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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02090114
Recruitment Status : Recruiting
First Posted : March 18, 2014
Last Update Posted : May 14, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Tracking Information
First Submitted Date  ICMJE March 4, 2014
First Posted Date  ICMJE March 18, 2014
Last Update Posted Date May 14, 2019
Study Start Date  ICMJE June 2014
Estimated Primary Completion Date April 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 13, 2019)
  • Prostate Specific Antigen (PSA) response to Bipolar Androgen Therapy (BAT) [ Time Frame: up to 18 months ]
    Number of participants with ≥50% PSA reduction from pre-BAT baseline level
  • PSA response to enzalutamide or abiraterone acetate post Bipolar Androgen Therapy [ Time Frame: up to 24 months ]
    Number of participants with ≥50% PSA reduction after enzalutamide or abiraterone acetate post-BAT from baseline
  • PSA response to castrate levels of testosterone post Bipolar Androgen Therapy [ Time Frame: up to 18 months ]
    Number of participants who return to castrate levels of testosterone post Bipolar Androgen Therapy
Original Primary Outcome Measures  ICMJE
 (submitted: March 14, 2014)
  • PSA response to Bipolar Androgen Therapy [ Time Frame: On average at 18 months ]
    PSA response to BAT (≥50% PSA reduction from pre-BAT baseline level).
  • PSA response to enzalutamide or abiraterone acetate post Bipolar Androgen Therapy [ Time Frame: On average at 24 months ]
    PSA response to enzalutamide or abiraterone acetate post-BAT (≥50% PSA reduction from baseline PSA level obtained at initiation of enzalutamide or abiraterone acetate post-BAT)
Change History Complete list of historical versions of study NCT02090114 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 13, 2019)
  • PSA progression on enzalutamide or abiraterone acetate or castrate levels post-BAT [ Time Frame: up to 18 months ]
    Time to PSA progression on enzalutamide or abiraterone acetate or return to castrate levels of testosterone post-BAT
  • PSA progression on BAT (Bipolar Androgen Therapy ) [ Time Frame: up to 18 months ]
    Time to PSA progression on BAT
  • Disease response as defined by RECIST 1.1 (soft tissue lesions) and PCWG2 criteria (bone lesions) [ Time Frame: up to 18 months ]
    Number of participants with complete or partial response post-BAT and post-treatment with enzalutamide or abiraterone acetate as defined by RECIST 1.1 (for soft tissue lesions) and PCWG2 criteria (for bone disease), or return to castration-only post-BAT.
  • Initiation of docetaxel chemotherapy [ Time Frame: up to 18 months ]
    Time to initiation of docetaxel chemotherapy
  • Quality of Life (QoL) as assessed by FACIT-F score [ Time Frame: Change from baseline to 18 months ]
    Functional Assessment of Chronic Illness Therapy, Fatigue Subscale (FACIT-F) assesses Fatigue with a total score range of 0-52, with a higher score reflecting better QoL.
  • Safety and Tolerability as assessed by Number of Participants with Adverse Events [ Time Frame: 18 months ]
    Number of participants who experience adverse events, as defined by NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0.
  • Fasting glucose [ Time Frame: 18 months ]
    Fasting blood glucose level (mg/dL)
  • Hemoglobin A1c [ Time Frame: 18 months ]
    Serum percent glycosylated hemoglobin (Hemoglobin A1C)
  • Fasting insulin [ Time Frame: 18 months ]
    Fasting insulin levels
  • Serum C-telopeptide [ Time Frame: 18 months ]
    Serum C-telopeptide levels (pg/mL)
  • Osteocalcin [ Time Frame: On average at 18 months ]
    Serum Osteocalcin levels (ng/mL)
  • Effect of treatment with testosterone and abiraterone acetate or enzalutamide on Bone Scan with SPECT CT [ Time Frame: 18 months ]
    Effect of treatment with testosterone and abiraterone acetate or enzalutamide as determined by Change in Tc-99 MDP uptake on quantitative Bone Scan with SPECT CT
  • Quality of Life (QoL) as assessed by RANDSF-36 [ Time Frame: Change from baseline to 18 months ]
    RAND 36-Item Short Form (RANDSF-36) assesses physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, general health perceptions, and perceived change in health with a total score range of 0-100, with a higher score reflecting better QoL.
  • Quality of Life (QoL) as assessed by BPI [ Time Frame: Change from baseline to 18 months ]
    Brief Pain Inventory (BPI) assesses the severity of pain and its impact on functioning with scales ranging from 0-10, with a higher score indicating a higher level of pain.
  • Quality of Life (QoL) as assessed by IIEF [ Time Frame: Change from baseline to 18 months ]
    International Index of Erectile Function (IIEF-5) is a diagnostic tool for erectile dysfunction, with a total score range of 5-25, with the lowest score indicating a higher degree of dysfunction.
  • Quality of Life (QoL) as assessed by PANAS [ Time Frame: Change from baseline to 18 months ]
