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

NCT02090114 | Completed Phase 2 Results DMC

• 3 other identifiers: J1416NA_000933441R01CA184012-01
• Study Type: interventional
• Target: 112
• Locations: 1 country
• Sites: 2

Brief 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).

Conditions

Prostate Cancer

Keywords

Bipolar Androgen Therapy; Testosterone; Enzalutamide; Abiraterone; Androgen Ablative Therapies

Outcome Measures

Primary Outcomes (2)

• Prostate Specific Antigen (PSA) Response to Bipolar Androgen Therapy (BAT)

  Number of participants with ≥50% PSA reduction from pre-BAT baseline level

  up to 18 months

• PSA Response to Enzalutamide or Abiraterone Acetate Post Bipolar Androgen Therapy

  Number of participants with ≥50% PSA reduction after enzalutamide or abiraterone acetate post-BAT from baseline

  up to 24 months

Secondary Outcomes (10)

• PSA Progression on Enzalutamide or Abiraterone Acetate or Castrate Levels Post-BAT

  up to 18 months

• PSA Progression on BAT (Bipolar Androgen Therapy )

  up to 18 months

• Disease Response as Defined by RECIST 1.1 (Soft Tissue Lesions) and PCWG2 Criteria (Bone Lesions)

  up to 18 months

• Initiation of Docetaxel Chemotherapy

  up to 18 months

• Quality of Life (QoL) as Assessed by FACIT-F Score

  up to 18 months

Study Arms (4)

Cohort A:Post-enzalutamide

EXPERIMENTAL

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.

Drug: Testosterone cypionate; Drug: Testosterone Enanthate; Drug: Enzalutamide

Cohort B: Post-abiraterone

EXPERIMENTAL

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.

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

Cohort C: Castration Only

EXPERIMENTAL

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.

Drug: Testosterone cypionate; Drug: Testosterone Enanthate

Cohort D: Mutation

EXPERIMENTAL

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).

Drug: Testosterone cypionate; Drug: Testosterone Enanthate

Interventions

Testosterone cypionate DRUG

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.

Also known as: DEPO-Testosterone Injection

Cohort A:Post-enzalutamide; Cohort B: Post-abiraterone; Cohort C: Castration Only; Cohort D: Mutation

Testosterone Enanthate DRUG

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.

Also known as: Delatestryl

Cohort A:Post-enzalutamide; Cohort B: Post-abiraterone; Cohort C: Castration Only; Cohort D: Mutation

Abiraterone acetate DRUG

Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each ZYTIGA tablet contains 250 mg of abiraterone acetate.

Also known as: Zytiga

Cohort B: Post-abiraterone

Enzalutamide DRUG

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.

Also known as: Xtandi

Cohort A:Post-enzalutamide

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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 \[per Endocrine Society Clinical Practice Guidelines (67)\].

Sponsors & Collaborators

• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: lead
• National Cancer Institute (NCI): collaborator

Study Sites (2)

Sibley Memorial Hospital

Washington D.C., District of Columbia, 20016, United States

Location

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, 21231, United States

Location

Related Publications (3)

• Markowski MC, Wang H, Sullivan R, Rifkind I, Sinibaldi V, Schweizer MT, Teply BA, Ngomba N, Fu W, Carducci MA, Paller CJ, Marshall CH, Eisenberger MA, Luo J, Antonarakis ES, Denmeade SR. A Multicohort Open-label Phase II Trial of Bipolar Androgen Therapy in Men with Metastatic Castration-resistant Prostate Cancer (RESTORE): A Comparison of Post-abiraterone Versus Post-enzalutamide Cohorts. Eur Urol. 2021 May;79(5):692-699. doi: 10.1016/j.eururo.2020.06.042. Epub 2020 Jul 2.

  PMID: 32624280 RESULT

• Sena LA, Wang H, Lim ScM SJ, Rifkind I, Ngomba N, Isaacs JT, Luo J, Pratz C, Sinibaldi V, Carducci MA, Paller CJ, Eisenberger MA, Markowski MC, Antonarakis ES, Denmeade SR. Bipolar androgen therapy sensitizes castration-resistant prostate cancer to subsequent androgen receptor ablative therapy. Eur J Cancer. 2021 Feb;144:302-309. doi: 10.1016/j.ejca.2020.11.043. Epub 2020 Dec 29.

  PMID: 33383350 RESULT

• Teply BA, Wang H, Luber B, Sullivan R, Rifkind I, Bruns A, Spitz A, DeCarli M, Sinibaldi V, Pratz CF, Lu C, Silberstein JL, Luo J, Schweizer MT, Drake CG, Carducci MA, Paller CJ, Antonarakis ES, Eisenberger MA, Denmeade SR. Bipolar androgen therapy in men with metastatic castration-resistant prostate cancer after progression on enzalutamide: an open-label, phase 2, multicohort study. Lancet Oncol. 2018 Jan;19(1):76-86. doi: 10.1016/S1470-2045(17)30906-3. Epub 2017 Dec 14.

  PMID: 29248236 RESULT

MeSH Terms

Conditions

Prostatic Neoplasms

Interventions

testosterone 17 beta-cypionate; testosterone enanthate; Abiraterone Acetate; enzalutamide

Condition Hierarchy (Ancestors)

Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Androstenes; Androstanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Results Point of Contact

• Title: Samuel Denmeade, M.D.
• Organization: Johns Hopkins University School of Medicine

denmesa@jhmi.edu

410-502-8341

Study Officials

• Samuel Denmeade, MD

  Johns Hopkins School of Medicine - Sidney Kimmel Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 4, 2014
• First Posted: March 18, 2014
• Study Start: August 25, 2014
• Primary Completion: November 11, 2021
• Study Completion: November 11, 2021
• Last Updated: June 27, 2022
• Results First Posted: June 27, 2022

Record last verified: 2022-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)