RE-sensitizing With Supraphysiologic Testosterone to Overcome REsistance (The RESTORE Study)
Condition: Prostate Cancer
MeSH terms: Prostatic Neoplasms
Intervention: Testosterone cypionate; Testosterone Enanthate; Abiraterone acetate; Enzalutamide
Intervention description: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days.; Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.; Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each ZYTIGA tablet contains 250 mg of abiraterone acetate.; XTANDI is provided as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides.
Intervention MeSH terms: Methyltestosterone; Abiraterone Acetate; Testosterone; Testosterone undecanoate; Testosterone enanthate; Testosterone 17 beta-cypionate
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 112.0
Sex: Male
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Bipolar Androgen Therapy; Testosterone; Enzalutamide; Abiraterone; Androgen Ablative Therapies

Summary:

      Single-arm, single site, open label study of the effects of parenteral testosterone followed
      by enzalutamide, abiraterone or castration-only therapy in men with metastatic CRPC who
      previously progressed on one of these forms of therapy. The study will enroll four cohorts of
      patients: men with metastatic CRPC who have progressed on enzalutamide (Cohort A; n=30); men
      with metastatic CRPC who have progressed on abiraterone acetate (Cohort B; n=30); men with
      metastatic CRPC who have progressed on first line castration-only therapy (Cohort C; n=30);
      men with metastatic CRPC with inactivating somatic or germline mutations in ≥2 of the genes
      TP53, PTEN, or RB1 (Cohort D; n=20).
    

Eligibility criteria:

        Inclusion Criteria:

          -  Performance status ≤2

          -  Age ≥18 years

          -  Histologically-confirmed adenocarcinoma of the prostate

          -  Progressing on continuous androgen ablative therapy (either surgical castration or
             LHRH agonist).

          -  Documented castrate level of serum testosterone (<50 ng/dl).

          -  For Cohorts A and B, patients must have progressed on prior treatment with
             enzalutamide or abiraterone acetate + prednisone (by PSA criteria or
             radiographically).

          -  For castration-only Cohort C, patients must have developed castrate resistant prostate
             cancer after progressing on first line hormone therapy with either surgical castration
             or LHRH agonist or LHRH agonist plus an anti-androgen.

          -  For Cohort D patients must have inactivating somatic or germline mutations in ≥2 of
             the genes TP53, PTEN, RB1

          -  Patients progressing on LHRH agonist plus an anti-androgen as first line therapy must
             be off anti-androgen for 4 weeks prior to first treatment with testosterone.

          -  Patients with rising PSA on two successive measurements at least two weeks apart.

          -  For Cohort A (enzalutamide) and Cohort B (abiraterone acetate):

               -  Prior treatment with up to 2 additional second line hormone therapies, including
                  ketoconazole is allowed.

               -  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).

               -  Patients must be withdrawn from enzalutamide or abiraterone acetate for ≥ 4 weeks
                  and have documented PSA increase after the withdrawal period.

               -  Patients receiving prednisone in conjunction with abiraterone acetate must be
                  weaned off prednisone prior to starting BAT.

          -  For Cohort C (castration-only):

               -  Patients must continue on castrating therapy throughout BAT treatment.

               -  No prior second line hormone treatment with flutamide, bicalutamide, nilutamide,
                  enzalutamide, abiraterone, ketoconazole, ARN-509 or other investigational
                  androgen ablative therapies is permitted for Cohort C.

          -  For Cohort D (mutation cohort):

               -  Patients must continue on castrating therapy throughout BAT treatment.

               -  Treatment with first-generation hormonal therapy (i.e. flutamide, bicalutamide,
                  nilutamide), is allowed

               -  Patient must have received at least one and not more than two second generation
                  hormone therapies (i.e. enzalutamide, abiraterone, apalutamide).

          -  For Cohorts A-D, prior docetaxel for hormone-sensitive prostate cancer is permitted if
             ≤ 6 doses were given in conjunction with first-line androgen deprivation therapy and
             >12 months since last dose of docetaxel

          -  For Cohort D, one line of prior chemotherapy with docetaxel or cabazitaxel for
             metastatic castrate resistant prostate cancer is allowed

          -  Acceptable liver function:

               -  Bilirubin < 2.5 times institutional upper limit of normal (ULN)

               -  AST (SGOT) and ALT (SGPT) < 2.5 times ULN

          -  Acceptable renal function:

             -- Serum creatinine < 2.5 times ULN, OR

          -  Acceptable hematologic status:

               -  Absolute neutrophil count (ANC) ≥ 1500 cells/mm3 (1.5 ×109/L)

               -  Platelet count ≥ 100,000 platelet/mm3 (100 ×109/L)

               -  Hemoglobin ≥ 9 g/dL.

          -  At least 4 weeks since prior surgery with full recovery (no persistent toxicity ≥
             Grade 1).

          -  Ability to understand and willingness to sign a written informed consent document.

        Exclusion Criteria:

          -  Pain due to metastatic prostate cancer requiring opioid analgesics.

          -  >5 sites of visceral disease in lung or liver (nonspecific lung nodules ≤1 cm in
             diameter are permitted).

          -  Prior treatment with docetaxel or cabazitaxel for metastatic castration-resistant
             prostate cancer is prohibited.

          -  Prior treatment with one line of chemotherapy for metastatic castration-resistant
             prostate cancer is allowed for Cohort D

          -  Requires urinary catheterization for voiding due to obstruction secondary to prostatic
             enlargement thought to be due to prostate cancer or benign prostatic hyperplasia

          -  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).

          -  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.

          -  Active uncontrolled infection, including known history of AIDS or hepatitis B or C.

          -  Any psychological, familial, sociological, or geographical condition that could
             potentially interfere with compliance with the study protocol and follow-up schedule.

          -  Prior history of a thromboembolic event within the last two years and not currently on
             systemic anticoagulation.

          -  Hematocrit >50%, untreated severe obstructive sleep apnea, uncontrolled or poorly
             controlled heart failure [per Endocrine Society Clinical Practice Guidelines (67)].