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

• Nature, frequency and severity of adverse events [ Time Frame: Until documented disease progression (up to 24 months) ] [ Designated as safety issue: No ]
• Safety assessed by laboratory tests, vital signs, 12 lead electrocardiograms (ECGs) and physical examinations [ Time Frame: Until documented disease progression (up to 24 months) ] [ Designated as safety issue: No ]

• Testosterone concentration in bone marrow aspirate and blood [ Time Frame: Baseline and Week 9 ] [ Designated as safety issue: No ]
• Dihydrotestosterone (DHT) concentration in bone marrow aspirate and blood [ Time Frame: Baseline and Week 9 ] [ Designated as safety issue: No ]
• Expression and localization of androgen receptor [ Time Frame: Baseline and Week 9 ] [ Designated as safety issue: No ]
• Splice variants [ Time Frame: Baseline and Week 9 ] [ Designated as safety issue: No ]
• CYP17 expression [ Time Frame: Baseline and Week 9 ] [ Designated as safety issue: No ]
• Prostate-specific antigen (PSA) levels) [ Time Frame: 24 months ] [ Designated as safety issue: No ]
• Progression free survival (PFS) [ Time Frame: 24 months ] [ Designated as safety issue: No ]
  Defined as the time interval from the date of starting treatment until the date of documented progression or death in absence of progression.
• Objective response according to Response Evaluation Criteria in Solid Tumors 1.1 (RECIST) [ Time Frame: 24 months ] [ Designated as safety issue: No ]
  Partial or complete response
• Bone scan results [ Time Frame: Week 13, Week 25 and every subsequent 12 weeks (up to 24 months) ] [ Designated as safety issue: No ]
• Bone specific alkaline phosphatase [ Time Frame: 24 months ] [ Designated as safety issue: No ]
  Marker of bone metabolism
• Urine N-telopeptides [ Time Frame: Baseline and Week 9 ] [ Designated as safety issue: No ]
  Marker of bone metabolism

The purpose of this study is to explore the safety and tolerability of enzalutamide in combination with abiraterone acetate plus prednisone. Subjects diagnosed with cancer of the prostate that is getting worse and spread to the bone despite receiving hormone treatment will be enrolled and receive study treatment until disease progression.

For the study duration, all subjects will maintain androgen deprivation with a gonadotropin releasing hormone (GnRH) agonist or antagonist or orchiectomy. Study drug will be administered until disease progression. Disease progression is 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.

• Drug: enzalutamide
  oral
  Other Name: MDV3100
• Drug: abiraterone acetate
  oral
• Drug: prednisone
  oral

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 antiandrogren):

  • 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