Clinical Trials /

A Trial of BXCL701 and Pembrolizumab in Patients With mCRPC.

NCT03910660

Description:

An open-label, multicenter, Phase 1b/2 study to determine the composite response rate of BXCL701 administered orally and daily, combined wit PEMBRO, in patients with mCRPC enrolled in Stage 2, with either Small Cell Neuroendocrine Prostate Cancer(SCNC)(Cohort A) or adenocarcinoma phenotype (Cohort B). This study will also assess other efficacy parameters as well as the safety of the combined treatment. This study will consist of two (2) stages. Lead-in Stage, in which the safety and tolerability of the combination will be assessed and confirmed. And the Efficacy Stage, in which patients will be treated with BXCL701 combined with PEMBRO.

Related Conditions:
  • Prostate Adenocarcinoma
  • Prostate Neuroendocrine Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Trial of BXCL701 and Pembrolizumab in Patients With mCRPC.
  • Official Title: Phase 1b/2 Study of BXCL701, a Small Molecule Inhibitor of Dipeptidyl Peptidases, Administered in Combination With the Anti-Programmed Cell Death 1 Monoclonal Antibody Pembrolizumab in Patients With mCRPC Either Small Cell Neuroendocrine Prostate Cancer or Adenocarcinoma Phenotype

Clinical Trial IDs

  • ORG STUDY ID: BXCL701-201
  • NCT ID: NCT03910660

Conditions

  • Prostate Cancer
  • Neuroendocrine Tumors
  • Small Cell Carcinoma

Interventions

DrugSynonymsArms
Talabostat Mesylate plus PembrolizumabBXCL701 plus PembroEfficacy Stage

Purpose

An open-label, multicenter, Phase 1b/2 study to determine the composite response rate of BXCL701 administered orally and daily, combined wit PEMBRO, in patients with mCRPC enrolled in Stage 2, with either Small Cell Neuroendocrine Prostate Cancer(SCNC)(Cohort A) or adenocarcinoma phenotype (Cohort B). This study will also assess other efficacy parameters as well as the safety of the combined treatment. This study will consist of two (2) stages. Lead-in Stage, in which the safety and tolerability of the combination will be assessed and confirmed. And the Efficacy Stage, in which patients will be treated with BXCL701 combined with PEMBRO.

Detailed Description

      This is an open-label, multicenter, Phase 1b/2 study to determine the composite response rate
      of BXCL701 administered orally and daily, combined with PEMBRO, in patients with mCRPC with
      either SCNC or adenocarcinoma phenotype. The study will also assess other efficacy
      parameters, such as rPFS, PSA PFS, OS and DOR, as well as the safety of the combined
      treatment. The study will consist of 2 stages:

        1. Lead-in Stage - in which the safety and tolerability of the combination of BXCL701
           administered once daily (QD) on Days 1 to 14 of a 21-day cycle plus PEMBRO 200 mg
           administered intravenously (IV) on Day 1 of every 21 days will be assessed and confirmed
           in patients with metastatic castration-resistant prostate cancer (mCRPC). In Cohort 1,
           the initial dose level of BXCL701 will be 0.4 mg; if there are no safety concerns, this
           will be escalated to a total daily dose of 0.6 mg.

        2. Efficacy Stage (Simon 2-Stage) - in which patients will be treated with BXCL701 combined
           with PEMBRO. Patients will be assigned to 1 of 2 cohorts based on phenotype.

             -  Cohort A: Patients with any Small Cell/Neuroendocrine features, either de novo or
                treatment-emergent included mixed SCNC.

             -  Cohort B: Cohort B: Patients with adenocarcinoma and no evidence of small cell or
                neuroendocrine features.

      Lead-in Stage:

      Patients will be observed for dose-limiting toxicity (DLT) during Cycle 1. Three patients
      will be treated initially with 0.4 mg BXCL701 plus PEMBRO:

        -  If there are no DLTs in Cycle 1, the dose of BXCL701 will be escalated to a total daily
           dose of 0.6 mg in the next cohort of 3 patients.

