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

NCT02987829 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: 253PC101
• Study Type: interventional
• Target: 72
• Locations: 1 country
• Sites: 5

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).

Conditions

Metastatic Castrate-resistant Prostate Cancer; Adenocarcinoma, Prostate

Outcome Measures

Primary Outcomes (1)

• Number of Patients Who Experience Dose Limiting Toxicities by Dose Level

  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.

  5 weeks

Secondary Outcomes (5)

• 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

Study Arms (6)

Dose Level 1: TRC253 40 mg daily

EXPERIMENTAL

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

Drug: TRC253

Dose Level 2: TRC253 80 mg

EXPERIMENTAL

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

Drug: TRC253

Dose Level 3: TRC253 160 mg

EXPERIMENTAL

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

Drug: TRC253

Dose Level 4: TRC253 240 mg

EXPERIMENTAL

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

Drug: TRC253

Dose Level 5: TRC253 280 mg

EXPERIMENTAL

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

Drug: TRC253

Dose Level 6: TRC253 320 mg

EXPERIMENTAL

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

Drug: TRC253

Interventions

TRC253 DRUG

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.

Also known as: AR Antagonist

Dose Level 1: TRC253 40 mg daily; Dose Level 2: TRC253 80 mg; Dose Level 3: TRC253 160 mg; Dose Level 4: TRC253 240 mg; Dose Level 5: TRC253 280 mg; Dose Level 6: TRC253 320 mg

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 1.
• 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.
• For patients previously treated with first generation anti-androgens (i.e., flutamide, nilutamide, or bicalutamide), discontinuation of flutamide or nilutamide therapy must occur \>4 weeks (\>6 weeks for bicalutamide) prior to start of study drug with no evidence of an anti-androgen withdrawal response (i.e., no decline in serum PSA).
• For patients previously treated with chemotherapy, targeted therapy, immunotherapy, or treatment with an investigational anticancer agent, discontinuation must have occurred ≥2 weeks, or after at least 4 half-lives, whichever is longer, prior to study drug administration. For enzalutamide and apalutamide, the washout period will be at least 3 weeks prior to start of study drug with no evidence of an anti-androgen withdrawal response (i.e., no decline in serum PSA).
• For patients previously treated with other agents approved for the treatment of prostate cancer (5-α reductase inhibitors, estrogens, others), discontinuation of therapy must have occurred ≥4 weeks prior to start of study drug.
• Palliative radiotherapy (to bone or soft tissue lesions) must be completed \>2 weeks prior to start of study drug.
• For patients receiving bone-loss prevention treatment (e.g., bisphosphonates or denosumab), the patient must be on stable dose ≥4 weeks prior to start of study drug.

You may not qualify if:

• 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.
• Enrollment in another interventional study.
• Major surgery (e.g., requiring general anesthesia) within 3 weeks before screening, or has not fully recovered from prior surgery (i.e., unhealed wound), or surgery planned during the time the patient is expected to participate in the study. Note: patients with planned surgical procedures to be conducted under local anesthesia may participate.
• Plan to father a child while enrolled in this study or within 90 days after the last dose of study drug.

Sponsors & Collaborators

• Tracon Pharmaceuticals Inc.: lead
• Janssen Pharmaceutica N.V., Belgium: collaborator

Study Sites (5)

University of Alabama at Birmingham

Birmingham, Alabama, 35233, United States

Location

Honor Health

Scottsdale, Arizona, 85258, United States

Location

University of California at Los Angeles

Santa Monica, California, 90404, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

University of Utah

Salt Lake City, Utah, 84112, United States

Location

Related Publications (1)

• Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, Antonarakis ES, Beer TM, Carducci MA, Chi KN, Corn PG, de Bono JS, Dreicer R, George DJ, Heath EI, Hussain M, Kelly WK, Liu G, Logothetis C, Nanus D, Stein MN, Rathkopf DE, Slovin SF, Ryan CJ, Sartor O, Small EJ, Smith MR, Sternberg CN, Taplin ME, Wilding G, Nelson PS, Schwartz LH, Halabi S, Kantoff PW, Armstrong AJ; Prostate Cancer Clinical Trials Working Group 3. Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol. 2016 Apr 20;34(12):1402-18. doi: 10.1200/JCO.2015.64.2702. Epub 2016 Feb 22.

  PMID: 26903579 BACKGROUND

MeSH Terms

Conditions

Adenocarcinoma

Interventions

Androgen Receptor Antagonists

Condition Hierarchy (Ancestors)

Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms

Intervention Hierarchy (Ancestors)

Androgen Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Pharmacologic Actions; Chemical Actions and Uses

Results Point of Contact

• Title: Charles Theuer, MD PhD
• Organization: Tracon Pharmaceuticals Inc.

ctheuer@traconpharma.com

8585500780

Study Officials

• James Freddo, MD

  Tracon Pharmaceuticals Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: GT60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 5, 2016
• First Posted: December 9, 2016
• Study Start: May 23, 2017
• Primary Completion: October 6, 2019
• Study Completion: November 9, 2020
• Last Updated: April 23, 2021
• Results First Posted: April 23, 2021

Record last verified: 2021-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (5)