CompletedNCT03910660ClinicalTrials.gov record

A Trial of Talabostat (BXCL701) and Pembrolizumab in Participants With Metastatic Castrate-Resistant Prostate Cancer (mCRPC) Either Small Cell Neuroendocrine Prostate Cancer or Adenocarcinoma Phenotype

Prostate Cancer · Neuroendocrine Tumors · Small Cell Carcinoma

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THE QUICK READ

What this study involves

The registry does not currently label this study as recruiting. Ask about its status before planning a screening visit.

Study type: Interventional
Phase: Phase 1 / Phase 2
Age range: 18 years - Not specified
Sex eligible: Male
Healthy volunteers: Not accepted
Participants: 97 Actual

These are starting points, not an eligibility decision. The research team must review the full requirements.

About the research

An open-label, multicenter, Phase 1b/2 study to identify the recommended Phase 2 dose and assess the efficacy and safety of talabostat administered orally, as monotherapy and in combination with pembrolizumab, in participants with mCRPC. Participants enrolled in the Phase 2a portion of the study will have either SCNC (Cohort A) or adenocarcinoma phenotype (Cohort B), while the Phase 2b randomized portion of the study will enroll only the histologic subtype(s) showing preliminary evidence in Phase 2a. The study will also assess other efficacy parameters, such as radiographic progression-free survival (rPFS), prostate-specific antigen progression-free survival (PSA PFS), overall survival (OS), and duration of response (DOR), as well as the safety of the combined treatment.

Read the full description

The study will consist of three components.

1. Phase 1b: Safety and tolerability of the combination of talabostat administered once daily (QD) on Days 1 to 14 of a 21-day cycle plus pembrolizumab 200 milligrams (mg) administered intravenously (IV) on Day 1 of every 21 days will be assessed and confirmed in participants with mCRPC. In the first cohort enrolled in the study, the initial dose level of talabostat 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. Phase 2a (Simon 2 Stage): Participants will be treated with talabostat in combination with pembrolizumab. Participants will be grouped in 1 of 2 cohorts based on phenotype.

Cohort A: Participants with any Small Cell/Neuroendocrine features, either de novo or treatment-emergent included mixed SCNC.
Cohort B: Cohort B: Participants with adenocarcinoma and no evidence of small cell or neuroendocrine features.

Phase 2b (for the histologic subtype\[s\] showing preliminary efficacy in Phase 2a): Participants within a given subtype will be randomized 2:1 to receive either talabostat combined with pembrolizumab or talabostat monotherapy.

Phase 1b:

Participants will be observed for dose-limiting toxicity (DLT) during Cycle 1. Three participants will be treated initially with talabostat 0.4 mg plus pembrolizumab:

If there are no DLTs in Cycle 1, the dose of talabostat will be escalated to a total daily dose of 0.6 mg in the next cohort of 3 participants.
If ≥1 of the 3 original participants has a DLT in Cycle 1, after a discussion between the sponsor and the investigator, either 3 participants (if 1 participant experiences a DLT) or 6 to 9 participants (if 2 or 3 participants experiences a DLT) will be added at the 0.4 mg talabostat dose level. For this expanded 0.4 mg cohort:

If none of the participants experience a DLT, consideration will be given to dose escalation to talabostat 0.6 mg plus pembrolizumab
If 1/3 of the participants experience a DLT, the Phase 2 can commence
If \>1/3 of the participants experience a DLT, a discussion will be held between the investigators and sponsors as to how to proceed.

Following dose escalation to talabostat 0.6 mg plus pembrolizumab in 3 participants :

If there are no DLTs at this dose level, the Phase 2a can commence.
If ≥1/3 participants have a DLT in Cycle 1, after a discussion between the sponsor and the investigator, 6 to 9 participants will be added at the 0.6 mg talabostat total daily dose level; and consideration of an alternate dosing (e.g., split dose) schedule may be given.
For this additional cohort of 6 to 9 participants :

If \</= 1/3 of the participants experience a DLT, the Phase2a can commence.
If \>1/3 of the participants experience a DLT, consideration will be given to the use of a 0.4 mg total daily dose of talabostat, or an intermediate dose, plus pembrolizumab in the Phase 2a.

