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.
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.
