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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02987829
Recruitment Status : Completed
First Posted : December 9, 2016
Last Update Posted : December 17, 2020
Janssen Pharmaceutica N.V., Belgium
Information provided by (Responsible Party):
Tracon Pharmaceuticals Inc.

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).

Condition or disease Intervention/treatment Phase
Metastatic Castrate-resistant Prostate Cancer Adenocarcinoma, Prostate Drug: TRC253 Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 71 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
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
Actual Study Start Date : May 23, 2017
Actual Primary Completion Date : October 6, 2019
Actual Study Completion Date : November 9, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Prostate Cancer

Arm Intervention/treatment
Experimental: TRC253
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.
Drug: TRC253
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

Primary Outcome Measures :
  1. Recommended Phase 2 dose (RP2D) of TRC253 [ Time Frame: 8 months ]
    The recommended phase 2 dose of TRC253 will be determined.

Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. Exposure-QTcF relationship: mean change in QTcF at Cmax [ Time Frame: 18 months ]
    Mean change in QTcF at Cmax

  4. 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.

  5. 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.

Other Outcome Measures:
  1. 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.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Must have received at least 2 prior therapies approved for CRPC; including a prior AR inhibitor (e.g., enzalutamide or apalutamide). (Part 1 only)
  2. Must have received enzalutamide or apalutamide. (Note: additional therapies approved for CRPC prior to enzalutamide or apalutamide are allowed.) (Part 2 only)
  3. 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:

  4. Histologically confirmed adenocarcinoma of the prostate with metastatic disease.
  5. Male ≥18 years of age.
  6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  7. Prior orchiectomy or serum testosterone levels <50 ng/dL determined within 4 weeks prior to start of study drug.
  8. Adequate baseline organ function.
  9. 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.
  10. 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).
  11. 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).
  12. 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.
  13. Palliative radiotherapy (to bone or soft tissue lesions) must be completed >2 weeks prior to start of study drug.
  14. 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.
  15. A man who is sexually active with a woman of childbearing potential must agree to use a barrier method of birth control during the study and for 4 weeks after receiving the last dose of study drug. All men must also not donate sperm during the study and for 90 days after receiving the last dose of study drug.
  16. Patient must be willing and able to adhere to the prohibitions and restrictions specified in this protocol.
  17. Each patient must sign an informed consent form (ICF) indicating that he understands the purpose of and procedures required for the study and is willing to participate in the study. Consent is to be obtained prior to the initiation of any study-related tests or procedures that are not part of standard-of-care for the patient's disease.

Exclusion Criteria:

  1. History of seizures.
  2. Previously documented or current brain metastases.
  3. Untreated spinal cord compression.
  4. Positive test result for human immunodeficiency virus.
  5. History of clinically significant cardiovascular disease including.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. Known allergies, hypersensitivity, or intolerance to TRC253 or its excipients.
  11. Enrollment in another interventional study.
  12. 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.
  13. Plan to father a child while enrolled in this study or within 90 days after the last dose of study drug.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02987829

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United States, Alabama
University of Alabama at Birmingham
Birmingham, Alabama, United States, 35233
United States, Arizona
Honor Health
Scottsdale, Arizona, United States, 85258
United States, California
University of California at Los Angeles
Santa Monica, California, United States, 90404
United States, New York
Memorial Sloan Kettering Cancer Center
New York, New York, United States, 10065
United States, Utah
University of Utah
Salt Lake City, Utah, United States, 84112
Sponsors and Collaborators
Tracon Pharmaceuticals Inc.
Janssen Pharmaceutica N.V., Belgium
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Study Director: James Freddo, MD Tracon Pharmaceuticals Inc.
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Responsible Party: Tracon Pharmaceuticals Inc. Identifier: NCT02987829    
Other Study ID Numbers: 253PC101
First Posted: December 9, 2016    Key Record Dates
Last Update Posted: December 17, 2020
Last Verified: December 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Prostatic Diseases
Androgen Receptor Antagonists
Androgen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs