3-arm Study of Abiraterone Acetate Alone, Abiraterone Acetate Plus Degarelix, a GnRH Antagonist, and Degarelix Alone for Patients With Prostate Cancer With a Rising PSA or a Rising PSA and Nodal Disease Following Definitive Radical Prostatectomy

Study Overview
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Brief Summary
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In April 2011, the United States Food and Drug Administration (FDA) approved the oral drug abiraterone acetate (Zytiga ®) in combination with prednisone (a steroid) to treat patients with metastatic castration-resistant prostate cancer who have received prior docetaxel (chemotherapy). In December 2012, the FDA approved Zytiga ® in combination with prednisone to treat patients with metastatic castration-resistant prostate cancer who have not received prior chemotherapy. Degarelix (Firmagon ®), a testosterone lowering agent given as a monthly injection, is FDA approved for the treatment of patients with advanced prostate cancer. The purpose of this study is to evaluate abiraterone acetate and prednisone in combination with degarelix as a possible treatment for PSA recurrent prostate cancer as compared to abiraterone acetate alone and degarelix alone. This will be the first time these drugs will be used together.

Official Title
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A Phase 2, Randomized, 3-arm Study of Abiraterone Acetate Alone, Abiraterone Acetate Plus Degarelix, a GnRH Antagonist, and Degarelix Alone for Patients With Prostate Cancer With a Rising PSA or a Rising PSA and Nodal Disease Following Definitive Radical Prostatectomy

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Abiraterone acetate
* Drug: Abiraterone acetate plus degarelix
* Drug: Degarelix


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to provide written informed consent and Authorization for Use and Release of Health and Research Study Information (HIPAA authorization) NOTE: HIPAA authorization may be either included in the informed consent or obtained separately. Male aged 18 years and above Patients must have undergone local treatment via radical prostatectomy Patients who have received primary radiation therapy followed by a salvage radical prostatectomy are eligible. Patients who have had post-operative radiation therapy for presumed locally recurrent disease are eligible Histologically confirmed prostate cancer (per standards at Institution of participant registration) currently with progressive disease, defined as: Rising PSA (50% or more increase to a level of 1 ng/mL or more, based on at least 3 PSA determinations obtained at least 1 week apart). The 50% rise in PSA is across the 3 determinations, and these determinations do not need to be sequential AND PSADT ≤ 9 months as calculated according to the Memorial Sloan-Kettering Cancer Center nomogram (http://www.mskcc.org/mskcc/html/10088.cfm) OR Rising PSA as defined above AND Metastatic disease limited to the presence of pelvic and/or retroperitoneal nodes < 2 cm in short axis. Patients must have a serum testosterone of 150 ng/dL or greater ECOG performance status of ≤ 2 (Appendix A) Adequate bone marrow, hepatic, and renal function, as evidenced within 14 days prior to treatment initiation by: Absolute neutrophil count (ANC) ≥ 1500/mm3 Platelet count ≥ 100,000/mm3 Hemoglobin ≥ 9 g/dL without need for hematopoietic growth factor or transfusion support within 30 days prior to treatment initiation Aspartate aminotransferase (AST) ≤ 1.5 times the upper limit of the normal range (x ULN) Alanine aminotransferase (ALT) ≤ 1.5 x ULN Total bilirubin ≤ 1.5 x ULN Serum creatinine of ≤ 1.5 mg/dl or Calculated creatinine clearance of ≥ 60 mL/min Serum albumin ≥ 3.0 g/dL Serum potassium ≥ 3.5 mEq/L Prothrombin time (PT) ≤ 1.5 x ULN (or international normalized ratio [INR] ≤ 1.3) unless the patient is receiving anticoagulant therapy Partial thromboplastin time (PTT) ≤ 1.5 x ULN unless the patient is receiving anticoagulant therapy At least 4 weeks and recovery to Grade 0-1 from reversible effects of prior surgery (i.e., incisional pain, wound drainage) Able to swallow the study drug whole as a tablet Willing to take abiraterone acetate on an empty stomach; no food should be consumed at least two hours before and for at least one hour after the dose of abiraterone acetate is taken Patients who have partners of childbearing potential must be willing to use a method of birth control with adequate barrier protection as determined to be acceptable by the principal investigator during the study and for 1 week after last dose of abiraterone acetate. Exclusion Criteria: Prior cytotoxic chemotherapy or biologic therapy for prostate cancer More than 8 months of prior hormonal therapy (e.g., gonadotropin-releasing hormone analogs, megestrol acetate, or Casodex) Note: Patients who have been on prior hormonal therapy must wait at least 1 year after the drug is fully metabolized to start treatment on protocol. Prior ketoconazole, abiraterone acetate, or enzalutamide for the treatment of prostate cancer. Known brain metastasis or evidence of metastatic disease by CT scan, physical exam, or bone scan within 4 weeks of registration Patients with equivocal uptake on a bone scan that in the clinician's opinion do not definitively constitute metastatic disease are eligible Currently active second malignancy Significant medical condition other than cancer, that would prevent consistent and compliant participation in the study that would, in the opinion of the investigator, make this protocol unreasonably hazardous including but not limited to: Active infection or other medical condition that would make prednisone/prednisolone (corticosteroid) use contraindicated Severe hepatic impairment (Child-Pugh Class C) History of gastrointestinal disorders (medical disorders or extensive surgery) that may interfere with the absorption of the study agents Uncontrolled hypertension (systolic BP ≥ 160 mmHg or diastolic BP ≥ 95 mmHg); patients with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment Active or symptomatic viral hepatitis or chronic liver disease History of pituitary or adrenal dysfunction Clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or New York Heart Association (NYHA) Class III or IV heart disease or cardiac ejection fraction measurement of < 50 % at baseline Atrial fibrillation, or other cardiac arrhythmia requiring medical therapy Uncontrolled diabetes mellitus Active psychiatric condition Use of any prohibited concomitant medications (Section 5.5) within 30 days prior to Cycle 1, Day 1 Pre-existing condition that warrants long-term corticosteroid use in excess of study dose Grade > 2 treatment-related toxicity from prior therapy Known allergies, hypersensitivity or intolerance to abiraterone acetate, prednisone or degarelix Administration of an investigational therapeutic within 30 days of Cycle 1, Day1 Any condition which, in the opinion of the investigator, would preclude participation in this trial

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Abiraterone acetate<br>Group 1 Abiraterone acetate 1000 mg daily x 8 months Prednisone 5 mg once daily x 8 months | Drug: Abiraterone acetate<br>* Patients randomized to abiraterone acetate and prednisone (Group 1) will be instructed to take 1000 mg (four 250 mg tablets) of abiraterone acetate orally (PO) at least 1 hour before a meal and 2 hours after a meal every day. These patients will also be treated with prednisone 5 mg once daily with food.<br>|
| Experimental: Abiraterone acetate and Degarelix<br>Group 2 Abiraterone acetate 1000 mg daily x 8 months Prednisone 5 mg once daily x 8 months Degarelix subcutaneous depot injection q 1 month x 8 months | Drug: Abiraterone acetate plus degarelix<br>* Patients randomized to abiraterone acetate plus degarelix and prednisone (Group 2) will be instructed to take 1000 mg (four 250 mg tablets) of abiraterone acetate orally (PO) at least 1 hour before a meal and 2 hours after a meal every day and prednisone 5 mg once daily with food. Patients will also be given two subcutaneous injections of degarelix 120 mg on Cycle 1, Day 1(starting dose) and 80 mg subcutaneous doses (maintenance doses) every 28 days (±3 days) thereafter.<br>|
| Experimental: Degarelix<br>Group 3 • Degarelix subcutaneous depot injection q 1 month x 8 months | Drug: Degarelix<br>* Patients randomized to degarelix alone (Group 3) will be given two subcutaneous injections of degarelix 120 mg on Cycle 1, Day 1 (starting dose) and 80 mg subcutaneous doses (maintenance doses) every 28 days (± 3 days) thereafter.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | defined as an undetectable PSA (using a routine non-ultrasensitive PSA assay) with non-castrate level of testosterone (>150 ng/dL) at 18 months from the time of treatment initiation (PSA0). | 18 months | 
| Soft Tissue Complete Response | In addition to an undetectable PSA, any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm (Complete Response per RECIST) in order to meet the criteria for PFS. Outcome in subjects who develop radiographically evident metastatic disease while on study will be considered treatment failures independent of their respective PSA values. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PSA Response Rate | The percentage of patients with a non-castrate level of testosterone (>150 ng/dL) and an undetectable PSA at 8 months from PSA0 will be measured. | 8 months | 
| Overall Quality of Life | with particular attention to libido, potency, anxiety, depression, hot flashes, and fatigue. Effects of each arm on health-related quality of life will be assessed via PRO Survey (Appendix C) completed on paper by the patient at the following study visits: Up to 30 Days Prior to Randomization, each Day 1 of Treatment Cycle, End of Treatment, and each Post-Treatment Follow-up.Effects of each arm on quality of life, | 1 year | 
| Non-hematologic Adverse Events | Safety will be evaluated according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Safety assessments will be based on medical review of adverse event reports and the results of vital sign measurements, physical examinations and clinical laboratory tests throughout the conduct of the study. | 1 year | 
| Testosterone and Luteinizing Hormone (LH) Recovery Rates | Testosterone and LH recovery rates will be measured at 8 months from the start of randomization and at each month of the 10 month follow up period. | 8 -10 months | 
| Correlative Tissue Analysis | Tissue samples will be utilized for morphologic assessment, percent tumor involvement (if applicable), and immunohistochemistry. The immunohistochemical markers assessed may be AR, PTEN, PSMA, fatty acid synthase (FASN), phospho-AMPK, phospho-ACC, phospho-S6 kinase, phospho-Akt for the assessment of the AMPK, lipid synthesis, mTOR pathways, and immunological markers. | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ABIRATERONE ACETATE (CB 7630), DEGARELIX, PREDNISONE, 12-187