A Phase 1/2A Study of TRC253, an Androgen Receptor Antagonist, in Metastatic Castration-resistant Prostate Cancer Patients
|Metastatic Castrate-resistant Prostate Cancer Adenocarcinoma, Prostate||Drug: TRC253||Phase 1 Phase 2|
|Study Design:||Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
|Official Title:||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|
- Recommended Phase 2 dose (RP2D) of TRC253 [ Time Frame: 8 months ]The recommended phase 2 dose of TRC253 will be determined.
- Safety profile of TRC253 including adverse events assessed by CTCAE v4.03 [ Time Frame: 18 months ]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.
- Serum prostate-specific antigen (PSA) response at Week 12 according to Prostate Cancer Working Group (PCWG3) criteria [ Time Frame: 3 months ]PSA response at Week 12 will be evaluated according to PCWG3 criteria.
- Exposure-QTcF relationship: mean change in QTcF at Cmax [ Time Frame: 18 months ]Mean change in QTcF at Cmax
- Extent of receptor occupancy by FDHT-PET scan [ Time Frame: 18 months ]To confirm the RP2D, patients at select dose levels will undergo PET scans using FDHT, a radiopharmaceutical specifically designed to image binding to AR.
- Preliminary anti-tumor effects of TRC253: time to PSA progression and radiographic PFS according to PCWG3 [ Time Frame: 18 months ]Time to PSA progression, and radiographic PFS.
- Resistance markers assessed from circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) [ Time Frame: 18 months ]CTC enumeration and molecular characterization of a panel of markers including AR-V7.
|Anticipated Study Start Date:||April 2017|
|Estimated Study Completion Date:||September 2018|
|Estimated Primary Completion Date:||October 2017 (Final data collection date for primary outcome measure)|
Single-agent TRC253 to be administered as oral capsules once daily. The proposed TRC253 doses are 40 mg, 80 mg, 160 mg, 240 mg, 320 mg, and 400 mg.
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 Name: AR Antagonist
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT02987829
|Contact: Clinical Trials Informationemail@example.com|
|United States, Arizona|
|Pinnacle Oncology Hematology||Recruiting|
|Scottsdale, Arizona, United States, 85258|
|Contact: Christie Collins, CCRC 480-860-5000 firstname.lastname@example.org|
|Principal Investigator: Frank Yung-Chin Tsai, MD|
|Study Director:||James Freddo, MD||Tracon Pharmaceuticals Inc.|