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

• ClinicalTrials.gov Identifier: NCT02007512
• Recruitment Status: Active, not recruiting
• First Posted: December 10, 2013
• Results First Posted: February 6, 2018
• Last Update Posted: April 26, 2024
• Sponsor: Pfizer
• Collaborators: Astellas Pharma Inc; Medivation, Inc.
• Information provided by (Responsible Party): Pfizer

Tracking Information

• First Submitted Date: December 3, 2013
• First Posted Date: December 10, 2013
• Results First Submitted Date: September 21, 2017
• Results First Posted Date: February 6, 2018
• Last Update Posted Date: April 26, 2024
• Actual Study Start Date: December 13, 2013
• Actual Primary Completion Date: September 23, 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 12, 2018)

• Progression Free Survival (PFS): Intent-to-Treat (ITT) Population By Interactive Web Recognition System (IWRS) [ Time Frame: 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) ]
  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.
• Progression Free Survival (PFS): Diagnostic Positive (DX+) Population By Interactive Web Recognition System (IWRS) [ Time Frame: 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) ]
  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.

Original Primary Outcome Measures (submitted: December 5, 2013)

Progression Free Survival (PFS) [ Time Frame: 24 Months ]

To determine the benefit of exemestane plus enzalutamide versus exemestane plus placebo as assessed by progression-free survival (PFS) in patients with advanced breast cancer that is estrogen or progesterone receptor-positive or both (ER+/PgR+) and human epidermal growth factor receptor 2 (HER2)-normal

Current Secondary Outcome Measures (submitted: January 10, 2018)

• Clinical Benefit Rate-24 (CBR-24) [ Time Frame: From randomization up to 3 years ]
  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.
• Best Objective Response Rate [ Time Frame: From randomization until CR or PR, whichever occurred first (up to 3 years) ]
  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.
• Duration of Objective Response [ Time Frame: 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) ]
  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.
• Time to Response [ Time Frame: 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 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.
• Time to Progression [ Time Frame: From randomization until PD or last tumor assessment without PD before new antitumor treatment initiation, whichever occurred first (up to 3 years) ]
  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.
• Progression Free Survival (PFS) at 6 Months [ Time Frame: Month 6 ]
  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.
• Concentration Versus Time Summary of Enzalutamide [ Time Frame: Predose on Day 29, 57 and 113 ]
  Concentration versus time summary was calculated by setting concentration values below limit of quantitation to zero.
• Concentration Versus Time Summary of Exemestane [ Time Frame: Predose, 1 and 6 hour postdose on Day 29, 57, 113 and 169 ]
  Concentration versus time summary was calculated by setting concentration values below limit of quantitation to zero.
• Concentration Versus Time Summary of N-desmethyl Enzalutamide [ Time Frame: Predose on Day 29, 57 and 113 ]
  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.

Original Secondary Outcome Measures (submitted: December 5, 2013)

• Clinical Benefit Rate [ Time Frame: 24 Months ]
  Clinical benefit rate, defined as the proportion of patients with a best response of complete response(CR), partial response (PR), or of stable disease (SD) lasting ≥ 24 weeks;

  • Best objective response rate;
  • Duration of response;
  • Time to response;
  • Time to progression;
  • PFS rate at 6 months.
• Pharmacokinetics [ Time Frame: 24 months ]
  Cmax for enzalutamide and exemestane one hour pre dose and exemestane 6 hours post dose at specified study visits.

Current Other Pre-specified Outcome Measures (submitted: October 12, 2018)

