A Study to Determine Safety and Tolerability of Enzalutamide (MDV3100) in Combination With Abiraterone Acetate in Bone Metastatic Castration-Resistant Prostate Cancer Patients

Study Overview
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Brief Summary
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The purpose of this study was to explore the safety and tolerability of enzalutamide in combination with abiraterone acetate plus prednisone. Subjects diagnosed with cancer of the prostate that was getting worse and spreading to the bone despite receiving hormone treatment were enrolled and received study treatment until disease progression.

Detailed Description
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For the study duration, all subjects maintained androgen deprivation with a gonadotropin releasing hormone (GnRH) agonist or antagonist or orchiectomy. Study drug was administered until disease progression. Disease progression was defined as a composite endpoint consisting of either clinical deterioration, radiographic progression or prostate-specific antigen (PSA) progression according to the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria.

Official Title
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A Phase 2 Study Determining Safety and Tolerability of Enzalutamide (Formerly MDV3100) in Combination With Abiraterone Acetate in Bone Metastatic Castration-Resistant Prostate Cancer Patients

Conditions
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Metastatic Castration-Resistant Prostate Cancer

Intervention / Treatment
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* Drug: enzalutamide
* Drug: abiraterone acetate
* Drug: prednisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features Presence of metastatic disease to the bone Ongoing androgen deprivation therapy with a gonadotropin releasing hormone (GnRH) analogue or orchiectomy (i.e., surgical or medical castration) Subject receiving bisphosphonate or denosumab therapy must have been on stable doses for at least 4 weeks prior to Day 1 Progressive disease defined as one or more of the following three criteria (Note: subjects who received an antiandrogen must demonstrate disease progression following discontinuation of antiandrogen): PSA progression defined by a minimum of two rising PSA levels with an interval of ≥ 1 week between each determination. The PSA value at the Screening visit should be ≥ 2 ng/mL Soft tissue disease progression as defined by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) Bone disease progression defined by PCWG2 criteria (two or more new lesions on bone scan compared with prior scan) Subject previously treated with chemotherapy must have no more than two prior chemotherapy regimens for the treatment of metastatic prostate cancer Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 Agree to use a double-barrier method of contraception which involves the use of a condom in combination with one of the following: contraceptive sponge, diaphragm, or cervical ring with spermicidal gel or foam, if having sex with a woman of child-bearing potential during the length of the study and for one week after abiraterone is discontinued and for at least three months after enzalutamide is discontinued Subject agrees not to participate in another interventional study while on treatment Exclusion Criteria: Known or suspected metastases in the brain Absolute neutrophil count < 1,000/μL, platelet count < 75,000/μL, and hemoglobin < 9 g/dL (NOTE: subject may not have received any growth factors or blood transfusions within seven days of the hematologic laboratory values obtained at the Screening visit) Total bilirubin (TBL), alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 times the upper limit of normal Creatinine (Cr) > 2 mg/dL Treatment with androgen receptor antagonists (bicalutamide, flutamide, nilutamide), 5-α reductase inhibitors (finasteride, dutasteride), estrogens, chemotherapy, or biologic therapy within 4 weeks of Day 1 visit Radiation therapy within 3 weeks (if single fraction of radiotherapy within 2 weeks) of Day 1 visit, or radionuclide therapy within 8 weeks of Day 1 Planned palliative procedures for alleviation of bone pain such as radiation therapy or surgery Structurally unstable bone lesions suggesting impending fracture History of seizure or any condition that may predispose to seizure including, but not limited to underlying brain injury, stroke, primary brain tumors, brain metastases, or alcoholism. Also, history of loss of consciousness or transient ischemic attack within 12 months of enrollment (Day 1 visit) Clinically significant cardiovascular disease including: Myocardial infarction within 6 months of Screening visit; Uncontrolled angina within 3 months of Screening visit; Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or subjects with history of congestive heart failure NYHA class 3 or 4 in the past, or history of anthracycline or anthracenedione (mitoxantrone) treatment, unless a screening echocardiogram or multi-gated acquisition scan (MUGA) performed within three months of the Screening visit results in a left ventricular ejection fraction that is ≥ 45% History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsade de pointes) Prolonged corrected QT interval by the Fridericia correction formula (QTcF) on the Electrocardiogram (ECG) > 470 msec. History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place Hypotension (systolic blood pressure < 86 mmHg or bradycardia with a heart rate of <50 beats per minute on the ECG., unless pharmaceutically induced and thus reversible (i.e. beta blockers). Uncontrolled hypertension as indicated by a resting systolic blood pressure >170 mmHg or diastolic blood pressure >105 mmHg Prior use of ketoconazole, abiraterone acetate or enzalutamide, or participation in a previous clinical trial of ketoconazole, abiraterone acetate or enzalutamide History of significant bleeding disorder unrelated to cancer, including: Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease) Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies) of Screening visit History of GI bleeding within 6 months of Screening visit Active or symptomatic viral hepatitis or chronic liver disease Known history of pituitary or adrenal dysfunction
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: Enzalutamide + Abiraterone + Prednisone<br>Participants received enzalutamide combined with abiraterone acetate once daily plus prednisone twice daily. | Drug: enzalutamide<br>* Participants received 160 mg of enzalutamide orally once daily (4 capsules, 40 mg each).<br>* Other names: MDV3100;Drug: abiraterone acetate<br>* Participants received 1000 mg of abiraterone acetate orally once daily (4 tablets, 250 mg each).<br>Drug: prednisone<br>* Participants received 5 mg of prednisone orally twice daily (2 tablets, 5 mg each).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) | A treatment-emergent adverse event (TEAE) was defined as an adverse event occurring or worsening between the start of study treatment date and the latest date of 30 days after the last dose date or the 30-day follow-up visit date, and not later than the data cut-off date or the date of death. AEs, including abnormal clinical laboratory values, were graded using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) guidelines (V4.03). | From the first dose of study drug administration up 30 days following the last dose of study drug date, with a median duration of treatment of 10.1 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Testosterone Concentration in Bone Marrow Aspirate | Testosterone concentration in bone marrow aspirate was measured by laboratory results derived from bone marrow samples processed through liquid chromatography mass spectrometry. | Baseline and Week 9 | 
| Change From Baseline in Dihydrotestosterone (DHT) Concentration in Bone Marrow Aspirate | DHT concentration in bone marrow aspirate was to be measured by laboratory results derived from bone marrow samples processed through liquid chromatography mass spectrometry. DHT bone data were not collected. | Baseline and Week 9 | 
| Change From Baseline in Cortisol in Bone Marrow Aspirate | Cortisol in bone marrow aspirate was measured by laboratory results derived from bone marrow samples. | Baseline and Week 9 | 
| Change From Baseline in Androstenedione in Bone Marrow Aspirate | Androstenedione in bone marrow aspirate was measured by laboratory results derived from bone marrow samples. | Baseline and Week 9 | 
| Change From Baseline in Progesterone in Bone Marrow Aspirate | Progesterone in bone marrow aspirate was measured by laboratory results derived from bone marrow samples. | Baseline and Week 9 | 
| Change From Baseline in Pregnenolone in Bone Marrow Aspirate | Pregnenolone in bone marrow aspirate was measured by laboratory results derived from bone marrow samples. | Baseline and Week 9 | 
| Change From Baseline in Testosterone Concentration in Blood | Testosterone concentration in blood was measured by laboratory results derived from plasma samples. Plasma samples were derived from collected blood samples processed through liquid chromatography mass spectrometry. | Baseline and Week 9 | 
