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A Trial of BXCL701 and Pembrolizumab in Patients With mCRPC.

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ClinicalTrials.gov Identifier: NCT03910660
Recruitment Status : Recruiting
First Posted : April 10, 2019
Last Update Posted : November 5, 2020
Sponsor:
Information provided by (Responsible Party):
BioXcel Therapeutics Inc

Tracking Information
First Submitted Date  ICMJE January 4, 2019
First Posted Date  ICMJE April 10, 2019
Last Update Posted Date November 5, 2020
Actual Study Start Date  ICMJE February 12, 2019
Estimated Primary Completion Date April 2, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 6, 2020)
Estimate the composite response rate of the combination of BXCL701 + PEMBRO [ Time Frame: up to 36 months ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: April 8, 2019)
Estimate the composite response rate of the combination of BXCL701 + PEMBRO in patients with SCNC. [ Time Frame: up to 36 months ]
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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 6, 2020)
  • 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 ]
    The median time frame with progression-free survival with the use of BXCL701 in combination with Pembro determined by radiographic evidence.
  • 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 ]
    The median time frame with progression-free survival with the use of BXCL701 in combination with Pembro
  • Estimate the median overall survival (OS) of the combination of BXCL701 and PEMBRO in Cohort A and B. [ Time Frame: up to 36 months ]
    The median time frame with overall survival with the use of BXCL701 in combination with Pembro
  • 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 ]
    The timeframe in which the tumor reacts to BXCL701 in combination with Pembro
  • Determine the risk profile of the use of BXCL701 in combination with PEMBRO. [ Time Frame: up to 36 months ]
    Determines the frequency and severity of known and unknown adverse events with the use of BXCL701 in combination with Pembro
Original Secondary Outcome Measures  ICMJE
 (submitted: April 8, 2019)
  • Estimate the median radiographic progression-free survival (rPFS) of the combination of BXCL701 and PEMBRO [ Time Frame: up to 36 months ]
    The median time frame with progression-free survival with the use of BXCL701 in combination with Pembro determined by radiographic evidence.
  • Estimate the median PSA progression-free survival (PSA PFS) of the combination of BXCL701 and PEMBRO in patients with SCNC. [ Time Frame: up to 36 months ]
    The median time frame with progression-free survival with the use of BXCL701 in combination with Pembro
  • Estimate the median overall survival (OS) of the combination of BXCL701 and PEMBRO [ Time Frame: up to 36 months ]
    The median time frame with overall survival with the use of BXCL701 in combination with Pembro
  • Estimate the median duration of response (DOR) of the combination of BXCL701 and PEMBRO [ Time Frame: up to 36 months ]
    The timeframe in which the tumor reacts to BXCL701 in combination with Pembro
  • Determine the risk profile of the use of BXCL701 in combination with PEMBRO. [ Time Frame: up to 36 months ]
    Determines the frequency and severity of known and unknown adverse events with the use of BXCL701 in combination with Pembro
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Trial of BXCL701 and Pembrolizumab in Patients With mCRPC.
Official Title  ICMJE 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
Brief Summary 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Prostate Cancer
  • Neuroendocrine Tumors
  • Small Cell Carcinoma
Intervention  ICMJE Drug: Talabostat Mesylate plus Pembrolizumab

BXCL701 tablets dosage strengths include 0.05mg, 0.1mg, and 0.2mg tablets for oral administration.

BXCL701 will be administered orally as 0.05mg, 0.1mg and 0.2mg tablets. Patients will take the prescribed number of tablets on Days 1 to 14 of each cycle, for a total daily dose of 0.4 mg, 0.6 mg, or an intermediate dose. BXCL701 will be continued until PD or unacceptable toxicity, or closure of the study by the sponsor; no maximum duration of therapy has been set.

BXCL701 should not be taken on an empty stomach.

On days when PD studies are being performed, BXCL701 should be administered at the study center and should be administered at approx. the same time of day on each treatment day in the cycle. In cycles in which PD are not evaluated, BXCL701 also should be administered at approx. the same time of day on each treatment day.

The PEMBRO dose will be 200 mg, administered as an IV infusion over 30 mins. on Day 1 of each 21-day cycle.

Other Name: BXCL701 plus Pembro
Study Arms  ICMJE
  • Lead-in Stage

    Patients 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.

    Intervention: Drug: Talabostat Mesylate plus Pembrolizumab
  • Efficacy Stage
    After 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.
    Intervention: Drug: Talabostat Mesylate plus Pembrolizumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 8, 2019)
40
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 2, 2022
Estimated Primary Completion Date April 2, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Valery Chatikhine, MD, PhD 908-432-3776 valery.chatikhine@iqvia.com
Listed Location Countries  ICMJE United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03910660
Other Study ID Numbers  ICMJE BXCL701-201
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party BioXcel Therapeutics Inc
Study Sponsor  ICMJE BioXcel Therapeutics Inc
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account BioXcel Therapeutics Inc
Verification Date November 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP