Sequential Testosterone and Enzalutamide Prevents Unfavorable Progression

A Randomized Phase II Study Comparing Sequential High Dose Testosterone and Enzalutamide to Enzalutamide Alone in Asymptomatic Men With Castration Resistant Metastatic Prostate Cancer

Sponsors

Lead Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Collaborator: United States Department of Defense

Source Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Brief Summary

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.

Overall Status Active, not recruiting
Start Date August 19, 2020
Completion Date July 2026
Primary Completion Date July 2025
Phase Phase 2
Study Type Interventional
Primary Outcome
Measure Time Frame
Clinical or Radiographic Progression free survival Up to 2 years
Secondary Outcome
Measure Time Frame
Safety of cyclical parenteral testosterone as assessed by the revised National Cancer Institute Common Toxicity Criteria Up to 2 years
Prostate-Specific Antigen Response Rate Up to 2 years
Objective Response Rate as Determined by RECIST Up to 2 years
Quality of Life as Assessed by FACIT Fatigue Scale Up to 1 year
Quality of Life as Assessed by Short Form 36 Up to 1 year
Time to Overall Survival Up to 3 years
Radiographic Progression free survival Up to 2 years
Enrollment 90
Condition
Intervention

Intervention Type: Drug

Intervention Name: Testosterone cypionate

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.

Arm Group Label: Arm B: Testosterone cypionate or Testosterone enanthate

Other Name: Depo-Testosterone Injection

Intervention Type: Drug

Intervention Name: Enzalutamide

Description: 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.

Arm Group Label: Arm A: Enzalutamide

Other Name: Cytoxan

Intervention Type: Drug

Intervention Name: Testosterone enanthate

Description: 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.

Arm Group Label: Arm B: Testosterone cypionate or Testosterone enanthate

Other Name: Delatestryl

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.

Gender: Male

Minimum Age: 18 Years

Maximum Age: 90 Years

Healthy Volunteers: No

Overall Official
Last Name Role Affiliation
Samuel Denmeade, MD Principal Investigator SKCCC at Johns Hopkins
Location
Facility: Johns Hopkins University/Sidney Kimmel Cancer Center
Location Countries

United States

Verification Date

August 2020

Responsible Party

Type: Sponsor

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Label: Arm A: Enzalutamide

Type: Experimental

Description: Patients randomized to Arm A will receive continuous therapy with standard dose Enzalutamide (160 mg oral daily).

Label: Arm B: Testosterone cypionate or Testosterone enanthate

Type: Experimental

Description: Patients randomized to Arm B will receive intramuscular injection with testosterone cypionate or testosterone enanthate at a dose of 400 mg every 56 days

Patient Data No
Study Design Info

Allocation: Randomized

Intervention Model: Parallel Assignment

Primary Purpose: Treatment

Masking: None (Open Label)

Source: ClinicalTrials.gov