Clinical Trials /

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

NCT02987829

Description:

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).

Related Conditions:
  • Prostate Adenocarcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 253PC101
  • NCT ID: NCT02987829

Conditions

  • Metastatic Castrate-resistant Prostate Cancer
  • Adenocarcinoma, Prostate

Interventions

DrugSynonymsArms
TRC253AR AntagonistTRC253

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
TRC253ExperimentalSingle-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

Eligibility Criteria

        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.
      
Maximum Eligible Age:99 Years
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended Phase 2 dose (RP2D) of TRC253
Time Frame:8 months
Safety Issue:
Description:The recommended phase 2 dose of TRC253 will be determined.

Secondary Outcome Measures

Measure:Safety profile of TRC253 including adverse events assessed by CTCAE v4.03
Time Frame:18 months
Safety Issue:
Description: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.
Measure:Serum prostate-specific antigen (PSA) response at Week 12 according to Prostate Cancer Working Group (PCWG3) criteria
Time Frame:3 months
Safety Issue:
Description:PSA response at Week 12 will be evaluated according to PCWG3 criteria.
Measure:Exposure-QTcF relationship: mean change in QTcF at Cmax
Time Frame:18 months
Safety Issue:
Description:Mean change in QTcF at Cmax
Measure:Extent of receptor occupancy by FDHT-PET scan
Time Frame:18 months
Safety Issue:
Description:To confirm the RP2D, patients at select dose levels will undergo PET scans using FDHT, a radiopharmaceutical specifically designed to image binding to AR.
Measure:Preliminary anti-tumor effects of TRC253: time to PSA progression and radiographic PFS according to PCWG3
Time Frame:18 months
Safety Issue:
Description:Time to PSA progression, and radiographic PFS.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Tracon Pharmaceuticals Inc.

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