Who may be able to participate?

The list below is the sponsor’s full registry wording. It can include conditions, prior treatment, test results and other requirements. A match in search does not mean you qualify.

Inclusion Criteria:

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

1. Participant has evidence of progressive, metastatic castration-resistant disease, as defined by Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria.

a. Participant 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. Phases 2a and 2b Only:

SCNC - Cohort A of Phase 2a only:
1. Participant 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. Participant has previously received at least 1 prior line of cytotoxic chemotherapy. Participants 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 participants without safely accessible lesion or for participants with evaluable archival metastatic tumor tissue
4. Has measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) criteria.

Adenocarcinoma - Cohort B of Phase 2a; randomized population for Phase 2b
1. Participant has histologically or cytologically confirmed adenocarcinoma of the prostate without small cell neuroendocrine features.
2. Participants with soft tissue disease must provide a fresh core or excisional biopsy or archival tissue 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 androgen receptor (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 metastatic castration-sensitive prostate cancer (mCSPC) or mCRPC setting. Participants 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. Participant has serum testosterone \<50 ng/dL during Screening except for those with de novo small cell prostate cancer.

a. Participants 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 participants with de novo small cell prostate cancer.
5. Participant has Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
6. Participant is ≥18 years of age.
7. Participant'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. Participant 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 (participants with hepatic metastases must have AST/ALT ≤5 × ULN).
9. Participant 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 participants 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 participants 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 childbearing 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. Participant has signed informed consent prior to initiation of any study-specific procedures or treatment.
12. Participant is able to adhere to the study visit schedule and other protocol requirements, including follow-up for overall survival (OS).

Exclusion Criteria:

1. Participant 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. Participant 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. Participant has received treatment with an investigational systemic anticancer agent within 14 days prior to study drug administration.
4. Participant 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. Participant has an additional active malignancy that may confound the assessment of the study endpoints. If the participant 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. Participants 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. Participant 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. Participant has uncontrolled, clinically significant pulmonary disease (e.g., chronic obstructive pulmonary disease, pulmonary hypertension) that in the opinion of the investigator would put the participant at significant risk for pulmonary complications during the study.
9. Participant has brain or leptomeningeal metastases that are symptomatic and progressive on imaging. Participants 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 participants with a prior history of CNS metastases should be compared to prior imaging to discern disease progression.
10. Participant 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. Participant 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. Participant has uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, suspected or active Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, disseminated intravascular coagulation, or psychiatric illness/social situations that would limit compliance with study requirements.
13. Participant has known positive status for human immunodeficiency virus, active or chronic Hepatitis B, or Hepatitis C. Screening is not required.
14. Participant has any medical condition which, in the opinion of the investigator, places the participant at an unacceptably high risk for toxicity.
15. Any dysphagia, odynophagia, esophageal dysmotility or stricture, known gastro-intestinal (GI) malabsorption syndrome, or intractable diarrhea that may significantly alter the absorption of orally administered study drug.
16. Participants 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.

Understand screening

Treatment, groups and participation

The registry may describe treatments and study duration without a complete visit calendar. Ask the study team for the exact schedule, procedures, risks, costs and alternatives. Keep your usual care plan unless your treating clinician tells you otherwise.

Assignment: Random assignment
Masking: No masking

Phase 1B: Talabostat 0.4 mg QD + Pembrolizumab 200 mg

Participants will receive the combination of talabostat 0.4 mg QD orally on Days 1 to 14 of a 21-day cycle plus pembrolizumab 200 mg IV on Day 1 of each 21-day cycle. There will be a 7-day rest period following the last dose of talabostat and Day 1 of the subsequent cycle.

Drug: Talabostat · Drug: Pembrolizumab

Phase 1B: Talabostat 0.6 mg QD + Pembrolizumab 200 mg

Participants will receive the combination of talabostat 0.6 mg QD orally on Days 1 to 14 of a 21-day cycle plus pembrolizumab 200 mg IV on Day 1 of each 21-day cycle. There will be a 7-day rest period following the last dose of talabostat and Day 1 of the subsequent cycle.

