Abiraterone Acetate: Abbreviated Clinical Study Report Synopsis COU-AA-BE
`
`SYNOPSIS
`14 October 2010
`Issue Date:
`Document No.: EDMS-ERI-13494974:2.0
`Name of Sponsor/Company
`Cougar Biotechnology, Inc.
`Name of Finished Product
`abiraterone acetate
`Name of Active Ingredient(s)
`abiraterone acetate, JNJ-212082
`
`Protocol No.: COU-AA-BE
`
`Title of Study: A Pharmacokinetics Study to Assess the Oral Administration of CB7630 (abiraterone
`acetate) Capsule Formulation and Tablet Formulation in Patients with Prostate Cancer
`
`EudraCT Number: 2006-006650-10
`
`NCT No.: NCT00600535
`
`Principal Investigator: Robert J. Jones, MD, Beatson Cancer Center, 1053 Great Western Road, Glasgow;
`United Kingdom
`
`Study Centers: Royal Marsden Hospital NHS Trust, Downs Road, Sutton, Surrey, United Kingdom;
`Beatson Cancer Center, Great Western Road; Glasgow, United Kingdom; and UCLA Medical Center,
`Department of Hematology & Oncology, VA Greater LA Healthcare System Building, Los Angeles, CA,
`USA
`
`Publication (Reference): None
`
`Study Period: 11 June 2007 to 22 January 2010
`
`Phase of Development: 1
`
`Objectives: The primary objective of this study was to evaluate the pharmacokinetics of abiraterone
`acetate administered in capsule formulation with that in tablet formulation under fasted and fed conditions
`in subjects with prostate cancer.
`
`Secondary objectives were to: 1) evaluate safety and tolerability of daily administration of abiraterone
`acetate tablet; 2) assess antitumor activities of daily administration of abiraterone acetate tablet; and
`3) evaluate the role of circulating tumor cell (CTC) enumeration (optional) and tumor characterization
`(optional) in the assessment of prognosis and treatment response in the study population.
`
`The main purpose of this abbreviated study report is to present the safety and tolerability data of
`abiraterone acetate in this study up to 22 January 2010.
`
`Methodology: This was a Phase 1 multi-center, open-label, 2–arm study with a 4-stage design to evaluate
`the pharmacokinetics of abiraterone acetate administered in a capsule formulation and in a tablet
`formulation under fed and fasted conditions in subjects with adenocarcinoma of the prostate. Eligible
`subjects were enrolled sequentially alternating between Arms 1 (fed) and 2 (fasted). The study had a
`screening period of 14 days prior to Day 1 of Stage I. Stage I was a single dose pharmacokinetic study,
`with a cross-over design for comparison of capsules and tablets and parallel design for comparison of fed
`versus fasting. In Group 1, subjects received capsules (four 250 mg capsules of abiraterone acetate) on
`Day 1 and tablets (four 250 mg tablets of abiraterone acetate) on Day 8 and in Group 2, subjects received
`tablets on Day 1 and capsules on Day 8 under fed (Arm 1) condition. A similar design was used for
`subjects under fasted condition (Arm 2). Fasted condition was defined as an overnight fast for at least
`10 hours and continued fast for 4 hours after drug administration. Fed condition was defined as an
`overnight fast followed by a meal of 800 to 1000 calories within approximately 30 minutes before drug
`administration and continued fast for 4 hours. Stage II was a daily dose study of abiraterone acetate tablets
`(four 250 mg tablets) under fed versus fasted conditions. Subjects were to receive daily doses of abiraterone
`1
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`Abiraterone Acetate: Abbreviated Clinical Study Report Synopsis COU-AA-BE
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`acetate under fed or fasted conditions until disease progression, death, or availability of abiraterone acetate
`through healthcare provider(s) or the development program ceased. Fasted condition was defined as an
`overnight fast and study drug administration 1 hour before or 2 hours after a meal. Fed condition was
`defined as a normal breakfast in the morning or a meal during the day followed by study drug
`administration. Stage III and Stage IV were conducted to evaluate safety and to measure antitumor activity
`of the abiraterone acetate tablets (four 250 mg tablets) under fasted condition. Subjects who had completed
`12 cycles of abiraterone acetate in Stage III and continued to receive clinical benefit were to enter Stage IV
`for additional 12 cycles (total 24 cycles). Each cycle was of 28±7 days. Subjects in Stage III and Stage IV
`were concurrently taking prednisolone/prednisone 5 mg twice daily or dexamethasone 0.5 mg once daily.
`After the end of the study visit, subjects were to be followed up every 3 months for disease progression and
`survival for up to 3 years.
`
`Number of Subjects (planned and analyzed): Planned: Twelve to 20 subjects for the crossover
`bioavailability study were to be enrolled into each of the 2 arms (6 to 10 per group) for Stage I, and
`consequently a total of 24 to 40 subjects were to be enrolled in the study. Analyzed: Of the 33 subjects
`enrolled in the study, 31 received at least 1 dose of abiraterone acetate and comprised the safety analysis
`set. Twenty-nine subjects met criteria for prostate specific antigen (PSA) evaluations (ie, had baseline and
`at least 1 post-baseline PSA assessment) and comprised the PSA-evaluable population used to determine
`the antitumor activity of abiraterone acetate.
`
`Diagnosis and Main Criteria for Inclusion: Men with adenocarcinoma of the prostate undergoing
`androgen deprivation therapy and with serum testosterone levels of less than 50 ng/dL were eligible for this
`study. Eastern Cooperative Oncology Group (ECOG) performance status had to be less than 2 (or
`Karnofsky Performance Status of greater than or equal to 50%). Subjects were not to receive radiotherapy,
`chemotherapy, or immunotherapy within 30 days of administration of study drug, and toxicities related to
`prior chemotherapy and radiotherapy had to resolve to a National Cancer Institute Common Terminology
`Criteria for Adverse Events (NCI CTCAE, Version 3.0) Grade 1 or less. Subjects with adrenal
`insufficiency or hyperaldosteronism were excluded from the study. Subjects with New York Heart
`Association (NYHA) classification of III or IV heart disease or with any other medical conditions that
`could interfere with their participation in the study were excluded.
`
`Test Product, Dose and Mode of Administration, Batch No.: Abitraterone acetate 250 mg (batch
`numbers: 0079C, A06490, 9405.001, 9405.003, 9405.004, and 9405.006) was supplied as tablets and
`capsules for oral administration. Subjects received abiraterone acetate 1000 mg (4×250 mg as capsules or
`tablets) once daily. Starting with Stage III, oral dosing with prednisone/prednisolone 5 mg twice daily or
`dexamethasone 0.5 mg once daily was initiated. Commercially available prednisone/prednisolone and
`dexamethasone were used.
`
`Reference Therapy, Dose and Mode of Administration, Batch No.: Not applicable.
`
`Duration of Treatment: In Stage I, Group 1 subjects received abiraterone acetate (1000 mg) as capsules
`(4x250 mg) on Day 1 and as tablets (4x250 mg) on Day 8, and Group 2 subjects received the same dose as
`tablets on Day 1 and as capsules on Day 8 under fed (Arm 1) condition. A similar design was used for
`subjects under fasted condition (Arm 2). In Stage II, subjects received daily doses of abiraterone acetate
`(1000 mg) as tablets (4x250 mg) under fed versus fasted condition. In Stages III and IV, subjects received
`12 cycles each (28±7 days/cycle) of abiraterone acetate (1000 mg once daily, total of 24 cycles) under
`fasted condition.
`
`Criteria for Evaluation: Pharmacokinetics: For the determination of plasma concentrations of abiraterone
`acetate and abiraterone, blood samples were taken during Stage I on Days 1 and 8 ( capsules/tablets versus
`tablets/capsules) under fed (Arm 1) and fasting (Arm 2) conditions. Blood samples were taken predose and
`1, 2, 4, 6, 8, 24, 48 and 72 hrs postdose. Efficacy: The antitumor activities of abiraterone acetate were
`evaluated by measuring PSA. Prostate specific antigen response rates, time to PSA response, and time to
`PSA progression were analyzed in subjects with baseline and at least 1 post-baseline PSA measurement.
`Eastern Cooperative Oncology Group (ECOG) performance status was also measured. Optional efficacy
`parameters included CTC enumeration and tumor characterization. Safety: Safety and tolerability were
`evaluated by assessment of adverse events, clinical laboratory tests (hematology, chemistry, and
`
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`Abiraterone Acetate: Abbreviated Clinical Study Report Synopsis COU-AA-BE
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`urinalysis), vital sign measurements (pulse and blood pressure), physical examination, 12-lead
`electrocardiograms (ECGs), and tumor imaging (chest X-ray, computed tomography scan or magnetic
`resonance imaging) and bone scans.
`
`Statistical Methods: Sample size determination: No formal justification for the sample size was
`performed. Pharmacokinetics: The bioavailability of both formulations of abiraterone acetate was based
`upon the 90% confidence intervals (CIs) of the relative means (tablet or capsule) of back-transformed
`values of area under the curve (AUC) and maximum concentration (Cmax). Both formulations were to be
`considered equivalent if the 90% confidence limits were within a 0.80 to 1.25 range (80% to 125%) for
`AUC and within a 0.75 to 1.33 range (75% to 133%) for other parameters. Efficacy: All CIs for the
`estimations were reported using 2-sided 95% CIs, unless otherwise specified. Continuous endpoints were
`summarized using descriptive statistics, which
`included
`the number of subjects with a valid
`measurement (n), mean, standard deviation, median, and range. Descriptive statistics were used to
`summarize CTC enumeration and tumor characterization. Binary and multinomial endpoints were
`summarized using frequencies and percentages. Percentages were calculated by dividing the number of
`subjects with the characteristic of interest by the number of subjects in the analysis population. The
`exact (Clopper-Pearson) 95% confidence limits were provided for the PSA response rate estimate. A
`waterfall graph was produced for the maximal PSA decline. The Kaplan-Meier product-limit method was
`used to estimate the median time-to-PSA progression. The corresponding 95% CI for the median
`time-to-PSA progression estimate was calculated. ECOG performance status was summarized using
`descriptive statistics. Safety: The safety of abiraterone acetate was evaluated from the signing of the
`informed consent through post-treatment (ie, 30 days after the last dose of abiraterone acetate) by
`examining the incidence, severity, relationship to study medication, and type of adverse events; changes in
`clinical laboratory test results, physical examination and vital sign measurements; concomitant
`medication/therapy; 12-lead ECGs; and tumor images and bone scans. Data were summarized using
`descriptive statistics.
`
`RESULTS:
`
`STUDY POPULATION: Thirty-three subjects were enrolled in this study, and 31 subjects were treated
`with abiraterone acetate. All subjects had adenocarcinoma of the prostate, and the most common site of
`metastasis was bone (71%). The median age of the study population was 70 years. All treated subjects
`(31 [100%]) received prior androgen deprivation therapy for prostate cancer as mandated by the protocol.
`Of these, 30 subjects (97%) received luteinizing-hormone-releasing hormone. Twenty-four (77%) subjects
`had prior radiotherapy, and 20 (65%) subjects had prior chemotherapy for the treatment of prostate cancer
`with most (55%) subjects receiving prior docetaxel therapy.
`
`PHARMACOKINETIC RESULTS: Significant increases in drug exposures (AUClast) and maximum drug
`concentrations (Cmax) were observed when abiraterone acetate was administered concomitantly with food,
`in comparison with the fasting state, for both the capsule and tablet formulations. Under fed conditions,
`tablets and capsules resulted in similar, but not equivalent, exposures to abiraterone. Likewise, under fasted
`conditions, tablets and capsules resulted in similar, but not equivalent, exposures. However, the highly
`variable results preclude definitive conclusions. In addition, disposition of the study drug was similar with
`tablets and capsules under fed and fasted conditions.
`
`EFFICACY RESULTS: Antitumor activity was assessed on the basis of declines in PSA levels
`post-baseline. A decline in PSA levels of 50% or greater was confirmed in 48% of PSA evaluable subjects.
