucosal route oral/gastrointestinal
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
  • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
  • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

• the present disclosure relates to a treatment regimen for treating cancer comprising administering Talabostat or a pharmaceutically acceptable salt thereof and Pembrolizumab.
• Cancer is a multistep process that begins with minor pre-neoplastic changes, which may progress to neoplasia, the neoplastic lesions possibly developing an increasing capacity for invasion, growth, metastasis, and heterogeneity.
• Current therapies for the treatment of cancer involve surgery, hormonal therapy, radiation therapy, chemotherapy and immunotherapy.
• Immunotherapy for the treatment of cancer has evolved alongside our improved understanding of the immune system.
• an appreciation of the ability of cancer cells to subvert the antitumor immune response has provided a rationale for the development of novel immunotherapies that target immune checkpoints responsible for tumor cells escaping detection and destruction by the immune system.
• Such immune escape mechanisms are mediated either directly by the tumor cells or by the tumor microenvironment.
• Tumor cells are known to express membrane proteins, secreted products, enzymes, anti-inflammatory cytokines, and chemokines to produce changes in their genome that aid in immune evasion and immune inhibition.
• a key role is played by the tumor microenvironment.
• Immune checkpoint molecules such as PD-1, PD-L1, CTLA-4 are cell surface signaling receptors that play important roles in modulating the T-cell response in the tumor microenvironment. Tumor cells have been shown to utilize these checkpoints to their benefit by up-regulating their expression and activity. Therefore, immune checkpoint inhibitors have been developed which can unleash the immune system’s cancer-destroying properties. Recent discoveries have identified immune checkpoints or targets like PD-1, PD-L1, PD-L2, CTLA4, TIM3, LAG3, CCR4, 0X40, OX40L, IDO, and A2AR as proteins responsible for immune evasion, acting as “brakes” of the immune system.
• checkpoint inhibitors including antibodies against CTLA-4, the PD-1 receptor and its ligand PD-L1 have produced impressive results in the clinic, leading to FDA approvals for Yervoy® (Ipilimumab; CTLA-4 antagonist), Opdivo® (Nivolumab; PD-1 antagonist) and KEYTRUDA® (Pembrolizumab; PD-1 antagonist) in multiple tumor indications and with on-going clinical trials in many more.
• Yervoy® Ipilimumab; CTLA-4 antagonist
• Opdivo® Nevolumab; PD-1 antagonist
• KEYTRUDA® Plethrelapse in ab
• checkpoint inhibitors suffer from several limitations. Only a minority of patients treated with checkpoint inhibitors exhibit robust anti-tumor responses, and most responses are partial and temporary. Often patients initially respond, but then relapse due to the emergence of resistant pathways, which mainly occur due to the generation by the tumor cells of a non-immune permissive microenvironment.
• Talabostat also known as PT-100 (Val-boroPro; L-valinyl-L-boroproline), was originally developed by Point Therapeutics, during 2000 to 2007. It is an orally available synthetic selective inhibitor of dipeptidyl peptidases like FAP and DPP8 and DPP9.
• the stereoisomer of the Talabostat molecule disclosed in the U.S. Patent No. 6,825,169 while its oral formulation such as tablet, capsule, lozenges is disclosed in the U.S. Patent No.7, 265, 118.
• Talabostat plays an important role in immune evasion and regulates both innate and/or acquired immunity.
• Talabostat has been reported to exhibit a number of side effects at therapeutically effective doses, with the most common adverse events being edema/peripheral swelling, hypotension, hypovolemia, and dizziness. These reported adverse events, as well as insufficient primary and secondary outcomes in certain cancer clinical trials, have led to the limited use of Talabostat as an anti -cancer agent.
• 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 comprising administering Talabostat or a pharmaceutically acceptable salt thereof at a dose of about 0.3 mg twice daily on one or more days of a treatment cycle, and Pembrolizumab on day 1 of a treatment cycle is a safe and effective therapy to treat subjects afflicted with prostate cancer or an advanced solid tumors.
• the treatment regimen is well tolerated and produces less severe adverse effects relative to a subject with same cancer that is administered 0.6 mg once daily dose of Talabostat.
• the present disclosure provides a regimen or a method for treating prostate cancer in a subject in need thereof, comprising administering to said subject, Talabostat or a pharmaceutically acceptable salt thereof at a dose of about 0.3 mg twice daily on one or more days of a treatment cycle and an effective amount of Pembrolizumab on day 1 of a treatment cycle.
• the method comprises at least one administration cycle (e.g. 1, 2, 3, 4, 5, 6 or more cycles), and each treatment cycle is of about 21 days.
• said treatment is administered for at least 12 weeks, or at least 24 weeks.
• the patient achieves a complete response within 2-4 weeks after treatment.
• the separate pharmaceutical formulations of Talabostat or a pharmaceutically acceptable salt thereof and Pembrolizumab are administered to the subject at relevant times, and in suitable amounts, during one or more treatment cycles of about 21 days, to maximize their combined immunotherapeutic effect.
• Talabostat or a pharmaceutically acceptable salt thereof is administered orally (e.g. as a tablet formulation) at a dose of 0.3 mg twice a day.
• Pembrolizumab is administered intravenously at a total dose of about 200 mg.
• Talabostat or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 0.2 mg twice daily on day 1-7 of the first treatment cycle followed by about 0.3 mg twice daily on day 8-14 of the first treatment cycle.
• Talabostat or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 0.3 mg twice daily on day 1-3 of the first treatment cycle followed by rest period of 4 days then about 0.3 mg twice daily on day 8-11 of the first treatment cycle,
• the subject afflicted with prostate cancer has experienced dose-limiting adverse effects (or DLT) with a single 0.6mg daily dose of Talabostat.
• the prostate cancer is selected from the group consisting of small cell neuroendocrine prostate cancer; (SCNC), neuroendocrine prostate cancer (NEPC), treatment emergent neuroendocrine prostate cancer (tNEPC), castration resistant prostate cancer (CrPC), metastatic castration resistant prostate cancer (mCrPC) and adenocarcinoma type prostate cancer).
• SCNC small cell neuroendocrine prostate cancer
• NEPC neuroendocrine prostate cancer
• tNEPC treatment emergent neuroendocrine prostate cancer
• CrPC castration resistant prostate cancer
• mCrPC metastatic castration resistant prostate cancer
• adenocarcinoma type prostate cancer adenocarcinoma type prostate cancer.
• the prostate cancer is adenocarcinoma type prostate cancer.
• the prostate cancer is small cell neuroendocrine prostate cancer.
• the prostate cancer is treatment emergent neuroendocrine prostate cancer (tNEPC).
• the prostate cancer is metastatic.
• the prostate cancer is at an advanced stage.
• the present disclosure provides methods for treating one or more solid tumors (e.g. an advanced solid tumor) in a subject in need thereof, comprising administering to said subject, Talabostat or a pharmaceutically acceptable salt thereof at a dose of about 0.3 mg twice daily on one or more days of a treatment cycle and Pembrolizumab on day 1 of the treatment cycle.
• one or more solid tumors e.g. an advanced solid tumor
• Talabostat or a pharmaceutically acceptable salt thereof at a dose of about 0.3 mg twice daily on one or more days of a treatment cycle and Pembrolizumab on day 1 of the treatment cycle.
• the solid cancer is selected from the group consisting of castrate resistant prostate cancer, endometrial cancer, dedifferentiated liposarcoma, basal cell carcinoma, leiomyosarcoma, squamous cell carcinoma of unknown primary, skin melanoma, mucosal melanoma, pleomorphic sarcoma, colorectal/colon cancer, astrocytoma, triple negative breast cancer, uterine sarcoma and uveal melanoma.
• the subject was not previously treated with PD-1/PD-L1 or CTLA-4 antibodies (or treatment naive).
• the subject has relapsed with PD-1/PD-L1 or CTLA-4 antibodies (or treatment experienced).
• the subject has progressed with PD-1/PD-L1 or CTLA-4 antibodies.
• the subject administered with such a treatment regimen achieves a 50% or greater prostate-specific antigen (PSA) decline from baseline by week 12 of treatment.
• PSA prostate-specific antigen
• the subject administered with such a treatment regimen achieves a stable disease response or better, as measured by RECIST 1.1.
• the subject administered with such a treatment regimen achieves a partial disease response or better, as measured by RECIST 1.1.
• the subject administered with such a treatment regimen achieves a complete disease response or better, as measured by RECIST 1.1.
• the present disclosure provides a method of enhancing an innate immune response in a subject afflicted with prostate cancer (e.g. small cell neuroendocrine prostate cancer; (SCNC), neuroendocrine prostate cancer (NEPC), treatment emergent neuroendocrine prostate cancer (tNEPC), castration resistant prostate cancer (CrPC), metastatic castration resistant prostate cancer (mCrPC), adenocarcinoma type prostate cancer), the method comprising administering to said subject, Talabostat or a pharmaceutically acceptable salt thereof at a dose of about 0.3 mg twice daily on one or more days of a treatment cycle and Pembrolizumab on day 1 of the treatment cycle, wherein the enhanced innate immune response is associated with increased tumoricidal natural killer cells and macrophages, as well as the activity of NK cells and CD8+ T cells.
• the enhanced innate immune response is associated with suppression of T-regulatory cells.
• the disclosure provides a method of enhancing an innate immune response in a subject afflicted with one or more solid tumors (e.g. an advanced solid tumor) , comprising administering to said subject, Talabostat or a pharmaceutically acceptable salt thereof at a dose of about 0.3 mg twice daily on one or more days of a treatment cycle (e.g. day 1 to 14) and Pembrolizumab on day 1 of the treatment cycle, wherein the enhanced innate immune response is associated with increased tumoricidal natural killer cells and macrophages, as well as the activity of NK cells and CD8+ T cells.
• the enhanced innate immune response is associated with suppression of T-regulatory cells.
• the present disclosure provides a method of enhancing proinflammatory cytokine release in a subject afflicted with prostate cancer, the method comprising administering to said subject, Talabostat or a pharmaceutically acceptable salt thereof at a dose of about 0.3 mg twice daily on one or more days of a treatment cycle and Pembrolizumab on day 1 of the treatment cycle, wherein the enhanced proinflammatory cytokine release is associated with activation of Natural Killer (NK) cells and T cells resulting in increased antitumor response.
• NK Natural Killer
• the proinflammatory cytokines are one or more of IL-18, IL-Ib and IFN-g.
• the subject experiences an increase in pro-inflammatory cytokines relative to a subject that is administered a single 0.6 mg daily dose of Talabostat.
• a time -dependent increase in IL- 18 levels with maximum increase on day 14 of continuous dosing is observed.
• the subject is afflicted with one or more solid tumors (e.g. an advanced solid tumor).
• one or more solid tumors e.g. an advanced solid tumor.
• the present disclosure provides a method of reducing the treatment related adverse effects (TRAEs) in a subject afflicted with prostate cancer, comprising administering to said subject, Talabostat or a pharmaceutically acceptable salt thereof at a dose of about 0.3 mg twice daily on one or more days and Pembrolizumab on day 1 of a treatment cycle.
• the subject experiences lesser treatment-related adverse events (TRAEs) or (no DLT) relative to a subject with same cancer that is administered a single 0.6 mg once daily dose of Talabostat.
• the TRAEs are selected from one or more of hypotension, dizziness, headache, syncope, dyspnea, chills, pyrexia, malaise, weakness, edema/peripheral swelling, hypovolemia, hypothermia, fatigue, nausea, vomiting, diaphoresis, flushing, migraine, diarrhea, constipation, alopecia, pharyngitis, chest pain, anorexia, weight increase, weight decrease, vertigo, syncope, conjunctivitis, blurred vision, pallor, pruritus, rash, fungal vaginosis, hyperglycemia, hyperkalemia, hypokalemia, hoarseness, dyspnea, anoxia, deep venous thrombosis, upper respiratory infection, blood in stool, dizziness, rigors, sepsis, pain, hypereosinophilia, dehydration, electrolyte imbalance, arthralgia, rhabdom
• the subject experiences no TRAEs. In other embodiment, the subject experiences TRAEs that are consistent with cytokine release.
• the prostate cancer is selected from small cell neuroendocrine prostate cancer (SCNC), neuroendocrine prostate cancer (NEPC), treatment emergent neuroendocrine prostate cancer (tNEPC), castration resistant prostate cancer (CrPC), metastatic castration resistant prostate cancer (mCrPC), adenocarcinoma type prostate cancer.
• SCNC small cell neuroendocrine prostate cancer
• NEPC neuroendocrine prostate cancer
• tNEPC treatment emergent neuroendocrine prostate cancer
• CrPC castration resistant prostate cancer
• mCrPC metastatic castration resistant prostate cancer
• adenocarcinoma type prostate cancer adenocarcinoma type prostate cancer.
• the solid cancer is selected from the group comprising castrate resistant prostate cancer, endometrial cancer, dedifferentiated liposarcoma, basal cell carcinoma, leiomyosarcoma, squamous cell carcinoma of unknown primary, skin melanoma, mucosal melanoma, pleomorphic sarcoma, colorectal/colon cancer, astrocytoma, triple negative breast cancer, uterine sarcoma, uveal melanoma.
• FIG. 1 shows the scheme for administering Talabostat mesylate and Pembrolizumab to subjects with mCrPC during the treatment Lead-in Stage and the Efficacy Stage according to Example 1.
• FIG. 2 shows the prostate specific antigen (PSA) levels in ten subjects according to Example 1.
• FIG 3 shows the scheme for administering Talabostat mesylate and Pembrolizumab to subjects with advanced solid cancers during the treatment Lead-in Stage according to Example 2.
• FIG. 4 shows the Phase lb/2 scheme according to Example 1.
• FIG. 5 shows the plasma concentration of individual subjects over multiple dosing cycles after 0.4 mg or 0.6 mg total daily dose of Talabostat mesylate [individual plots] according to Example 1.
• FIG. 6 shows the plasma concentration profiles in 3 cycles after 0.4mg or 0.6 mg according to Example 1
• FIG. 18 shows best change in sum of target lesions per RECIST 1.1 according to Example 2
• FIG. 19A shows partial response (-64%) in a patient with MSS, PDL-1 negative endometrial cancer and 2 prior systemic therapies not including PD-1/PD-L1 or CTLA4 inhibitors according to Example 2. The patient continues on study for more than 4 months.
• FIG. 19B shows stable disease (-23%) in a patient with high grade pleomorphic sarcoma, MSS, PDL-1 negative and 3 prior systematic therapies including PD-1 antibody (best response: PD) to Example 2. The patient continues on study for more than 5 months.
• FIG. 20 shows serum PSA % change from baseline overtime in Phase lb and Phase 2 patients according to Example 1.
• FIG. 21 shows PSA Best Overall response in Phase lb and Phase 2 patients according to Example 1.
• A2AR A2A adenosine receptor
• ADT Androgen deprivation therapy
• ALK Anaplastic lymphoma kinase
• ALT Alanine aminotransferase
• ANC Absolute neutrophil count
• AR Androgen receptor
• AUC Area under the plasma concentration-time curve
• AUC 0-last Area under the plasma concentration time curve for the last measurable concentration
• BUN Blood urea nitrogen
• CAF Cancer associated fibroblast
• CLL Chronic lymphocytic leukemia
• CRPC Castration-resistant prostate cancer
• CT Computed tomography
• CTLA4 Cytotoxic T-lymphocyte associated protein 4
• DPP Dipeptidyl peptidase
• DKA Diabetic ketoacidosis
• DLT Dose limiting toxicity
• EGFR Epidermal growth factor receptor
• 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
• 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
• iRECIST Immune Response Evaluation Criteria In Solid tumors
• ITT Intent-to-Treat
• LAG3 Lymphocyte activation gene 3 protein
• LHRH Luteinizing hormone-releasing hormone
• mCrPC metastatic castration resistant prostate cancer
• MSI-H Microsatellite instability -high
• MDSC Myeloid derived suppressor cell
• 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
• PCWG3 Prostate Cancer Working Group 3
• PD -1 Programmed cell death 1
• PD LI Programmed death ligand 1
• PD L2 Programmed death ligand 2
• PD-1 Programmed Cell Death 1
• QTcB QT interval corrected for heart rate using Bazett’s formula
• SCNC Small cell neuroendocrine prostate cancer
• 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 mellitus
• Tmax Time of maximum observed concentration
• Talabostat or a pharmaceutically acceptable salt thereof: Talabostat is referred to interchangeably as PT-100, Talabostat (USAN), and [(2R)-1 - [(2S)-2-amino-3-methyl-l- oxobutyl]-2-pyrrolidinyl] boronic acid.
