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

Johns Hopkins Medicine

Status and phase: Completed; Phase 2

Conditions: Prostate Cancer

Treatments: Drug: Testosterone Enanthate; Drug: Enzalutamide; Drug: Testosterone cypionate; Drug: Abiraterone acetate

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT02090114

NA_00093344 (Other Identifier)

J1416

1R01CA184012-01 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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).

Full description

The trial will enroll up to 110 patients, 30 for each Cohorts A-C and 20 for Cohort D. 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 (Cohort B) or enzalutamide (Cohort A), whichever agent they had previously progressed on prior to study enrollment. Patients in Cohort C will remain on LHRH agonist therapy and receive no additional androgen ablative hormonal therapy while those in the mutation-positive Cohort D will receive enzalutamide regardless of prior therapy.

Enrollment: 112 patients

Sex: Male

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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)].

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Single Group Assignment

Masking: None (Open label)

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112 participants in 4 patient groups

Cohort A:Post-enzalutamide

Experimental group

Description:

Men with castration-resistant prostate cancer who have progressed on enzalutamide will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with enzalutamide 160 mg by mouth daily.

Treatment:

Drug: Enzalutamide

Drug: Testosterone cypionate

Drug: Testosterone Enanthate

Cohort B: Post-abiraterone

Experimental group

Description:

Men with castration-resistant prostate cancer who have progressed on abiraterone will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with abiraterone 1000 mg by mouth daily.

Treatment:

Drug: Abiraterone acetate

Drug: Testosterone cypionate

Drug: Testosterone Enanthate

Cohort C: Castration Only

Experimental group

Description:

Men with metastatic prostate cancer who have only received first line hormone therapy with LHRH agonist alone or LHRH agonist plus an anti-androgen. Patients who have developed castrate resistance to first line therapy and have then received second line hormone therapy of any kind (including flutamide, bicalutamide, nilutamide, ketoconazole, abiraterone, enzalutamide, ARN-509 and investigational anti-androgens) are not eligible for enrollment in this cohort.

Treatment:

Drug: Testosterone cypionate

Drug: Testosterone Enanthate

Cohort D: Mutation

Experimental group

Description:

Men with metastatic prostate cancer who have castrate resistant prostate cancer with inactivating somatic or germline mutations in the genes TP53, RB1 or PTEN identified using clinical grade sequencing of tumor tissue performed by qualified laboratory. Patients must have mutations in ≥2 of these genes to be eligible. Eligible patients must have progressed on first line hormone therapy with LHRH agonist alone and must have received at least one but not more than two second generation androgen ablative therapy (i.e. Abiraterone, Enzalutamide or Apalutamide).

Treatment:

Drug: Testosterone cypionate

Drug: Testosterone Enanthate