A Phase II Study of Increased-Dose Abiraterone Acetate in Patients With Castration Resistant Prostate Cancer

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase II Study of Increased-Dose Abiraterone Acetate in Patients With Castration Resistant Prostate Cancer (CRPC)

Conditions
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Castration Resistant Prostate Cancer

Intervention / Treatment
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* Drug: Abiraterone Acetate
* Drug: Prednisone


Participation Criteria
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Eligibility Criteria
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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 Total bilirubin ≤ 1.5 x ULN (In patients with known Gilbert Syndrome, a total bilirubin ≤ 3.0 x ULN, with direct bilirubin ≤ 1.5 x ULN is acceptable) Have a platelet count of ≥ 100,000/μL Have an absolute neutrophil count of > 1500 cell/mm3 Have a calculated creatinine clearance ≥ 60 mL/min Have a hemoglobin of ≥ 9.0 g/dL Have histologically confirmed adenocarcinoma of the prostate. No prior therapy with chemotherapy for metastatic prostate cancer. Have metastatic disease based on a positive bone scan or objective imaging on CT scan. Have ongoing gonadal androgen deprivation therapy with Luteinizing hormone-releasing hormone (LHRH) analogues or orchiectomy. Patients who have not had an orchiectomy must be maintained on effective LHRH analogue therapy for the duration of the trial. Testosterone < 50 ng/dL. Progressive disease after androgen deprivation: PSA evidence for progressive prostate cancer consists of a PSA level of at least 2 ng/ml which has risen on at least 2 successive occasions, at least 2 weeks apart. If the confirmatory PSA value is less than the screening PSA value, then an additional test for rising PSA will be required to document progression. Antiandrogen Withdrawal (AAWD): Patients who are receiving an antiandrogen as part of primary androgen ablation must demonstrate disease progression following discontinuation of antiandrogen. Disease progression after antiandrogen withdrawal is defined as 2 consecutive rising PSA values, obtained at least 2 weeks apart, or documented osseous or soft tissue progression. For patients receiving flutamide, at least one of the PSA values must be obtained 4 weeks or more after flutamide discontinuation. For patients receiving bicalutamide or nilutamide, at least one of the PSA values must be obtained 6 weeks or more after antiandrogen discontinuation. No antiandrogen withdrawal response is expected in patients in whom antiandrogen therapy did NOT result in a decline in PSA or in those patients in whom the response to antiandrogens was < 3 months. Therefore, it is not necessary to wait for AAWD in patients without PSA decline on an anti-androgen or in those in whom a PSA response lasted < 3 months. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 Life expectancy of ≥ 12 weeks. 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 Have a pre-existing condition that warrants long-term corticosteroid use in excess of study dose Have known allergies, hypersensitivity, or intolerance to abiraterone acetate or prednisone or their excipients Any condition which, in the opinion of the investigator, would preclude participation in this trial. Pure small cell carcinoma of the prostate or any mixed histology cancer of the prostate (eg: neuroendocrine) which contains < 50% adenocarcinoma. Therapy with other hormonal therapy, including any dose of megestrol acetate (Megace), finasteride (Proscar), dutasteride (Avodart) any herbal product known to decrease PSA levels (e.g., Saw Palmetto and PC-SPES), or any systemic corticosteroid within 4 weeks prior to first dose of study drug. Prior therapy with Abiraterone Acetate or other CYP17 inhibitor(s) including TAK-700 or TOK-001, or investigational agent(s) targeting the androgen receptor for metastatic prostate cancer. Prior therapy with ketoconazole for > 2 weeks for prostate cancer. Therapy with supplements or complementary medicines/botanicals within 4 weeks of first dose of study drug, except for any combination of the following: Conventional multivitamin supplements Selenium Lycopene Soy supplements Prior radiation therapy completed < 4 weeks prior to enrollment Prior chemotherapy for castration resistant prostate cancer. Patients who have received chemotherapy for early stage prostate cancer (e.g. as part of a neoadjuvant or adjuvant trial) or for other malignancies are eligible provided that >1 year has passed since the administration of the last chemotherapy dose. Any currently active second malignancy, other than non-melanoma skin cancer. Patients are not considered to have a currently active malignancy, if they have completed therapy and are considered by their physician to be at least less than 30% risk of relapse over next year. Active psychiatric illnesses/social situations that would limit compliance with protocol requirements. Patients in whom urgent chemotherapy, in the opinion of the treating physician, is indicated should not be enrolled in this study.