• European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life Core Questionnaire (QLQ-C30) [ Time Frame: Month 24 ]
• European Organization for Research and Treatment of Cancer (EORTC) Breast Cancer Module (QLQ-BR23) [ Time Frame: Month 24 ]
• Number of Participants With Positive Androgen Receptor (AR) Expression by Immunohistochemistry (IHC) [ Time Frame: Day 1, 29, 57, 113 and 169 ]
• Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Baseline up to 30 days after the last dose of study drug or before initiation of a new antitumor treatment, whichever occurred first (up to 3 years) ]
  An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. A treatment emergent AE was defined as an event that emerged during the treatment period that was absent before treatment, or worsened during the treatment period relative to the pretreatment state. AEs included both serious and non-serious AEs.
• Number of Participants With Treatment-Emergent Adverse Events of Grade 3 or Higher Severity [ Time Frame: Baseline up to 30 days after the last dose of study drug or before initiation of a new antitumor treatment, whichever occurred first (up to 3 years) ]
  An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Severity of the AEs was graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Only the participants with treatment-emergent AEs of grade 3 (severe) or higher grade were reported in this outcome measure.
• Number of Participants With Clinically Significant Vital Sign Abnormalities [ Time Frame: Baseline up to 30 days after the last dose of study drug or before initiation of a new antitumor treatment, whichever occurred first (up to 3 years) ]
  Criteria for clinically significant vital sign abnormalities: Systolic blood pressure (SBP): absolute SBP <90 millimeters of mercury (mmHg) and decrease from baseline (DFB) >30 mmHg, absolute SBP>180 mmHg and increase from baseline (IFB) >40 mmHg, final visit or 2 consecutive visits SBP >=20 mmHg change from baseline (CFB), most extreme post-baseline SBP >=140 mmHg, most extreme post-baseline SBP >=180 mmHg, most extreme SBP >=140 mmHg and >=20 mmHg CFB, most extreme SBP >=180 mmHg and >=20 mmHg CFB; diastolic blood pressure (DBP): absolute DBP > 105 mmHg and IFB >30 mmHg, absolute DBP <50 mmHg and DFB >20 mmHg, final visit or 2 consecutive visits DBP >=15 mmHg CFB, most extreme post-baseline DBP >=90 mmHg, most extreme post-baseline DBP >=105 mmHg, most extreme DBP >=90 mmHg and >=15 mmHg CFB, most extreme DBP >=105 mmHg and >=15 mmHg CFB; heart rate <50 beats per minute (BPM) and DFB >20 BPM or heart rate >120 BPM and IFB >30 BPM.
• Number of Participants With Clinically Significant Laboratory Abnormalities [ Time Frame: Baseline up to 30 days after the last dose of study drug or before initiation of a new antitumor treatment, whichever occurred first (up to 3 years) ]
  Laboratory tests included hematology (hematocrit, hemoglobin, platelet count, red blood cell count, total neutrophils [absolute] and white blood cell count with differential) and serum chemistry (albumin, alkaline phosphatase, alanine aminotransferase [ALT], aspartate transaminase [AST], blood urea nitrogen and creatinine, calcium, sodium, potassium, chloride, glucose (non-fasting), lactate dehydrogenase, magnesium, phosphorus/phosphate, total bilirubin, total bicarbonate, total protein and uric acid). Clinically significant abnormality evaluation was based on clinical investigator's judgment.
• Progression Free Survival (PFS): By Electronic Data Capture (EDC) [ Time Frame: 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) ]
  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 >=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. Cht 1: Enz + Exe = Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg; Cht 2: Enz + Exe= Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg
• Progression Free Survival (PFS): Diagnostic Positive (DX+) Population By Electronic Data Capture (EDC) [ Time Frame: 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) ]
  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.

Original Other Pre-specified Outcome Measures (submitted: December 5, 2013)

• Health-related Quality of Life [ Time Frame: 24 Months ]
  Assessments of health-related quality of life will be performed using the European Organization for Research and Treatment of Cancer (EORTC) quality-of-life core questionnaire (QLQ-C30) and breast cancer module(QLQ-BR23) at specified intervals and at time of disease progression.
• Androgen Receptor (AR) Expression by Immunohistochemistry (IHC) [ Time Frame: 24 Months ]
  To determine the percent of androgen receptor (AR) nuclear expression and signaling in breast tissue and to evaluate the relationship of this expression with enzalutamide effects on circulating tumor biomarkers, circulating hormones, and clinical outcomes.

Descriptive Information

• Brief Title: Efficacy and Safety Study of Enzalutamide in Combination With Exemestane in Patients With Advanced Breast Cancer
• Official Title: 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
• Brief Summary: 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: 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.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Breast Cancer

Intervention

• Drug: Enzalutamide
  160 mg/day administered as four 40mg soft gelatin capsules by mouth once daily with or without food.
  Other Names:

  • MDV3100
  • XTANDI
• Drug: exemestane
  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.
  Other Name: Aromasin
• Drug: Placebo (for enzalutamide)
  Sugar pill manufactured to mimic enzalutamide administered as four soft gelatin capsules by mouth once daily with or without food.
• Drug: exemestane
  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.
  Other Name: Aromasin

Study Arms

• Experimental: Enzalutamide & exemestane
  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.
  Interventions:

  • Drug: Enzalutamide
  • Drug: exemestane
• Active Comparator: Placebo & exemestane
  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.
  Interventions:

  • Drug: exemestane
  • Drug: Placebo (for enzalutamide)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: April 16, 2015): 247
• Original Estimated Enrollment (submitted: December 5, 2013): 240
• Estimated Study Completion Date: June 28, 2024
• Actual Primary Completion Date: September 23, 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: Female
• Gender Based Eligibility: Yes

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, Canada, Ireland, Italy, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT02007512
• Other Study ID Numbers: MDV3100-12; 2013-002717-35 ( EudraCT Number ); C3431008 ( Other Identifier: Alias Study Number )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.
• URL: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests

• Current Responsible Party: Pfizer
• Original Responsible Party: Medivation, Inc.
• Current Study Sponsor: Pfizer
• Original Study Sponsor: Medivation, Inc.

Collaborators

• Astellas Pharma Inc
• Medivation, Inc.

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

• PRS Account: Pfizer
• Verification Date: April 2024