An Open-label Phase 1 / 2A Study To Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of TRC253, an Androgen Receptor Antagonist, in Patients With Metastatic Castration-resistant Prostate Cancer
18 - 99 Years, Male
This is a multi-center, first-in-human, open-label, Phase 1 / 2A dose-escalation study in which eligible patients with metastatic castration-resistant prostate carcinoma (mCRPC) will receive oral doses of TRC253. The study will be conducted in 2 parts: part 1 (dose escalation) and part 2 (dose expansion).
The patient population consists of men =18 years of age with adenocarcinoma of the prostate
with metastatic disease. Patients who have not undergone orchiectomy must have serum
testosterone levels <50 ng/dL determined within 4 weeks prior to start of study drug, and, if
applicable, must have discontinued treatment with first or second generation anti-androgens
as specified in the inclusion criteria.
During Part 1 of the study, patients will be assigned sequentially to increasing TRC253
doses. The starting dose of TRC253 is 40 mg once daily, orally. TRC253 doses will be
escalated in subsequent cohorts after all patients enrolled in a given cohort have completed
the 28-day dose-limiting toxicity (DLT) evaluation period. Dose escalation in Part 1 will
follow single-patient dose escalation design until drug-related toxicity occurs. When an
initial drug-related toxicity occurs or DLT in a single patient the cohort will be expanded
according to 3+3 design rules. Subsequent dose levels will enroll patients based on 3+3
design. At the maximum tolerated dose (MTD) or minimum efficacious dose (MED), up to twelve
patients may be enrolled.
Part 2 will consist of two cohorts of initially up to 30 patients (Cohort 1) and up to 30
patients (Cohort 2) to receive TRC253 at the recommended Phase 2 dose (RP2D). The objective
of Part 2 is to gather additional information on the safety, pharmacokinetics (PK) and
pharmacodynamic (PD) characteristics, and the clinical efficacy of TRC253 in a pre-defined
population of patients with metastatic castrate-resistant prostate cancer (mCRPC). Patients
enrolled into Part 2 will have received prior treatment with enzalutamide or apalutamide and
showed characteristics of acquired resistance based on changes in PSA serum levels. Patients
will be centrally screened for the presence of the AR F876L (androgen receptor F876L)
mutation from a plasma sample and enrolled into Cohort 1 (AR F876L positive) or Cohort 2 (AR
F876L negative). Cohort 2 may be expanded if a specific molecular mechanism sensitizing the
mCRPC to TRC253 therapy can be identified retrospectively. Additional patients may be
prospectively selected for this specific molecular resistance mechanism and added to Cohort 2
upon recommendation by the medical monitor and Principal Investigators.