        -  If ≥1 of the 3 original patients has a DLT in Cycle 1, after a discussion between the
           sponsor and the investigator, either 3 patients (if 1 patient experiences a DLT) or 6 to
           9 patients (if 2 or 3 patients experiences a DLT) will be added at the 0.4 mg BXCL701
           dose level. For this expanded 0.4 mg cohort:

             -  If less than one-third of the patients experience a DLT, consideration will be
                given to dose escalation to 0.6 mg BXCL701 plus PEMBRO

             -  If one-third of the patients experience a DLT, the Efficacy Stage can commence

             -  If more than one-third of the patients experience a DLT, a discussion will be held
                between the investigators and sponsors as to how to proceed.

      Efficacy Stage:

      After assessment of the safety and confirmation of the BXCL701/PEMBRO dose schedule (i.e.,
      either 0.6 mg, 0.4mg, or an intermediate total daily dose of BXCL701) to be used in the
      subsequent stage, the Efficacy Stage will begin. Eligible patients will receive BXCL701 QD on
      Days 1 to 14 of a 21-day cycle plus PEMBRO 200 mg administered IV on Day 1 every 21 days.
    

Trial Arms

NameTypeDescriptionInterventions
Lead-in StageOtherPatients will be observed for dose-limiting toxicity (DLT) during Cycle 1. 3 patients will be treated initially with 0.4 mg Talabostat Mesylate plus PEMBRO: If there are no DLTs, the dose of Talabostat Mesylate will be escalated to 0.6 mg in the next cohort. If ≥1/3 of patients has a DLT in Cycle 1, either 3 patients (if 1 experiences a DLT) or 6 to 9 patients (if 2 or 3 experiences a DLT) will be added at the 0.4 mg Talabostat Mesylate dose. For the 0.4 mg cohort: If <1/3 of the patients experience a DLT, consideration will be given to dose to 0.6 mg Talabostat Mesylate plus PEMBRO. If 1/3 of the patients experience a DLT, the Efficacy Stage can commence. If >1/3 of the patients experience a DLT, a discussion will be held as to how to proceed. Following dose escalation to 0.6 mg. If there are no DLTs, the Efficacy Stage can commence. If ≥1/3 patients have a DLT in Cycle 1, after a discussion, 6 to 9 patients will be added at the 0.6 mg Talabostat Mesylate dose level.
  • Talabostat Mesylate plus Pembrolizumab
Efficacy StageOtherAfter assessment of the safety and confirmation of the Talabostat Mesylate/PEMBRO dose schedule to be used in the subsequent stage, the Efficacy Stage will begin. Eligible patients will receive Talabostat Mesylate QD on Days 1 to 14 of a 21-day cycle plus PEMBRO 200 mg administered IV on Day 1 every 21 days.
  • Talabostat Mesylate plus Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

        All patients must satisfy the following inclusion and exclusion criteria to be eligible for
        entry into the trial.

          1. Patient has evidence of progressive, metastatic castration-resistant disease, as
             defined by PCWG3 criteria.

             a. Patients with de novo small cell prostate cancer are not required to have received
             androgen deprivation therapy (ADT).

          2. Progression during or following completion of at least 1 prior line of systemic
             therapy for locally advanced or metastatic prostate cancer.

          3. Efficacy Stage Only:

             For Cohort A (SCNC)

               1. Patient has histologic evidence of SCNC either with archival tissue or a fresh
                  tumor biopsy obtained during screening. Tumor biopsy tissue must be submitted for
                  a central laboratory pathology review; however, enrollment can proceed if SCNC is
                  determined by a local pathology review.

               2. Patient has previously received at least 1 prior line of cytotoxic chemotherapy.
                  Patients who either have refused chemotherapy or are considered unsuitable for
                  chemotherapy may be eligible following discussion with the sponsor.

               3. Must be willing to undergo metastatic tumor biopsy during Screening. Requirement
                  may be waived in patients without safely accessible lesion or for patients with
                  evaluable archival metastatic tumor tissue

               4. Has measurable disease per RECIST 1.1 criteria.

             For Cohort B (Adenocarcinoma)

               1. Patient has histologically or cytologically confirmed adenocarcinoma of the
                  prostate without small cell neuroendocrine features.

               2. 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 may proceed if
                  predominant adenocarcinoma without small cell neuroendocrine features is
                  determined by local pathology review.

               3. Has been treated with at least 1 but no more than 2 second generation AR pathway
                  target agents (e.g., abiraterone acetate and/or enzalutamide or other next
                  generation agent) and at least 1 regimen/line of taxane containing chemotherapy
                  in the mCSPC or mCRPC setting. Patients with known actionable mutations should
                  have progressed on applicable standard care targeted therapy or have documented
                  intolerance to or be unsuitable for such therapy.

               4. RECIST 1.1 measurable disease or detectable bone metastases by whole body bone
                  scintigraphy.

          4. Patient has serum testosterone <50 ng/dL during Screening except for those with de
             novo small cell prostate cancer.

             a. Patients with treatment-emergent SCNC without a history of bilateral orchiectomy
             are required to remain on luteinizing hormone-releasing hormone (LHRH) analog during
             the course of protocol therapy except for patients with de novo small cell prostate
             cancer.

          5. Patient has Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

          6. Patient is ≥18 years of age.

          7. Patient's acute toxic effects of previous anticancer therapy have resolved to ≤Grade 1
             except for Grade 2-3 peripheral neuropathy or any grade of alopecia.

          8. Patient has adequate baseline organ function, as demonstrated by the following:

               1. Serum creatinine ≤1.5 times institutional upper limit of normal (ULN) or
                  calculated creatinine clearance >50 mL/min;

               2. Serum albumin ≥2.5 g/dL;

               3. Total bilirubin ≤1.5 × ULN;

               4. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 ×
                  institutional ULN (patients with hepatic metastases must have AST/ALT ≤5 × ULN).

          9. Patient has adequate baseline hematologic function, as demonstrated by the following:

               1. Absolute neutrophil count (ANC) ≥1.5 × 109/L.

               2. Hemoglobin ≥8 g/dL and no red blood cell transfusions during the prior 14 days.

               3. Platelet count ≥100 × 109/L and no platelet transfusions during the prior 14
                  days.

         10. Male patients and their female partners of childbearing potential must agree and
             commit to use a barrier contraception throughout the duration of the study until at
             least 6 months following the last dose of study drug, in addition to their female
             partners using either an intrauterine device or hormonal contraception and continuing
             until at least 6 months following the last dose of study drug. This criterion may be
             waived for male patients who have had a vasectomy >6 months before signing the
             informed consent form.

             Exception: In the United States, female partners of study participants are not
             required to use contraception as a condition of their partners' eligibility, but
             female partners with child bearing potential should consider use of effect methods of
             contraception for the duration of their male partners' study participation and for at
             least 6 months following the last dose of study medication.

         11. Patient has signed informed consent prior to initiation of any study-specific
             procedures or treatment.

         12. Patient is able to adhere to the study visit schedule and other protocol requirements,
             including follow-up for overall survival (OS).

        Exclusion Criteria:

          1. Patient has received treatment with >2 cytotoxic chemotherapy regimens for
             castration-resistant prostate cancer (CRPC). Chemotherapy in the hormone-sensitive
             setting does not count in this assessment provided the last dose was >6 months before
             study entry. A change in chemotherapy agents due to intolerance after brief exposure
             may not count in this assessment, pending review with Medical Monitor.

          2. Patient has received external-beam radiation or another systemic anticancer therapy
             within 14 days or 5 half-lives, whichever is shorter, prior to study treatment.

          3. Patient has received treatment with an investigational systemic anticancer agent
             within 14 days prior to study drug administration.

          4. Patient has received prior treatment with an anti-PD-1, anti-PD-L1, 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) or
             requires concomitant treatment with DPP4 inhibitors.