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: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Simon's 2 stage minimax design for accrual.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Standard Dose<br>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 | Drug: Abiraterone Acetate<br>* Standard dose participants: 1,000 mg, once daily, oral administration. Dose escalation participants: 1,000 mg, twice daily, oral administration<br>* Other names: Zytiga;Drug: Prednisone<br>* 5 mg, twice daily, oral administration<br>|
| Experimental: Escalated Dose<br>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 | Drug: Abiraterone Acetate<br>* Standard dose participants: 1,000 mg, once daily, oral administration. Dose escalation participants: 1,000 mg, twice daily, oral administration<br>* Other names: Zytiga;Drug: Prednisone<br>* 5 mg, twice daily, oral administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With PSA Response From 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. | Up to 12 weeks from start of dose escalation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Worst-grade, Treatment-related Toxicities for Dose Escalation Group | Frequency of any treatment-related toxicity with increased-dose Abiraterone Acetate by maximum observed grade will be tabulated for the study cohort. Toxicities will be graded for management according to NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 as a measure of patient safety. | Up to 24 months | 
| Time to PSA Progression for Dose Escalation Cohort | Time to PSA progression as defined by RECIST criteria or by the Prostate Cancer Working Group 2 (PCWG) criteria for patients whom were treated with increased dose Abiraterone Acetate. | up to 24 months | 
| Progression Free Survival for Dose Escalation Cohort | Progression free survival for patients treated with increased dose Abiraterone Acetate | up to 24 months | 
| Serum Concentration Levels of Abiraterone Acetate Over Time | Pharmacokinetic assessment at the initiation of standard dose therapy, at the time of initial disease progression, at the time of a response to increased dose of abiraterone acetate and at the time of disease progression on increased-dose therapy. | Up to 24 months | 
| Correlation of Circulating Testosterone Levels at Baseline and Week 12 | Pearson's correlation coefficients (r) will be calculated to summarize the relationship between testosterone values at baseline and at 12 weeks. Testosterone labs will be obtained at an earlier time point if the patient comes off study for disease progression before week 12. Coefficients are on a continuous scale ranging from -1 to +1 with a value of -1 indicating a perfect negative linear association of testosterone levels between the 2 time points, a value of 0 indicating no association between testosterone levels between the two time points, and a value of +1 indicating a positive linear association of testosterone levels between the two time points. | Baseline and Week 12 | 
| Comparison of Circulating Testosterone Levels Between Primary-Resistant Patients and Responders | The distribution of the baseline testosterone levels and the change in hormone level at 12 weeks will be compared between patients experiencing a PSA decline >30% (responders) and patients without such a PSA decline (primary-resistant) using a two group t statistic. Measurements will be obtained at an earlier time point if the patient comes off study for disease progression before week 12. | Baseline and Week 12 | 
| Correlation of Circulating Dehydroepiandrosterone (DHEA) Levels From Baseline to Week 12 | Pearson's correlation coefficients (r) will be calculated to summarize the relationship between DHEA values at baseline and at 12 weeks. DHEA labs will be obtained at an earlier time point if the patient comes off study for disease progression before week 12. Coefficients are on a continuous scale ranging from -1 to +1 with a value of -1 indicating a perfect negative linear association of DHEA levels between the 2 time points, a value of 0 indicating no association between DHEA levels between the two time points, and a value of +1 indicating a positive linear association of DHEA levels between the two time points. | Baseline and Week 12 | 
| Comparison of Circulating DHEA Levels Between Primary-Resistant and Responders | The distribution of the baseline DHEA levels and the change in hormone level at 12 weeks will be compared between patients experiencing a PSA decline >30% (responders) and patients without such a PSA decline (primary-resistant) using a two group t statistic. Measurements will be obtained at an earlier time point if the patient comes off study for disease progression before week 12. | Baseline and Week 12 | 
| Correlation of Circulating Dehydroepiandrosterone-sulfate (DHEA-S) Levels at Baseline and Week 12 | Pearson's correlation coefficients (r) will be calculated to summarize the relationship between DHEA-S values at baseline and at 12 weeks. DHEA-S labs will be obtained at an earlier time point if the patient comes off study for disease progression before week 12. Coefficients are on a continuous scale ranging from -1 to +1 with a value of -1 indicating a perfect negative linear association of DHEA-S levels between the 2 time points, a value of 0 indicating no association between DHEA-S levels between the two time points, and a value of +1 indicating a positive linear association of DHEA-S levels between the two time points. | Baseline and Week 12 | 
| Comparison of Circulating DHEA-S Levels Between Primary-Resistant Patients and Responders | The distribution of the baseline DHEA-S levels and the change in hormone level at 12 weeks will be compared between patients experiencing a PSA decline >30% (responders) and patients without such a PSA decline (primary-resistant) using a two group t statistic. Measurements will be obtained at an earlier time point if the patient comes off study for disease progression before week 12. | Baseline and Week 12 | 
| Correlation of Circulating Androstenedione Levels at Baseline and Week 12 | Pearson's correlation coefficients (r) will be calculated to summarize the relationship between androstenedione values at baseline and at 12 weeks. Androstenedione labs will be obtained at an earlier time point if the patient comes off study for disease progression before week 12. Coefficients are on a continuous scale ranging from -1 to +1 with a value of -1 indicating a perfect negative linear association of androstenedione levels between the 2 time points, a value of 0 indicating no association between androstenedione levels between the two time points, and a value of +1 indicating a positive linear association of androstenedione levels between the two time points. | Baseline and Week 12 | 
| Comparison of Circulating Androstenedione Levels Between Primary-Resistant Patients and Responders | The distribution of the baseline androstenedione levels and the change in hormone level at 12 weeks will be compared between patients experiencing a PSA decline >30% (responders) and patients without such a PSA decline (primary-resistant) using a two group t statistic. Measurements will be obtained at an earlier time point if the patient comes off study for disease progression before week 12. | Baseline and Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CRPC, Prostate, Cancer