Testosterone Revival Abolishes Negative Symptoms, Fosters Objective Response and Modulates Enzalutamide Resistance
Condition: Castration Resistant Metastatic Prostate Cancer
MeSH terms: Prostatic Neoplasms
Intervention: Testosterone cypionate; Enzalutamide; Testosterone Enanthate
Intervention description: 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.; Enzalutamide is a white crystalline non-hygroscopic solid. It is practically insoluble in water. Enzalutamide is provided as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides. The inactive ingredients are caprylocaproyl polyoxylglycerides, butylated hydroxyanisole, butylated hydroxytoluene, gelatin, sorbitol sorbitan solution, glycerin, purified water, titanium dioxide, and black iron oxide.; 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.
Intervention MeSH terms: Methyltestosterone; Testosterone; Testosterone undecanoate; Testosterone enanthate; Testosterone 17 beta-cypionate
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 222.0
Sex: Male
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: Testosterone; Enzalutamide; Abiraterone; Androgen Ablative Therapies; Bipolar Androgen Therapy

Summary:

      Asymptomatic men with progressive metastatic Castration-resistant prostate cancer (CRPC)
      post- treatment with abiraterone acetate (pre-chemotherapy for metastatic disease) will be
      treated on a randomized, multi-Institutional open label study to determine if treatment with
      intramuscular T given on a dose/schedule designed to result in rapid cycling from the polar
      extremes of supraphysiologic to near castrate levels [i.e. Bipolar Androgen Therapy (BAT)]
      will improve primary and secondary objectives vs. enzalutamide as standard therapy.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Eastern Cooperative Oncology Group Performance status ≤2

          -  Age ≥18 years

          -  Histologically-confirmed adenocarcinoma of the prostate

          -  Treated with continuous androgen ablative therapy (either surgical castration or
             luteinizing hormone-releasing hormone agonist/antagonist)

          -  Documented castrate level of serum testosterone (<50 ng/dl)

          -  Metastatic disease radiographically documented by CT/MRI or bone scan.

          -  Must have had disease progression while on abiraterone acetate alone or abiraterone
             acetate in combination with other investigational agents based on:

               -  Prostate-specific antigen progression defined as an increase in Prostate-specific
                  antigen, 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 PCWG2 for patients with bone disease

               -  Screening Prostate-specific antigen must be ≥ 1.0 ng/mL.

               -  Prior treatment with additional second line hormone therapies is allowed.

               -  No prior treatment with enzalutamide, Apalutamide (ARN-509), Darolutamide
                  (ODM-201), galeterone or other investigational androgen receptor targeted
                  treatment is allowed.

               -  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.

               -  Prior treatment with Provenge vaccine and 223Radium (Xofigo) is allowed if >4
                  weeks from last dose.

               -  Patients must be withdrawn from abiraterone for ≥ 2 weeks.

               -  Patients must be weaned off prednisone and be off therapy for ≥ 1 week prior to
                  starting therapy.

               -  Acceptable liver function:

          -  Bilirubin < 2.5 times institutional upper limit of normal (ULN)

          -  aspartate aminotransferase (SGOT) and alanine aminotransferase (SGPT) < 2.5 times ULN

             - Acceptable renal function:

          -  Serum creatinine < 2.5 times ULN

             - 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 wks since prior radiation.

               -  Ability to understand and willingness to sign a written informed consent
                  document.

               -  Patients on either treatment arm will be considered for crossover if they
                  demonstrate evidence of radiographic disease progression.

        Exclusion Criteria:

          -  Pain due to metastatic prostate cancer requiring treatment intervention.

          -  Eastern Cooperative Oncology Group Performance status ≥3

          -  Prior treatment with enzalutamide is prohibited

          -  Prior treatment with docetaxel or cabazitaxel for metastatic castration-resistant
             prostate cancer is prohibited.

          -  Requires urinary catheterization for voiding due to obstruction secondary to prostatic
             enlargement well documented to be due to prostate cancer or benign prostatic
             hyperplasia (BPH).

          -  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)

          -  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 HIV/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.

          -  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].

          -  Patients with prior history of a thromboembolic event within the last 12 months that
             is not being treated with systemic anticoagulation are excluded.

          -  Patients allergic to sesame seed oil or cottonseed oil are excluded.

          -  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.