          5. Patient has an additional active malignancy that may confound the assessment of the
             study endpoints. If the patient has a past cancer history (active malignancy within 2
             years prior to study entry) with substantial potential for recurrence, this must be
             discussed with the sponsor before study entry. Patients with the following concomitant
             neoplastic diagnoses are eligible: non-melanoma skin cancer and carcinomas in situ
             (including transitional cell carcinoma, anal carcinoma, and melanoma in situ).

          6. Patient has 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).

          7. QT interval corrected for heart rate using Bazett's formula (QTcB) >480 msec at
             Screening.

          8. Patient has uncontrolled, clinically significant pulmonary disease (e.g., chronic
             obstructive pulmonary disease, pulmonary hypertension) that in the opinion of the
             investigator would put the patient at significant risk for pulmonary complications
             during the study.

          9. Patient has brain or leptomeningeal metastases that are symptomatic and progressive on
             imaging. Patients with a history of central nervous system (CNS) metastases must have
             received appropriate treatment. Central nervous system imaging is not required prior
             to study entry unless there is a history of CNS involvement or clinical suspicion of
             CNS involvement. Imaging of patients with a prior history of CNS metastases should be
             compared to prior imaging to discern disease progression.

         10. Patient has an active autoimmune disease or Grade ≥3 non-infectious pneumonitis that
             has required systemic treatment in the past 2 years (i.e., with use of disease
             modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy
             (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for
             adrenal or pituitary insufficiency) or treatment with drugs (e.g., neomercazol,
             carbimazole) that function to decrease the generation of thyroid hormone by a
             hyperfunctioning thyroid gland (e.g., in Graves' disease) is not considered a form of
             systemic treatment of an autoimmune disease.

         11. Patient has a diagnosis of immunodeficiency or is 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).

         12. Patient has 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.

         13. Patient has known positive status for human immunodeficiency virus, active or chronic
             Hepatitis B, or Hepatitis C. Screening is not required.

         14. Patient has any medical condition which, in the opinion of the investigator, places
             the patient at an unacceptably high risk for toxicity.

         15. Any dysphagia, odynophagia, esophageal dysmotility or stricture, known GI
             malabsorption syndrome, or intractable diarrhea that may significantly alter the
             absorption of orally administered study drug.

         16. Patients with history of symptomatic orthostatic hypotension within 3 months prior to
             enrollment. 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Estimate the composite response rate of the combination of BXCL701 + PEMBRO
Time Frame:up to 36 months
Safety Issue:
Description:Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria; circulating tumor cell (CTC) conversion from >5/7.5 mL to <5/7.5 mL12; and a greater than 50% prostate-specific antigen (PSA) decline from baseline.

Secondary Outcome Measures

Measure:Estimate the median radiographic progression-free survival (rPFS) of the combination of BXCL701 and PEMBRO in Cohort A and B
Time Frame:up to 36 months
Safety Issue:
Description:The median time frame with progression-free survival with the use of BXCL701 in combination with Pembro determined by radiographic evidence.
Measure:Estimate the median PSA progression-free survival (PSA PFS) of the combination of BXCL701 and PEMBRO in Cohort A and B.
Time Frame:up to 36 months
Safety Issue:
Description:The median time frame with progression-free survival with the use of BXCL701 in combination with Pembro
Measure:Estimate the median overall survival (OS) of the combination of BXCL701 and PEMBRO in Cohort A and B.
Time Frame:up to 36 months
Safety Issue:
Description:The median time frame with overall survival with the use of BXCL701 in combination with Pembro
Measure:Estimate the median duration of response (DOR) of the combination of BXCL701 and PEMBRO in Cohort A and B.
Time Frame:up to 36 months
Safety Issue:
Description:The timeframe in which the tumor reacts to BXCL701 in combination with Pembro
Measure:Determine the risk profile of the use of BXCL701 in combination with PEMBRO.
Time Frame:up to 36 months
Safety Issue:
Description:Determines the frequency and severity of known and unknown adverse events with the use of BXCL701 in combination with Pembro

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:BioXcel Therapeutics Inc

Last Updated

November 5, 2020