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Genital Diseases, Male

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Androgens

Androgen Receptor Antagonists

Androgen Antagonists

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Hormone Antagonists

40 mg of single-agent TRC253 to be administered as oral capsules once daily

80 mg of single-agent TRC253 to be administered as oral capsules once daily

160 mg of single-agent TRC253 to be administered as oral capsules once daily

240 mg of single-agent TRC253 to be administered as oral capsules once daily

280 mg of single-agent TRC253 to be administered as oral capsules once daily

320 mg of single-agent TRC253 to be administered as oral capsules once daily

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.

TRC253

James Freddo, MD

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.

Phase 1/2A Study of TRC253, an Androgen Receptor Antagonist, in Metastatic Castration-resistant Prostate Cancer Patients

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

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.

Serum prostate-specific antigen (PSA) response according to Prostate Cancer Working Group (PCWG3) criteria is defined as at least a 50% decrease in PSA from baseline confirmed at least 4 weeks later

Maximum change in QTcF from baseline by dose level

To confirm the recommended phase 2 dose (RP2D), patients at select dose levels will undergo positron emission tomography scan (PET) scans using fluoro-5alpha-dihydrotestosterone (FDHT), a radiopharmaceutical specifically designed to image binding to androgen receptor (AR). Imaging occurred at one center under their existing investigational new drug application (IND) and institutional protocol. A negative change from baseline in the standard uptake value indicate a decrease in metabolic activity of the tumor and indicate increased receptor occupancy of TRC253.

Preliminary anti-tumor effects of TRC253 as assessed by median time to progression by Prostate Cancer Working Group 3 (PCWG3) criteria by dose level

Determine the number of patients who achieved the target concentration of TRC253 at steady state (target efficacy concentration of 335 ng/mL based on preclinical models).

Janssen Pharmaceutica N.V., Belgium

Tracon Pharmaceuticals Inc.

Single-agent TRC253 to be administered as oral capsules once daily.

40 mg TRC253/Daily

80 mg TRC253/Daily

160 mg TRC253/Daily

240 mg TRC253/Daily

280 mg TRC253/Daily

320 mg TRC253/Daily

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Race/Ethnicity

Race/Ethnicity, Customized

United States

Region of Enrollment

Charles Theuer, MD PhD

Determination of the maximum tolerated dose.

One dose limiting toxicity occurred at 320 mg daily of grade 3 QTc prolongation therefore the 280 mg dose was determined to be the maximum tolerated dose and selected as the phase 2 dose.

All patients who received at least a portion of a dose of TRC253 are included in the analysis.

Number of Patients Who Experience Dose Limiting Toxicities by Dose Level

Patients with a baseline PSA and at least 1 on study PSA that were confirmed at least 4 weeks later.

Number of Participants With a Serum Prostate-specific Antigen (PSA) Response According to Prostate Cancer Working Group (PCWG3) Criteria

Patients who received at least a portion of a dose of TRC253 with a baseline ECG and at least 1 on study ECG.

Maximum Change in QTcF

TRC253 4 week FDHT-PET response mean SUV based on the 5 hottest lesions (uncorrected)

Percent Change From Baseline in Standard Uptake Value (SUV) to Assess TRC253 Receptor Occupancy

40 mg TRC253/Daily Dose Levels Combined

80 mg TRC253/Daily Dose Levels Combined

160 mg TRC253/Daily Dose Levels Combined

In order to be eligible for efficacy analysis patients must have had a baseline CT scan and at least 1 on study CT scan.

Median Time to Progression by Dose Level

Patients who received at least 75% of planned continuous daily dosing after 28 days of daily dosing enrolled in part 1 of the study.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Phase 1/2A Study of TRC253, an Androgen Receptor Antagonist, in Metastatic Castration-resistant Prostate Cancer Patients	NCT02987829	Metastatic Cast... Adenocarcinoma,...	TRC253	18 Years - 99 Years	Tracon Pharmaceuticals Inc.
Phase 1/2A Study of TRC253, an Androgen Receptor Antagonist, in Metastatic Castration-resistant Prostate Cancer Patients	NCT02987829	Metastatic Cast... Adenocarcinoma,...	TRC253	18 Years - 99 Years	Tracon Pharmaceuticals Inc.

Spots Global Cancer Trial Database for trc253

Every month we try and update this database with for trc253 cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for trc253

Every month we try and update this database with for trc253 cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for trc253 cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.