Phase II Clinical Trial of Abiraterone Acetate Without Exogenous Glucocorticoids in Men With Castration-resistant Prostate Cancer With Correlative Assessment of Hormone Intermediates.
Overview
- Phase
- Phase 2
- Intervention
- abiraterone acetate
- Conditions
- Castration-resistant Prostate Cancer
- Sponsor
- Dana-Farber Cancer Institute
- Enrollment
- 60
- Locations
- 8
- Primary Endpoint
- Number of Participants With Toxicities That Required the Addition of Prednisone to Manage Symptoms of Persistent or Severe Mineralocorticoid Excess
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
This study is comparing the safety and effectiveness of abiraterone acetate alone, followed by the addition of prednisone (when the participant's disease worsens or the physician feels it would lessen symptoms of toxicity) versus the current approved treatment regimen which involves the concomitant use of prednisone in conjunction with abiraterone acetate. Additionally, this study is also examining why participants stop responding to treatment with abiraterone acetate by evaluating blood and tissue.
Detailed Description
Participants will be treated with abiraterone acetate (AA) in 28-day cycles. Participants will be monitored (weekly for the first two cycles, then on Day 1 of each subsequent cycle) for symptoms of persistent or severe mineralocorticoid excess (including hypertension, hypokalemia). For participants who experience symptoms of persistent or severe hypertension or hypokalemia as detailed in the above schema, prednisone 5 mg by mouth twice daily will be added. We will monitor for other symptoms of AA toxicity to include fluid retention and fatigue. For participations who tolerate AA monotherapy without the addition of prednisone to manage symptoms of persistent or severe mineralocorticoid excess, prednisone 5 mg by mouth twice daily will be added at Prostate Specific Antigen (PSA) progression. Participants will be continued on study until symptomatic or radiographic progression or taken off study for another reason as detailed in protocol.
Investigators
Mary-Ellen Taplin, MD
Principal Investigators
Dana-Farber Cancer Institute
Eligibility Criteria
Inclusion Criteria
- •Participants must meet the following criteria on screening examination to be eligible to participate in the study:
- •Be a male ≥ 18 years of age.
- •Participants must have histologically or cytologically confirmed adenocarcinoma of the prostate without \>50% neuroendocrine differentiation or small cell histology.
- •Participants must have progressive disease as defined by one or more of the following:
- •Castrate resistant disease as defined by Prostate cancer working Group (PCWG).\[30\] Participants must have a rise in PSA on two successive determinations at least one week apart and PSA levels ≥ 2 ng/ml (only the screening PSA needs to be ≥ 2 ng/ml) and testosterone levels \< 50 ng/dL.
- •Soft tissue progression defined by Response Evaluation Criteria In Solid Tumors (RECIST) 1.
- •Bone disease progression defined by Prostate Cancer Clinical Trials Working Group 2 (PCWG2) with two or more new lesions on bone scan.\[30\]
- •Castration-resistant prostate cancer (CRPC) with metastatic disease with at least one site of metastatic disease must be amenable to needle biopsy. Soft tissue biopsy sites include: lymph node or visceral metastases. Bone sites include lumbar vertebrae, pelvic bones and long bones. Excluded sites are thoracic, cervical vertebrae, skull and rib lesions. Biopsy site will be selected with guidance of interventional radiologist determining best site to optimize balance of obtaining useful tissue for analysis and minimizing risk.
- •Participants without orchiectomy must be maintained on Luteinizing hormone-releasing hormone (LHRH) agonist/antagonist therapy.
- •Participants may have had any number of previous hormonal therapies (antiandrogens including enzalutamide, steroids, estrogens, finasteride, dutasteride, ketoconazole) provided these were discontinued ≥ 4 weeks before starting the trial.
Exclusion Criteria
- •Participants who exhibit any of the following conditions at screening will not be eligible for admission into the study.
- •Uncontrolled illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements or would make prednisone/prednisolone (corticosteroid) use contraindicated.
- •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.
- •Thromboembolism within 6 months of Cycle 1, Day
- •Severe hepatic impairment (Child-Pugh Class C).
- •History of pituitary or adrenal dysfunction.
- •Poorly controlled diabetes.
- •History of gastrointestinal disorders (medical disorders or extensive surgery) which may interfere with the absorption of the study drug.
- •Have a pre-existing condition that warrants long-term corticosteroid use.
- •Individuals with a history of a different malignancy are ineligible except for the following circumstances: 1) individuals with a history of other malignancies are eligible if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence of that malignancy, or 2) individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: superficial bladder cancer, basal cell or squamous cell carcinoma of the skin.
Arms & Interventions
abiraterone acetate
Participants will be treated with four 250 mg tablets (1,000 mg) of abiraterone acetate (AA) orally on 28-day cycles. For participants who experience persistent or severe mineralocorticoid excess or have PSA progression, prednisone 5 mg by mouth twice daily will be added. Patients will be treated until radiographic disease progression and unacceptable AE or taken off study for other reason.
Intervention: abiraterone acetate
Outcomes
Primary Outcomes
Number of Participants With Toxicities That Required the Addition of Prednisone to Manage Symptoms of Persistent or Severe Mineralocorticoid Excess
Time Frame: Patients were on abiraterone acetate up to 57 months and toxicities of mineralocorticoid excess were monitored each cycle (1cycle = 28 days).
Patients requiring prednisone to manage toxicities such as COU-302 any grade or COU-301 grade 3-4 hypertension, hypokalemia and edema per CTCAE v. 4.0 were summarized using frequency and percentage.
Secondary Outcomes
- Safety and Tolerability Associated With AA Monotherapy and the Addition of Prednisone to AA.(Adverse events were assessed continuously on treatment and up to 30 days after going off treatment (up to 55 months).)
- Number of Participants Requiring the Addition of Prednisone to Manage Symptoms of Severe Fatigue.(Patients were on abiraterone acetate up to 57 months.)
- Changes in BMI Between Cycle 1 and Next Cycle(1 month)
- Changes in Serum Concentrations of Corticosteroid Intermediates Between the First and Second Assessment Visits.(1 month)
- Changes in Serum Concentrations of ACTH Between Cycle 1 and Cycle 2.(1 month)
- Percent Changes in Serum Concentrations of Androgen (Including Testosterone, DHT and Androgen Precursors) Between Cycle 1 and Cycle 2.(1 month)
- Changes in Hemoglobin-A1c Between Cycle 1 and Next Cycle (Cycle 4)(3 months)
- PSA Response and Its Duration to AA Monotherapy.(PSA was measured every cycle (up to 25 months))
- Response of Measurable Disease to AA Monotherapy.(Imaging was performed every 12 weeks up to 23 months.)
- Number of Patients Who Progressed With Measurable Disease at Pre-study Among Those Who Were Added of Prednisone to AA at Time of PSA Progression on AA Monotherapy.(Imaging was performed every 12 weeks up to 23 months.)
- PSA Response and Its Duration to Addition of Prednisone to AA at Time of PSA Progression on AA Monotherapy.(PSA was measured every cycle (up to 25 months))
- Response of Measurable Disease to Addition of Prednisone to AA at Time of PSA Progression on AA Monotherapy.(Imaging was performed every 12 weeks up to 23 months.)
- Number of Patients Who Received AA Monotherapy and Progressed With Measurable Disease at Pre-study(Imaging was performed every 12 weeks up to 23 months.)
- Subsequent Lines of Therapy(Data not collected.)