`The median time to PSA response was 1.4 months (43 days; 95% CI: 38.00, 48.00), and the median
`duration of response was 7.4 months (225 days). The median time to PSA progression was 8.7 months
`(264 days). Optional secondary endpoints, CTC enumeration and tumor characterization, were not
`evaluated.
`
`SAFETY RESULTS: The median duration of treatment with abiraterone acetate was 23.3 weeks
`(5.4 months), and the longest treatment duration was 94 weeks. Ninety percent of subjects discontinued
`from treatment at the cut-off date. The primary reason for discontinuation of treatment was reported as
`progressive disease (58%).
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`Abiraterone Acetate: Abbreviated Clinical Study Report Synopsis COU-AA-BE
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`The most frequently reported treatment-emergent adverse events were nausea (32%, all with a severity of
`Grade 1 or 2) followed by hypokalemia (23%; 6 subjects with a severity Grade 1, 1 with a severity Grade 4,
`and 1 with a severity Grade 5) and arthralgia (23%, all with a severity of Grade 1 or 2). The majority of
`abiraterone acetate treated-subjects (74%) experienced at least 1 drug-related treatment-emergent adverse
`event. Hypokalemia (23%), increased blood pressure (16%), nausea (10%), fatigue (10%), and lethargy
`(10%) were the most common drug-related adverse events reported; hypokalemia and increased blood
`pressure are known mineralocorticoid-related toxicities. Grade 3 or 4 treatment-emergent adverse events
`were reported by 19% of subjects; spinal cord compression was reported by 2 (6%) subjects, and all other
`Grade 3 or 4 adverse events (by preferred term) were reported by no more than 1 subject.
`
`Two subjects died within 30 days of the last dose of abiraterone acetate. One subject died of a cardiac arrest
`that was assessed by the investigator as unrelated to the study medication. The second subject experienced
`a serious Grade 5 adverse event of hypokalemia and died. The Grade 5 hypokalemia was assessed by the
`investigator as probably related to the study medication. In response to the Grade 5 hypokalemia, the
`following changes in study conduct were implemented: 1) Treatment with prednisolone/prednisone 5 mg
`twice daily or dexamethasone 0.5 mg once daily was initiated; 2) Potassium supplementation was initiated
`when serum potassium levels were 3.5 mM or lower. Treatment included the intravenous administration of
`potassium when serum potassium levels were less than 3.0 mM.; 3) Frequent monitoring of electrolytes
`was initiated; and 4) Cardiac monitoring was initiated for subjects with serum potassium levels less than
`3.0 mM.
`
`Treatment-emergent serious adverse events were reported in 29% of abiraterone acetate-treated subjects. Of
`these, 1 subject experienced a Grade 4 serious adverse event of hypokalemia. In addition, 1 subject
`experienced a Grade 5 serious adverse event of hypokalemia (as noted above). Four (13%) subjects
`reported adverse events leading to discontinuation of study treatment. No subject discontinued study
`treatment due to a drug-related adverse event.
`
`Sixty-eight percent of subjects reported treatment-emergent adverse events of special interest (ie, adverse
`events related to the known pharmacologic mechanism of action of abiraterone acetate which leads to
`mineralocorticoid excess [eg, hypokalemia, hypertension, fluid retention/edema, etc.] as well as adverse
`event related to liver function abnormalities and cardiac disorders). The most commonly reported
`treatment-emergent adverse events of special interest were hypokalemia (23%), increased blood pressure
`(16%), fluid retention (10%), and edema peripheral (10%). The majority of these treatment-emergent
`adverse events of special interest were Grade 1 or 2 severity events.
`
`With the exception of alkaline phosphatase, few (2 or less) subjects experienced Grade 3 or 4 chemistry
`abnormalities. Five subjects had vital sign abnormalities reported (change in pulse rate and/or blood
`pressure).
`
`STUDY LIMITATIONS: The pharmacokinetic variability of abiraterone acetate and the small number of
`subjects evaluated are the known limitations of this study.
`
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`Disclaimer
`
`Information in this posting shall not be considered to be a claim for any marketed
`product. Some information in this posting may differ from, or not be included in,
`the approved labeling for the product. Please refer to the full prescribing
`information for indications and proper use of the product.
`
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