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
Overview
- Phase
- Phase 1
- Intervention
- TRC253
- Conditions
- Metastatic Castrate-resistant Prostate Cancer
- Sponsor
- Tracon Pharmaceuticals Inc.
- Enrollment
- 72
- Locations
- 5
- Primary Endpoint
- Number of Patients Who Experience Dose Limiting Toxicities by Dose Level
- Status
- Completed
- Last Updated
- 5 years ago
Overview
Brief 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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Must have received at least 2 prior therapies approved for CRPC; including a prior AR inhibitor (e.g., enzalutamide or apalutamide). (Part 1 only)
- •Must have received enzalutamide or apalutamide. (Note: additional therapies approved for CRPC prior to enzalutamide or apalutamide are allowed.) (Part 2 only)
- •Must have shown clinical characteristics of acquired resistance to enzalutamide or apalutamide defined as: decline in serum PSA ≥50% compared to baseline serum levels by week 12 (±4 weeks) of enzalutamide or apalutamide treatment and before disease progression by PCWG3 PSA criteria, OR disease progression by PCWG3 radiographic criteria. (Part 2 only)
- •Parts 1 and 2:
- •Histologically confirmed adenocarcinoma of the prostate with metastatic disease.
- •Male ≥18 years of age.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or
- •Prior orchiectomy or serum testosterone levels \<50 ng/dL determined within 4 weeks prior to start of study drug.
- •Adequate baseline organ function.
- •Ongoing androgen depletion therapy with a gonadotropin-releasing hormone (GnRH) analog or inhibitor, or orchiectomy (i.e., surgical or medical castration). Note: patients who have not undergone orchiectomy must continue GnRH analog therapy for the duration of this protocol.
Exclusion Criteria
- •History of seizures.
- •Previously documented or current brain metastases.
- •Untreated spinal cord compression.
- •Positive test result for human immunodeficiency virus.
- •History of clinically significant cardiovascular disease including.
- •Active or chronic hepatitis B or hepatitis C as demonstrated by hepatitis B surface antigen positivity and/or anti- hepatitis C virus positivity, respectively. Patients with clinically active or chronic liver disease, including liver cirrhosis of Child-Pugh class C, are also excluded.
- •Second primary malignancy that has not been in remission for greater than 3 years. Exceptions that do not require a 3 year remission include: related non-melanoma skin cancer or resected melanoma in situ.
- •Any serious underlying medical or psychiatric condition (e.g., alcohol or drug abuse), dementia or altered mental status or any issue that would impair the ability of the patient to receive or tolerate the planned treatment, to understand informed consent or that in the opinion of the investigator would contraindicate the patient's participation in the study or that would confound the results of the study.
- •Evidence of active viral, bacterial, or systemic fungal infection requiring systemic treatment within 7 days prior to the first dose of study drug. Patients requiring any systemic antiviral, antifungal, or antibacterial therapy for active infection must have completed treatment no less than 7 days prior to the first dose of study drug.
- •Known allergies, hypersensitivity, or intolerance to TRC253 or its excipients.
Arms & Interventions
Dose Level 1: TRC253 40 mg daily
40 mg of single-agent TRC253 to be administered as oral capsules once daily
Intervention: TRC253
Dose Level 2: TRC253 80 mg
80 mg of single-agent TRC253 to be administered as oral capsules once daily
Intervention: TRC253
Dose Level 3: TRC253 160 mg
160 mg of single-agent TRC253 to be administered as oral capsules once daily
Intervention: TRC253
Dose Level 4: TRC253 240 mg
240 mg of single-agent TRC253 to be administered as oral capsules once daily
Intervention: TRC253
Dose Level 5: TRC253 280 mg
280 mg of single-agent TRC253 to be administered as oral capsules once daily
Intervention: TRC253
Dose Level 6: TRC253 320 mg
320 mg of single-agent TRC253 to be administered as oral capsules once daily
Intervention: TRC253
Outcomes
Primary Outcomes
Number of Patients Who Experience Dose Limiting Toxicities by Dose Level
Time Frame: 5 weeks
The trial began with single patient dose escalation rules. If 1 of 1 patients at a given dose experienced a DLT, the study transitioned to a 3+3 design. If 1 of 3 patients experienced a DLT, the dose level was expanded to 6 patients. The maximum tolerated dose (MTD) would have been exceeded if ≥ 33% of patients experience DLT at a given dose level. DLT occurred when a patient had 1 or more toxicities outlined in the protocol that was considered at least possibly related to TRC253 during the first 5 weeks of study participation in the trial. In addition, any dose level could be expanded to further explore PK (the target PK concentration associated with activity in preclinical models was 335 ng/mL). The number of DLTs by dose cohort have been presented.
Secondary Outcomes
- Number of Participants With a Serum Prostate-specific Antigen (PSA) Response According to Prostate Cancer Working Group (PCWG3) Criteria(12 weeks)
- Maximum Change in QTcF(18 months)
- Percent Change From Baseline in Standard Uptake Value (SUV) to Assess TRC253 Receptor Occupancy(4 Weeks)
- Median Time to Progression by Dose Level(18 months)
- Number of Patients Who Achieved the Target Concentration of TRC253 at Steady State(28 days)