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Clinical Trial 19867

Cancer Type: Genitourinary
Study Type: Treatment
NCT#: NCT03910660

Phase: Phase I/II
Principal Investigator: Zhang, Jingsong

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Study Title

A Phase 1b/2 Study of BXCL701, a Small Molecule Inhibitor of Dipeptidyl Peptidases (DPP), Administered in Combination with the Anti-Programmed Cell Death 1 (PD-1) Monoclonal Antibody Pembrolizumab (PEMBRO; Keytruda®) in Patients with Small Cell Neuroendocrine Prostate Cancer (SCNC; NEPC)


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 Small Cell Neuroendocrine Prostate Cancer(SCNC). 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 with SCNC will be treated with BXCL701 combined with PEMBRO.


Primary objectives of the study are: - To estimate the composite response rate of the combination of BXCL701 + PEMBRO in patients with SCNC. Composite response rate is defined as achieving 1 or more of the following: o Objective response by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria o Circulating tumor cell (CTC) conversion from >5/7.5 mL to <5/7.5 mL per Veridex assay by completion of Week 12 of protocol therapy o Greater than 50% prostate-specific antigen (PSA) decline from baseline by completion of Week 12 of protocol therapy Secondary Objectives The secondary objectives of the study include: - To estimate the median radiographic progression-free survival (rPFS) of the combination of BXCL701 and PEMBRO in patients with SCNC. - To estimate the median PSA progression-free survival (PSA PFS) of the combination of BXCL701 and PEMBRO in patients with SCNC. - To estimate the median overall survival (OS) of the combination of BXCL701 and PEMBRO in patients with SCNC. - To estimate the median duration of response (DOR) of the combination of BXCL701 and PEMBRO in patients with SCNC. To continue to characterize the safety profile of BXCL701 in combination with PEMBRO. - To assess population pharmacokinetics of BXCL701 using sparse pharmacokinetic sampling. - To assess the pharmacodynamic profile of the combination of BXCL701 and PEMBRO by measuring relevant effects on those cytokines previously shown to be modulated by BXCL701 in humans. Exploratory Objectives - To determine the response rate by Immune Response Evaluation Criteria In Solid Tumors (iRECIST) criteria with BXCL701 in combination with PEMBRO. - To evaluate the quantitative and qualitative effects of BXCL701 in combination with PEMBRO on relevant immune effector cytokines and various immunological effector cells, including neutrophils, myeloid derived suppressor cells (MDSCs), dendritic cells, cancer associated fibroblast (CAF) and T-cells in blood and, whenever feasible, in tumor tissues. - To explore the predictive value of baseline programmed death-ligand 1 (PD-L1) tumor expression in metastatic tumor tissue and CTCs with subsequent clinical outcomes - To explore the relationship between baseline and on-treatment circulating tumor neoantigens and T-cell repertoire and clinical outcomes (Central Laboratory) - To explore the relationship between baseline tumor messenger ribonucleic acid (mRNA) immune profiling panel and clinical outcomes.





BXCL701 (); Pembrolizumab (Keytruda)

Inclusion Criteria

  • For patients with histologic evidence of Small Cell Neuroendocrine Prostate Cancer (SCNC) either with archival tissue or a fresh tumor biopsy obtained during Screening. Archival or fresh 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.
  • Has evidence of progressive, metastatic castration-resistant disease, as defined by PCWG3 criteria. Patients with de novo small cell prostate cancer are not required to have received androgen deprivation therapy (ADT).
  • Progression during or following completion of at least 1 prior line of systemic therapy for locally advanced or metastatic prostate cancer.
  • Efficacy Stage Only: (a) 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. (b) 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. (c) 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
  • Serum testosterone > Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
  • 18 years of age or older
  • Acute toxic effects of previous anticancer therapy have resolved to ≤Grade 1 except for Grade 2-3 peripheral neuropathy or any grade of alopecia.
  • Adequate baseline organ function, as defined per protocol.
  • Adequate baseline hematologic function, as defined per protocol.
  • Male patients and their female partners of childbearing potential must agree and commit to use a barrier contraception (e.g., condom with spermicidal foam/gel/film/cream/ suppository) 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..
  • Able to adhere to the study visit schedule and other protocol requirements, including follow-up for overall survival (OS).

  • Exclusion Criteria

  • 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.
  • Has received external-beam radiation or another systemic anticancer therapy within 14 days or 5 half-lives, whichever is shorter, prior to study treatment.
  • Has received treatment with an investigational systemic anticancer agent within 14 days prior to study drug administration.
  • 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 (e.g; gliptins.
  • 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).
  • 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).
  • QT interval corrected for heart rate using Bazett's formula (QTcB) >480 msec at Screening.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • Known positive status for human immunodeficiency virus, active or chronic Hepatitis B, or Hepatitis C. Screening is not required.
  • Any medical condition which, in the opinion of the investigator, places the patient at an unacceptably high risk for toxicity.

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