Testosterone Therapy Followed by Enzalutamide or Abiraterone Acetate in Treating Patients with Prostate Cancer That Is Progressing on Combined Androgen Therapies

Status: Active

Description

This phase II trial studies how well testosterone therapy followed by enzalutamide or abiraterone acetate works in treating patients with prostate cancer that has become worse or spread on combined androgen therapies. Androgens, such as testosterone, can cause the growth of prostate cancer cells. Androgen therapies, such as enzalutamide and abiraterone acetate, suppress or block the production or action of testosterone. Rapid treatment with testosterone may make the cancer cells become sensitive to retreatment with enzalutamide or abiraterone acetate. Giving testosterone prior to enzalutamide or abiraterone acetate may have an effect on the growth of prostate cancer in men who have not responded to long term therapy to lower testosterone in their blood (castrating therapy).

Eligibility Criteria

Inclusion Criteria

  • Performance status =< 2
  • Histologically-confirmed adenocarcinoma of the prostate
  • Progressing on continuous androgen ablative therapy (either surgical castration or luteinizing hormone-releasing hormone [LHRH] agonist)
  • Documented castrate level of serum testosterone (< 50 ng/dl)
  • For Cohorts A and B, patients must have progressed on prior treatment with enzalutamide or abiraterone acetate + prednisone (by PSA criteria or radiographically)
  • 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
  • For Cohort D patients must have inactivating somatic or germline mutations in >= 2 of the genes TP53, PTEN, RB1
  • 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
  • Patients with rising PSA on two successive measurements at least two weeks apart
  • For Cohort A (enzalutamide) and Cohort B (abiraterone acetate): prior treatment with up to 2 additional second line hormone therapies, including ketoconazole is allowed
  • For Cohort A (enzalutamide) and Cohort B (abiraterone acetate): 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 acetate [abiraterone] then enzalutamide would receive retreatment with enzalutamide post-BAT)
  • For Cohort A (enzalutamide) and Cohort B (abiraterone acetate): patients must be withdrawn from enzalutamide or abiraterone acetate for >= 4 weeks and have documented PSA increase after the withdrawal period
  • For Cohort A (enzalutamide) and Cohort B (abiraterone acetate): patients receiving prednisone in conjunction with abiraterone acetate must be weaned off prednisone prior to starting BAT
  • For Cohort C (castration-only): * Patients must continue on castrating therapy throughout BAT treatment * 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
  • For Cohort D (mutation cohort): * Patients must continue on castrating therapy throughout BAT treatment * Treatment with first-generation hormonal therapy (i.e. flutamide, bicalutamide, nilutamide), is allowed * Patient must have received at least one and not more than two second generation hormone therapies (i.e. enzalutamide, abiraterone, apalutamide)
  • For Cohorts A-D, 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
  • For Cohort D, one line of prior chemotherapy with docetaxel or cabazitaxel for metastatic castrate resistant prostate cancer is allowed
  • Bilirubin < 2.5 times institutional upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 2.5 times ULN
  • Serum creatinine < 2.5 times ULN, OR
  • Absolute neutrophil count (ANC) >= 1500 cells/mm^3 (1.5 x 10^9/L)
  • Platelet count >= 100,000 platelet/mm^3 (100 x 10^9/L)
  • Hemoglobin >= 9 g/dL
  • At least 4 weeks since prior surgery with full recovery (no persistent toxicity >= grade 1)
  • Ability to understand and willingness to sign a written informed consent document

Exclusion Criteria

  • Pain due to metastatic prostate cancer requiring opioid analgesics
  • > 5 sites of visceral disease in lung or liver (nonspecific lung nodules =< 1 cm in diameter are permitted)
  • Prior treatment with docetaxel or cabazitaxel for metastatic castration-resistant prostate cancer is prohibited for Cohorts A-C
  • Prior treatment with one line of chemotherapy for metastatic castration-resistant prostate cancer is allowed for Cohort D
  • Requires urinary catheterization for voiding due to obstruction secondary to prostatic enlargement thought to be due to prostate cancer or benign prostatic hyperplasia
  • 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)
  • 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 acquired immune deficiency syndrome (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
  • Prior history of a thromboembolic event within the last two years and not currently on systemic anticoagulation
  • Prior myocardial infarction within one year of study entry
  • Hematocrit > 50%, untreated severe obstructive sleep apnea, uncontrolled or poorly controlled heart failure (per Endocrine Society Clinical Practice Guidelines)

Locations & Contacts

District of Columbia

Washington
Sibley Memorial Hospital
Status: Active
Contact: Samuel Ray Denmeade
Phone: 410-955-8875

Maryland

Baltimore
Johns Hopkins University / Sidney Kimmel Cancer Center
Status: Active
Contact: Samuel Ray Denmeade
Phone: 410-955-8875

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. Prostate-specific antigen (PSA) response to bipolar androgen therapy (BAT) (>= 50% PSA reduction from pre-BAT baseline level).

II. PSA response to enzalutamide or abiraterone acetate or first line castration-only therapy post-BAT (>= 50% PSA reduction from baseline PSA level obtained at initiation of enzalutamide or abiraterone acetate or first line castration-only therapy post-BAT).

SECONDARY OBJECTIVES:

I. Time to PSA progression on enzalutamide or abiraterone acetate or first line castration-only therapy post-BAT.

II. Time to PSA progression on BAT.

III. Measurable disease response post-BAT and post-treatment with enzalutamide or abiraterone acetate or first line castration-only therapy post-BAT.

IIIa. For soft tissue lesions, based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

IIIb. For bone disease, based on Prostate Cancer Working Group 2 criteria.

IV. Time to initiation of docetaxel chemotherapy.

V. Quality of Life Effects (Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F], Research and Development Short Form Healthy Survey-36 ([RANDSF-36], Brief Pain Inventory, International Index of Erectile Function [IIEF], Positive and Negative Affect Schedule [PANAS]) and metabolic studies.

VI. To measures changes in CD4, CD8, FOXP3, Ki-67, PD-1, PD-L1 tumor levels with BAT alone compared to archival tissue. (Cohort D)

VII. To measures immunohistochemistry (IHC)-based changes in gamma-H2AX, RAD51, 53BP1 (deoxyribonucleic acid [DNA] damage markers) following treatment with BAT compared to archival tissue. (Cohort D)

VIII. To develop a messenger ribonucleic acid (mRNA) expression signature associated with response to BAT. (Cohort D)

IX. Safety and tolerability.

OUTLINE:

Patients receive testosterone cypionate or testosterone enanthate intramuscularly (IM) on day 1 and continue to receive androgen ablative therapy with luteinizing hormone-releasing hormone (LHRH) agonist (goserelin acetate, leuprolide acetate, or triptorelin pamoate). Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. At the time of progression on BAT, patients continue LHRH agonist therapy alone for one month. Patients then receive enzalutamide orally (PO) daily on days 1-28 or abiraterone acetate PO daily and prednisone PO twice daily (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients experiencing PSA progression above nadir value have the option to receive re-treatment with BAT.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
Johns Hopkins University / Sidney Kimmel Cancer Center

Principal Investigator
Samuel Ray Denmeade

Trial IDs

Primary ID J1416
Secondary IDs NCI-2014-01366, NA_00093344, CIR00011018, CIR00006889
Clinicaltrials.gov ID NCT02090114