A Study of Enzalutamide, Enzalutamide in Combination With Mifepristone, or Chemotherapy in People With Metastatic Breast Cancer

Study Overview
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Brief Summary
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The researchers are doing this study to find out if the study drug, enzalutamide, alone or combined with the study drug, mifepristone, is effective in treating advanced or metastatic androgen receptor-positive (AR+) triple negative breast cancer (TNBC) or estrogen receptor-low breast cancer (ER-low BC), and whether these study treatments work as well as standard chemotherapy with carboplatin, paclitaxel, capecitabine, or eribulin.

Official Title
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A RANDOMIZED, PHASE II STUDY OF ENZALUTAMIDE, ENZALUTAMIDE WITH MIFEPRISTONE, and TREATMENT OF PHYSICIAN'S CHOICE IN PATIENTS WITH AR+ METASTATIC TRIPLE-NEGATIVE OR ER-LOW BREAST CANCER

Conditions
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Metastatic Breast Cancer

Intervention / Treatment
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* Drug: Enzalutamide
* Drug: Mifepristone
* Drug: TPC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female or male Pathologically confirmed invasive breast cancer that is unresectable, locally advanced, or metastatic TNBC (ER/PgR <1%) or ER-low defined as: ER and PgR 1-10% HER2 negative per American Society of Clinical Oncology/College of American Pathologists guidelines Local testing for ER/PgR and HER2 is acceptable for eligibility. Tumor must be AR positive. AR is considered positive by IHC if ≥10% of cell nuclei are immunoreactive. °AR testing performed locally must use protocol specified methodology to be acceptable for eligibility. Central testing is an option for those unable to perform local testing per this methodology. Please refer to the Section entitled Treatment Plan for AR testing methodology or refer to the laboratory manual. Evaluable or measurable disease per RECIST version 1.1; subjects with no evaluable AND no measurable disease (e.g., malignant effusions or bone marrow as the only manifestations of disease) are not eligible for enrollment. Eligible for one of the chemotherapy options listed as TPC (eribulin, capecitabine, paclitaxel, or carboplatin), as per investigator assessment. A representative, formalin-fixed, paraffin-embedded tumor specimen that enables the diagnosis of breast cancer, with adequate viable tumor cells in a tissue block (preferred) or 15 freshly cut unstained slides and 1 H&E slide. Tissue from a metastatic site is preferred. If not available, tissue from the primary site may be obtained. Patients may have received up to 1 prior line of chemotherapy for metastatic breast cancer. Patients with ER-low breast cancer may receive any number of lines of endocrine therapy +/- targeted therapy (i.e., CDK4/6 inhibitors, PI3K inhibitors). Patients with PD-L1 positive breast cancer (CPS ≥ 10) should have received prior treatment with pembrolizumab in combination with chemotherapy in the first line setting unless there is a contraindication to checkpoint inhibitor therapy. Patients may receive bisphosphonate or denosumab. ECOG performance status 0-2. Age ≥18 years. Able to understand and the willingness to provide informed consent. Patients must not have another active malignancy that requires treatment. Women of child-bearing potential and men must agree to use 2 forms of adequate contraception (i.e., barrier contraception, abstinence, intrauterine device, or sterilization method) during study period and for 7 months following treatment end. Women must not breast feed while on study and for at least 3 months after final drug administration. Ability to swallow intact enzalutamide and mifepristone. Patient must be recovered from any recent major surgery. Radiation must have completed 14 days prior to study start. If treated in the second-line setting, the last chemotherapy or investigational anticancer therapy dose must be at least 14 days prior. Adequate organ and marrow function, as defined below: ANC ≥1000, hemoglobin ≥9 g/dL, platelets ≥100,000 Total bilirubin ≤1.5x upper limit of normal (ULN), except for patients with known Gilbert syndrome; AST/ALT ≤3x ULN (≤5x ULN if liver metastases); creatinine ≤ 1.5x ULN. Cortisol within normal limits Patients must agree to research biopsy at study entry until 40 patients randomized to Arm A and 40 patients randomized to Arm B and 20 patients randomized to Arm C have been biopsied. Biopsy requirement may be waived in consultation with the study PI (Drs. Traina or Nanda) if not medically feasible. Exclusion Criteria: History of seizure or any condition that may predispose to seizure (e.g., prior cortical stroke, significant brain trauma) at any time in the past. History of loss of consciousness or transient ischemic attack within 12 months. History of brain metastases or leptomeningeal disease. Prior antiandrogen therapy (AR antagonist or CYP17 inhibitors). Other concurrent investigational anticancer agents. Confirmed QT interval with Fridericia correction (QTcF) > 480 msec. Any severe concurrent disease, infection, or comorbid condition that renders the patient inappropriate for enrollment in the opinion of the investigator or that interferes with the patient's ability to participate in the study requirements. Pregnant patients are not eligible for study. Women with a history of unexplained vaginal bleeding or with endometrial hyperplasia with atypia or endometrial carcinoma are excluded from study. An active gastrointestinal disorder affecting absorption (e.g., gastrectomy, uncontrolled celiac disease). Use of concurrent or chronic daily corticosteroid use. Topical or inhaled corticosteroids are permitted. Use of concurrent medications that are strong inducers/inhibitors or substrates of CYP3A4. Patients may be switched to alternative medications for eligibility purposes. A list of CYP3A4 substrates, inducers, and/or inhibitors Hypersensitivity reaction to the active pharmaceutical ingredient or any of the tablet components, including Labrasol, butylated hydroxyanisole, and butylated hydroxytoluene.