| Change From Baseline in DHT Concentration in Blood | DHT concentration in blood was measured by laboratory results derived from plasma samples. Plasma samples were derived from collected blood samples processed through liquid chromatography mass spectrometry. The endpoint could not be analyzed since no participants had DHT levels over the lower limit of quantification (LLOQ). | Baseline and Week 9 | 
| Change From Baseline in Cortisol Concentration in Blood | Cortisol concentration in blood was measured by laboratory results derived from plasma samples. Plasma samples were derived from collected blood samples processed through liquid chromatography mass spectrometry. | Baseline and Week 9 | 
| Change From Baseline in Androstenedione Concentration in Blood | Androstenedione concentration in blood was measured by laboratory results derived from plasma samples. Plasma samples were derived from collected blood samples processed through liquid chromatography mass spectrometry. | Baseline and Week 9 | 
| Change From Baseline in Progesterone Concentration in Blood | Progesterone concentration in blood was measured by laboratory results derived from plasma samples. Plasma samples were derived from collected blood samples processed through liquid chromatography mass spectrometry. | Baseline and Week 9 | 
| Change From Baseline in Pregnenolone Concentration in Blood | Pregnenolone concentration in blood was measured by laboratory results derived from plasma samples. Plasma samples were derived from collected blood samples processed through liquid chromatography mass spectrometry. | Baseline and Week 9 | 
| Change From Baseline to End-of-Treatment (EoT) in Prostate-Specific Antigen (PSA) Levels | Prostate-specific antigen progression by Prostate Cancer Clinical Trials Working Group 2 (PCWG2) was defined as a PSA increase ≥25% and ≥2 ng/ml above the post-baseline nadir, and which was confirmed by the first subsequent value of 3 or more weeks later. | Baseline and EoT; the median duration of treatment was 10.1 months. | 
| Progression Free Survival (PFS) | PFS was measured as the time from the date of first dose of any drug of the study combination treatment until the first evidence of documented progression (a composite endpoint consisting of radiographic progression or PSA progression by PCWG2 or clinical deterioration) or death in the absence of progression (whichever came first) or the date last known to be progression free. The Kaplan-Meier (KM) 95% CI was based on Brookmeyer and Crowley robust non-parametric method. | Up to 1849 days | 
| Percentage of Participants With Objective Response for Soft Tissue Lesions According to Response Evaluation Criteria in Solid Tumors 1.1 (RECIST) | Objective response was based on RECIST version 1.1 for soft tissue lesion on Magnetic resonance imaging (MRI) / Computerized tomography (CT) and the PCWG2 guidelines for bone lesions on bone scans and was defined as partial response (PR) or complete response (CR) based on the investigators' assessments of target, non-target and new lesions while on study treatment. The 95% for objective response rate was based on exact binomial 95% confidence interval (Clopper-Pearson). | Up to 1849 days | 
| Bone Scan Response at EoT | PD: ≥1 of 3 criteria: PSA progression: ≥2 rising PSA levels, interval of ≥1 week between each determination. Soft tissue disease progression: RECIST 1.1. Bone disease progression: PCWG2 criteria (≥2 or new lesions on bone scan compared with prior scan). Target lesion CR: disappearance of all target lesions, PR as ≥30% decrease in sum of longest diameter (LD) of target lesions, referencing baseline sum LD, SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, referencing smallest sum LD since treatment start, PD ≥20% increase in sum of LD of target lesions, referencing smallest sum LD recorded since treatment start or appearance of ≥1 new lesions. Non-target lesions CR: disappearance of all non-target lesions and normalization of tumor marker level, SD: persistence of ≥1 non-target lesions and/or maintenance of tumor marker level above normal limits, PD: appearance of ≥1 new lesions and/or unequivocal progression of existing non-target lesions. | EoT; the median duration of treatment was 10.1 months. | 
| Change From Baseline to EoT in Bone Specific Alkaline Phosphatase | Bone metabolism marker bone specific alkaline phosphatase levels were derived from blood samples collected. | Baseline and EoT; the median duration of treatment was 10.1 months. | 
| Change From Baseline in Urine N-Telopeptide | Bone metabolism marker urine N-telopeptide levels were derived from urine samples collected. | Baseline and Week 9 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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abiraterone acetate, prednisone, enzalutamide, cancer, prostate, MDV3100