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).
Name: TRC253
Description: 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.Type: DrugTRC253
Description: The recommended phase 2 dose of TRC253 will be determined.
Measure: Recommended Phase 2 dose (RP2D) of TRC253 Time: 8 monthsDescription: Safety assessments will be based on medical review of adverse event reports and the results of clinical laboratory tests, electrocardiograms, vital sign measurements, and physical examinations.
Measure: Safety profile of TRC253 including adverse events assessed by CTCAE v4.03 Time: 18 monthsDescription: PSA response at Week 12 will be evaluated according to PCWG3 criteria.
Measure: Serum prostate-specific antigen (PSA) response at Week 12 according to Prostate Cancer Working Group (PCWG3) criteria Time: 3 monthsDescription: Mean change in QTcF at Cmax
Measure: Exposure-QTcF relationship: mean change in QTcF at Cmax Time: 18 monthsDescription: To confirm the RP2D, patients at select dose levels will undergo PET scans using FDHT, a radiopharmaceutical specifically designed to image binding to AR.
Measure: Extent of receptor occupancy by FDHT-PET scan Time: 18 monthsDescription: Time to PSA progression, and radiographic PFS.
Measure: Preliminary anti-tumor effects of TRC253: time to PSA progression and radiographic PFS according to PCWG3 Time: 18 monthsDescription: CTC enumeration and molecular characterization of a panel of markers including AR-V7.
Measure: Resistance markers assessed from circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) Time: 18 monthsSingle Group Assignment
There is one SNP
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). --- F876L ---
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). --- F876L --- --- F876L ---
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). --- F876L --- --- F876L --- --- F876L ---
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). --- F876L --- --- F876L --- --- F876L --- --- F876L ---