• Talabostat has a CAS registration number of 149682- 77-9.
• Talabostat also known as Val-boro-pro (L-valinyl-L-boroproline), is disclosed in PCT Appl. Publication No. 1989/003223.
• talabostat is [(2R)-l-[(2S)-2-amino- 3-methylbutanoyl]pyrrolidin-2-yl]boronic acid.
• Talabostat (PubChem ID: 6918572), or a pharmaceutically acceptable salt thereof, such as, for example, talabostat mesylate (PubChem CID: 11522448).
• the free base may be used.
• the Talabostat or a pharmaceutically acceptable salt thereof may be a solvate.
• Talabostat is provided as a salt form, e.g. Talabostat mesylate.
• Talabostat has two chiral centers with a R, S configuration.
• Talabostat or a pharmaceutically acceptable salt thereof can exist as both linear and cyclic forms (RJ Snow et al., J. Am. Chem. Soc., 1994, 116 (24), pp 10860- 10869).
• Talabostat or a pharmaceutically acceptable salt thereof is effective for the treatment of cancer by modulating multiple intracellular and extracellular dipeptidyl peptidases. More specifically, intracellular and extracellular dipeptidyl peptidases comprise Fibroblast Activation Protein, DPP 8/9, CD26/DPP4 and DPP2.
• Intracellular and extracellular dipeptidyl peptidases comprise Fibroblast Activation Protein, DPP 8/9, CD26/DPP4 and DPP2.
• Talabostat or a pharmaceutically acceptable salt thereof has a dual mechanism of action which includes stromal targeted activity via FAP inhibition and targeted immunostimulatory activity via DPP 8/9 inhibition. Talabostat inhibits FAP enzymatic activity thereby suppressing tumor growth.
• Talabostat or a pharmaceutically acceptable salt thereof also inhibits DPP8/9 thereby inducing an IL 1b response (via caspase-1) in the stroma of tumor and lymph nodes.
• Talabostat s dual mechanism of action introduces a novel approach to the treatment of cancer because it combines both tumor-targeted and immune -stimulatory activity in a single agent.
• Pembrolizumab (also known as MK-3475, Lambrolizumab, KEYTRUDA®, and SCH-900475) is a humanized antibody, which targets the PD-1 receptor of lymphocytes, thereby blocking PD-1 inhibitory signal transduction. Pembrolizumab may be readily procured from the marketplace.
• the present disclosure is based, in part, on an improved regimen to treat prostate cancer (e.g. SCNC, NEPC, tNEPC, CrPC, mCrPC, adenocarcinoma) comprising administering Talabostat or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of Pembrolizumab, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.3 mg twice daily on one or more days of a treatment cycle and Pembrolizumab is administered on day 1 of the treatment cycle.
• SCNC prostate cancer
• NEPC e.g. SCNC, NEPC, tNEPC, CrPC, mCrPC, adenocarcinoma
• Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.3 mg twice daily on one or more days of a treatment cycle and Pembrolizumab is administered on day 1 of the treatment cycle.
• Talabostat or a pharmaceutically acceptable salt thereof and Pembrolizumab may produce an overall enhanced anti-cancer effect, such as improved T-cell priming, increased T cell stimulation, increased infdtration of neutrophil and macrophages across tumor microenvironment, decreased tumor volume, increased activation of natural killer cells, enhanced activation of dendritic cells, synergistic increase in pro-inflammatory cytokine (IL1, IL2, IL18, IFN gamma, IL6, IL12p40, IL 15, IL 7, G-CSF and GM-CSF), enhanced anti-tumor memory response, reduced metastasis and reduced toxicity.
• an overall enhanced anti-cancer effect such as improved T-cell priming, increased T cell stimulation, increased infdtration of neutrophil and macrophages across tumor microenvironment, decreased tumor volume, increased activation of natural killer cells, enhanced activation of dendritic cells, synergistic increase in pro-inflammatory cytokine (IL1, IL2, IL18, IFN gamm
• the present disclosure provides a method of treating a subject afflicted with one or more solid tumors (e.g. an advanced solid tumor), comprising administering Talabostat or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of Pembrolizumab, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.3 mg twice daily on one or more days of a treatment cycle and Pembrolizumab is administered on day 1 of the treatment cycle.
• the method comprises one or more treatment cycles, wherein each cycle of about 21 days duration.
• An advantage of using the particular regimen of Talabostat or a pharmaceutically acceptable salt thereof and Pembrolizumab of this disclosure is in the curtailment of the progression of prostate cancer (e.g. SCNC, NEPC, tNEPC, CrPC, mCrPC, adenocarcinoma) reduction in tumor burden, reduced metastasis and/or inducement of tumor regression in a subject.
• prostate cancer e.g. SCNC, NEPC, tNEPC, CrPC, mCrPC, adenocarcinoma
• the present disclosure provides a method of delaying progression of or preventing or delaying tumor recurrence, tumor growth or spread of tumor in a subject afflicted with prostate cancer (e.g. SCNC, NEPC, tNEPC, CrPC, mCrPC, adenocarcinoma), comprising administering Talabostat or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of Pembrolizumab, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.3 mg twice daily on one or more days of a treatment cycle and Pembrolizumab is administered on day 1 of the treatment cycle.
• a subject afflicted with prostate cancer e.g. SCNC, NEPC, tNEPC, CrPC, mCrPC, adenocarcinoma
• Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.3 mg twice daily on one or more days of a treatment cycle and Pembrolizumab is administered on
• the present disclosure provides a method of delaying or preventing the progression of tumor recurrence, tumor growth or spread of a tumor in a subject afflicted with one or more solid tumors (e.g. an advanced solid tumor) , comprising administering Talabostat or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of Pembrolizumab, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.3 mg twice daily on one or more days of a treatment cycle and Pembrolizumab is administered on day 1 of the treatment cycle.
• a method of delaying or preventing the progression of tumor recurrence, tumor growth or spread of a tumor in a subject afflicted with one or more solid tumors e.g. an advanced solid tumor
• Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.3 mg twice daily on one or more days of a treatment cycle and Pembrolizumab is administered on day 1 of the treatment cycle.
• a method for initiating, sustaining or enhancing an anti-tumor immune response in a subject afflicted with prostate cancer comprising administering Talabostat or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of Pembrolizumab, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.3 mg twice daily on one or more days of a treatment cycle and Pembrolizumab is administered on day 1 of the treatment cycle.
• a method for initiating, sustaining or enhancing an anti-tumor immune response in a subject afflicted with one or more solid tumors comprising administering Talabostat or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of Pembrolizumab, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.3 mg twice daily on one or more days of a treatment cycle and Pembrolizumab is administered on day 1 of the treatment cycle.
• the treatment regimen described herein results in a sustained response in the subject after cessation of the treatment.
• the subject has a prostate cancer that may be at an early stage or a late stage.
• the prostate cancer is metastatic.
• the cancer is an advanced malignant solid neoplasm or cancer. In some embodiments, the cancer is recurrent malignant solid neoplasm. In some embodiments, the subject is a human.
• the solid cancer is selected from the group comprising of castrate resistant prostate cancer, endometrial cancer, dedifferentiated liposarcoma, basal cell carcinoma, leiomyosarcoma, squamous cell carcinoma of unknown primary, mucosal melanoma, skin melanoma, pleomorphic sarcoma, colorectal/colon cancer, astrocytoma, triple negative breast cancer, uterine sarcoma, uveal melanoma.
• the patient is pretreated with PD-1/PD-L1 or CTLA-4 antibodies.
• the patient is PD-1/PD-L1 or CTLA-4 naive.
• the subject has relapsed or progressed with PD-1/PD-L1 or CTLA-4 antibodies.
• the present disclosure provides a method for reducing the treatment related adverse effects (TRAEs) in a subject afflicted with prostate cancer (e.g. SCNC, NEPC, tNEPC, CrPC, mCrPC, adenocarcinoma), comprising administering Talabostat or a pharmaceutically acceptable salt thereof and Pembrolizumab in the treatment regimen described herein.
• TEEs treatment related adverse effects
• TRAEs contemplated within the scope of this invention are readily apparent to a person of ordinary skill in the art, and include, but are not limited to hypotension, dizziness, headache, syncope, dyspnea, chills, pyrexia, malaise, weakness, edema/peripheral swelling, hypovolemia, hypothermia, fatigue, nausea, vomiting, diaphoresis, flushing, migraine, diarrhea, constipation, alopecia, pharyngitis, chest pain, anorexia, weight increase, weight decrease, vertigo, syncope, conjunctivitis, blurred vision, pallor, pruritus, rash, fungal vaginosis, hyperglycemia, hyperkalemia, hypokalemia, hoarseness, dyspnea, anoxia, deep venous thrombosis, upper respiratory infection, blood in stool, dizziness, rigors, sepsis, pain, hypereosinophilia, dehydration
• a subject with one or more solid tumors experiences less TRAEs relative to a subject with the same cancer administered a single 0.6 mg daily dose of Talabostat. In some embodiments, the subject experiences no TRAEs.
• the treatment regimen of the present disclosure produces an increased innate immune response as compared to the innate immune response when the subject is administered Talabostat alone.
• the innate immune response may be increased by infiltration of innate immune cells, in particular macrophages into the blood, and NK-cells into the tumor.
• the present treatment regimen comprising Talabostat or a pharmaceutically acceptable salt thereof and Pembrolizumab can produce suppression of the Treg function that is greater than that obtained using Talabostat alone.
• the prostate cancer is selected from small cell neuroendocrine prostate cancer (SCNC), neuroendocrine prostate cancer (NEPC), treatment emergent neuroendocrine prostate cancer (tNEPC), castration resistant prostate cancer (CrPC), adenocarcinoma type prostate cancer.
• SCNC small cell neuroendocrine prostate cancer
• NEPC neuroendocrine prostate cancer
• tNEPC treatment emergent neuroendocrine prostate cancer
• CrPC castration resistant prostate cancer
• adenocarcinoma type prostate cancer adenocarcinoma type prostate cancer.
• the solid cancer is selected from the group comprising castrate resistant prostate cancer, endometrial cancer, dedifferentiated liposarcoma, basal cell carcinoma, leiomyosarcoma, squamous cell carcinoma of unknown primary, mucosal melanoma, skin melanoma, pleomorphic sarcoma, colorectal/colon cancer, astrocytoma, triple negative breast cancer, uterine sarcoma, uveal melanoma.
• the present treatment regimen comprising Talabostat or a pharmaceutically acceptable salt thereof and Pembrolizumab can also significantly increase the tumor infiltration of immune sub-populations, such as NK-cells and macrophages, compared to monotherapies using Talabostat or a pharmaceutically acceptable salt thereof and Pembrolizumab.
• each treatment cycle is of 21 -days duration and Talabostat or a pharmaceutically acceptable salt thereof is administered on each of days 1 to 14 and Pembrolizumab is administered on day 1.
• Said regimen is effective to treat a subject afflicted with various forms of prostate cancer (e.g. SCNC, NEPC, tNEPC, CrPC, mCrPC, adenocarcinoma).
• the regimen herein disclosed for treating prostate cancer e.g. SCNC, NEPC, tNEPC, CrPC, mCrPC, adenocarcinoma
• Pembrolizumab may conveniently be administered as a single dose in the regimen of this disclosure to effectively treat a subject afflicted with prostate cancer (e.g. SCNC, NEPC, tNEPC, CrPC, mCrPC, adenocarcinoma) or a subject afflicted with a solid tumor, e.g. an advanced solid tumor.
• prostate cancer e.g. SCNC, NEPC, tNEPC, CrPC, mCrPC, adenocarcinoma
• a subject afflicted with a solid tumor e.g. an advanced solid tumor.
• Pembrolizumab may be administered at a total dose of about 1 mg/kg to about 10 mg/kg, conveniently by injection (e.g., intravenously), most preferably as continuous infusion for 30 minutes.
• a suitable dose of Pembrolizumab administered intravenously in the treatment regimen of the present disclosure may conveniently be from about 100 mg to about 500 mg, e.g. about 200 mg.
• Pembrolizumab is administered intravenously at a total dose of about 200 mg on day 1 of each treatment regimen.
• Pembrolizumab (MK-3475) is administered as a liquid medicament which comprises 25 mg/ml MK-3475, 7% (w/v) sucrose, 0.02% (w/v) polysorbate 80 in 10 mM histidine buffer pH 5.5, and the selected dose of the medicament is administered by IV infusion over a time period of about 30 minutes.
• Talabostat or a pharmaceutically acceptable salt thereof is administered twice a day. In some embodiments, Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of 0.3 mg twice a day. In some embodiments, Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose 0.2 mg twice a day for a sufficient time (e.g. for 1 to 30 days) followed by 0.3 mg twice a day thereafter. For example, Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose 0.2 mg twice a day for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,
• Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.2 mg twice daily on days 1-7 of the first treatment cycle followed by about 0.3 mg twice daily on days 8-14 of the first treatment cycle.
• Talabostat or a pharmaceutically acceptable salt thereof may be administered at 0.3 mg as a morning dose (e.g. about 5 am, about 6 am, about 7 am, about 8 am, about 9 am, about 10 am, or about 11 am) and 0.3 mg as an evening dose (e.g. about 5 pm, about 6 pm, about 7 pm, about 8 pm, about 9 pm, about 10 pm, or about 11 pm).
• each treatment cycle is from 1 to 30 days in duration.
• each treatment cycle is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days.
• each treatment cycle is 21 days in duration.
• the subject is administered Talabostat or a pharmaceutically acceptable salt thereof and Pembrolizumab for one or more treatment cycles.
• the subject is administered Talabostat or a pharmaceutically acceptable salt thereof and Pembrolizumab for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 treatment cycles.
• the subject is administered Talabostat or a pharmaceutically acceptable salt thereof and Pembrolizumab for more than one treatment cycle.
• the Talabostat and Pembrolizumab are administered according to an intermittent dosing regimen.
• intermittent dosing regimen refers to repeating cycles of drug administration in which the drug is administered on one or more consecutive days (“days on”) followed by one or more consecutive days of rest on which the drug is not administered (“days off’).
• the cycles may be regular, in that the pattern of days on and days off is the same in each cycle, or may be irregular.
• the cycle is 21 days and Talabostat or a pharmaceutically acceptable salt thereof is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive days followed by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days where the patient takes no Talabostat.
• this intermittent dosing schedule occurs multiple times within the same cycle.
• the cycle is 21 days and Pembrolizumab is administered intravenously on day 1 and Talabostat or a pharmaceutically acceptable salt thereof is administered for 3 consecutive days followed by 4 days where the patient takes no Talabostat, and this 7 day pattern repeats once (i.e. no Talabostat is administered on days 15-21) or twice.
• Talabostat or a pharmaceutically acceptable salt thereof is administered orally (e.g. by tablet) on each of days 1 to 14 and Pembrolizumab is administered intravenously on day 1 and no drug is administered on days 15-21.
• the subject experiences an increase in pro-inflammatory cytokines relative to a subject that is administered a single 0.6 mg daily dose of Talabostat.
• Pro-inflammatory cytokines contemplated within the scope of this invention are readily apparent to a person of ordinary skill in the art, and include, but are not limited to IL-6, IL-8, IL-18, IFN-g, and IL-Ib.
