A Phase II Study of Increased-Dose Abiraterone Acetate in Patients With Castration Resistant Prostate Cancer (CRPC)
Overview
- Phase
- Phase 2
- Intervention
- Abiraterone Acetate
- Conditions
- Castration Resistant Prostate Cancer
- Sponsor
- Terence Friedlander, MD
- Enrollment
- 41
- Locations
- 2
- Primary Endpoint
- Number of Patients With PSA Response From Dose Escalation
- Status
- Completed
- Last Updated
- 5 years ago
Overview
Brief Summary
The purpose of this study is to find out what effects, good and/or bad,an increased dose of Abiraterone Acetate in combination with prednisone has on patients and their prostate cancer. This study will investigate whether an increased-dose (2,000mg daily) is safe and potentially effective when given to patients whose cancer has grown while taking the standard dose.
Detailed Description
This is a phase II multicenter trial of Abiraterone Acetate (AA) in patients with progressive prostate cancer despite androgen deprivation with a particular focus on the pharmacokinetic, pharmacodynamic, and pharmacogenomic events occurring at the time of apparent drug resistance. All eligible patients will have baseline (prior to taking the first dose of Abiraterone Acetate 1000mg/daily) measures of routine clinical variables along with measurements of baseline and treatment related changes in testosterone, androgen, and endocrine levels, genotyping of single-nucleotide polymorphisms (SNP) in the selected enzymes known to be directly inhibited by Abiraterone Acetate, and collection of circulating tumor cells. All patients will be requested to consent for biopsies which will be performed prior to treatment and at the time of disease progression on standard dose Abiraterone Acetate therapy. These biopsies will be analyzed for expression of an androgen receptor (AR)-signature as well as for microarray analysis to explore changes in methylation, and expression of CYP17A1 and other androgen synthesis genes. Subjects will then begin daily oral therapy with Abiraterone Acetate 1000mg po daily with physiologic prednisone 5mg BID replacement. No food should be consumed for at least 2 hours before the dose of Abiraterone Acetate and for at least 1 hour after the dose of Abiraterone Acetate is taken. Prostate-specific antigen (PSA) will be followed monthly. Abiraterone Acetate will be supplied by Janssen Services. At the end of the first month, the third month, and then every three months thereafter, Abiraterone Acetate, testosterone, and androgen levels will be followed. Subjects not achieving a greater than or equal to 30% PSA decline at 12 weeks will be taken off study. At the time of progression (defined by RECIST criteria OR by the Prostate Cancer Working Group 2 (PCWG) criteria as a 25% increase in PSA above the nadir and an increase in the absolute value PSA of at least 2ng/dl or back to baseline confirmed at least 2 weeks afterward) for subjects who achieved an initial greater than or equal to 30% PSA decline (referred to as Progressive Disease (PD) #1), subjects will begin taking Abiraterone Acetate 1000 mg po BID. Patients will continue to take prednisone 5mg twice a day (BID) and will continue this therapy until a second progression at which point they will be withdrawn from the study. While 1000 mg po BID is not the FDA recommended dose, it is the dose to be investigated in this study.
Investigators
Terence Friedlander, MD
Assistant Clinical Professor
University of California, San Francisco
Eligibility Criteria
Inclusion Criteria
- •Have signed an informed consent document indicating that the subjects understands the purpose of and procedures required for the study and are willing to participate in the study
- •Be willing/able to adhere to the prohibitions and restrictions specified in this protocol
- •Written Authorization for Use and Release of Health and Research Study Information has been obtained
- •Male aged 18 years and above
- •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 and sponsor during the study and for 1 week after last study drug administration.
- •Have a baseline serum potassium of ≥ 3.5 milliequivalents per litre (mEq/L)
- •Have aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin levels \< 1.5 x upper limit of normal (ULN)
- •Have a serum albumin of ≥ 3.0 g/dL
Exclusion Criteria
- •Active infection or other medical condition that would make prednisone/prednisolone (corticosteroid) use contraindicated
- •Known brain metastasis
- •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 II-IV heart disease or cardiac ejection fraction measurement of \< 50 % at baseline
- •Atrial Fibrillation, or other cardiac arrhythmia requiring medical therapy
- •Administration of an investigational therapeutic within 30 days of screening
- •Have poorly controlled diabetes
- •Have a history of gastrointestinal disorders (medical disorders or extensive surgery) that may interfere with the absorption of the study agents
Arms & Interventions
Standard Dose
1000 milligrams (mg) abiraterone acetate in combination with prednisone taken once a day until progression defined by RECIST criteria OR by the Prostate Cancer Working Group 2 (PCWG) criteria
Intervention: Abiraterone Acetate
Standard Dose
1000 milligrams (mg) abiraterone acetate in combination with prednisone taken once a day until progression defined by RECIST criteria OR by the Prostate Cancer Working Group 2 (PCWG) criteria
Intervention: Prednisone
Escalated Dose
Participants who progressed on the standard dose will be assigned 1000 milligrams (mg) abiraterone acetate in combination with prednisone taken twice a day for at least 12 weeks until progression as defined by RECIST criteria OR by the Prostate Cancer Working Group 2 (PCWG) criteria
Intervention: Abiraterone Acetate
Escalated Dose
Participants who progressed on the standard dose will be assigned 1000 milligrams (mg) abiraterone acetate in combination with prednisone taken twice a day for at least 12 weeks until progression as defined by RECIST criteria OR by the Prostate Cancer Working Group 2 (PCWG) criteria
Intervention: Prednisone
Outcomes
Primary Outcomes
Number of Patients With PSA Response From Dose Escalation
Time Frame: Up to 12 weeks from start of dose escalation
A PSA response for the dose escalation group is defined as a participant with a documented PSA decline after 12 weeks of therapy with standard-dose, then had disease progression, and then achieved a ≥30% PSA decline after 12 weeks from the start of dose escalation therapy.
Secondary Outcomes
- Comparison of Circulating DHEA Levels Between Primary-Resistant and Responders(Baseline and Week 12)
- Correlation of Circulating Dehydroepiandrosterone-sulfate (DHEA-S) Levels at Baseline and Week 12(Baseline and Week 12)
- Number of Participants With Worst-grade, Treatment-related Toxicities for Dose Escalation Group(Up to 24 months)
- Time to PSA Progression for Dose Escalation Cohort(up to 24 months)
- Comparison of Circulating Testosterone Levels Between Primary-Resistant Patients and Responders(Baseline and Week 12)
- Comparison of Circulating Androstenedione Levels Between Primary-Resistant Patients and Responders(Baseline and Week 12)
- Correlation of Circulating Androstenedione Levels at Baseline and Week 12(Baseline and Week 12)
- Progression Free Survival for Dose Escalation Cohort(up to 24 months)
- Correlation of Circulating Dehydroepiandrosterone (DHEA) Levels From Baseline to Week 12(Baseline and Week 12)
- Comparison of Circulating DHEA-S Levels Between Primary-Resistant Patients and Responders(Baseline and Week 12)
- Serum Concentration Levels of Abiraterone Acetate Over Time(Up to 24 months)
- Correlation of Circulating Testosterone Levels at Baseline and Week 12(Baseline and Week 12)