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
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
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.
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.
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
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
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
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).
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
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.