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: Crossover Assignment
Interventional Model Description: This phase II study will randomize.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Enzalutamide<br>Enzalutamide 160 mg/day, continuous daily dosing in a 21-day cycle | Drug: Enzalutamide<br>* mouth once daily (160 mg/day)<br>|
| Experimental: Enzalutamide with Mifepristone<br>Enzalutamide 120mg/day and mifepristone 300mg/day, continuous daily dosing in a 21-day cycle | Drug: Enzalutamide<br>* mouth once daily (160 mg/day)<br>Drug: Mifepristone<br>* mouth once daily 300-mg tablet<br>|
| Active Comparator: Chemotherapy:Carboplatin, Paclitaxel, Eribulin or Capecitabine (TPC)<br>The treating physician must select from one of the following regimens. Eribulin 1.4 mg/m2 IV Day 1 and Day 8 in a 21-day cycle Capecitabine 1000-1250 mg/m2 twice daily, orally Day 1-14 in a 21-day cycle Paclitaxel 80 mg/m2 IV Day 1, Day 8 in a 21-day cycle Carboplatin AUC 6 IV Day 1 in a 21-day cycle Carboplatin AUC 2 IV Day 1, Day 8 and Day 15 in a 21-day cycle Patients randomized to TPC may be offered crossover to enzalutamide plus mifepristone treatment at the time of disease progression if they continue to meet eligibility criteria. | Drug: TPC<br>* The treating physician must select from one of the following regimens: Eribulin 1.4 mg/m2 IV Day 1 and Day 8 in a 21-day cycle Capecitabine 1000-1250 mg/m2 twice daily, orally Day 1-14 in a 21-day cycle Paclitaxel 80 mg/m2 IV Day 1, Day 8 in a 21-day cycle Carboplatin AUC 6 IV Day 1 in a 21-day cycle Carboplatin AUC 2 IV Day 1, Day 8 and Day 15 in a 21-day cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| progression-free survival (PFS) | Response and progression will be evaluated in this study using the international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) Committee (version 1.1). | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Eribulin, Enzalutamide, Mifepristone, Carboplatin, Paclitaxel, Capecitabine, Triple-negative, Androgen receptor positive, 22-334