Clinical Trials /

Sequential Testosterone and Enzalutamide Prevents Unfavorable Progression

NCT04363164

Description:

Asymptomatic men without pain due to prostate cancer progressing with metastatic CRPC after treatment with combination or sequential ADT + Abi will be treated on a randomized, open label study to determine if sequential treatment with high dose T and Enza will improve primary and secondary objectives vs. continuous Enza as standard therapy.

Related Conditions:
  • Prostate Adenocarcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Sequential Testosterone and Enzalutamide Prevents Unfavorable Progression
  • Official Title: A Randomized Phase II Study Comparing Sequential High Dose Testosterone and Enzalutamide to Enzalutamide Alone in Asymptomatic Men With Castration Resistant Metastatic Prostate Cancer

Clinical Trial IDs

  • ORG STUDY ID: IRB00246118
  • NCT ID: NCT04363164

Conditions

  • Castration Resistant Metastatic Prostate Cancer

Interventions

DrugSynonymsArms
Testosterone cypionateDepo-Testosterone InjectionArm B: Testosterone cypionate or Testosterone enanthate
EnzalutamideCytoxanArm A: Enzalutamide
Testosterone enanthateDelatestrylArm B: Testosterone cypionate or Testosterone enanthate

Purpose

Asymptomatic men without pain due to prostate cancer progressing with metastatic CRPC after treatment with combination or sequential ADT + Abi will be treated on a randomized, open label study to determine if sequential treatment with high dose T and Enza will improve primary and secondary objectives vs. continuous Enza as standard therapy.

Detailed Description

      Eligible patients are those who have progressive disease after treatment with Abi either in
      combination with ADT as initial therapy or as second-line therapy after development of
      resistance to primary ADT. Patients will continue on ADT with Luteinizing hormone-releasing
      hormone (LHRH) agonist (i.e. Zoladex, Trelstar, Eligard or Lupron) or LHRH antagonist
      (Degarelix) if not surgically castrated throughout the duration of the study to inhibit
      endogenous testosterone production. Patients will be randomized 1:2 and stratified based on
      whether patients received Abi in combination with ADT or in sequence after progression on ADT
      and based on duration of response to Abi (<6 or ≥ 6 months). Patients randomized to Arm A
      will receive continuous therapy with standard dose Enza (160 mg po q day). Patients
      randomized to Arm B will receive Sequential Testosterone and Enzalutamide (STE). Patients in
      Arm B will receive intramuscular injection with testosterone cypionate (T) at a dose of 400
      mg every 28 days x 2 (i.e. cycle 1). This dose was selected based on data demonstrating that
      it produces an initial high dose serum level of T (i.e. > 1500 ng/dL or 3-10 times normal
      level) with eugonadal levels achieved at the end of two weeks and near castrate levels after
      28 days. On Day 1 of cycle 2, patients will stop testosterone and begin enzalutamide 160 mg
      po q day for 56 days. Each cycle is 56 days. On Day 1 of cycle 3, patient will not take
      enzalutamide and will again receive injection of testosterone. Patients will continue to
      alternate one cycle of testosterone (2 injections) with one cycle of 56 days of enzalutamide.

      Patients will have prostate-specific antigen (PSA) level and symptoms assessment checked
      every cycle. Every 2 cycles (~4 months) patients will have repeat bone/CT scans to evaluate
      treatment response status. On CT scan, radiographic progression will be defined by RECIST
      criteria (i.e. >20% increase in the sum of target lesions). On bone scan, radiographic
      progression will be defined by PCWG3 criteria as ≥ 2 new bone lesions.

      Patients with PSA progression but with disease response or stable disease on imaging studies
      will remain on study until clinical or radiographic progression criteria are met. Patients
      with radiographic disease progression will stop treatment and come off study. Patients with
      clinical progression due to pain flare after first two injection of testosterone can remain
      on study. If pain persists after first cycle of enzalutamide, patients will stop treatment
      and come off study. If pain resolves on enzalutamide, but returns with next or subsequent
      cycles of testosterone, patients will stop treatment and come off study.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A: EnzalutamideExperimentalPatients randomized to Arm A will receive continuous therapy with standard dose Enzalutamide (160 mg oral daily).
  • Enzalutamide
Arm B: Testosterone cypionate or Testosterone enanthateExperimentalPatients randomized to Arm B will receive intramuscular injection with testosterone cypionate or testosterone enanthate at a dose of 400 mg every 56 days
  • Testosterone cypionate
  • Testosterone enanthate

Eligibility Criteria

        Inclusion Criteria:

          1. Eastern Cooperative Oncology Group (ECOG) Performance status ≤2.

          2. Age ≥18 years.

          3. Histologically-confirmed adenocarcinoma of the prostate.

          4. Treated with continuous androgen ablative therapy (either surgical castration or LHRH
             agonist/antagonist).

          5. Documented castrate level of serum testosterone (<50 ng/dl).

          6. Metastatic disease radiographically documented by CT or bone scan.

          7. Must have had disease progression while on abiraterone acetate alone or abiraterone
             acetate in combination with other ADT.:

          8. PSA progression defined as an increase in PSA, as determined by 2 separate
             measurements taken at least 1 week apart And/ Or Radiographic disease progression,
             based on RECIST 1.1 in patients with measurable soft tissue lesions or PCWG3 for
             patients with bone disease

          9. Screening PSA must be ≥ 1.0 ng/mL.

         10. Patients with soft tissue lesion amenable to biopsy must agree to biopsy collection
             pre-treatment and at a defined point on treatment to perform tumor tissue analysis.

