Efficacy and Safety Study of Enzalutamide in Combination With Paclitaxel Chemotherapy or as Monotherapy Versus Placebo With Paclitaxel in Patients With Advanced, Diagnostic-Positive, Triple-Negative Breast Cancer

• Drug: Enzalutamide
  
  Enzalutamide will be administered as four 40-mg capsules once daily (160 mg/day).
  Other Names:
  

  • Xtandi
  • MDV3100
• Drug: Placebo
• Drug: Paclitaxel
  
  Paclitaxel (90 mg/m2) will be administered by constant-rate intravenous infusion of ? 1 hour once weekly for 16 weeks. Dose reductions or alterations to the schedule are allowed to maintain patient safety.

• Experimental: Double-blind enzalutamide with paclitaxel
  
  Interventions:
  

  • Drug: Enzalutamide
  • Drug: Paclitaxel
• Placebo Comparator: Double-blind placebo with paclitaxel
  
  Interventions:
  

  • Drug: Placebo
  • Drug: Paclitaxel
• Experimental: Open-label enzalutamide monotherapy followed by paclitaxel
  
  At the time of disease progression, enzalutamide treatment will be discontinued and paclitaxel will be administered if considered to be an appropriate treatment by the treating physician until second disease progression.
  Interventions:
  

  • Drug: Enzalutamide
  • Drug: Paclitaxel

Inclusion Criteria:

• Adult women and men at least 18 years of age and willing and able to provide informed consent.
• Has advanced TNBC:
• TNBC is defined as staining by immunohistochemistry (IHC) < 1% or Allred score < 2 for estrogen receptor (ER) and progesterone receptor (PgR), and 0 or 1+ by IHC for human epidermal growth factor receptor 2 (HER2) or negative for gene amplification (average HER2 copy number < 4 signals/cell; HER2:CEP17 ratio < 2.0).
• Advanced disease is defined as locally advanced or metastatic disease not amenable to curative intent surgery or radiotherapy.
• Has diagnostic-positive status as determined by a central diagnostic testing laboratory.
• Received 0 or 1 prior line of systemic therapy in the advanced disease setting.
• Patients who received 1 prior line of therapy for locally advanced or metastatic TNBC must have objective disease progression as assessed by the investigator.
• Has measurable and/or disease that is not measurable but is evaluable using RECIST 1.1 (eg, bone metastases, pathologic lymph nodes, or skin lesions).
• Patients with nonmeasurable and nonevaluable TNBC (eg, malignant effusions or bone marrow as the only manifestations of disease) are not eligible for enrollment.
• Patients with metastatic disease limited to the bone must have disease adequately visualized by computed tomography (CT) with bone windows, magnetic resonance imaging (MRI), or x-ray.
• Has an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 at screening and a life expectancy of at least 3 months from randomization.

Exclusion Criteria:

• Received a taxane regimen ? 28 days in duration in the advanced disease setting.
• Prior taxane therapy for neoadjuvant and/or adjuvant disease is permitted.
• A single dose of a taxane given as part of an every-3-weeks regimen is permitted.
• Two doses of a taxane given as part of a once-weekly regimen is permitted.
• Had a disease-free interval of ? 12 months from the last dose of taxane when used as part of adjuvant therapy for patients who did not receive prior therapy for locally advanced or metastatic breast cancer.
• Has history of or known central nervous system (CNS) metastasis or active leptomeningeal disease; brain imaging is required for all patients during screening.
• Received any anticancer agent (commercially available or investigational) within 14 days before randomization.
• Received treatment with any of the following medications within 14 days before randomization:
• Estrogens, including hormone replacement therapy
• Androgens (eg, testosterone, dehydroepiandrosterone)
• Systemic radionuclides (eg, samarium, strontium)
• Had major surgery within 4 weeks before randomization.
• Has a history of another invasive cancer within 3 years before randomization, with the exception of fully treated cancers with a remote probability of recurrence.
• Has a history of a seizure condition or any condition that may predispose to seizure (eg, prior cortical stroke or significant brain trauma).
• Has known hypersensitivity to any of the enzalutamide/placebo capsule components.
• Had a hypersensitivity reaction to Cremophor EL (polyoxyethylated castor oil) or a drug formulated in Cremophor EL, such as paclitaxel, unless successfully treated and rechallenged with appropriate premedications.

• Astellas Pharma Inc
• Medivation, Inc.