Drug: Talabostat · Drug: Pembrolizumab

Phase 1B: Talabostat 0.6 mg TDD + Pembrolizumab 200 mg

Participants will receive the combination of talabostat 0.3 mg twice daily (BID) (at a total daily dose \[TDD\] of 0.6 mg) orally on Days 1 to 14 of a 21-day cycle plus pembrolizumab 200 mg IV on Day 1 of each 21-day cycle. There will be a 7-day rest period following the last dose of talabostat and Day 1 of the subsequent cycle.

Drug: Talabostat · Drug: Pembrolizumab

Phase 2A (SCNC): Talabostat + Pembrolizumab 200 mg

Participants with SCNC will receive the combination of talabostat 0.6 mg QD orally on Days 1 to 14 a 21-day cycle plus pembrolizumab 200 mg IV on Day 1 of each 21-day cycle. There will be a 7-day rest period following the last dose of talabostat and Day 1 of the subsequent cycle.

Drug: Talabostat · Drug: Pembrolizumab

Phase 2A (Adenocarcinoma): Talabostat + Pembrolizumab 200 mg

Participants with adenocarcinoma will receive the combination of talabostat 0.6 mg QD orally on Days 1 to 14 a 21-day cycle plus pembrolizumab 200 mg IV on Day 1 of each 21-day cycle. There will be a 7-day rest period following the last dose of talabostat and Day 1 of the subsequent cycle.

Drug: Talabostat · Drug: Pembrolizumab

Phase 2B (Adenocarcinoma): Talabostat + Pembrolizumab 200 mg

Drug: Talabostat · Drug: Pembrolizumab

Phase 2B (Adenocarcinoma): Talabostat Monotherapy

Participants with adenocarcinoma will receive talabostat 0.6 mg QD orally on Days 1 to 14 a 21-day cycle. There will be a 7-day rest period following the last dose of talabostat and Day 1 of the subsequent cycle.

Drug: Talabostat

Talabostat DRUG

Oral Tablets

Pembrolizumab DRUG

Intravenous injection

Prepare your questions

What researchers are measuring

Outcome measures describe what is being studied. They are not proof that a treatment works.

Primary measures

Phase 2a: Composite Response Rate (CRR)

Time frame: Up to approximately 4 years and 4 months

CRR was defined as the percentage of participants who achieved 1 or more of the following: objective response by Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) criteria; ≥50% decline from baseline in serum Prostate-Specific Antigen (PSA); or Circulating Tumor Cell (CTC) conversion from ≥5/7.5 milliliters (mL) to \<5/7.5 mL per Veridex assay. Objective response rate was defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR) among participants with evaluable lesions by RECIST v1.1. CR=disappearance of all target and non-target lesions and no new lesions. PR = ≥30% decrease in the sum of diameters (SOD) of target lesions compared to baseline and no new non-target lesion.

Phase 2b: Objective Response Rate (ORR)

Time frame: Up to approximately 4 years and 4 months

The ORR was defined as the percentage of participants with a confirmed CR or PR among participants with evaluable lesions by RECIST v1.1. CR=disappearance of all target and non-target lesions and no new lesions. PR = ≥30% decrease in the sum of the diameters of target lesions compared to baseline and no new non-target lesion.

Secondary measures

Phase 2a: Radiographic Progression-free Survival (rPFS)

Time frame: Up to approximately 6 years 2 months

The rPFS was defined as the time from the first dose to the date measurement criteria are first met for disease progression (PD) by RECIST 1.1/Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria or death from any cause, whichever occurred first. PD for soft tissue was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum on study, including baseline, and an absolute increase of at least 5 millimeters (mm) in the SOD of target lesions; progression of non-target lesions; the appearance of one or more new lesions according to RECIST v1.1. PD for bone lesions was defined as 2 or more new lesions compared to baseline followed by a confirmatory bone scan at least 6 weeks later according to the PCWG3 criteria. Kaplan-Meier (KM) estimate was used to determine the median rPFS.

Phase 2a: Prostate Specific Antigen (PSA) Progression-free Survival (PFS)