Clinical Trials /

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

NCT02090114

Description:

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).

Related Conditions:
  • Prostate Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: RE-sensitizing With Supraphysiologic Testosterone to Overcome REsistance (The RESTORE Study)
  • 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

Clinical Trial IDs

  • ORG STUDY ID: J1416
  • SECONDARY ID: NA_00093344
  • SECONDARY ID: 1R01CA184012-01
  • NCT ID: NCT02090114

Conditions

  • Prostate Cancer

Interventions

DrugSynonymsArms
Testosterone cypionateDEPO-Testosterone InjectionPost-abiraterone or post-enzalutamide or post-castration only
Testosterone EnanthateDelatestrylPost-abiraterone or post-enzalutamide or post-castration only
Abiraterone acetateZytigaPost-abiraterone or post-enzalutamide or post-castration only
Enzalutamide (Cohort A = CLOSED TO ACCRUAL)XtandiPost-abiraterone or post-enzalutamide or post-castration only

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Post-abiraterone or post-enzalutamide or post-castration onlyExperimentalMen 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).
  • Testosterone cypionate
  • Testosterone Enanthate
  • Abiraterone acetate
  • Enzalutamide (Cohort A = CLOSED TO ACCRUAL)

Eligibility Criteria

        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)].
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Prostate Specific Antigen (PSA) response to Bipolar Androgen Therapy (BAT)
Time Frame:up to 18 months
Safety Issue:
Description:Number of participants with ≥50% PSA reduction from pre-BAT baseline level

Secondary Outcome Measures

Measure:PSA progression on enzalutamide or abiraterone acetate or castrate levels post-BAT
Time Frame:up to 18 months
Safety Issue:
Description:Time to PSA progression on enzalutamide or abiraterone acetate or return to castrate levels of testosterone post-BAT
Measure:PSA progression on BAT (Bipolar Androgen Therapy )
Time Frame:up to 18 months
Safety Issue:
Description:Time to PSA progression on BAT
Measure:Disease response as defined by RECIST 1.1 (soft tissue lesions) and PCWG2 criteria (bone lesions)
Time Frame:up to 18 months
Safety Issue:
Description: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.
Measure:Initiation of docetaxel chemotherapy
Time Frame:up to 18 months
Safety Issue:
Description:Time to initiation of docetaxel chemotherapy
Measure:Quality of Life (QoL) as assessed by FACIT-F score
Time Frame:Change from baseline to 18 months
Safety Issue:
Description: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.
Measure:Safety and Tolerability as assessed by Number of Participants with Adverse Events
Time Frame:18 months
Safety Issue:
Description:Number of participants who experience adverse events, as defined by NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0.
Measure:Fasting glucose
Time Frame:18 months
Safety Issue:
Description:Fasting blood glucose level (mg/dL)
Measure:Hemoglobin A1c
Time Frame:18 months
Safety Issue:
Description:Serum percent glycosylated hemoglobin (Hemoglobin A1C)
Measure:Fasting insulin
Time Frame:18 months
Safety Issue:
Description:Fasting insulin levels
Measure:Serum C-telopeptide
Time Frame:18 months
Safety Issue:
Description:Serum C-telopeptide levels (pg/mL)
Measure:Osteocalcin
Time Frame:On average at 18 months
Safety Issue:
Description:Serum Osteocalcin levels (ng/mL)
Measure:Effect of treatment with testosterone and abiraterone acetate or enzalutamide on Bone Scan with SPECT CT
Time Frame:18 months
Safety Issue:
Description: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
Measure:Quality of Life (QoL) as assessed by RANDSF-36
Time Frame:Change from baseline to 18 months
Safety Issue:
Description: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.
Measure:Quality of Life (QoL) as assessed by BPI
Time Frame:Change from baseline to 18 months
Safety Issue:
Description: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.
Measure:Quality of Life (QoL) as assessed by IIEF
Time Frame:Change from baseline to 18 months
Safety Issue:
Description: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.
Measure:Quality of Life (QoL) as assessed by PANAS
Time Frame:Change from baseline to 18 months
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Trial Keywords

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

Last Updated

May 10, 2019