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

Study Overview
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Brief Summary
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The purpose of this study is to evaluate and compare the clinical benefit and safety of treatment with enzalutamide in combination with paclitaxel chemotherapy or as monotherapy versus placebo with paclitaxel in patients with locally advanced or metastatic, diagnostic-positive, triple-negative breast cancer (TNBC).

Official Title
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A Phase 3, Randomized, International Study Comparing the Efficacy and Safety of Enzalutamide in Combination With Paclitaxel Chemotherapy or as Monotherapy Versus Placebo With Paclitaxel in Patients With Advanced, Diagnostic-Positive, Triple-Negative Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Enzalutamide
* Drug: Placebo
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Double-blind enzalutamide with paclitaxel<br> | Drug: Enzalutamide<br>* Enzalutamide will be administered as four 40-mg capsules once daily (160 mg/day).<br>* Other names: MDV3100;Drug: Paclitaxel<br>* 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.<br>|
| Placebo Comparator: Double-blind placebo with paclitaxel<br> | Drug: Placebo<br> <br> Drug: Paclitaxel<br>* 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.<br>|
| Experimental: Open-label enzalutamide monotherapy followed by paclitaxel<br>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. | Drug: Enzalutamide<br>* Enzalutamide will be administered as four 40-mg capsules once daily (160 mg/day).<br>* Other names: MDV3100;Drug: Paclitaxel<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) |  | Anticipated in about 31 months following first patient enrolled | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival |  | Anticipated in about 40 months following first patient enrolled | 
| PFS assessed by the investigator using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 |  | Anticipated in about 31 months following first patient enrolled | 
| Time to treatment failure |  | Anticipated in about 31 months following first patient enrolled | 
| Best overall response | Best overall response is defined as the best tumor response (complete response [CR], partial response [PR], stable disease, progressive disease, not evaluable) based on investigator assessment per RECIST 1.1 over all tumor assessments performed any time on study. Best objective response rate is defined as the proportion of patients with a best overall response of CR or PR for all patients based on investigator assessment per RECIST 1.1. The 2-sided 95% Confidence Interval (CI) will be reported for each treatment group using the Clopper-Pearson method. | Anticipated in about 31 months following first patient enrolled | 
| Duration of response |  | Anticipated in about 31 months following first patient enrolled | 
| Time to second disease progression in patients randomly assigned to enzalutamide monotherapy who subsequently receive paclitaxel |  | Anticipated in about 31 months following first patient enrolled | 
| Clinical benefit rate at 24 weeks (CBR24): From the start of treatment D1 assessed every 8 weeks +/- 1 week while on study treatment | CBR (complete, partial response, or stable disease lasting 24 weeks or longer) assessed per RECIST 1.1 | 24 weeks | 
| Safety as assessed by percentage of patients with any Adverse Event (AE), AE leading to Study Drug Discontinuation, AE leading to death, Serious Adverse Event (SAE), AE related to study drug, SAE related to study drug |  | Anticipated in about 31 months following first patient enrolled | 
| Time to functional status deterioration using the Functional Assessment of Cancer Therapy-Breast (FACT-B) trial outcome index (physical, functional, breast) (TOI-PFB) |  | Anticipated in about 31 months following first patient enrolled | 
| Pharmacokinetics of enzalutamide as assessed by trough plasma concentrations |  | Anticipated in about 31 months following first patient enrolled | 
| Pharmacokinetics of the active metabolite N-desmethyl enzalutamide as assessed by trough plasma concentrations |  | Anticipated in about 31 months following first patient enrolled | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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metastatic, triple negative