A Study to Assess the Efficacy and Safety of Enzalutamide With Trastuzumab in Patients With Human Epidermal Growth Factor Receptor 2 Positive (HER2+), Androgen Receptor Positive (AR+) Metastatic or Locally Advanced Breast Cancer

Phase 2

Completed

Conditions: HER2 Amplified
Human Epidermal Growth Factor Receptor 2 (HER2)
Advanced Breast Cancer

Interventions: Drug: Enzalutamide
Drug: Trastuzumab

Registration Number: NCT02091960

Lead Sponsor: Astellas Pharma Global Development, Inc.

Brief Summary: The purpose of this study was to evaluate the efficacy of enzalutamide with trastuzumab in patients with HER2+ AR+ metastatic or locally advanced breast cancer.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 103

Inclusion Criteria

The subject has histologically or cytologically proven adenocarcinoma of the breast that is HER2+
The subject has AR+ breast cancer
The subject has metastatic disease or has locally advanced disease that is not amendable to curative treatment
The subject has measurable disease or nonmeasurable, evaluable disease per RECIST 1.1. (NOTE: pleural effusions, ascites or other third fluid space are not evaluable diseases per RECIST 1.1).
The subject has received at least 1 line of therapy in the metastatic or locally advanced disease setting. The subject has been documented to have progressed by determination of the investigator on a regimen containing an anti-HER2 agent as the most recent regimen or the most recent anti-HER2 regimen was discontinued for any toxicity, with the exception of a cardiotoxicity.
The subject has adequately recovered from toxicities due to prior therapy.
The subject has an Eastern Cooperative Oncology Group performance (ECOG) status ≤ 1 at Screening and Day 1
The subject has available at the site a representative, formalin-fixed, paraffin-embedded, tumor specimen that enabled the definitive diagnosis of breast cancer with adequate viable tumor cells in a tissue block (preferred) or ≥ 10 (20 preferred) freshly cut, unstained, serial slides and the associated pathology report

Exclusion Criteria

The subject has a severe concurrent disease, infection, or comorbidity that would make the subject inappropriate for enrollment.
The subject has current or previously treated brain metastasis or active leptomeningeal disease. Brain imaging is required during screening in all subjects to exclude the presence of unequivocal central nervous system disease.
The subject has a history of a non-breast cancer malignancy with the following exceptions:
- The subject with a previous history of a non-invasive carcinoma is eligible if he/she has had successful curative treatment any time prior to Screening.
- For all other malignancies, the subject is eligible if they have undergone potentially curative therapy and they have been considered disease free for at least 5 years prior to Screening.
The subject has a history of seizure or any condition that may predispose to seizure (e.g., prior cortical stroke, significant brain trauma).
The subject has a history of loss of consciousness, cerebrovascular accident, or transient ischemic attack within 12 months before the Day 1 visit.
The subject has had a hypoglycemic episode requiring medical intervention while on insulin (or other anti-diabetic) treatment within 12 months before Day 1.
The subject had a major surgical procedure, substantial open biopsy, or significant traumatic experience within 28 days before the Day 1 visit, or anticipation of need for major surgical procedure during the course of the study.
The subject has had palliative radiation therapy to bone metastases within 14 days prior to the Day 1 visit (side effects from radiation must be resolved).
The subject has received chemotherapy, immunotherapy, or any other systemic anticancer therapy, with the exception of anti-HER2 therapy (e.g., trastuzumab), within 14 days prior to the Day 1 visit.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Enzalutamide + Trastuzumab	Enzalutamide	Participants received 160 mg enzalutamide orally once daily and 6 mg/kg trastuzumab administered by intravenous infusion or subcutaneous injection every 21 days. Participants continued on treatment until disease progression, unacceptable toxicity or any other discontinuation criteria were met.
Enzalutamide + Trastuzumab	Trastuzumab	Participants received 160 mg enzalutamide orally once daily and 6 mg/kg trastuzumab administered by intravenous infusion or subcutaneous injection every 21 days. Participants continued on treatment until disease progression, unacceptable toxicity or any other discontinuation criteria were met.

