Phase 1/2A Study of TRC253, an Androgen Receptor Antagonist, in Metastatic Castration-resistant Prostate Cancer Patients
Condition: Metastatic Castrate-resistant Prostate Cancer; Adenocarcinoma, Prostate
MeSH terms: Prostatic Neoplasms
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      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).
    

Detailed description: 
      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.
    

Intervention name(s): TRC253
Intervention type(s): Drug
Intervention description(s): TRC253 is a high-affinity, small molecule antagonist of the androgen receptor (AR) with inhibitory activity against wild type AR and specific mutated variants of AR. TRC253 blocks AR nuclear translocation as well as AR binding to DNA and is an antagonist of transcription for wild type AR and mutated AR. TRC253 is orally active and does not have agonist activity towards either the wild type or mutated ARs. TRC253 treatment in the Hershberger assay results in complete inhibition of androgen sensitive organ development. TRC253 is efficacious in an LNCaP xenograft model driven by F876L (also known as F877L) mutant AR.
Other intervention name(s): AR Antagonist
Intervention MeSH terms: Androgen Receptor Antagonists
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Primary purpose: Treatment