    Positive and Negative Affect Schedule (PANAS) is a self-report measure that is made up of two mood scales, one measuring positive affect and the other measuring negative affect, with a total score range from 10-50 with a higher score on the positive scale indicating greater levels of positive affect and a lower score on the negative scale indicating less of a negative affect.
Original Secondary Outcome Measures  ICMJE
 (submitted: March 14, 2014)
  • PSA progression on enzalutamide or abiraterone acetate post-BAT [ Time Frame: On average at 18 months ]
    Time to PSA progression on enzalutamide or abiraterone acetate post-BAT
  • PSA progression on BAT (Bipolar Androgen Therapy ) [ Time Frame: On average at 18 months ]
    Time to PSA progression on BAT
  • Measurable disease response [ Time Frame: On average at 18 months ]
    Measurable disease response post-BAT and post-treatment with enzalutamide or abiraterone acetate post-BAT.
    1. For soft tissue lesions, based on RECIST 1.1.
    2. For bone disease, based on PCWG2 criteria.
  • Initiation of docetaxel chemotherapy [ Time Frame: On average at 18 months ]
    Time to initiation of docetaxel chemotherapy
  • Quality of life [ Time Frame: On average at 18 months ]
    The following quality of life surveys will be administered: FACIT-F, RANDSF-36, Brief Pain Inventory, IIEF and PANAS,
  • Safety and Tolerability [ Time Frame: On average at 18 months ]
    Adverse events will be collected at each clinic visit and classified for severity according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0.
  • Fasting glucose [ Time Frame: On average at 18 months ]
    Fasting blood glucose level
  • Hemoglobin A1c [ Time Frame: On average at 18 months ]
    Hemoglobin A1c level
  • Fasting insulin [ Time Frame: On average at 18 months ]
    Fasting insulin levels
  • Serum N-telopeptide [ Time Frame: On average at 18 months ]
    Serum N-telopeptide levels
  • Osteocalcin [ Time Frame: On average at 18 months ]
    Osteocalcin levels
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE RE-sensitizing With Supraphysiologic Testosterone to Overcome REsistance (The RESTORE Study)
Official Title  ICMJE 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
Brief Summary Single-arm, single site, open label study of the effects of parenteral testosterone followed by enzalutamide or abiraterone or castration-only therapy in men with metastatic CRPC who previously progressed on one of these forms of therapy. The study will enroll three cohorts of patients: men with metastatic CRPC who have progressed on enzalutamide (Cohort A); men with metastatic CRPC who have progressed on abiraterone acetate (Cohort B); and men with metastatic CRPC who have progressed on first line castration-only therapy (Cohort C).
Detailed Description The trial will enroll up to 90 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) or remain on LHRH agonist therapy and receive no additional androgen ablative hormonal therapy.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Prostate Cancer
Intervention  ICMJE
  • Drug: Testosterone cypionate
    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.
    Other Name: DEPO-Testosterone Injection
  • Drug: Testosterone Enanthate
    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.
    Other Name: Delatestryl
  • Drug: Abiraterone acetate
    Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each ZYTIGA tablet contains 250 mg of abiraterone acetate.
    Other Name: Zytiga
  • Drug: Enzalutamide (Cohort A = CLOSED TO ACCRUAL)
    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.
    Other Name: Xtandi
Study Arms  ICMJE Experimental: Post-abiraterone or post-enzalutamide or post-castration only
Men with castration-resistant prostate cancer who have progressed on either abiraterone or enzalutamide or castration-only therapy will be enrolled to this arm. 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 either abiraterone 1000 mg by mouth daily or enzalutamide 160 mg by mouth daily, depending on which drug they previously received or remain on LHRH agonist alone for one month to re-establish a castrate level of testosterone (<50 ng/dL).
Interventions:
  • Drug: Testosterone cypionate
  • Drug: Testosterone Enanthate
  • Drug: Abiraterone acetate
  • Drug: Enzalutamide (Cohort A = CLOSED TO ACCRUAL)
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 25, 2017)
90
Original Estimated Enrollment  ICMJE
 (submitted: March 14, 2014)
60
Estimated Study Completion Date  ICMJE April 2021
Estimated Primary Completion Date April 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Performance status ≤2
  2. Age ≥18 years
  3. Histologically-confirmed adenocarcinoma of the prostate
  4. Progressing on continuous androgen ablative therapy (either surgical castration or LHRH agonist).
  5. Documented castrate level of serum testosterone (<50 ng/dl).
  6. For Cohorts A and B, patients must have progressed on prior treatment with enzalutamide or abiraterone acetate + prednisone (by PSA criteria or radiographically).
  7. 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.
  8. 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.
  9. Patients with rising PSA on two successive measurements at least two weeks apart.
  10. For Cohort A (enzalutamide) and Cohort B (abiraterone acetate):

