RE-sensitizing With Supraphysiologic Testosterone to Overcome REsistant (The RESTORE Study)

Condition(s) targeted: Prostate Cancer

Intervention: Testosterone cypionate (Drug); Testosterone Enanthate (Drug); Abiraterone acetate (Drug); Enzalutamide (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: Sidney Kimmel Comprehensive Cancer Center

Official(s) and/or principal investigator(s):
Samuel Denmeade, MD, Principal Investigator, Affiliation: Johns Hopkins School of Medicine - Sidney Kimmel Comprehensive Cancer Center

Overall contact:
Rana Sullivan, Phone: 410-614-6337, Email: tomalra@jhmi.edu

Single-arm, single site, open label study of the effects of parenteral testosterone followed by enzalutamide or abiraterone in men with metastatic CRPC who previously progressed on either of these agents. The study will enroll two cohorts of patients: men with metastatic CRPC who have progressed on enzalutamide (Cohort A); and men with metastatic CRPC who have progressed on abiraterone acetate (Cohort B).

Official title: A Phase II Study to Determine Sequential Response to Bipolar Androgen Therapy (BAT) Followed by Enzalutamide or Abiraterone Post-BAT in Men With Prostate Cancer Progressing on Combined Androgen Ablative Therapies

Study design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

PSA response to Bipolar Androgen Therapy

PSA response to enzalutamide or abiraterone acetate post Bipolar Androgen Therapy

Secondary outcome:

PSA progression on enzalutamide or abiraterone acetate post-BAT

PSA progression on BAT (Bipolar Androgen Therapy )

Measurable disease response

initiation of docetaxel chemotherapy

Quality of life

Safety and Tolerability

Fasting glucose

hemoglobin A1c

Fasting insulin

Serum N-telopeptide

Osteocalcin

Detailed description: The trial will enroll up to 60 patients, 30 for each cohort. Eligible patients will continue on androgen ablative therapy with LHRH agonist (i. e. Zoladex, Trelstar, Eligard or Lupron) if not surgically castrated to suppress endogenous testosterone production. Patients will also receive intramuscular injection with either testosterone cypionate or testosterone enanthate at a dose of 400 mg every 28 days. This dosing scheme was designed to produce rapidly fluctuating serum testosterone levels from the supraphysiologic to the near-castrate range (i. e. Bipolar Androgen Therapy [BAT]). Assessments for response to testosterone will be made approximately every 3 months. Upon displaying evidence of progression, patients will then go on to receive either abiraterone or enzalutamide (whichever agent they had previously progressed on prior to study enrollment).

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Male.

Criteria:

Inclusion Criteria: 1. Performance status ≤2 2. Age ≥18 years 3. Histologically-confirmed adenocarcinoma of the prostate 4. Treated with continuous androgen ablative therapy (either surgical castration or LHRH agonist) 5. Documented castrate level of serum testosterone (<20 ng/dl) 6. Must have progressed on prior treatment with enzalutamide or abiraterone acetate + prednisone (by PSA criteria or radiographically). 7. Patients with rising PSA on two successive measurements at least two weeks apart 8. Prior treatment with up to 2 additional second line hormone therapies, including ketoconazole is allowed. 9. Patients who have progressed on both enzalutamide and abiraterone acetate are eligible and post-BAT will be retreated with the last second line agent they had received (e. g. patient receiving abiraterone then enzalutamide would receive retreatment with enzalutamide post-BAT). 10. Patients must be withdrawn from enzalutamide or abiraterone acetate for ≥ 4 weeks and have documented PSA increase after the withdrawal period. 11. Patients receiving prednisone in conjunction with abiraterone acetate must be weaned off prednisone prior to starting BAT. 12. Acceptable liver function: 1. Bilirubin < 2. 5 times institutional upper limit of normal (ULN) 2. AST (SGOT) and ALT (SGPT) < 2. 5 times ULN 13. Acceptable renal function: a. Serum creatinine < 2. 5 times ULN, OR 14. Acceptable hematologic status: 1. Absolute neutrophil count (ANC) ≥ 1500 cells/mm3 (1. 5 ×109/L) 2. Platelet count ≥ 100,000 platelet/mm3 (100 ×109/L) 3. Hemoglobin ≥ 9 g/dL. 15. At least 4 weeks since prior surgery with full recovery (no persistent toxicity ≥ Grade 1) 16. Ability to understand and willingness to sign a written informed consent document. Exclusion Criteria: 1. Pain due to metastatic prostate cancer requiring opioid analgesics 2. >5 sites of visceral disease in lung or liver (nonspecific lung nodules ≤1 cm in diameter are permitted). 3. Prior treatment with docetaxel or cabazitaxel for metastatic castration-resistant prostate cancer is prohibited. 4. Prior seizures while on enzalutamide therapy. 5. Requires urinary catheterization for voiding due to obstruction secondary to prostatic enlargement thought to be due to prostate cancer or benign prostatic hyperplasia. 6. Evidence of disease in sites or extent that, in the opinion of the investigator, would put the patient at risk from therapy with testosterone (e. g. femoral metastases with concern over fracture risk, spinal metastases with concern over spinal cord compression, lymph node disease with concern for ureteral obstruction). 7. Evidence of serious and/or unstable pre-existing medical, psychiatric or other condition (including laboratory abnormalities) that could interfere with patient safety or provision of informed consent to participate in this study 8. Active uncontrolled infection, including known history of AIDS or hepatitis B or C. 9. Prior history of a thromboembolic event within the last two years and not currently on systemic anticoagulation. 10. Prior myocardial infarction within one year of study entry. 11. Hematocrit >50%, untreated severe obstructive sleep apnea, uncontrolled or poorly controlled heart failure [per Endocrine Society Clinical Practice Guidelines (67)]. 12. Any psychological, familial, sociological, or geographical condition that could potentially interfere with compliance with the study protocol and follow-up schedule.

Rana Sullivan, Phone: 410-614-6337, Email: tomalra@jhmi.edu

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231, United States; Recruiting
Rana Sullivan, Phone: 410-614-6337, Email: tomalra@jhmi.edu
Donna Dowling, Phone: 410-614-9526, Email: ddowlin1@jhmi.edu
Samuel Denmeade, MD, Principal Investigator

Starting date: June 2014
Last updated: June 9, 2015