• the pro-inflammatory cytokines are one or more of IL-18 and IFN-g.
• wherein the maximum increase in cytokines is observed at day 14 of continuous dosing.
• SCNC, NEPC, tNEPC, CrPC, mCrPC, adenocarcinoma) include, for example, administering to the patient Talabostat or a pharmaceutically acceptable salt thereof at a dose of 0.3 mg twice daily and effective amount of Pembrolizumab.
• the regimen comprises one or more administration cycles (e.g. 1, 2, 3, 4, 5, 6 or more cycles). In some embodiments, each cycle is a period of about 21 days.
• Talabostat or a pharmaceutically acceptable salt thereof is administered orally (e.g. by tablet) on each of days 1 to 14 and Pembrolizumab is administered intravenously on day 1 where no drug is administered on days 15-21.
• the same regimen treatment may be used generally to treat a human patient afflicted with one or more solid tumors (e.g. an advanced solid tumor).
• Talabostat is administered on days 1 to 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.
• the daily dose of Talabostat or a pharmaceutically acceptable salt thereof may be varied overtime.
• Talabostat or a pharmaceutically acceptable salt thereof may be administered at a lower daily dose than during subsequent cycles (e.g. Efficacy Stage).
• Talabostat or a pharmaceutically acceptable salt thereof may conveniently be administered during the Lead-in Stage at a daily dose of about 0.4 mg, and, if there are no side effects or other criteria preventing further treatment, the subject is allowed to enter the Efficacy Stage and administered in divided doses, during Efficacy Stage, a total daily dose of about 0.6 mg.
• the Lead-in Stage and the Efficacy Stage occur in the same cycle (e.g. the dose of Talabostat in the Lead in Stage is 0.2 mg twice a day on days 1-7, followed a dose of 0.3 mg twice a day thereafter during the Efficacy Stage).
• Talabostat or a pharmaceutically acceptable salt thereof may be administered in divided doses during the Lead- in Stage at total daily dose of about 0.6 mg and during the Efficacy Stage a daily dose of about 0.4 mg.
• the patient is treated directly in the Efficacy Stage using a daily dose of about 0.4 mg or about 0.6 mg.
• the patient is treated directly in the Efficacy Stage using a total daily dose of about 0.6 mg.
• the patient is treated directly in the Efficacy Stage using a total daily dose of about 0.6 mg administered as a split dose 0.3 mg twice a day.
• Talabostat or a pharmaceutically acceptable salt thereof and Pembrolizumab are administered to a subject afflicted with prostate cancer (e.g. SCNC, NEPC, tNEPC, CrPC, mCrPC) in any desired number of treatment cycles as long as a clinical benefit is observed or until there is a complete response, confirmed progressive disease or unmanageable toxicity.
• the treatment regimen is administered to a subject afflicted with one or more solid tumors (e.g. an advanced solid tumor) in any desired number of treatment cycles as long as a clinical benefit is observed or until there is a complete response, confirmed progressive disease or unmanageable toxicity.
• the daily dosages of Talabostat or a pharmaceutically acceptable salt thereof and Pembrolizumab used according to the treatment regimen of this disclosure may be lower than the daily dosages of one or both of Talabostat or a pharmaceutically acceptable salt thereof and Pembrolizumab administered as single agents to treat a subject afflicted with prostate cancer (e.g. SCNC, NEPC, tNEPC, CrPC, mCrPC, adenocarcinoma).
• the subject is afflicted with one or more solid tumors (e.g. an advanced solid tumor).
• the combination therapy comprising 0.3 mg twice daily dose of Talabostat or a pharmaceutically acceptable salt thereof and 200 mg of pembrolizumab is administered for at least 12 weeks (three 4-week cycles or four 3-week cycles) or at least 24 weeks six 4-week cycles or eight 3-week cycles). In some embodiments, the combination therapy is administered for at least 1-4 weeks after the patient achieves a complete response.
• a single administration cycle comprises 21 days (a 21- day cycle).
• Talabostat mesylate is administered once daily (QD) on Days 1 to 14 of a 21 -day cycle plus pembrolizumab 200 mg administered intravenously (IV) on Day 1 every 21 days.
• a single administration cycle comprises 21 days (21 -day cycle).
• Talabostat mesylate is administered twice daily at a dose of 0.3 mg on Days 1 to 14 of a 21-day cycle plus pembrolizumab 200 mg administered intravenously (IV) on Day 1 every 21 days.
• Talabostat mesylate is administered at a dose of about 0.3 mg in the morning and about 0.3 mg in the evening on Days 1 to 14 of a 21-day cycle plus pembrolizumab 200 mg administered intravenously (IV) on Day 1 every 21 days.
• Talabostat mesylate is administered thrice daily at a dose of about 0.2 mg on Days 1 to 14 of a 21 -day cycle plus pembrolizumab 200 mg administered intravenously (IV) on Day 1 every 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 to 14 of a 21 -day cycle plus pembrolizumab 200 mg administered intravenously (IV) on Day 1 every 21 days.
• 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 to 14 of a 21-day cycle plus pembrolizumab 200 mg administered intravenously (IV) on Day 1 every 21 days.
• Talabostat mesylate is administered twice daily at a dose of about 0.2 mg on Days 1 to 7 of a 21 -day cycle plus pembrolizumab 200 mg administered intravenously (IV) on Day 1 every 21 days followed by Talabostat mesylate is administered twice daily at a dose of about 0.3 mg on Days 8 to 14 of a 21-day cycle.
• Talabostat mesylate is administered twice daily at a dose of about 0.3 mg on Days 1 to 3 of a 21-day cycle plus pembrolizumab 200 mg administered intravenously (IV) on Day 1 every 21 days followed by rest period from day 4-7 (no dose of Talabostat given) and then followed by Talabostat mesylate is administered twice daily at a dose of about 0.3 mg on Days 8 to 11 of a 21-day cycle
• a combination therapy of the disclosure is administered to a patient who has not been previously treated with a biotherapeutic or chemotherapeutic agent (i.e. is treatment-naive).
• the combination therapy is administered to a patient who failed to achieve a sustained response after prior therapy with a biotherapeutic or chemotherapeutic agent (i.e. is treatment-experienced).
• the subject was treated with a single daily 0.6 mg dose of Talabostat mesylate and experienced dose-limiting side effects.
• a suitable time period of therapy can be determined by one skilled in the art (e.g., a physician). As can be appreciated in the art, a suitable period of time can be determined by one skilled in the art based on one or more of: the stage of disease in the patient, the mass and sex of the patient, clinical trial guidelines (e.g., those on the fda.gov website), and information on the approved drug label.
• a suitable time period of therapy can be, e.g., from 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,
• the present disclosure provides for use in the treatment regimen herein 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.
• 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.
• any of the pharmaceutically acceptable carriers or adjuvants described herein, or known in the art may be used.
• the term "pharmaceutical formulation” refers to a formulation comprising Talabostat or a pharmaceutically acceptable salt thereof or a formulation comprising Pembrolizumab, wherein each formulation also comprises one or more pharmaceutically acceptable carriers or adjuvants.
• Pharmaceutically acceptable carriers or adjuvants are well-known to those skilled in the art, and usually depend on the chosen route of administration.
• 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 are administered according to the treatment regimen disclosed herein to produce a synergistic effect in treating a subject afflicted with prostate cancer (e.g. SCNC, NEPC, tNEPC, CrPC, adenocarcinoma).
• SCNC NEPC
• tNEPC tNEPC
• CrPC adenocarcinoma
• 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 are administered according to the treatment regimen disclosed herein to produce a synergistic effect in treating a subject afflicted with one or more solid tumors e.g. an advanced solid tumor.
• the pharmaceutical formulations may be formulated in a variety of ways, including for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories.
• compositions may be formulated as the injectable or infusible solutions.
• the formulation is in a form suitable for oral, intravenous, intraarterial, intramuscular, subcutaneous, parenteral, transmucosal, transdermal, or topical administration.
• the formulation may be formulated as an immediate, controlled, extended or delayed release composition.
• the formulation comprising Talabostat or a pharmaceutically acceptable salt thereof may be administered orally.
• the formulation comprising Pembrolizumab may be administered parenterally.
• parenteral includes subcutaneous, intravenous, intra-arterial, intraperitoneal, intracardiac, intrathecal, and intramuscular injection, as well as infusion injections.
• Liquid pharmaceutical formulations for parenteral administration may be formulated for administration by injection or continuous infusion.
• parenteral formulations can include prefilled syringes, vials, powder for infusion for reconstitution, concentrate for infusion to be diluted before delivery (ready to dilute), solutions (ready to use).
• injectable pharmaceutical formulations can be aqueous isotonic solutions or suspensions, and suppositories can be prepared from fatty emulsions or suspensions.
• compositions formulated for parenteral administration may conveniently include a liquid carrier, or may be reconstituted into a liquid solution or suspension for parenteral administration.
• such formulations typically comprise a pharmaceutically acceptable carrier or adjuvant.
• pharmaceutically acceptable means approved by a government regulatory agency or listed in the U.S. Pharmacopoeia or another generally recognized pharmacopoeia for use in animals, particularly in humans.
• compositions of Pembrolizumab for intravenous administration may be purchased from the marketplace or prepared using conventional formulation techniques.
• Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed, and include, but are not limited to: buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium 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 (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulfolli
• Exemplary pharmaceutically acceptable carriers herein further include interstitial drug dispersion agents such as soluble neutral-active hyaluronidase glycoproteins (sHASEGP), for example, 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.
• 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.
• the composition must be sterile and should be fluid to the extent that easy syringeability exists. It should be stable under the conditions of manufacture and storage and will preferably be 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, or 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).
• the formulation includes isotonic agents, for example, sugars, polyalcohols, such as mannitol, sorbitol, or sodium chloride.
• suitable carriers include physiological saline, bacteriostatic water, Cremophor EL (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminium monostearate and gelatin.
• Sterile injectable solutions can be prepared by incorporating the molecule, by itself or in combination with other active agents, in the required amount in an appropriate solvent with one or a combination of ingredients enumerated herein, as required, followed by fdtered sterilization.
• dispersions are prepared by incorporating the active compound into a sterile vehicle, which contains a basic dispersion medium and the required other ingredients from those enumerated above.
• sterile powders for the preparation of sterile injectable solutions one method of preparation is vacuum drying and freeze-drying, which yields a powder of an active ingredient plus any additional desired ingredient from a previously sterile-fdtered solution thereof.
• the preparations for injections are processed, fdled into containers such as ampoules, bags, bottles, syringes or vials, and sealed under aseptic conditions according to methods known in the art.
• Such articles of manufacture will preferably have labels or package inserts indicating that the associated compositions are useful for treating a subject suffering from or predisposed to autoimmune or neoplastic disorders.
• the pharmaceutical formulations may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.
• Solution or suspension formulations used for subcutaneous application typically include one or more of the following components: a sterile carrier such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates; and agents for the adjustment of tonicity 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 ampoules, disposable syringes or multiple dose vials made of glass or plastic.
• compositions of Talabostat or a pharmaceutically acceptable salt thereof for oral use herein may be administered, for example, in the form of tablets, capsules, powders, dispersible granules, sachets etc., or as aqueous solutions or suspensions, preferably tablets.
• Oral compositions generally include an inert carrier (for example, diluent) or an edible carrier.
• the formulations may be enclosed in a gelatin capsule or compressed into a tablet.
• Pharmaceutically compatible binding agents, and/or adjuvant materials can 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 com starch; a lubricant such as magnesium stearate or stearates; aglidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavouring agent such as peppermint, methyl salicylate, or orange flavouring.
• 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 com starch
• a lubricant such as magnesium stearate or stearates
• an oral pharmaceutical formulation comprising Talabostat or a pharmaceutically acceptable salt thereof described herein may comprise one or more pharmaceutically acceptable carriers or adjuvants selected from the group comprising a bulking agent, buffer, surfactant, and pH modifier.
• the pharmaceutical formulation may be adjusted to give an appropriate pH.
• Talabostat or a pharmaceutically acceptable salt thereof is formulated as a tablet for oral administration according to the treatment regimen of this disclosure.
• the pharmaceutical tablet may be an immediate release or a modified release tablet. Tablet may be in the form of matrix or coated form.
• An exemplary immediate release tablet comprises 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 modifying agents and combinations thereof.
• Diluents comprise, 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, mixture of microcrystalline cellulose and guar gum (Avicel CE-15), mixture of mannitol, polyplasdone and syloid (Pharmaburst), mixture of mannitol, crospovidone and polyvinyl acetate (Ludiflash), isomalt, Panexcea, F-Melt, sucrose, calcium salts and similar inorganic salts, heavy magnesium carbonate and the like, and the mixtures thereof.
• it is lactose or microcrystalline cellulose.
• Binders comprise, but are not limited to, low-substituted hydroxypropyl cellulose, xanthan gum, polyvinylpyrrolidone (povidone), gelatin, sugars, glucose, natural gums, gums, synthetic celluloses, polymethacrylate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, methyl cellulose, and other cellulose derivatives and the like, and the mixtures thereof.
• the binder is polyvinylpyrrolidone or hydroxypropyl cellulose or hydroxypropyl methylcellulose.
• Disintegrants comprise, but are not limited to, at least one or a mixture of sodium starch glycolate, croscarmellose sodium, crospovidone, sodium alginate, gums, starch, and magnesium aluminium silicate.
• the disintegrant is sodium starch glycolate.
• Lubricants one or lubricants comprise, but are not limited to sodium stearyl fumarate, sodium lauryl sulphate, magnesium stearate, polyethylene glycol, metal stearates, hydrogenated castor oil and the like, and the mixtures thereof.
• the lubricant is magnesium stearate.
• Glidant one or glidants comprise, but are not limited to, stearic acid, colloidal silicon dioxide, talc, aluminium silicate and the like, and the mixtures thereof. Preferably, it is talc.
• pH modifying agents one or more pH modifying agents comprise, but are not limited to organic acid or its salts like phosphoric acid, citric acid and the like.
• Talabostat or a pharmaceutically acceptable salt thereof may be formulated as a modified release matrix tablet.
• An exemplary extended release tablet comprises an effective amount of Talabostat or a pharmaceutically acceptable salt thereof and pharmaceutically-acceptable carriers or adjuvants are selected from diluents, binders, modified release material, glidants, lubricants, colorants and combinations thereof.
• a modified release tablet comprises immediate release core and coating wherein said coating comprises modified release material and other pharmaceutical excipients.
• Modified release materials comprise, but are not limited to: polyvinylpyrrolidone (K90), Hydroxypropylmethylcellulose (K4M, K10), hydroxypropylcellulose (high viscosity grade), camauba wax, glyceryl behenate, castor wax, polyvinyl acetate, carboxymethyl ethyl cellulose, ethylcellulose, cellulose phthalates or succinates, in particular cellulose acetate phthalate and hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose succinate or hydroxypropylmethylcellulose acetate succinate; high molecular polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide and the like.
• modified release materials include polyvinylpyrrolidone (K90), hydroxypropylmethylcellulose (K4M, K10), hydroxypropylcellulose (high viscosity grade-HF), polyethylene oxide and the like.
• K90 polyvinylpyrrolidone
• K4M hydroxypropylmethylcellulose
• K10 hydroxypropylcellulose
• high viscosity grade-HF polyethylene oxide
• a modified release material may conveniently be present in the range of 10-50% wt. of the tablet.
• the amount of Talabostat in a unit dose is about 50 micrograms per tablet, 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, about 800 micrograms per tablet.
• Various methods can be used for manufacturing tablets of Talabostat or a pharmaceutically acceptable salt thereof for use in the treatment regimen of this disclosure.
• One process includes dissolving Talabostat in a suitable solvent (with or without binder) and this solution is distributed uniformly over filler particles (which may contain other materials) to form agglomerated particles/granules.
• Wet granulation, coating or spraying processes can also be used.
