Study of Abiraterone Acetate Without Exogenous Glucocorticoids in Men With Castration-resistant Prostate Cancer

Study Overview
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Brief Summary
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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
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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.

Official Title
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Phase II Clinical Trial of Abiraterone Acetate Without Exogenous Glucocorticoids in Men With Castration-resistant Prostate Cancer With Correlative Assessment of Hormone Intermediates.

Conditions
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Castration-resistant Prostate Cancer

Intervention / Treatment
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* Drug: abiraterone acetate


Participation Criteria
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Eligibility Criteria
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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) 1.1. 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. Participants may have had up to two previous cytotoxic therapeutic regimens provided these were discontinued ≥ 4 weeks before starting the trial. At least a 4 week interval from previous prostate cancer treatment other than LHRH agonist/antagonist therapy or bisphosphonates to the start of protocol therapy. Participants receiving bisphosphonates therapy can be maintained on this therapy. If participants have not started bisphosphonates, it is recommended that they start treatment after the first biopsy. Eastern Cooperative Oncology Group (ECOG) performance status < 2 (Karnofsky >60%, see Appendix A). Participants must have normal organ and marrow function as defined below: Platelets > 50,000/microliter (mcL) Serum potassium ≥ 3.5 mmol/L (independent of potassium supplementation) Serum albumin ≥ 3.0 g/dL Aspartate transaminase (AST), Alanine transaminase (ALT), and total bilirubin ≤ 1.5 x Institutional Upper Limit of Normal (ULN). Partial thromboplastin time (PTT) ≤ 60, International Normalized Ratio (INR) ≤ 1.5 Institutional ULN unless on warfarin therapy (investigator would need to determine if safe for participant to stop warfarin prior to biopsy) Controlled blood pressure (systolic blood pressure < 140 and diastolic blood pressure <90) on no more than three anti-hypertensive agents. Drug formulations containing two or more anti-hypertensive agents will be counted based on the number of active agents in each formulation. EKG showing a normal QTc interval (QTc < 450 msec). Left ventricular ejection fraction ≥ 50%. 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 (US sites only) has been obtained. Able to swallow the study drug whole as a tablet. Willing to take AA on an empty stomach; no food should be consumed at least two hours before and for at least one hour after the dose AA is taken. Participants 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 PI during the treatment period and for 1 week after last dose of AA. 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 1. 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. Known brain metastasis. Prior therapy with AA. Have known allergies, hypersensitivity, or intolerance to AA or prednisone or their excipients. Surgery or local prostatic intervention within 30 days of the first dose. In addition, any clinically relevant issues from the surgery must have resolved prior to Cycle 1, Day 1. Major surgery or radiation therapy within 4 weeks of Cycle 1, Day 1. Strontium-89 or samarium-153 therapy within 4 weeks of Cycle 1, Day 1. Radiotherapy, chemotherapy or immunotherapy within 4 weeks, or single fraction of palliative radiotherapy within 14 days of administration of Cycle 1, Day 1. Current enrollment in an investigational drug or device study or participation in such a study within 30 days of Cycle 1, Day 1. Any acute toxicities due to prior chemotherapy and/or radiotherapy that have not resolved to a NCI Common Toxicity Criteria for Adverse Effects (CTCAE) version 4 grade of ≤ 1. Chemotherapy induced alopecia and grade 2 peripheral neuropathy are allowed. Condition or situation which, in the investigator's opinion, may put the participant at significant risk, may confound the study results, or may interfere significantly with participant's participation in the study. Individuals not willing to comply with the procedural requirements of this protocol. HIV-positive individuals on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AA.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: abiraterone acetate<br>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. | Drug: abiraterone acetate<br>* Abiraterone acetate is a selective and irreversible inhibitor of CYP17 which has demonstrated clinical efficacy in patients with CRPC. Currently, AA is administered with concomitant prednisone.<br>* Other names: JNJ21208;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Toxicities That Required the Addition of Prednisone to Manage Symptoms of Persistent or Severe Mineralocorticoid Excess | 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. | Patients were on abiraterone acetate up to 57 months and toxicities of mineralocorticoid excess were monitored each cycle (1cycle = 28 days). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability Associated With AA Monotherapy and the Addition of Prednisone to AA. | Grade 3 or higher toxicities attribution to AA monotherapy with or without prednisone were summarized descriptively. | 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. | Participants initiated treatment with prednisone for ≥grade 3 fatigue were summarized using frequency and percentage. | Patients were on abiraterone acetate up to 57 months. | 
| Changes in Serum Concentrations of Corticosteroid Intermediates Between the First and Second Assessment Visits. | Percent change in corticosterone level between the first visit and the second visit was summarized by whether patients initiated prednisone for hypertension and hypokalemia. | 1 month | 
| Changes in Serum Concentrations of ACTH Between Cycle 1 and Cycle 2. | Changes in serum concentrations of ACTH at second assessment referent to the value at the first visit were summarized descriptively. | 1 month | 
| Percent Changes in Serum Concentrations of Androgen (Including Testosterone, DHT and Androgen Precursors) Between Cycle 1 and Cycle 2. | Change in corticosterone level between cycle 2 and cycle 1 was summarized by whether patients initiated prednisone for hypertension and hypokalemia. | 1 month | 
| Changes in BMI Between Cycle 1 and Next Cycle | Changes in BMI between cycle 1 and cycle 2 were summarized descriptively. | 1 month | 
| Changes in Hemoglobin-A1c Between Cycle 1 and Next Cycle (Cycle 4) | Changes in HbA1c at cycle 1 and next measurement at cycle 4 were summarized descriptively. | 3 months | 
| PSA Response and Its Duration to AA Monotherapy. | PSA response was defined per PCWG2 criteria (PSA reduction of ≥50%) and duration of PSA response is defined as time from PSA response to PSA progression or death, whichever occurs first. | PSA was measured every cycle (up to 25 months) | 
| PSA Response and Its Duration to Addition of Prednisone to AA at Time of PSA Progression on AA Monotherapy. | Among those who initiated prednisone due to PSA progression, duration of PSA response was calculated as time from PSA response (PSA reduction ≥50%) to PSA progression or death, whichever occurs first. | PSA was measured every cycle (up to 25 months) | 
| Response of Measurable Disease to AA Monotherapy. | Radiographic response of measurable disease is defined using RECIST v 1.1 for soft-tissue and visceral disease and PCWG2 for bone disease. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Response is tabulated descriptively. | 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 | Radiographic disease progression is defined using RECIST v 1.1 for soft-tissue and visceral disease and PCWG2 for bone disease (2 or more new lesions on bone scan and for the first 12-week assessment, defining disease progression requires a confirmatory scan performed 6 or more weeks later which shows a minimum of 2 additional new lesions). | Imaging was performed every 12 weeks up to 23 months. | 
| Response of Measurable Disease to Addition of Prednisone to AA at Time of PSA Progression on AA Monotherapy. | Radiographic response of measurable disease is defined using RECIST v 1.1 for soft-tissue and visceral disease and PCWG2 for bone disease. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Response is tabulated descriptively. | 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. | Radiographic response of measurable disease is defined using RECIST v 1.1 for soft-tissue and visceral disease and PCWG2 for bone disease. Due to small number patients, patients who experienced progressive disease were summarized using frequency and time to progression using Kaplan-Meier method was not calculated. | Imaging was performed every 12 weeks up to 23 months. | 
| Subsequent Lines of Therapy | Subsequent lines of therapy following study drug discontinuation were not collected for this trial. | Data not collected. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Castration-resistant Prostate Cancer, Abiraterone Acetate