         11. No prior treatment with enzalutamide, apalutamide, darolutamide, or other
             investigational androgen receptor (AR) targeted treatment is allowed.

         12. Prior treatment with testosterone is allowed.

         13. Prior treatment with docetaxel (≤ 6 doses)for hormone-sensitive prostate cancer is
             allowed.

         14. Prior treatment with Provenge vaccine and 223Radium (Xofigo) is allowed if >4 weeks
             from last dose.

         15. Patients must be withdrawn from abiraterone for ≥ 2 weeks.

         16. Attempts must be made to wean patients off prednisone and be off therapy for ≥ 1 week
             prior to starting therapy. Patients who cannot be weaned due to symptoms may continue
             on lowest dose of prednisone achieved during weaning period.

         17. Acceptable liver function:

             Bilirubin < 2.5 times institutional upper limit of normal (ULN) aspartate transaminase
             (AST) (SGOT) and aka alanine aminotransferase (ALT) (SGPT) < 2.5 times ULN

         18. Acceptable renal function:

             Serum creatinine < 2.5 times ULN

         19. 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.

         20. At least 4 weeks since prior radiation or chemotherapy.

         21. Ability to understand and willingness to sign a written informed consent document.

        Exclusion Criteria:

          1. Pain due to metastatic prostate cancer requiring treatment intervention.

          2. ECOG Performance status ≥3

          3. Prior treatment with enzalutamide is prohibited.

          4. Prior chemotherapy with docetaxel or cabazitaxel for castration resistant prostate
             cancer is prohibited.

          5. Requires urinary self-catheterization for voiding due to obstruction secondary to
             prostatic enlargement well documented to be due to prostate cancer or benign prostatic
             hyperplasia (BPH). Patients with indwelling Foley or suprapubic catheter for
             obstructive symptoms are eligible.

          6. 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, severe and extensive spinal metastases with concern over
             spinal cord compression, extensive liver metastases).

          7. 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.

          8. Active uncontrolled infection, including known history of HIV/AIDS or hepatitis B or
             C.

          9. Any psychological, familial, sociological, or geographical condition that could
             potentially interfere with compliance with the study protocol and follow-up schedule.

         10. Patients receiving anticoagulation therapy with Coumadin are not eligible for study.
             [Patients on non-coumadin anticoagulants (Lovenox, Xarelto, etc.) are eligible for
             study. Patients on Coumadin who can be transitioned to lovenox prior to starting study
             treatments will be eligible].

         11. Patients are excluded with prior history of a thromboembolic event within the last 12
             months that is not being treated with systemic anticoagulation.

         12. Hematocrit >51%, untreated severe obstructive sleep apnea, uncontrolled or poorly
             controlled heart failure [per Endocrine Society Clinical Practice Guidelines (34)]

         13. Patients allergic to sesame seed oil or cottonseed oil are excluded.

         14. Major surgery (eg, requiring general anesthesia) within 3 weeks before screening, or
             has not fully recovered from prior surgery (ie, unhealed wound). Note: subjects with
             planned surgical procedures to be conducted under local anesthesia may participate.
      
Maximum Eligible Age:90 Years
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Clinical or Radiographic Progression free survival
Time Frame:Up to 2 years
Safety Issue:
Description:Time from the date of the randomization to the date of first documented radiological progression per RECIST 1.1 for soft tissue or PCWG3 for bone lesions, or clinical progression or death, whichever occurs first.

Secondary Outcome Measures

Measure:Safety of cyclical parenteral testosterone as assessed by the revised National Cancer Institute Common Toxicity Criteria
Time Frame:Up to 2 years
Safety Issue:
Description:Safety of cyclical parenteral testosterone in asymptomatic men with recurrent castrate resistant prostate cancer. Safety will be evaluated by adverse events as assessed by the revised National Cancer Institute Common Toxicity Criteria (NCI CTC), version 4.0
Measure:Prostate-Specific Antigen Response Rate
Time Frame:Up to 2 years
Safety Issue:
Description:Number of participants achieving a Prostate-Specific Antigen decline ≥ 50% according to Prostate Cancer Working Group (PCWG2) criteria.
Measure:Objective Response Rate as Determined by RECIST
Time Frame:Up to 2 years
Safety Issue:
Description:Number of participants with partial (PR) or complete response (CR) as defined by response evaluation criteria in solid tumors (RECIST), where CR is a disappearance of all target lesions and PR is ≥30% reduction in the sum of the longest diameter of target lesions.
Measure:Quality of Life as Assessed by FACIT Fatigue Scale
Time Frame:Up to 1 year
Safety Issue:
Description:The Functional Assessment of Chronic Illness Therapy - Fatigue has a score range of 0-52 with higher scores indicating better quality of life.
Measure:Quality of Life as Assessed by Short Form 36
Time Frame:Up to 1 year
Safety Issue:
Description:All questions are scored on a scale from 0 to 100. The total score from all of the questions answered is divided by the total number of the questions answered yielding a global score from 0-100 with 100 representing the highest level of functioning possible.
Measure:Time to Overall Survival
Time Frame:Up to 3 years
Safety Issue:
Description:Time to overall survival will be calculated as months from date of off treatment up to 3 years.
Measure:Radiographic Progression free survival
Time Frame:Up to 2 years
Safety Issue:
Description:Number of months until 20% increase in the sum of target lesions on CT scans or greater than 2 new bone lesions on bone scan.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Trial Keywords

  • Testosterone
  • Enzalutamide
  • Androgen Deprivation Therapy (ADT)

Last Updated

April 23, 2020