• Granules may be appropriately sized or may be further processed by a dry granulation/slugging/roller compaction method followed by a milling step to achieve suitable granules of specific particle size distribution.
• the sized granules may be further blended with other components and/or and then lubricated in a suitable blender and compressed into tablets of specific dimensions using appropriate tooling. Coating of the tablets, where appropriate, may be performed using conventional methods and standard equipment.
• kits [0222]
• the kit includes a formulation comprising Talabostat or pharmaceutically acceptable salt thereof and a formulation comprising Pembrolizumab with or without instructions for their use.
• the combined therapeutics can be manufactured and/or formulated by the same or different manufacturers.
• the combination therapeutics may thus be entirely separate pharmaceutical dosage forms or pharmaceutical compositions that are also sold independently of each other.
• instructions for their combined use are provided: (i) prior to release to physicians (e.g. in the case of a "kit of part" comprising a first therapeutic agent and the other therapeutic agent); (ii) by the physicians themselves (or under the guidance of a physician) shortly before administration; (iii) the patient themselves by a physician or medical staff.
• a single bolus dose may be administered.
• several divided doses may be administered over time.
• a dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.
• Dosage unit form refers to physically discrete units suited as unitary dosages for treating mammalian subjects. Each unit may contain a predetermined quantity of active compound calculated to produce a desired therapeutic effect. In some embodiments, the dosage unit forms of the disclosure are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic or prophylactic effect to be achieved.
• the kit comprises a package insert comprising instructions for using Talabostat or pharmaceutically acceptable salt thereof and Pembrolizumab to treat or delay progression of cancer in a subject or to enhance immune function of a subject having cancer.
• the kit comprises Talabostat or pharmaceutically acceptable salt thereof and Pembrolizumab and package insert comprising instructions for using the same to treat or delay progression of cancer in a subject or to enhance immune function of a subject having cancer.
• the kit comprises Talabostat or pharmaceutically acceptable salt thereof and Pembrolizumab, and a package insert comprising instructions for using the same to treat or delay progression of cancer in a subject or to enhance immune function of a subject having cancer.
• the kit comprises a container that includes, but is not limited to bottles, vials (e.g., dual chamber vials), syringes (such as single or dual chamber syringes) and test tubes.
• the container may be formed from a variety of materials such as glass or plastic.
• the kit may comprise a label (e.g., on or associated with the container) or a package insert.
• the label or the package insert may indicate that the compound contained therein may be useful or intended for treating or delaying progression of cancer in a subject or for enhancing immune function of a subject having cancer.
• the kit may further comprise other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.
• Patients afflicted with prostate cancer e.g. SCNC, NEPC, tNEPC, CrPC, mCrPC
• SCNC prostate cancer
• NEPC NEPC
• tNEPC tNEPC
• CrPC tNEPC
• mCrPC a pharmaceutically acceptable salt thereof
• improvement may be measured by a reduction in the quantity and/or size of measurable tumor lesions.
• lesions can be measured using X-rays or CT or MRI scans.
• cytology or histology can be used to evaluate responsiveness to the therapy.
• extension of progression free survival and/or overall survival may be provided to a patient afflicted with prostate cancer (e.g. SCNC, NEPC, tNEPC, CrPC). In another embodiment, extension of progression free survival and/or overall survival may be provided to a patient afflicted with advanced solid cancer.
• prostate cancer e.g. SCNC, NEPC, tNEPC, CrPC.
• the anti-tumor response is a tumor specific response, a clinical response, a decrease in tumor size/volume, a decrease in tumor specific biomarkers, increase in anti-tumor cytokines or a combination thereof.
• the clinical response is a decreased tumor growth and/or a decrease in tumor size.
• the initiating, sustaining or enhancing an anti tumor immune response is for the treatment of cancer.
• the anti-tumor response is inhibiting tumor growth, inducing tumor cell death, tumor regression, preventing or delaying tumor recurrence, tumor growth, tumor spread or tumor elimination.
• the anti-tumor response is reduction in metastasis, delay in metastasis or prevention of metastasis. In some embodiments, the anti -tumor response is prevention of metastasis.
• the tumor response is a decrease in the number of tumor cells. In some embodiments, the tumor response is a decreased rate in tumor growth. In some embodiments, the tumor response is a block in the dipeptidyl peptidase enzyme activity. In some embodiments, the tumor response is an induction of proinflammatory cytokine response and a cytotoxic T cell response.
• the treatment regimen described herein may result in an inhibition of tumor size more than about 10%, more than about 20%, more than about 21%, more than about 22%, more than about 23% , more than about 24%, more than about 25%, more than about 26%, more than about 27%, more than about 28%, more than about 29%, more than about 30%, more than about 31%, more than about 32%, more than about 33% , more than about 34%, more than about 35%, more than about 36%, more than about 37%, more than about 38%, more than about 39%, more than about 40%, more than about 41%, more than about 42%, more than about 43%, more than about 44%, more than about 45%, more than about 46%, more than about 47%, more than about 48%, more than about 49%, more than about 50%, more than about 51%, more than about 52%, more than about 53%, more than about 54%, more than about 55%, more than about 56%, more than about 57%, more than about 58%, more than about 4
• the regimen and methods provided herein can result in a 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 95%, 2% to 90%, 2% to 85%, 2% to 80%, 2% to 75%, 2% to 70%, 2% to 65%, 2% to 60%, 2% to 55%, 2% to 50%, 2% to 45%, 2% to 40%, 2% to 35%, 2% to 30%, 2% to 25%, 2% to 20%, 2%
• 1 month and 6 months between 1 month and 6 months, between 1 month and 5 months, between 1 month and 4 months, between 1 month and 3 months, between 1 month and 2 months, between 2 months and 2 years, between 2 months and 22 months, between 2 months and 20 months, between 2 months and 18 months, between 2 months and 16 months, between
• 2 months and 14 months between 2 months and 12 months, between 2 months and 10 months, between 2 months and 9 months, between 2 months and 8 months, between 2 months and 7 months, between 2 months and 6 months, or between 2 months and 5 months, between 2 months and 4 months, between 3 months and 2 years, between 3 months and 22 months, between 3 months and 20 months, between 3 months and 18 months, between 3 months and 16 months, between 3 months and 14 months, between 3 months and 12 months, between 3 months and 10 months, between 3 months and 8 months, between 3 months and 6 months, between 4 months and 2 years, between 4 months and 22 months, between 4 months and 20 months, between 4 months and 18 months, between 4 months and 16 months, between 4 months and 14 months, between 4 months and 12 months, between 4 months and 10 months, between 4 months and 8 months, between 4 months and 6 months, between 6 months and 2 years, between 4 months and 22 months, between 4 months and 20 months, between 4 months and 18 months, between 4 months and 16 months, between 4 months and 14 months, between 4 months and 12 months, between 4 months
• the regimen or methods provided herein can provide for 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 5%, 1 % to 30%, 1 %to 25%, 1 %to 20%, 1 % to 15%, 1 % to 10%, 1 % to 5%, 2% to 99%, % to 95%, 2% to 90%, 2% to 85%, 2% to 80%, 2% to 75%, 2% to 70%, 2% to 65%, 2% to0%, 2% to 55%, 2% to 50%, 2% to 45%, 2% to 40%, 2% to 35%, 2% to 30%, 2% to 25%,% to 20%, 2% to 15%
• the treatment regimen or methods described herein can result in an increase (e.g, a 1 % to 400%, 1 % to 380%, 1 % to 360%, 1 % to 340%, 1 % to 320%, 1 % to 300%, 1 % to 280%, 1 % to 260%, 1 % to 240%, 1 % to 220%, 1 % to 200%, 1 % to 180%, 1 %to 160%, 1 % to 140%, 1 %to 120%, 1 % to 100%, 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%
• patients afflicted with prostate cancer e.g. SCNC, NEPC, tNEPC, CrPC, adenocarcinoma
• SCNC complete response
• NEPC partial response
• tNEPC tNEPC
• CrPC adenocarcinoma
• adenocarcinoma an effective amount of Pembrolizumab according to the treatment regimen disclosed herein may exhibit a complete response (CR), a partial response (PR), stable disease (SD), immune-related complete disease (irCR), immune-related partial response (irPR), or immune-related stable disease (irSD).
• CR complete response
• PR partial response
• SD stable disease
• irCR immune-related complete disease
• irPR immune-related partial response
• irSD immune-related stable disease
• patients afflicted with advanced solid cancer administered Talabostat or a pharmaceutically acceptable salt thereof and Pembrolizumab according to the treatment regimen disclosed herein may exhibit a complete response (CR), a partial response (PR), stable disease (SD), immune-related complete disease (irCR), immune- related partial response (irPR), or immune-related stable disease (irSD).
• CR complete response
• PR partial response
• SD stable disease
• irCR immune-related complete disease
• irPR immune-related partial response
• irPR immune-related partial response
• irPR immune-related stable disease
• irSD immune-related stable disease
• the patients afflicted with prostate cancer administered according to the treatment regimen achieves a stable disease response or better, as measured by RECIST 1.1.
• the patients afflicted with prostate cancer administered according to the treatment regimen achieves a partial disease response or better, as measured by RECIST 1.1.
• the patients afflicted with prostate cancer administered according to the treatment regimen achieves a complete response or better, as measured by RECIST 1.1.
• Complete response refers to disappearance of all target lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to ⁇ 10 mm.
• partial response refers to at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
• stable disease refers to neither sufficient shrinkage from the baseline study to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
• progressive disease refers to at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of 1 or more new lesions is also considered progression).
• the patients afflicted with an advanced solid tumor administered according to the treatment regimen achieves a complete or partial disease response or better, as measured by RECIST 1.1.
• the patients afflicted with advanced solid tumor administered according to the treatment regimen achieves a complete response or better, as measured by RECIST 1.1.
• the subject experiences less treatment-related adverse events (TRAEs) relative to a subject with same cancer administered a single 0.6 mg daily dose of Talabostat.
• TRAEs contemplated within the scope of this invention are readily apparent to a person of ordinary skill in the art, and include, but are not limited to hypotension, dizziness, headache, syncope, dyspnea, chills, pyrexia, malaise, weakness, edema/peripheral swelling, hypovolemia, hypothermia, fatigue, nausea, vomiting, diaphoresis, flushing, migraine, diarrhea, constipation, alopecia, pharyngitis, chest pain, anorexia, weight increase, weight decrease, vertigo, syncope, conjunctivitis, blurred vision, pallor, pruritus, rash, fungal vaginosis, hyperglycemia, hyperkalemia, hypokalemia, hoarseness, dyspnea, anoxia, deep venous thro
• the subject achieves about a 50% or greater prostate-specific antigen (PSA) decline from baseline by about week 12 of treatment.
• PSA prostate-specific antigen
• the subject achieves about a 50%, about a 51%, about a 52%, about a 53%, about a 54%, about a 55%, about a 56%, about a 57%, about a 58%, about a 59%, about a 60%, about a 61%, about a 62%, about a 63%, about a 64%, about a 65%, about a 66%, about a 67%, about a 68%, about a 69%, about a 70%, about a 71%, about a 72%, about a 73%, about a 74%, about a 75%, about a 76%, about a 77%, about a 78%, about a 79%, about a 80%, about a 81%, about a 82%, about a 83%, about a 84%, about a
• the the subject experiences an increase in pro-inflammatory cytokines relative to a subject that is administered a single 0.6 mg daily dose of Talabostat.
• Pro-inflammatory cytokines contemplated within the scope of this invention are readily apparent to a person of ordinary skill in the art, and include, but are not limited to IL-6, IL-8, IL-18, IFN-g, and IL-Ib.
• the pro-inflammatory cytokines are one or more of IL-18 and IFN- g.
• wherein the maximum increase in cytokines is observed at day 14 of continuous dosing.
• patients afflicted with prostate cancer e.g.
• SCNC, NEPC, tNEPC, CrPC, adenocarcinoma) administered a 0.3mg twice daily dose of Talabostat or a pharmaceutically acceptable salt thereof on one or more days of a treatment cycle and an effective amount of Pembrolizumab on day 1 of the treatment cycle, according to the treatment regimen disclosed herein may experience tumor shrinkage and/or decrease in growth rate, i.e., suppression of tumor growth. In another embodiment, unwanted cell proliferation may be reduced or inhibited.
• patients afflicted with advanced solid cancer administered a 0.3mg twice daily dose of Talabostat or a pharmaceutically acceptable salt thereof on one or more days of a treatment cycle, and an effective amount of Pembrolizumab on day 1 of the treatment cycle according to the treatment regimen disclosed herein may experience tumor shrinkage and/or decrease in growth rate, i.e., suppression of tumor growth. In another embodiment, unwanted cell proliferation may be reduced or inhibited.
• advanced solid cancer refers to a cancer that is not expected to be cured with available therapies.
• the objective for treatment in advanced cancers is to control the disease for as long as possible.
• one or more of the following may occur in patients afflicted with prostate cancer (e.g. SCNC, NEPC, tNEPC, CrPC, adenocarcinoma) administered 0.3mg twice daily dose of Talabostat or a pharmaceutically acceptable salt thereof on one or more days of a treatment cycle and about 200mg of Pembrolizumab on day 1 of the treatment cycle according to the treatment regimen disclosed herein: the number of cancer cells may be reduced; tumor size may be reduced; cancer cell infdtration into peripheral organs may be inhibited, retarded, slowed, or stopped; tumor metastasis may be slowed or inhibited; tumor growth may be inhibited; recurrence of tumor may be prevented or delayed; one or more of the symptoms associated with cancer may be alleviated.
• prostate cancer e.g. SCNC, NEPC, tNEPC, CrPC, adenocarcinoma
• the number of cancer cells may be reduced
• tumor size may be reduced
• patients afflicted with advanced solid cancer may experience one or more of the following after administration of Talabostat and Pembrolizumab: the number of cancer cells may be reduced; tumor size may be reduced; cancer cell in filtration into peripheral organs may be inhibited, retarded, slowed, or stopped; tumor metastasis may be slowed or inhibited; tumor growth may be inhibited; recurrence of tumor may be prevented or delayed; one or more of the symptoms associated with cancer may be alleviated.
• patients afflicted with prostate cancer e.g. SCNC, NEPC, tNEPC, CrPC, adenocarcinoma
• SCNC prostate cancer
• NEPC NEPC
• tNEPC tNEPC
• CrPC adenocarcinoma
• adenocarcinoma administered a 0.3 mg twice daily dose of Talabostat or a pharmaceutically acceptable salt thereof on one or more days of a treatment cycle and about 200mg of Pembrolizumab on day 1 of the treatment cycle according to the treatment regimen disclosed herein may exhibit at least one therapeutic effect selected from the group consisting of reduction in size of a tumor, reduction in number of metastatic lesions appearing over time, complete remission, partial remission, or stable disease.
• the patient afflicted with one or more solid tumors e.g. an advanced solid tumor
• one or more solid tumors administered a 0.3 mg twice daily dose of Talabostat or a pharmaceutically acceptable salt thereof on one or more days of a treatment cycle and about 200mg of Pembrolizumab on day 1 of the treatment cycle according to the treatment regimens disclosed herein may exhibit at least one therapeutic effect selected from the group consisting of reduction in size of a tumor, reduction in number of metastatic lesions appearing over time, complete remission, partial remission, or stable disease.
• the improvement of clinical benefit rate achieved using the treatment regimen of the present disclosure may be about 20%, 30%, 40%, 50%, 60%, 70%, 80% or more compared to treatment using Talabostat or Pembrolizumab alone.
• the treatment regimen of the present disclosure may result in the CD8+ T cells in the subject having enhanced priming, activation, proliferation and/or cytolytic activity when compared to administration of Talabostat or a pharmaceutically acceptable salt thereof, or Pembrolizumab alone.
• the number of CD4+ and/or CD 8+ T cells is elevated relative to prior to administration of the combination according to the treatment regimen described herein.
• the activated CD4+ and/or CD8+ T cells is characterized by y-IFN+ producing CD4+ and/or CD8+ T cells and/or enhanced cytolytic activity relative to prior to the administration of the combination according to the treatment regimen described herein.
• the CD4+ and/or CD8+ T cells exhibit increased release of cytokines selected from the group consisting of G-CSF, MCP-1, Eotaxin, IFN-g, KC, TNF-a and interleukins (IL-5, IL-6, IL-Ib, IL-12p70, IL 18).
• cytokines selected from the group consisting of G-CSF, MCP-1, Eotaxin, IFN-g, KC, TNF-a and interleukins (IL-5, IL-6, IL-Ib, IL-12p70, IL 18).
• the CD4+ and/or CD8+ T cell is an effector memory T cell.
• the CD4+ and/or CD8+ effector memory T cell is characterized by g- IFN+ producing CD4+ and/or CD8+ T cells and/or enhanced cytolytic activity.
• the serum levels of cytokine IL-18 and/or chemokine GM- CSF, G-CSF in the subject are increased in the presence of combination of Talabostat or a pharmaceutically acceptable salt thereof and Pembrolizumab when used according to the treatment regimen described herein as compared to single agent administration.
• the cancer has elevated levels of T-cell infiltration when a combination of Talabostat or a pharmaceutically acceptable salt thereof, and Pembrolizumab is used according to the treatment regimen described herein, when compared to administration of Talabostat or Pembrolizumab alone.
• the cancer has suppressed/decreased levels of T-regulatory cells in the presence of a combination of Talabostat or a pharmaceutically acceptable salt thereof and Pembrolizumab when used according to the treatment regimen described herein, when compared to administration of Talabostat or a pharmaceutically acceptable salt thereof, or Pembrolizumab alone.
• the cancer has increased levels of NK cells and macrophages in the presence of combination of Talabostat or a pharmaceutically acceptable salt thereof and Pembrolizumab when used according to the treatment regimen described herein, when compared to administration of Talabostat or a pharmaceutically acceptable salt thereof, or Pembrolizumab alone.
• responses to the treatment regimen described herein may include: Complete response (CR), Partial Response (PR), Progressive Disease (PD), Stable Disease (SD), Immune-related Complete Response (irCR), Immune-related Partial Response (irPR), Immune-related Progressive Disease (irPD) and Immune -related Stable Disease (irSD).
• CR Complete response
• PR Partial Response
• PD Progressive Disease
• SD Stable Disease
• irCR Immune-related Complete Response
• irPR Immune-related Partial Response
• irPR Immune-related Partial Response
• irPD Immune-related Progressive Disease
• irSD Immune -related Stable Disease
• responses to the treatment regimen described herein may include: Complete Response (CR), Progressive Disease (PD), Immune-related Complete Response (irCR) and Immune -related Progressive Disease (irPD).
• CR Complete Response
• PD Progressive Disease
• irCR Immune-related Complete Response
• irPD Immune -related Progressive Disease
• the patient treated exhibits a complete response (CR), a partial response (PR), stable disease (SD), immune-related complete disease (irCR), immune-related partial response (irPR), or immune-related stable disease (irSD).
• the patient treated experiences tumor shrinkage and/or decrease in growth rate, i.e., suppression of tumor growth.
• unwanted cell proliferation is reduced or inhibited.
• one or more of the following can occur: the number of cancer cells can be reduced; tumor size can be reduced; cancer cell infiltration into peripheral organs can be inhibited, retarded, slowed, or stopped; tumor metastasis can be slowed or inhibited; tumor growth can be inhibited; recurrence of tumor can be prevented or delayed; one or more of the symptoms associated with cancer can be relieved to some extent.
• measurable disease refers to presence of at least one measurable lesion. Measurable lesions must be accurately measured in at least 1 dimension (longest diameter in the plane of the measurement to be recorded) with a minimum size of:
• CT scan slice thickness no greater than 5 mm.
• malignant lymph nodes is defined to be pathologically enlarged and measurable, if a lymph node was >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis was measured and followed. [0271] Non-measurable lesions were all other lesions, including small lesions (longest diameter ⁇ 10 mm or pathological lymph nodes with >10 to ⁇ 15 mm short axis), as well as non- measurable lesions.
• target lesions refers to when more than one lesion is present at baseline all lesions up to a maximum of five lesions total representative of all involved organs are identified as target lesions. All other lesions including pathological lymph nodes are identified as “non-target lesions” and are also recorded at baseline.
• the duration of overall CR is measured from the time measurement criteria were first met for CR until the first date that recurrent disease was objectively documented.
• Stable disease was measured from the start of the treatment until the criteria for progression were met, taking as reference the smallest sum on study (if the baseline sum was the smallest, this was the reference for calculation of PD).
• non-CR/non-PD refers to persistence of one or more non target lesion(s) and/or maintenance of tumor marker level above the normal limits.
• progressive disease refers to unequivocal progression of existing non-target lesions.
• the term “unequivocal progression” as used herein refers to an overall level of substantial worsening in non-target disease such that even in presence of SD or PR in target disease, the overall burden had increased sufficiently to merit discontinuation of therapy.
• the term “not evaluable or NE” or “inevaluable” refers to when no imaging/measurement is done at all at a particular time point.
• Radiographic PFS is defined as the time from the date of initiation of protocol therapy to date measurement criteria were first met for PD by RECIST 1.1/PCWG3 criteria or death from any cause, whichever occurred first.
• PFS Progression Free Survival
• compositions comprising, “comprising”, “includes”, “including”, “having” and their conjugates mean “including but not limited to”. This term encompasses the terms “consisting of' and “consisting essentially of'.
• Consisting essentially of' means that the composition or method may include additional ingredients and/or steps, but only if the additional ingredients and/or steps do not materially alter the basic and novel characteristics of the claimed composition or method.
• method refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.
• Embodiment 1 A treatment regimen for treating prostate cancer in a subject in need thereof, comprising administering to said subject, about 0.3 mg twice daily dose of Talabostat or a pharmaceutically acceptable salt thereof on one or more days of a treatment cycle and an effective amount of Pembrolizumab on day 1 of the treatment cycle.
• Embodiment 2 A method of treating prostate cancer in a subject, comprising administering Talabostat or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of Pembrolizumab, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.3 mg twice daily on one or more days of a treatment cycle, and wherein the prostate cancer is selected from the group consisting of small cell neuroendocrine prostate cancer (SCNC), neuroendocrine prostate cancer (NEPC), treatment emergent neuroendocrine prostate cancer (tNEPC), castration resistant prostate cancer (CrPC), metastatic castration resistant prostate cancer (mCrPC), and adenocarcinoma type prostate cancer.
• SCNC small cell neuroendocrine prostate cancer
• NEPC neuroendocrine prostate cancer
• tNEPC treatment emergent neuroendocrine prostate cancer
• CrPC castration resistant prostate cancer
• mCrPC metastatic castration resistant prostate cancer
• adenocarcinoma type prostate cancer adenocarcino
• Embodiment 3 A method of enhancing an immune response in a subject suffering from prostate cancer (e.g. SCNC, NEPC, tNEPC, CrPC, mCrPC, adenocarcinoma), the method comprising administering to said subject Talabostat or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of Pembrolizumab, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.3 mg twice daily on one or more days of a treatment cycle. .
• SCNC e.g. SCNC, NEPC, tNEPC, CrPC, mCrPC, adenocarcinoma
• Embodiment 4 A method of enhancing an innate immune response in a subject afflicted with prostate cancer (e.g. SCNC, NEPC, tNEPC, CrPC, mCrPC, adenocarcinoma), the method comprising administering to said subject, Talabostat or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of Pembrolizumab, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.3 mg twice daily on one or more days of a treatment cycle and , wherein the enhanced innate immune response is associated with increased tumoricidal natural killer cells and macrophages, as well as the activity of NK cells and CD8+ T cells.
• SCNC e.g. SCNC, NEPC, tNEPC, CrPC, mCrPC, adenocarcinoma
• Embodiment 5 A method of enhancing an innate immune response in a subject with prostate cancer (e.g. SCNC, NEPC, tNEPC, CrPC, mCrPC, adenocarcinoma), the method comprising administering to said subject, Talabostat or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of Pembrolizumab, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.3 mg twice daily on one or more days of a treatment cycle and , wherein the enhanced innate immune response is associated with suppression of T-regulatory cells
• Embodiment6 A method for treating, delaying progression or preventing or delaying tumor recurrence, tumor growth or spread of tumor in a subject afflicted with prostate cancer (e.g. SCNC, neuroendocrine prostate cancer (NEPC), treatment emergent neuroendocrine prostate cancer(tNEPC), castration resistant prostate cancer (CrPC), metastatic castration resistant prostate cancer (mCrPC), adenocarcinoma type prostate cancer), the method comprising administering to the subject Talabostat or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of Pembrolizumab, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.3 mg twice daily on one or more days of a treatment cycle.
• prostate cancer e.g. SCNC, neuroendocrine prostate cancer (NEPC), treatment emergent neuroendocrine prostate cancer(tNEPC), castration resistant prostate cancer (CrPC), metastatic castration resistant prostate cancer (mCrPC), adenocarcinoma type
• Embodiment 7 A method of enhancing immune function in a subject afflicted with prostate cancer (e.g. SCNC, neuroendocrine prostate cancer (NEPC), treatment emergent neuroendocrine prostate cancer (tNEPC), castration resistant prostate cancer (CrPC), metastatic castration resistant prostate cancer (mCrPC), adenocarcinoma type prostate cancer), the method comprising administering to the subject, Talabostat or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of Pembrolizumab, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.3 mg twice daily on one or more days of a treatment cycle.
• SCNC neuroendocrine prostate cancer
• tNEPC treatment emergent neuroendocrine prostate cancer
• CrPC castration resistant prostate cancer
• mCrPC metastatic castration resistant prostate cancer
• adenocarcinoma type prostate cancer e.g. SCNC, neuroendocrine prostate cancer (NEPC), treatment emergent neuroendocrine
• Embodiment 8 A method for initiating, sustaining or enhancing an anti -tumor immune response in a subject afflicted with prostate cancer (e.g. SCNC, neuroendocrine prostate cancer (NEPC), treatment emergent neuroendocrine prostate cancer (tNEPC), castration resistant prostate cancer (CrPC), metastatic castration resistant prostate cancer (mCrPC), adenocarcinoma type prostate cancer), the method comprising administering to the subject Talabostat or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of Pembrolizumab, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.3 mg twice daily on one or more days of a treatment cycle.
• prostate cancer e.g. SCNC, neuroendocrine prostate cancer (NEPC), treatment emergent neuroendocrine prostate cancer (tNEPC), castration resistant prostate cancer (CrPC), metastatic castration resistant prostate cancer (mCrPC), adenocarcinoma type prostate cancer
• the method compris
• Embodiment 9 A method for reducing the treatment related adverse effects (TRAEs) in a subject afflicted with prostate cancer (e.g. SCNC, neuroendocrine prostate cancer (NEPC), treatment emergent neuroendocrine prostate cancer (tNEPC), castration resistant prostate cancer (CrPC), metastatic castration resistant prostate cancer (mCrPC), adenocarcinoma type prostate cancer), comprising administering Talabostat or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of Pembrolizumab, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.3 mg twice daily on one or more days of a treatment cycle.
• SCNC neuroendocrine prostate cancer
• tNEPC treatment emergent neuroendocrine prostate cancer
• CrPC castration resistant prostate cancer
• mCrPC metastatic castration resistant prostate cancer
• adenocarcinoma type prostate cancer comprising administering Talabostat or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount
• a method of treating an advanced solid tumor e.g. castrate resistant prostate cancer, endometrial cancer, dedifferentiated liposarcoma, basal cell carcinoma, leiomyosarcoma, squamous cell carcinoma of unknown primary, skin melanoma, mucosal melanoma, pleomorphic sarcoma, colorectal/colon cancer, astrocytoma, triple negative breast cancer, uterine sarcoma, uveal melanoma), in a subject in need thereof, the method comprising administering to the subject Talabostat or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of Pembrolizumab, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.3 mg twice daily on one or more days of a treatment cycle.
• an advanced solid tumor e.g. castrate resistant prostate cancer, endometrial cancer, dedifferentiated liposarcoma, basal cell carcinoma, leiomyo
• Embodiment 11 A method of enhancing an immune response in a subject suffering from an advanced solid tumor (e.g. castrate resistant prostate cancer, endometrial cancer, dedifferentiated liposarcoma, basal cell carcinoma, leiomyosarcoma, squamous cell carcinoma of unknown primary, skin melanoma, mucosal melanoma, pleomorphic sarcoma, colorectal/colon cancer, astrocytoma, triple negative breast cancer, uterine sarcoma, uveal melanoma), the method comprising administering to said subject a regimen comprising Talabostat or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of Pembrolizumab, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.3 mg twice daily on one or more days of a treatment cycle.
• an advanced solid tumor e.g. castrate resistant prostate cancer, endometrial cancer, dedifferentiated liposar
• Embodiment 12 A method of enhancing an innate immune response in a subject afflicted with advanced solid tumor (e.g. castrate resistant prostate cancer, endometrial cancer, dedifferentiated liposarcoma, basal cell carcinoma, leiomyosarcoma, squamous cell carcinoma of unknown primary, skin melanoma, mucosal melanoma, pleomorphic sarcoma, colorectal/colon cancer, astrocytoma, triple negative breast cancer, uterine sarcoma, uveal melanoma), the method comprising administering to said subject, Talabostat or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of Pembrolizumab, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.3 mg twice daily on one or more days of a treatment cycle and wherein the enhanced innate immune response is associated with increased tumoricidal natural killer cells and macrophages, as well
• Embodiment 13 A method of enhancing an innate immune response in a subject with an advanced solid tumor (e.g. castrate resistant prostate cancer, endometrial cancer, dedifferentiated liposarcoma, basal cell carcinoma, leiomyosarcoma, squamous cell carcinoma of unknown primary, skin melanoma, mucosal melanoma, pleomorphic sarcoma, colorectal/colon cancer, astrocytoma, triple negative breast cancer, uterine sarcoma, uveal melanoma), the method comprising administering to said subject Talabostat or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of Pembrolizumab, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.3 mg twice daily on one or more days of a treatment cycle and wherein the enhanced innate immune response is associated with suppression of T- regulatory cells.
• an advanced solid tumor e.g. castrate resistant prostate cancer,
• Embodiment 14 A method for treating, delaying progression or preventing or delaying tumor recurrence, tumor growth or spread of tumor in a subject afflicted with an advanced solid tumor (e.g. castrate resistant prostate cancer, endometrial cancer, dedifferentiated liposarcoma, basal cell carcinoma, leiomyosarcoma, squamous cell carcinoma of unknown primary, skin melanoma, mucosal melanoma, pleomorphic sarcoma, colorectal/colon cancer, astrocytoma, triple negative breast cancer, uterine sarcoma, uveal melanoma), the method comprising administering to the subject Talabostat or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of Pembrolizumab, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.3 mg twice daily on one or more days of a treatment cycle.
• an advanced solid tumor e.g. castrate resistant
• Embodiment 15 A method of enhancing immune function in a subj ect afflicted with an advanced solid tumor (e.g. castrate resistant prostate cancer, endometrial cancer, dedifferentiated liposarcoma, basal cell carcinoma, leiomyosarcoma, squamous cell carcinoma of unknown primary, skin melanoma, mucosal melanoma, pleomorphic sarcoma, colorectal/colon cancer, astrocytoma, triple negative breast cancer, uterine sarcoma, uveal melanoma), the method comprising administering to the subject Talabostat or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of Pembrolizumab, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.3 mg twice daily on one or more days of a treatment cycle.
• an advanced solid tumor e.g. castrate resistant prostate cancer, endometrial cancer, dedifferentiated lipo
• Embodiment 16 A method for initiating, sustaining or enhancing an anti-tumor immune response in a subject afflicted with an advanced solid tumor (e.g. castrate resistant prostate cancer, endometrial cancer, dedifferentiated liposarcoma, basal cell carcinoma, leiomyosarcoma, squamous cell carcinoma of unknown primary, mucosal melanoma, skin melanoma, pleomorphic sarcoma, colorectal/colon cancer, astrocytoma, triple negative breast cancer, uterine sarcoma, uveal melanoma), the method comprising administering to the subject Talabostat or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of Pembrolizumab, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.3 mg twice daily on one or more days of a treatment cycle.
• an advanced solid tumor e.g. castrate resistant prostate cancer, endometrial cancer
• Embodiment 17 A method for reducing the treatment related adverse effects (TRAEs) in a subject afflicted with an advanced solid tumor (e.g. castrate resistant prostate cancer, endometrial cancer, dedifferentiated liposarcoma, basal cell carcinoma, leiomyosarcoma, squamous cell carcinoma of unknown primary, skin melanoma, mucosal melanoma, pleomorphic sarcoma, colorectal/colon cancer, astrocytoma, triple negative breast cancer, uterine sarcoma, uveal melanoma), comprising administering to a subject Talabostat or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of Pembrolizumab, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.3 mg twice daily on one or more days of a treatment cycle.
• an advanced solid tumor e.g. castrate resistant prostate cancer, endometrial cancer, dedifferentiated
• Embodiment 18 The treatment regimen or method of treatment according to any of Embodiments 1-17, wherein 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, where each treatment cycle is of about 21 days duration.
• 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, where each treatment cycle is of about 21 days duration.
• Embodiment 19 The treatment regimen or method of treatment according to any of Embodiments 1-18, wherein after cessation of treatment the subject maintains a sustained response to progression of prostate cancer or an advanced solid tumor.
• Embodiment 20 The treatment regimen or method of treatment according to Embodiment 18 or 19, 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.
• Embodiment 21 The treatment regimen or method of treatment according to any of Embodiments 1-20, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered orally (e.g. as a tablet formulation).
• Embodiment 22 The treatment regimen or method of treatment according to any of Embodiments 1-20, wherein Pembrolizumab is administered by injection (e.g. intravenously).
• Embodiment 23 The treatment regimen or method of treatment according to any of Embodiments 1-22, wherein Pembrolizumab is administered at a dose of from about 1 mg/kg to about 10 mg/kg per day.
• Embodiment 24 The treatment regimen or method of treatment according to any of Embodiments 1-23, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.3 mg in the morning and about 0.3 mg in the evening.
• Embodiment25 The treatment regimen or method of treatment according to any of Embodiments 1-24, wherein Pembrolizumab is administered at a total dose of from about 100 mg to about 500 mg per day (e.g. about 200 mg per day).
• Embodiment 26 The treatment regimen or method of treatment according to any of Embodiments 1-24, wherein the total daily dose of Talabostat or a pharmaceutically acceptable salt thereof in cycle 1 is lower than the total daily dose of Talabostat or a pharmaceutically acceptable salt thereof in one or more subsequent cycles.
• Embodiment 27 The treatment regimen or method according to any of Embodiments 1 to 17, wherein the subject is administered Talabostat or a pharmaceutically acceptable salt thereof at a dose of about 0.2 mg twice daily for one or more consecutive days beginning on day 1 of the first treatment cycle.
• Embodiment 28 The treatment regimen or method according to any of Embodiments 1 to 17, wherein the subject is administered Talabostat or a pharmaceutically acceptable salt thereof at a dose of about 0.2 mg twice daily on days 1-7 of the first treatment cycle followed by about 0.3 mg twice daily on days 8-14 of the first treatment cycle.
• Embodiment 29 The treatment regimen or method according to any of Embodiments 1 to 17, wherein the subject is administered Talabostat or a pharmaceutically acceptable salt thereof at a dose of about 0.3 mg twice daily on days 1-3 of the first treatment cycle followed by rest period (day 4 to7) and then about 0.3 mg twice daily (on days 8-11) of the first treatment cycle.
• Embodiment 30 The treatment regimen or method according to Embodiments 1 to 9, wherein the prostate cancer is adenocarcinoma type prostate cancer.
• Embodiment 31 The treatment regimen or method of treatment according to Embodiment 30, wherein the subject with adenocarcinoma prostate cancer was treated with at least 1 but no more than 2 second generation AR pathway target inhibitors.
• Embodiment 32 The treatment regimen or method of treatment according to any of Embodiments 1 to 9, wherein the subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
• ECOG Eastern Cooperative Oncology Group
• Embodiment 33 The treatment regimen or method of treatment according to any of Embodiments 1 to 9, wherein the subject with adenocarcinoma prostate cancer has a serum testosterone ⁇ 50ng/dL during screening.
• Embodiment 34 The treatment regimen or method according to any of Embodiments 1 to 17, wherein the subject experiences less treatment-related adverse events (TRAEs) relative to a subject with same caner and administered a single 0.6 mg once daily dose of Talabostat
• Embodiment 35 The treatment regimen or method according to Embodiment 34, wherein the subject experiences no TRAEs.
• TRAEs treatment-related adverse events
• Embodiment 36 The treatment regimen or method according to Embodiment 34 or 35, wherein the TRAE are one or more of hypotension, dizziness, headache, syncope, dyspnea, chills, pyrexia, malaise, weakness, edema/peripheral swelling, hypovolemia, hypothermia, fatigue, nausea, vomiting, diaphoresis, flushing, migraine, diarrhea, constipation, alopecia, pharyngitis, chest pain, anorexia, weight increase, weight decrease, vertigo, syncope, conjunctivitis, blurred vision, pallor, pruritus, rash, fungal vaginosis, hyperglycemia, hyperkalemia, hypokalemia, hoarseness, dyspnea, anoxia, deep venous thrombosis, upper respiratory infection, blood in stool, dizziness, rigors, sepsis, pain, hypereosinophilia, dehydration, electrolyte imbalance,
• Embodiment 37 The treatment regimen or method according to any of preceding
• Embodiments wherein the subject achieves a stable disease response or better, as measured by RECIST 1.1.
• Embodiment 38 The treatment regimen or method according to any of preceding
• Embodiments wherein the subject achieves a partial response or better, as measured by RECIST 1.1.
• Embodiments 39 The treatment regimen or method of any of the preceding embodiments, wherein the subject achieves a complete response, as measured by RECIST 1.1.
• Embodiment 40 The treatment regimen or method according to any of preceding embodiments, wherein the subject achieves a 50% or greater prostate-specific antigen (PSA) decline from baseline by week 12 of treatment.
• PSA prostate-specific antigen
• Embodiment 41 The treatment regimen or method according to any of preceding embodiments, wherein the subject experiences an increase in pro-inflammatory cytokines relative to a subject that is administered a single 0.6 mg once daily dose of Talabostat.
• Embodiment 42 The method according to Embodiment 41, wherein the pro-inflammatory cytokines are one or more of IL-18 and IFN- g.
• Embodiment 43 The treatment regimen or method according to Embodiment 41, wherein the maximum increase in cytokines is observed at day 14 of continuous dosing.
• Embodiment 44 The treatment regimen or method according to any of Embodiments 10 to 17, wherein the subject was not previously treated with PD-1/PD-L1 or CTLA-4 antibodies.
• Embodiment 45 The treatment regimen or method according to any of Embodiments 10 to 16, wherein the subject has relapsed or progressed with PD-1/PD-L1 or CTLA-4 antibodies.
• Embodiment 46 The treatment regimen or method of treatment according to any of Embodiments 1-27, comprising administering Talabostat mesylate.
• Embodiment 47 A treatment regimen for treating prostate cancer ((e.g. SCNC, NEPC, tNEPC, CrPC, mCrPC, adenocarcinoma), in a subject in need thereof, the regimen comprising administering to the subject Talabostat mesylate and Pembrolizumab in one or more treatment cycles, where each treatment cycle is of about 21 days duration, and for each treatment cycle Talabostat is administered on each of days 1 to 14 and Pembrolizumab is administered on day 1, wherein Talabostat mesylate is administered orally as one or more tablets to provide a total daily dose of Talabostat of about 0.6 mg in divided doses and Pembrolizumab is administered as a single intravenous injection to provide a dose of from about 100 mg to about 500 mg per day.
• SCNC StemCrPC, adenocarcinoma
• Embodiment 48 The treatment regimen according to Embodiment 47, wherein Talabostat or a pharmaceutically acceptable salt thereof is administered orally in the morning and evening.
• Embodiment 49 The treatment regimen according to Embodiment 47, wherein the subject experiences less treatment-related adverse events (TRAEs) relative to a subject that is administered a single 0.6 mg once daily dose of Talabostat.
• TEEs treatment-related adverse events
• Embodiment 50 The treatment regimen according to Embodiment 47, wherein the subject experiences no TRAEs.
• Embodiment 51 The treatment regimen according to Embodiment 47, wherein the subject has a small cell neuroendocrine prostate cancer and has received at least one prior cytotoxic chemotherapy.
• Embodiment 52 The treatment regimen according to Embodiment 47, wherein the subject has a measurable disease as per RECIST 1.1 or iRECIST.
• Embodiment 53 The treatment regimen according to Embodiment 47, wherein the subject has a detectable bone metastases by whole body bone scintigraphy.
• Embodiment 54 The treatment regimen according to Embodiment 47, wherein the subject after the administration meets the CTC response as per Veridex assay.
• Embodiment 55 The treatment regimen according to Embodiment 47, wherein the subject achieves a stable disease response or better as per RECIST 1.1.
• Embodiment 56 The treatment regimen according to Embodiment 47, wherein the subject achieves a complete or a partial response or better as per RECIST 1.1
• Example 1 A Phase lb/2 Study of Talabostat mesylate, a Small Molecule Inhibitor of Dipeptidyl Peptidases (DPP), Administered in Combination with the Anti-Programmed Cell Death 1 (PD-1) Monoclonal Antibody Pembrolizumab (PEMBRO; Keytruda®) in Patients with Small Cell Neuroendocrine Prostate Cancer (SCNC; NEPC) or Adenocarcinoma Phenotype.
• DPP Dipeptidyl Peptidases
• Cohort B Patients with adenocarcinoma and no evidence of small cell or neuroendocrine features on recent histopathology.
• Composite response rate is defined as achieving 1 or more of the following: o Objective response by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria o Circulating tumor cell (CTC) conversion from >5/7.5 mL to ⁇ 5/7.5 mL per Veridex assay by completion of Week 12 of protocol therapy o Greater than 50% prostate-specific antigen (PSA) decline from baseline by completion of Week 12 of protocol therapy.
• RECIST Solid Tumors
• CTC Circulating tumor cell
• PSA PFS median PSA progression-free survival
• mRNA tumor messenger ribonucleic acid
• Study Design This was an open-label, multi -centre, Phase lb/2 study determined the composite response rate of talabostat mesylate administered orally and daily, combined with Pembrolizumab, in patients with mCRPC enrolled in stage 2 with either SCNC (Cohort A) or adenocarcinoma phenotype (Cohort B). The study assessed other efficacy parameters such as rPFS, PSA PFS, OS and DOR, as well as safety of the combined treatment.
• Efficacy stage (Simon 2-stage): in which patients were treated with talabostat mesylate combined with Pembrolizumab. Patients were assigned to 1 of 2 cohorts based on phenotype.
• o Cohort A Patients with any small cell /neuroendocrine (SCNC) features, either de novo or treatment-emergent including mixed SCNC.
• SCNC small cell /neuroendocrine
• o Cohort B Patients with adenocarcinoma and no evidence of small cell or neuroendocrine features
• DLT dose-limiting toxicity
• the Efficacy Stage could commence. o If more than one-third of the patients experienced a DLT, consideration was given to the use of 0.4 mg Talabostat mesylate total daily dose, or an intermediate dose, plus Pembrolizumab in the Efficacy Stage.
• a Safety Review Committee which comprised of both investigators and sponsor representatives, reviewed the safety during the Lead-In Stage and during the trial before the Efficacy Stage began. If an intermediate dose was selected for the Efficacy Stage, the committee monitored the first 6 patients enrolled in the efficacy stage through Cycle 1. [0336] All safety data from all patients enrolled in each cohort was reviewed to confirm any DLTs that were experienced and to determine enrolling the next cohort, as well as the Talabostat mesylate dosing regimen to be used in the Efficacy Stage.
• a patient Unless doses were held because of adverse events (AEs), a patient must had received >70% of his Talabostat mesylate doses in Cycle 1 (e.g., >10 of 14 planned doses) with Pembrolizumab dosed on Day 1 of Cycle 1 to be eligible for DLT assessment.
• AEs adverse events
• a DLT was defined as any of the following AEs occurring during Cycle 1 , regardless of investigator attribution to study treatment, unless the AE could be clearly and incontrovertibly attributed to an extraneous cause (e.g., PD) by the Principal Investigator PI: Any Grade 4 laboratory abnormality, regardless of duration
• Grade 3 non-hematologic AE with the exceptions of Grade 3 nausea, vomiting, diarrhea, constipation, fever, fatigue, skin rash, or non-clinically significant laboratory abnormality that resolved to Grade ⁇ 2 within 72 hours with optimal medical management.
• Efficacy Stage After assessment of the safety and confirmation of the Talabostat mesylate/Pembrolizumab dose regimen used in the subsequent stage, the Efficacy Stage began. Eligible SCNC patients received Talabostat mesylate on Days 1 to 14 of a 21-day cycle plus Pembrolizumab 200 mg administered IV on Day 1 every 21 days.
• Tumor measurements and disease response assessments were also performed at the end of Cycle 3 (approximately 9 weeks after the first study treatment dose), and then approximately every 9 weeks thereafter until development of progressive disease (PD). For patients with evidence of disease control (stable disease or better) at Week 27, tumor measurements and disease response assessments might be performed less frequently (approximately every 12 weeks) thereafter. Tumor measurements and disease response assessments also were performed at the End of Treatment (EOT) visit.
• EOT End of Treatment
• Treatment might continue beyond the first radiographic progression if there was clinical benefit.
• Eligibility Criteria All patients must satisfy the following inclusion and exclusion criteria to be eligible for entry into the trial.
• SCNC Cohort A
• a. Patient had a histologic evidence of SCNC either with archival tissue or a fresh tumor biopsy obtained during Screening. Archival or fresh tumor biopsy tissue must be submitted for a central laboratory pathology review; however, enrollment could proceed if SCNC was determined by a local pathology review. (Central pathology review was optional for patients enrolled in the lead-in.)
• b. Must be willing to undergo metastatic tumor biopsy during Screening. Requirement might be waived in patients without safely accessible lesion or for patients with evaluable archival metastatic tumor tissue
• a. Patient had histologically or cytologically confirmed adenocarcinoma of the prostate without small cell neuroendocrine features.
• b. Patients with soft tissue disease must provide a fresh core or excisional biopsy or archival tissue obtained ⁇ 3mo prior to study start from a site not previously irradiated for central pathology review; however enrollment might proceed if predominant adenocarcinoma without small cell neuroendocrine features was determined by local pathology review.
• a barrier contraception e.g., condom with spermicidal foam/gel/film/cream/ suppository
• This criterion might be waived for male patients who had a vasectomy >6 months before signing the informed consent form.
• an anti-PD-1, anti-PD-Ll, anti-programmed death-ligand 2 (PD-L2) agent or with an agent directed to another co-inhibitory T-cell receptor (e.g., cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4], OX-40, CD137).
• CTLA-4 cytotoxic T-lymphocyte-associated antigen 4
• OX-40 cytotoxic T-lymphocyte-associated antigen 4
• CD137 cytotoxic T-lymphocyte-associated antigen 4
• DPP-4 inhibitors e.g. gliptin
• Replacement therapy e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency
• drugs e.g., neomercazol, carbimazole, etc.
• drugs e.g., neomercazol, carbimazole, etc.
