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 Small Cell Neuroendocrine Prostate Cancer

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 SCNC. 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 every 21 days will be assessed and confirmed in patients with SCNC. In Cycle 1, the initial dose level of BXCL701 will be 0.4 mg; if there are no safety concerns, this will be escalated to 0.6 mg.
2. Efficacy Stage (Simon 2-Stage) - in which patients with SCNC will be treated with BXCL701 combined with PEMBRO.

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 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 or 0.4 mg BXCL701) to be used in the subsequent stage, the Efficacy Stage will begin. Eligible SCNC 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.

Inclusion Criteria:

All patients must satisfy the following inclusion and exclusion criteria to be eligible for entry into the trial. For patients with histologic evidence of Small Cell Neuroendocrine Prostate Cancer (SCNC) on archival tissue analysis, enrollment can proceed without obtaining pathology review of a fresh biopsy.

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:
   1. Patient has histologic evidence of SCNC on central pathology review of archival tumor tissue. Patients without evaluable archival metastatic tumor tissue may undergo fresh tumor biopsy during Screening.
   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. 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. Patient agrees to use acceptable contraceptive methods for the duration of time on the study and continue to use acceptable contraceptive methods for 6 months after the last treatment dose.
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.
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).
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 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, 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.