    1. Prior treatment with up to 2 additional second line hormone therapies, including ketoconazole is allowed.
    2. 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).
    3. Patients must be withdrawn from enzalutamide or abiraterone acetate for ≥ 4 weeks and have documented PSA increase after the withdrawal period.
    4. Patients receiving prednisone in conjunction with abiraterone acetate must be weaned off prednisone prior to starting BAT.
  11. For Cohort C (castration-only):

    1. Patients must continue on castrating therapy throughout BAT treatment.
    2. 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.
  12. 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.
  13. Acceptable liver function:

    1. Bilirubin < 2.5 times institutional upper limit of normal (ULN)
    2. AST (SGOT) and ALT (SGPT) < 2.5 times ULN
  14. Acceptable renal function:

    a. Serum creatinine < 2.5 times ULN, OR

  15. 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.
  16. At least 4 weeks since prior surgery with full recovery (no persistent toxicity ≥ Grade 1).
  17. 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. Requires urinary catheterization for voiding due to obstruction secondary to prostatic enlargement thought to be due to prostate cancer or benign prostatic hyperplasia.
  5. 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).
  6. 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.
  7. Active uncontrolled infection, including known history of AIDS or hepatitis B or C.
  8. Any psychological, familial, sociological, or geographical condition that could potentially interfere with compliance with the study protocol and follow-up schedule.
  9. Prior history of a thromboembolic event within the last two years and not currently on systemic anticoagulation.
  10. Hematocrit >50%, untreated severe obstructive sleep apnea, uncontrolled or poorly controlled heart failure [per Endocrine Society Clinical Practice Guidelines (67)].
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Irina Rifkind, RN, MSN 410-502-2043 irifkin1@jhmi.edu
Contact: Rana Sullivan, RN, BSN 410-614-6337 tomalra@jhmi.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02090114
Other Study ID Numbers  ICMJE J1416
NA_00093344 ( Other Identifier: JHM IRB )
1R01CA184012-01 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study Sponsor  ICMJE Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Samuel Denmeade, MD Johns Hopkins School of Medicine - Sidney Kimmel Comprehensive Cancer Center
PRS Account Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Verification Date May 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP