Efficacy and Safety Study of Enzalutamide in Combination With Exemestane in Patients With Advanced Breast Cancer

Study Overview
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Brief Summary
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The purpose of this study is to determine if enzalutamide given in combination with exemestane is safe and effective in patients with advanced breast cancer.

Detailed Description
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This is a Phase 2, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Efficacy and Safety of Enzalutamide in Combination With Exemestane in Patients With Advanced Breast Cancer That Is Estrogen or Progesterone Receptor Positive and HER2-Normal.

Official Title
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A PHASE 2, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTICENTER STUDY OF EFFICACY AND SAFETY OF ENZALUTAMIDE IN COMBINATION WITH EXEMESTANE IN PATIENTS WITH ADVANCED BREAST CANCER THAT IS ESTROGEN OR PROGESTERONE RECEPTOR-POSITIVE AND HER2-NORMAL

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Enzalutamide
* Drug: exemestane
* Drug: Placebo (for enzalutamide)
* Drug: exemestane


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to provide informed consent; Postmenopausal; Advanced histologically confirmed breast cancer that is ER+, PgR+, or both, and HER-2 normal; Up to one prior hormone therapy and up to one prior chemotherapy in the advanced setting is allowed; Availability of a representative, formalin-fixed, paraffin-embedded tumor specimen that enabled the diagnosis of breast cancer with viable tumor cells in a tissue block or unstained serial slides accompanied bay an associated pathology report; Measurable disease. Patients with non-measurable bone or skin disease as their only manifestation of advanced breast cancer are also eligible; Eastern Cooperative Oncology Group (ECOG) status of 0 or 1; Exclusion Criteria: Any severe concurrent disease, infection, or comorbid condition that renders the patient inappropriate for enrollment in the opinion of the investigator; Any condition or reason that interferes with the patient's ability to participate in the trial, that may cause undue risk, or complicates the interpretation of safety data, in the opinion of the investigator; Current or previously treated brain metastasis or leptomeningeal disease; Prior therapy (> 28 days) with exemestane in the metastatic setting (Patients receiving exemestane in the adjuvant setting and having disease recurrence more than 1 year after treatment discontinuation are eligible); Requires treatment for tuberculosis or HIV infection; Radiation therapy within 7 days before randomization; History of another invasive cancer within 5 years before randomization; History of seizure or any condition that may predispose to seizure; Clinically significant cardiovascular disease; Active gastrointestinal disorder; Major surgery within 28 days prior to randomization; Treatment with any oral anticancer or with any non-hormonal anticancer agent within 14 days before randomization; Treatment with any approved or investigational agent that blocks androgen synthesis or targets the androgen receptor; Treatments with any of the following medications within 14 days before randomization: Estrogens, Androgens, or Systemic radionuclides; Hypersensitivity reaction to exemestane.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Enzalutamide & exemestane<br>Enzalutamide 160 mg/day administered as four 40mg soft gelatin capsules by mouth once daily with or without food and exemestane 50mg (two 25mg tablets overencapsulated as a single capsule during the blinded portion of the study and two 25mg tablets after unblinding) once daily after food. | Drug: Enzalutamide<br>* 160 mg/day administered as four 40mg soft gelatin capsules by mouth once daily with or without food.<br>* Other names: XTANDI;Drug: exemestane<br>* 50mg (two 25mg tablets overencapsulated as a single capsule during the blinded portion of the study and two 25mg tablets after unblinding) by mouth once daily after food.<br>* Other names: Aromasin;|
| Active Comparator: Placebo & exemestane<br>Placebo and exemestane 25mg (overencapsulated to match 50mg dose during the blinded portion of the study and one 25mg tablet without placebo after unblinding) once daily after food. | Drug: exemestane<br>* 25mg (overencapsulated to match 50mg dose during the blinded portion of the study and one 25mg tablet after unblinding) by mouth once daily after food.<br>* Other names: Aromasin;Drug: Placebo (for enzalutamide)<br>* Sugar pill manufactured to mimic enzalutamide administered as four soft gelatin capsules by mouth once daily with or without food.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS): Intent-to-Treat (ITT) Population By Interactive Web Recognition System (IWRS) | PFS was defined as the time in months from randomization to the first documentation of progression of disease (PD) or death on study due to any cause, whichever occurred first. PD according to response evaluation criteria in solid tumors version 1.1 (RECIST 1.1) was defined as greater than or equal to (>=) 20 percent (%) increase in the sum of diameters of the target lesions taking as a reference the smallest sum recorded since the start of treatment or unequivocal progression in non-target lesions or the appearance of 1 or more new lesions. The analysis of PFS was based on investigator assessment of disease progression. Participants who were not known to have had a PFS event at the analysis date were censored at last tumor assessment date prior to data cutoff or date of new treatment initiation, whichever occurred first. | From randomization until PD, last tumor assessment without PD before new antitumor treatment initiation or death due to any cause, whichever occurred first (up to 3 years) | 