• Patient had a diagnosis of immunodeficiency or was receiving systemic steroid therapy at a prednisone equivalent dose of >10 mg daily for at least 1 week or other form of immunosuppressive therapy within 7 days prior to Cycle 1 Day 1 (C1D1).
• uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, suspected or active SARS-CoV-2 (Covid-19) infection disseminated intravascular coagulation, or psychiatric illness/social situations that would limit compliance with study requirements.
• Orthostatic hypotension is defined as a drop in systolic blood pressure (BP) of > 20 mmHg or diastolic BP of > 10 mmHg with assumption of an upright posture.
• BP systolic blood pressure
• SCNC Cohort A
• Cohort B adenocarcinoma without small cell histology
• Approximately 15 to 28 patients with SCNC were enrolled in each Cohort.
• a minimax 2-stage Simon design was applied separately for each cohort. In the first stage, 15 patients were accrued. If there are 2 or fewer composite responses in these 15 patients, accrual to the study arm was halted. Otherwise, 13 additional patients were accrued for a total of 28 patients.
• a composite response was defined as 1 or more of the following:
• the primary efficacy parameter was the composite response rate defined as achieving 1 or more of the following: o Objective response by RECIST 1.1 criteria o Circulating tumor cell (CTC) conversion from >5/7.5 mL to ⁇ 5/7.5 mL per Veridex assay by completion of Week 12 of protocol therapy o Greater than 50% prostate specific antigen (PSA) decline from baseline by completion of Week 12 of protocol therapy [0366] Secondary Efficacy Parameters:
• PFS Prostate specific antigen
• OS Overall survival
• Talabostat mesylate in combination with Pembrolizumab on relevant immune effector cytokines and various immunological effector cells, in blood and, whenever feasible, in tumor tissues.
• Study medication was administered in 21 -day cycles. Either Talabostat mesylate or Pembrolizumab may be administered first. However, on Cycle 1 Day 1, it was recommended that Pembrolizumab be administered first and that >1 hour should elapse before the administration of Talabostat mesylate so that it was easier to determine the relatedness of any AEs to study drug
• the starting dose regimen of Talabostat mesylate (i.e., the dose regimen in Cohort 1) was 0.4 mg QD on Days 1 to 14 every 21 days.
• the Talabostat mesylate dose regimen for any patient depended on the cohort in which the patient was enrolled in the Lead-in Stage. Additional dosing schedules were also evaluated during the Lead-in Stage.
• the patient might be monitored overnight at the discretion of the Investigator. If the overnight monitoring was not associated with any Grade 2 or greater AE or any other SAE criteria, the admission was not be considered an SAE. Longer periods of in-patient monitoring might be implemented at the discretion of the Investigator.
• any patients still tolerating treatment in a lower Talabostat mesylate dose cohort might have their Talabostat doses escalated to the recommended dose regimen with the start of the next cycle at the investigator’s discretion.
• Talabostat mesylate was administered orally as 0.2 mg, 0.1 mg or 0.05-mg tablet. Patients took the prescribed number of tablets daily on Days 1 to 14 of each cycle, for a total daily dose of 0.4 mg, 0.6 mg, or an intermediate dose. Talabostat mesylate was continued until PD or unacceptable toxicity. Talabostat mesylate should not be taken on an empty stomach. [0386] On days when pharmacodynamic studies were being performed Talabostat mesylate should be administered at the study center, and should be administered at (approximately) the same time of day on each treatment day in the cycle. In cycles in which pharmacodynamics was not evaluated, Talabostat mesylate also should be administered at (approximately) the same time of day on each treatment day in the cycle.
• the patient did not met criteria to increase their dose to 0.3mg BID during Cycle 1, they might continue on treatment at 0.2mg BID until the investigator decided to escalate the patient’s dose to 0.3mg BID.
• the patient performed at home blood pressure monitoring at least twice daily, once in the morning and once in the late aftemoon/evening, prior to dosing.
• the patient recorded blood pressure measurements on a log and was asked to bring the log with them to every clinic visit during the first cycle that their dose was escalated to 0.3mg BID.
• the patient was instructed that they must not take their dose if their blood pressure was below 100 mmHg systolic or 50 mmHg diastolic.
• the patient must report any values below this to study physician immediately.
• the study physician provided the patient further instruction as needed.
• the study team contacted the patient daily during the first week of treatment at the 0.3mg BID dose level to remind the patient of oral hydration guidelines, review side effects, and to review the patient’s self- administered blood pressure measurements.
• Talabostat mesylate dose modifications within a treatment cycle were not permitted in Cycle 1 in the absence of DLT. In Cycle >2, dose modifications within a treatment cycle was at the discretion of the investigator. Doses were taken at approximately the same time every day. Doses held because of AEs should not be made up on subsequent days within or following a cycle. A dose that was missed for reasons other than an AE (i.e., the patient forgets to take a dose) might be taken at least 6 hours prior to the next planned dose; otherwise, the missed dose might be administered on days subsequent to scheduled doses. Any additional adjustments should be discussed with the Medical Monitor or designee.
• a dose was vomited within approximately 10 minutes of dosing, the patient may be re-dosed. If the patient vomited>10 minutes after dosing, no further attempts at dosing that particular dose should take place; dosing should resume with the next dose. Under no circumstances should missed doses be made-up on a day when the patient was already taking a planned dose (i.e., no “doubling -up” to account for missed doses).
• an SAE thought to be related to Talabostat Mesylate occurred during the treatment period, dosing of Talabostat Mesylate was interrupted in that patient until the SAE resolved. If the investigator wished to continue the patient on Talabostat Mesylate, the medical monitor was contacted to discuss continuing Talabostat Mesylate at the same or reduced dose.
• Talabostat mesylate was supplied as 0.2-mg tablets, 0.1-mg tablets and 0.05-mg tablets in high-density polyethylene bottles with desiccant and child-resistant caps.
• the 0.2-mg strength was supplied as 30 tablets per bottle.
• the 0.1-mg tablets were supplied as 90 tablets per bottle.
• the 0.05-mg strength was supplied as 90 tablets per bottle.
• Talabostat mesylate should be stored under refrigerated conditions between 2°C to 8°C (36°F to 46°F) until use. During the period of use, meaning once dispensed for patient, Talabostat mesylate tablets might be stored in their original container for up to 30 days at room temperature, 15°-25°C (59°-77°F).
• the Pembrolizumab dose was 200 mg, administered as an IV infusion over 30 minutes on Day 1 of each 21 -day cycle. Premedication, according to standard local practices, was permitted
• the modified intent-to-treat (mITT) analysis population consisted of patients enrolled in the Efficacy Stage who met the eligibility criteria and received at least 1 dose of Talabostat mesylate and Pembrolizumab.
• the response evaluable patient population consisted of patients enrolled in the Efficacy Stage who completed at least 2 cycles of treatment with combined Talabostat mesylate and Pembrolizumab, with at least 1 post-baseline response assessment made by the investigator(s).
• the safety population consisted of all patients who received any dose of Talabostat mesylate / Pembrolizumab, either during the Lead-in or Efficacy Stages of the study.
• the pharmacodynamic analysis population consisted of all patients who received any dose of Talabostat mesylate / Pembrolizumab and had cytokine levels measured at least once.
• the pharmacokinetics population include all patients who received at least 1 dose of Talabostat mesylate and had at least 1 quantifiable Talabostat mesylate plasma concentration at a scheduled pharmacokinetics time point postdose.
• Stage 1 Analysis The Stage 1 analysis was performed for Cohort A and Cohort B, separately. In each cohort, when 15 patients had completed approximately 6 cycles of treatment and had 2 post-baseline tumor assessments and PSA or CTC measurements, the number of patients who met the composite response criteria of achieving 1 or more the following: 1) objective response by RECIST 1.1 criteria, 2) >50% decline from baseline in serum PSA by Week 12 of treatment, or 3) CTC conversion from >5/7.5 mL to ⁇ 5/7.5 mL per Veridex assay by completion of Week 12 of protocol therapy were evaluated.
• Stage 2 Analysis In each Cohort enrolling in Stage 2, when the additional 13 patients in stage 2 enrolled and treated had completed approximately 6 cycles of treatment, 2 post baseline assessments of tumor, and PSA and CTCs measurements, the number of patients who met at least 1 of the 3 criteria for the composite endpoint was evaluated. If the total number of patients who met the composite endpoint in 28 patients in both stages was 7 or less, then data were consistent with the null hypothesis of composite endpoint rate of 15% or lower with nominal 0.05 1-sided significance level.
• Sensitivity Analysis The composite endpoint rate were also be calculated for the mITT analysis population. Patients in the mITT population with missing composite endpoint were considered non-responders (e.g., not 1 of the 3 criteria for composite endpoint was met).
• Analysis of Secondary Parameter(s) Time-to-Event Response. The distribution of time-to-event response including rPFS, PSA, PFS, DOR, and OS was estimated by Kaplan- Meier methodology. The medians of these time-to-event efficacy responses, if available, and their 2-sided 95% Cl, was reported. In addition, the proportions of patients with events at selected time points, together with their 2-sided 95% Cl was presented. The calculations were performed based on fixed sample, single stage design.
• the primary analysis was performed using the mITT analysis population.
• time-to-event analysis was performed using the response evaluable analysis population.
• Cytokine Levels The analysis of the secondary efficacy endpoints including cytokine levels was reported for the PD analysis population. Descriptive statistics for levels of cytokines previously shown to be modulated by Talabostat mesylate in human was reported.
• Safety Analyses All patients in the safety population included in the final summaries and listings of safety data, separately for the lead-in patients grouped into cohorts. Summaries of AEs and other safety parameters was provided as appropriate. Emphasis in the analysis of AEs was placed on those that were treatment-emergent through 30 days after last dose of Talabostat mesylate/Pembrolizumab. Frequencies of patients experiencing at least 1 AE were displayed by body system and preferred term according to Medical Dictionary for Regulatory Activities (MedDRA) terminology. Intensity (severity) of the AE was graded according to NCI CTCAE.
• ADT androgen deprivation therapy
• ASI 2 nd Generation androgen signaling inhibitors
• Preliminary evaluation of anti-tumor activity from the Safety Lead-in portion of the study includes 1 patient with a PSA response and RECIST 1.1 Partial Response and three patients with stable disease per RECIST 1.1 including 1 patient still on treatment.
• Phase 2 efficacy portion of this study assessed the anti-tumor activity of the combination in patients with mCRPC of either SC/t-NEPC or adenocarcinoma phenotype of the combination in a setting where checkpoint inhibitor monotherapies demonstrated limited clinical benefit.
• Prior Systemic Therapy included: Bicalutamide; Abiraterone + Prednisone; Enzalutamide; Sipuleucel; Docetaxel/Cabazitaxel.
• Tempus molecular testing cfDNA peripheral blood- MSI-high not detected; no reportable treatment options found.
• On-treatment disease status Duration of Talabostat Mesylate +Pembrolizumab: 16+ cycles. PSA50 response by 6 weeks, max reduction 84%.
• Table 4 Phase lb - Safety Lead-in stage - Patient disease history ADT- Androgen deprivation therapy; ASI - Androgen signalling inhibitor; *For Patients with SC/t-NEPC mean age is 72 (range 62-84)
• # 1 patient each: Grade 3 syncope (DLT C1D6) and Grade 5 acidosis (C3)
• L 1 patient Grade 3 Fatigue, fatigue present at baseline, lpt Grade 3 pneumonitis, SOB, fatigue, hyponatremia, lpt Grade 3 lactic acid increase
• Patient 101-204 discontinued due to withdrawal of consent (progressive disease. Refused further treatment). Not evaluable for DLT.
• Patient 112-205 discontinued due to Investigator decision (clinical disease progression)
• IL-18 Changes post-dose Consistent dose and time dependent increases in IL-18 levels in the serum were observed with all the dose cohorts (Table 10 and FIGS. 7-9).
• the 0.6 mg split dose (0.3 mg BID-Talabostat mesylate) plus Pembrolizumab showed consistent increases in IL-18 on day 14 post dose (8-24-fold).
• Patient # 106-201 (0.6 mg QD + pembrolizumab) showed maximum IL-18 levels (45 -fold). Consistent dose and time dependent increases in IL-18 levels observed in 0.6 mg split dose, maximal changes noted on day 14.
• IFN-g Changes post-dose IFN- g is produced by activated T-cells and NK cells; high levels are associated with effective host defense and anti-tumor immunity. Time dependent increase in IFN-g levels was observed in 0.6mg qd and split dose cohorts (FIGS. 10-12).
• IL-Ib Changes post-dose IL-Ib is a pro-inflammatory cytokine produced by innate immune cells. IL-Ib is associated with safety and is pro-tumorigenic. IL-Ib levels did not change much in 0.4mg qd + pembrolizumab dose group, neither in 0.6mg qd and split dose cohorts during dosing (FIGS. 13-15)
• IL-6 (0.6mg split dose Talabostat mesylate + Pembrolizumab) : IL-6 is a pleiotropic cytokine. IL-6 helps tumor cell proliferation. Increased IL-6 associated with cytokine release syndrome. In the majority of patients, any increase in IL-6 quickly returned to baseline (FIG. 16).
• IL-8 (0.6 mg split dose Talabostat mesylate + Pembrolizumab): IL-8, neutrophil chemotactic factor, induces chemotaxis in neutrophils and granulocytes. Increased IL-8 associated with safety adverse events. Post-treatment IL-8 levels remained similar to baseline levels (FIG. 17)
• Table 10 shows the IL-18 changes (pg/ml) in the serum post dosing of Talabostat and
• Talabostat mesylate 0.3mg BID 0.6mg TDD
• Pembrolizumab administered on 200mg every 21 days.
• Splitting the TDD was associated with improved tolerability as evidenced by no reported DLTs and lower rates of other adverse events of interest such as hypotension and peripheral edema.
• Prior systemic therapy included leuprolide, sipuleucel, enzalutamide, docetaxel, cabazitaxel
• Prior systemic therapy included bicalutamide, leuprolide, enzalutamide, docetaxel, abiraterone + prednisone
• Table 11 Phase 2 - Efficacy stage (Cohort B- adenocarcinoma) - Patient disease history
• Table 12 Preliminary Activity Observed in Adenocarcinoma Population: a Patients who received > one dose of study therapy and 1 on-treatment tumor assessment; b Baseline value > 4ng/mL and one on-treatment PSA assessment c Baseline CTC value > 5/7.5 mL and one measurable on-treatment assessment d CTC conversion from > 5/7.5 mL to ⁇ 5/7.5 mL
• Table 13 Phase 2- Efficacy stage -Cohort B- Exposure Duration and Subject Disposition
• Step-up dosing was then implemented for all new patients with Talabostat mesylate 0.2 mg BID day 1 through day 7. Escalation to 0.3mg BID was permitted if no treatment related AEs Grade >1 or skipped doses due to hypotension or orthostasis occurred during the first week of treatment.
• Phase 2 summary Orally administered Talabostat mesylate in combination with pembrolizumab demonstrated anti-tumor activity in some heavily pre-treated, refractory mCRPC with adenocarcinoma phenotype, a setting where checkpoint inhibitor monotherapies have demonstrated limited clinical benefit and patients have limited treatment options. Despite limited efficacy follow-up in the Phase 2 portion of the study at this data cut-off, 1 ongoing patient has achieved a PSAso response plus CTC response and has had a 19% decrease in target lesions.
• a second patient has had a 40% reduction in PSA with a 27% reduction in target lesions.
• the disease control rate defined as PR+SD+non- CR/non-PD, is 80% among RECIST evaluable patients.
• PR+SD+non- CR/non-PD The disease control rate, defined as PR+SD+non- CR/non-PD, is 80% among RECIST evaluable patients.
• 1 ongoing patient with adenocarcinoma has a PSAso response and a RECIST 1.1 partial response. Efforts are underway to identify a potential predictive biomarker.