| Progression Free Survival (PFS): Diagnostic Positive (DX+) Population By Interactive Web Recognition System (IWRS) | PFS was defined as the time in months from randomization to the first documentation of PD or death on study due to any cause, whichever occurred first. PD according to RECIST 1.1, was defined as >= 20% increase in the sum of diameters of the target lesions taking as a reference the smallest sum recorded since the start of treatment or unequivocal progression in non-target lesions or the appearance of 1 or more new lesions. The analysis of PFS was based on investigator assessment of disease progression. Participants who were not known to have had a PFS event at the analysis date were censored at last tumor assessment date prior to data cutoff or date of new treatment initiation, whichever occurred first. | From randomization until PD, last tumor assessment without PD before new antitumor treatment initiation or death due to any cause, whichever occurred first (up to 3 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Benefit Rate-24 (CBR-24) | CBR-24: Percentage of participants with a best response of complete response (CR), partial response (PR), or stable disease (SD) sustained for atleast 24 weeks, as determined by investigator using RECIST 1.1. CR: Disappearance of all (target and non-target) lesions and normalization of tumor marker level for non-target lesions. All lymph nodes (target and non-target) must be non-pathological in size (less than [<] 10 millimeter [mm] short axis). PR: >=30% decrease in sum of diameters of target lesions, using baseline sum diameters as reference. SD: Neither sufficient reduction to qualify as PR nor sufficient increase to qualify as PD, using the smallest sum diameters during study as reference. PD: >=20% increase (an absolute increase of >=5 mm) in sum of diameters of target lesions, using the smallest sum during the study as a reference (including baseline sum), or unequivocal progression of existing non-target lesions, or appearance of atleast 1 new target or non-target lesions. | From randomization up to 3 years | 
| Best Objective Response Rate | Best objective response rate: Percentage of participants with measurable disease and with a best response of CR or PR according to RECIST 1.1. CR: Disappearance of all (target and non-target) lesions and normalization of tumor marker level for non-target lesions. All lymph nodes (target and non-target) must be non-pathological in size (<10 mm short axis). PR: Atleast 30% decrease in sum of diameters of target lesions, using baseline sum diameters as reference. Response evaluation was based on investigators' judgment. | From randomization until CR or PR, whichever occurred first (up to 3 years) | 
| Duration of Objective Response | Duration of objective response: Time from first documentation of CR or PR, to the first documentation of PD or death due to any cause, whichever occurred first as determined by investigator using RECIST 1.1. CR: Disappearance of all (target and non-target) lesions and normalization of tumor marker level for non-target lesions. All lymph nodes (target and non-target) must be non-pathological in size (<10 mm short axis). PR: >=30% decrease in sum of diameters of target lesions, using baseline sum diameters as reference. PD: >=20% increase (an absolute increase of >=5 mm) in sum of diameters of target lesions, using the smallest sum during the study as a reference (including baseline sum), or unequivocal progression of existing non-target lesions, or appearance of atleast 1 new target or non-target lesions. Participants with no PD or death (after initial CR or PR) at the analysis date were censored at last tumor assessment date prior to date of new antitumor treatment or data cutoff. | From first documentation of CR or PR until PD, or last tumor assessment without PD before new antitumor treatment initiation or death due to any cause, whichever occurred first (up to 3 years) | 
| Time to Response | Time to response: Time from randomization to first documentation of CR or PR. CR: Disappearance of all (target and non-target) lesions and normalization of tumor marker level for non-target lesions. All lymph nodes (target and non-target) must be non-pathological in size (<10 mm short axis). PR: >=30% decrease in sum of diameters of target lesions, using baseline sum diameters as reference. PD: >=20% increase (an absolute increase of >=5 mm) in sum of diameters of target lesions, using the smallest sum during the study as a reference (including baseline sum), or unequivocal progression of existing non-target lesions, or appearance of atleast 1 new target or non-target lesions. Participants who were not known to have had a CR or PR were censored at last tumor assessment date prior to data cutoff or date of new treatment initiation, whichever occurred first. | From randomization until first documentation of CR or PR, or last tumor assessment without PD or death prior to new antitumor treatment initiation, whichever occurred first (up to 3 years) | 
| Time to Progression | Time to progression was defined as the time from the date of randomization to PD defined by the investigator using RECIST 1.1. PD: >=20% increase (an absolute increase of >=5 mm) in sum of diameters of target lesions, using the smallest sum during the study as a reference (including baseline sum), or unequivocal progression of existing non-target lesions, or appearance of atleast 1 new target or non-target lesions. Participants who did not experience disease progression, time to progression was right censored at the date of the last tumor assessment prior to data cutoff or date of new antitumor treatment, whichever occurred first. | From randomization until PD or last tumor assessment without PD before new antitumor treatment initiation, whichever occurred first (up to 3 years) | 
| Progression Free Survival (PFS) at 6 Months | PFS at 6 months was defined as the percentage of participants with no event of disease progression at Month 6 landmark, estimated by Kaplan-Meier methods. PFS was defined as the time in months from randomization to the first documentation of PD or death on study due to any cause, whichever occurred first. PD: >=20% increase (an absolute increase of >=5 mm) in sum of diameters of target lesions, using the smallest sum during the study as a reference (including baseline sum), or unequivocal progression of existing non-target lesions, or appearance of atleast 1 new target or non-target lesions. The analysis of PFS was based on investigator assessment of disease progression. | Month 6 | 
| Concentration Versus Time Summary of Enzalutamide | Concentration versus time summary was calculated by setting concentration values below limit of quantitation to zero. | Predose on Day 29, 57 and 113 | 
| Concentration Versus Time Summary of Exemestane | Concentration versus time summary was calculated by setting concentration values below limit of quantitation to zero. | Predose, 1 and 6 hour postdose on Day 29, 57, 113 and 169 | 
| Concentration Versus Time Summary of N-desmethyl Enzalutamide | N-desmethyl enzalutamide was the active metabolite of enzalutamide. Concentration versus time summary was calculated by setting concentration values below limit of quantitation to zero. | Predose on Day 29, 57 and 113 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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advanced breast cancer, enzalutamide, MDV3100, Estrogen receptor positive (ER +), Progesterone receptor positive (PgR +), HER-2 normal