• the BID dosing schedule for Talabostat mesylate continues to demonstrate an acceptable safety profile when given in combination with pembrolizumab with primarily low grade on-target adverse events consistent with cytokine activation. This study continues to enroll patients with adenocarcinoma and SC/t-NEPC as per protocol.
• ALT alanine aminotransferase
• AST aspartate aminotransferase
• BP blood pressure
• BUN blood urea nitrogen
• Ca calcium
• Cl chloride
• Cr creatinine
• CxDx Cycle (number) Day (number);
• CBC complete blood count
• CT computed tomography
• CTC circulating tumor cell
• ECG electrocardiogram
• ECOG Eastern Cooperative Oncology Group
• eCRF electronic Case Report Form
• EOT End of Treatment
• FU Follow-Up
• HR heart rate
• IV intravenous
• K potassium
• LDH lactate dehydrogenase
• Mg magnesium
• MRI magnetic resonance imaging
• MSI microsatellite instability
• Na sodium
• PD progressive disease
• PEMBRO pembrolizumab
• PSA prostate- specific antigen
• QTcB QT interval corrected for heart rate using Bazett’s formula
• RR respiratory rate.
• Tumor assessment must include cross-sectional imaging (MRI or CT scanning with IV contrast whenever possible) of the chest/abdomen/pelvis plus whole-body bone scan. Other body sites (e.g., neck) included as clinically indicated. Tumor assessment was performed at Screening, C4D1 ( ⁇ 7 days), C7D1 ( ⁇ 7 days), C10D1 ( ⁇ 7 days), and Day 1 ( ⁇ 7 days) of every 3rd cycle thereafter.
• Either Talabostat mesylate or PEMBRO was administered first. However, on Cycle 1 Day 1, it was recommended that PEMBRO be administered first and that >1 hour should elapse before the administration of Talabostat mesylate so that it was easier to determine the relatedness of any AEs to study drug j.
• Cycle 3 and subsequent cycles, Day 8, and Day 15 For patients who did not experienced a laboratory abnormality since the start of treatment, or who had no worsening of baseline laboratory abnormality grade, the clinical laboratory assessments (hematology, serum chemistry, and liver function tests) on Day 8 and Day 15 of each cycle were not required. These patients continued clinical laboratory assessments on Day 1 of each cycle as required. For patients who experienced Grade >3 laboratory abnormalities after the start of treatment at Day 1 of any cycle beyond Cycle 3, these patients continued Day 8 and Day 15 clinical laboratory assessments until the resolution of the laboratory abnormality p. Serum chemistry included: Na, K, Cl, bicarbonate, Ca, Mg, phosphate, BUN/Cr, and LDH.
• TSH free T3 and free T4 at screening only. TSH, with reflexive free T3 and free T4 if TSH is abnormal, to be performed every other cycle (2, 4, 6, etc.) and EOT visit s.
• Serum collection for cytokines occured predose (recommended within 30 minutes prior to dosing) and 6 ( ⁇ 1 hour) and 24 ( ⁇ 4 hours) hours post dose on C1D1, C1D14, C2D1, and C2D14 and at C3D14 at Predose (recommended within 30 minutes prior to dosing) and 6 hours ( ⁇ 1 hour) after the morning dose.
• the Day 1 24-hour samples were collected prior to the Day 2 morning dose.
• Sample was collected within 30 minutes before morning dose was administered on C1D14 and C2D14(patient diary was kept to record the number of doses the patient had taken in the cycle).
• Cycle 1 Day 4 (+1) only, collected a PK sample predose (recommended within 30 minutes prior to dosing) w.
• Example 2 Phase 2 Basket Study of Talabostat mesylate, a Small Molecule Inhibitor of Dipeptidyl Peptidases (DPP), administered in combination with Pembrolizumab in Patients with Advanced Solid Cancers.
• DPP Dipeptidyl Peptidases
• DLT dose-limiting toxicities
• Talabostat mesylate in combination with pembrolizumab on various immunological effector cells, including neutrophils, myeloid derived suppressor cells (MDSCs), dendritic cells, cancer associated fibroblast (CAF), T-cells and macrophage density in pre-dose tumor biopsies and when feasible in post-dose tumor tissues.
• various immunological effector cells including neutrophils, myeloid derived suppressor cells (MDSCs), dendritic cells, cancer associated fibroblast (CAF), T-cells and macrophage density in pre-dose tumor biopsies and when feasible in post-dose tumor tissues.
• Efficacy Stage (BOP2-Stage) - in which patients with advanced solid cancers were treated with Talabostat mesylate combined with pembrolizumab. Patients enrolled to the Lead-in Stage were also evaluated in the efficacy stage. New patients enrolled were administered Talabostat mesylate at the starting dose of 0.2 mg orally twice a day for the first 7 days. If well tolerated and in the absence of signs and symptoms of clinically significant hypotension the dose was escalated to 0.3 mg orally twice a day. [0460] During the Lead-in Stage, patients were observed for dose-limiting toxicity (DLT) during Cycle 1. Six patients were treated initially with 0.3 mg BID Talabostat mesylate daily (Days 1 to 14) plus pembrolizumab 200mg:
• DLT dose-limiting toxicity
• NCI CTCAE National Cancer Institute Common Terminology Criteria for Adverse Events
• a DLT was defined as any of the following AEs occurring during Cycle 1, regardless of investigator attribution to study treatment, unless the AE could be clearly and incontrovertibly attributed to an extraneous cause (e.g., disease progression) by the Principal Investigator:
• Tumor measurements and disease response assessments were also to be performed at the end of Cycle 3 (approximately 9 weeks after the first study treatment dose), and then approximately every 9 weeks thereafter until development of progressive disease (PD). Intervals could be shortened to 6 weeks if clinically necessary per treating physician. For patients with evidence of disease control (stable disease or better) at Week 27, tumor measurements and disease response assessments might be performed less frequently (approximately every 12 weeks) thereafter. Tumor measurements and disease response assessments also were to be performed at the End of Treatment (EOT) visit.
• EOT End of Treatment
• Efficacy stage cohort A patients with advanced cancers not previously treated with PD1/PDL1 or CTLA4targeted therapies .
• Efficacy stage cohort B patients with advanced cancers which had relapsed or progressed with PD1/PDL1 or CTLA4targeted therapies .
• UPN institutional upper limit of normal
• ALT alanine aminotransferase
• Women of childbearing potential must had a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 14 days prior to the initiation of treatment and/or postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. Women of childbearing potential must agree and committed to the use of 2 highly effective methods of birth control throughout the duration of the study until at least 4 months following the last dose of study drug.
• HCG human chorionic gonadotropin
• Acceptable methods were defined as those that result, alone or in combination, in a low failure rate (i.e., less than 1% per year) when used consistently and correctly, such as surgical sterilization, an intrauterine device, or hormonal contraception in combination with a barrier method. It was currently unknown whether Talabostat mesylate or pembrolizumab might reduce the effectiveness of systemically acting hormonal contraceptives; therefore, women using systemically acting hormonal contraceptives should add a barrier method. In certain countries (if permitted by law), WOCBP may agree to abide by heterosexual sexual abstinence during the time of participation in this study.
• a barrier contraception e.g. condom with spermicidal foam/gel/film/cream/suppository
• This criterion might be waived for male patients who had a vasectomy > 6 months before signing the ICF.
• Patient had clinically significant cardiovascular disease e.g., uncontrolled or any New York Heart Association 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 or clinically significant arrhythmias not controlled by medication).
• cardiovascular disease e.g., uncontrolled or any New York Heart Association 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 or clinically significant arrhythmias not controlled by medication.
• Patient had a diagnosis of immunodeficiency or was receiving systemic steroid therapy at a prednisone equivalent dose of >10 mg daily for at least 1 week or other form of immunosuppressive therapy within 7 days prior to Cycle 1 Day 1 (C1D1).
• G-CSF granulocyte-colony stimulating factor
• Enrolled patients might not receive investigational or approved anticancer agents including cytotoxic chemotherapy agents, anticancer tyrosine kinase inhibitors, or therapeutic monoclonal antibodies.
• Efficacy was assessed during treatment using the RECIST 1.1 and iRECIST every 9 weeks (every 3 cycles). Intervals could be shortened to 6 weeks (every 2 cycles) if clinically necessary per treating physician. Tumor measurements were in QIAC.
• AEs were graded according to the revised NCI CTCAE, Version 5.0, (see http://ctep.cancer.gov/reporting/ctc.html). AEs occurring 30 days after the last dose of IPs did not need to be reported unless the investigator considered the event to be related to IPs.
• a life-threatening adverse drug experience any adverse experience that placed the patient, in the view of the initial reporter, at immediate risk of death from the adverse experience as it occurred. It did not include an adverse experience that, had it occurred in a more severe form, might have caused death.
• Study medication was administered in 21 -day cycles. Either Talabostat mesylate or Pembrolizumab may be administered first. However, on Cycle 1 Day 1, it was recommended that Pembrolizumab be administered first and that >1 hour should elapse before the administration of Talabostat mesylate so that it was easier to determine the relatedness of any AEs to study drug.
• Talabostat mesylate dosage and administration contained valine-proline boronic acid formulated as the methanesulfonate salt.
• Talabostat mesylate was administered orally as 0.2 mg, and 0.05-mg tablet. For a dose of 0.3 mg, patients took 1 x 0.2 mg tablet and 2 x 0.05 mg tablets together. Patients took 0.3 mg of the study drug twice a day, on Days 1 to 14 of each cycle, for a total daily dose of 0.6 mg. [0505] Talabostat mesylate was continued until disease progression or unacceptable toxicity. Newly enrolled patients were administered Talabostat mesylate at the starting dose of 0.2 mg orally twice a day. If well tolerated and in the absence of signs and symptoms of clinically significant hypotension the dose was escalated to 0.3 mg orally twice a day.
• Talabostat mesylate was administered at the study center, and administered at (approximately) the same time of day on each treatment day in the cycle. In cycles in which pharmacodynamics were not evaluated, Talabostat mesylate also was administered at (approximately) the same time of day on each treatment day in the cycle, preferably 0800 hours. If the patient forgot to take study medication, the dose was skipped.
• Talabostat mesylate dose modifications within a treatment cycle were discouraged in Cycle 1 unless required by AE and/or DLT. In Cycle >2, dose modifications within a treatment cycle were at the discretion of the investigator. Doses held because of AEs should not be made up on subsequent days within or following a cycle. A dose that was missed for reasons other than an AE (i.e., the patient forgets to take a dose) might be administered on days subsequent to scheduled doses; any such adjustments were discussed with the Investigator. Under no circumstances should missed doses be made-up on a day when the patient was already taking a planned dose (i.e., no “doubling-up” to account for missed doses).
• Grade 2 or higher AEs of edema/peripheral swelling, hypotension, dizziness, and hypovolemia • For Grade 3 AEs, Held Talabostat mesylate until resolution of these AEs to ⁇ Grade 1 or baseline. Thereafter, restarted Talabostat at a dose reduced by 0.2 mg (reduction of 0.1 mg twice day to 0.2 mg twice a day; 1 dose level reduction).
• All Talabostat mesylate dosing containers must be returned to the clinic at each visit. Patients should be queried regarding their compliance with the dosing regimen and medication containers should be reviewed at each visit to determine if any doses of Talabostat mesylate had been missed, and the number of missed doses recorded. Patients must be at least 70% compliant with taking Talabostat mesylate in Cycles 1 and 2 in order to be included in the per-protocol efficacy analyses.
• Talabostat mesylate was supplied as 0.2-mg and 0.05-mg tablets in high-density polyethylene bottles with desiccant and child-resistant caps. The 0.2-mg strength was supplied as 30 tablets per bottle. The 0.05-mg strength was supplied as 90 tablets per bottle. [0515] Supplies of Talabostat mesylate were appropriately labeled for clinical trial material. Talabostat mesylate was stored under refrigerated conditions between 2°C to 8°C (36°F to 46°F).
• Pembrolizumab administration, dose modifications and discontinuation [0517] Pembrolizumab was prepared, stored, and administered according to the current full Prescribing Information. Pembrolizumab was obtained from commercial supplies and was administered 200 mg intravenously over 30 minutes through a 0.2 to 5 micron sterile, nonpyrogenic, low-protein binding online or add-on filter. No other medication was infused through the infusion line. Infusion was interrupted and slowed for grade 1 or 2 infusion- related reactions and permanently discontinued for grade 3 or 4 infusion-related reactions. Pembrolizumab was administered until disease progression, unacceptable toxicity, or withdrawal of consent. [0518] AEs associated with pembrolizumab exposure might be immune-mediated.
• Immune-related AEs might occur any time after pembrolizumab administration and may affect multiple body systems. Early recognition and treatment were important to reduce complications. Most immune-related AEs were reversible and could be managed with discontinuation of pembrolizumab and initiation of steroids. Patients who required a dose hold of pembrolizumab of > 42 days were discontinued from the study.
• Pembrolizumab should not be used in conjunction with other immunosuppressive agents other than corticosteroids administered for control of immune reactions considered related to pembrolizumab.
• Each cohort enrolled 9 patients. If there was no complete (CR) or partial response (PR) in the first 9 patients the enrolment to that cohort was stopped. If there > 1 PR or CR in the first 9 patients the enrollment continued to enroll total of 17 patients. The treatment was considered promising for further exploration if > 3 CRs or PRs were observed in 17 patients.
• the expected Sample Size ranged from 9 (if terminated after safety lead in) to 34 patients. Accounted for ⁇ 20% of patients not being evaluable for efficacy, the actual number of patients to be recruited for the trial ranged from 11 to 42.
• PA was the response rate for cohort A
• PB was the response rate for cohort B
• cycle 1 of study treatment was completed. IND Office approval was obtained prior to advancing to the efficacy stage.
• Toxicity monitoring was also performed in this stage.
• Detailed information collected for each AE included: a description of the event, duration, whether the AE was serious, nature of the event (single episode versus multiple episode), intensity (i.e., NCI CTCAE version 5 grade), relationship to study drug, action taken, clinical outcome, and whether the AE resulted in surgery or alternate procedures.
• Intensity (severity) of the AEs was graded according the NCI CTCAE. The latest version of MedDRA and NCI CTCAE was used.
• BP blood pressure
• CT computed tomography
• ECOG Eastern Cooperative Oncology Group
• EOT End of Treatment
• FU follow-up
• HR heart rate
• MRI magnetic resonance imaging
• RR respiratory rate.
• Tumor assessment must include cross-sectional imaging (MRI or CT scanning with intravenous contrast whenever possible) of the chest/abdomen/pelvis plus whole-body bone scan. Other body sites (e.g., neck) to be included as clinically indicated. Tumor assessment to be performed at Screening, C4D1 ( ⁇ 7 days), C7D1 ( ⁇ 7 days), C10D1 ( ⁇ 7 days), and Day 1 ( ⁇ 7 days) of every 3rd cycle thereafter and at EOT. Intervals for scans could be shortened to 6 weeks (e.g. C3D1, C5D1 etc.) if clinically necessary per treating physician. e.
• Serum chemistry included: 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 included aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin, and albumin.
• Either Talabostat or pembrolizumab may be administered first.
• C1D5 visit had a window of -1 day and can happen on C1D4.
• u.T3, FT4 and TSH testing was performed at baseline, C4D1 ( ⁇ 7 days), C7D1 ( ⁇ 7 days), C10D1 ( ⁇ 7 days), and Day 1 ( ⁇ 7 days) of every 3rd cycle thereafter and at EOT.
• Table 19 showing the Patient characteristics (14 Patients enrolled till date)
• Talabostat mesylate in combination with pembrolizumab demonstrated encouraging signals of activity in selected difficult-to-treat cancers in patients with and without prior treatment with PD-1/PD-L1 and/or CTLA-4 inhibitors.
• Mitigation strategies e.g. intra-patient dose escalating dosing schedule for Talabostat mesylate; ambulatory blood pressure monitoring etc.
• Mitigation strategies to prevent events of high-grade hypotension during the first week of therapy are being implemented as per protocol amendment.

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