Primary Outcome Measures

Name	Time	Method
Clinical Benefit Rate (CBR)	Tumor assessments were performed every 8 weeks through week 49, and then every 12 weeks thereafter until disease progression or death; the median duration of treatment was 70 days, and the maximum was 660 days.	Clinical benefit rate was defined as the percentage of evaluable participants with best objective response of confirmed complete response or partial response per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, or prolonged stable disease (≥ 24 weeks). Complete response (CR) was defined as the disappearance of all target and non-target lesions and no new lesions, and lymph nodes all \< 10 mm in short axis. Partial response (PR) was defined as disappearance of target lesions or a ≥ 30% decrease in the size of target lesions, with persistence of non-target lesions and no new lesions. Stable disease (SD) was defined as \< 30% decrease and \< 20% increase in the size of target lesions, persistence of non-target lesions, and no new lesions. PR and CR required confirmation with equivalent or improved assessment no less than 4 weeks after the date that PR or CR was first observed. SD required confirmation with equivalent or improved assessment no less than 8 weeks after enrollment.

Secondary Outcome Measures

Name	Time	Method
Overall Response Rate at Week 24	24 weeks	Overall response rate was defined as the percentage of evaluable participants with a best objective response of confirmed complete response (CR) or partial response (PR) per RECIST 1.1. Complete response was defined as the disappearance of all target and non-target lesions and no new lesions, and lymph nodes all \< 10 mm in short axis. Partial response was defined as disappearance of target lesions or a ≥ 30% decrease in the size of target lesions with persistence of non-target lesions and no new lesions. PR and CR required confirmation with equivalent or improved assessment no less than 4 weeks after the date of scan that PR or CR was first observed.
Best Overall Response Rate	Tumor assessments were performed every 8 weeks through week 49, and then every 12 weeks thereafter until disease progression or death; the median duration of treatment was 70 days, and the maximum was 660 days.	Best overall response was the best response across all time points, based on investigator assessments. Best overall response rate was defined as the percentage of evaluable participants with a best objective response of confirmed complete response (CR) or partial response (PR) at any time during the study per RECIST 1.1. Complete response was defined as the disappearance of all target and non-target lesions and no new lesions, and lymph nodes all \< 10 mm in short axis. Partial response was defined as disappearance of target lesions or a ≥ 30% decrease in the size of target lesions with persistence of non-target lesions and no new lesions. PR and CR required confirmation with equivalent or improved assessment no less than 4 weeks after the date of scan that PR or CR was first observed.
Progression-free Survival	From the date of first dose of study drug until disease progression or death; the median duration of treatment was 70 days, and the maximum was 660 days.	Progression-free survival was defined as the time from the date of first dose of enzalutamide until the date of disease progression per RECIST 1.1, or death from any cause on study, whichever occurred first. Participants who initiated another antitumor therapy before documented progressive disease (PD) or death, or who progressed or died after missing 2 or more consecutive radiological assessments were censored at the date of the last radiological assessment showing no progression. Progressive disease was defined as a ≥ 20% increase in the size of target lesions and at least a 5 mm increase in size of target lesions from smallest size on study, or unequivocal progression of non-target lesions, or any new lesions.
Time to Progression	From the date of first dose of study drug until disease progression or death; the median duration of treatment was 70 days, and the maximum was 660 days.	Time to progression was defined as the time from the first date of enzalutamide treatment until the date of disease progression per RECIST 1.1. Participants who initiated another anti-tumor therapy before documented PD, who progressed after missing two or more consecutive radiological assessments or who died before disease progression were censored at the date of the last radiological assessment showing no progression.
Duration of Response	Tumor assessments were performed every 8 weeks through week 49, and then every 12 weeks thereafter until disease progression or death; the median duration of treatment was 70 days, and the maximum was 660 days..	Duration of response was defined as the time from the date of first documentation of response (CR or PR) until the date of disease progression per RECIST 1.1. Participants who initiated another anti-tumor therapy before documented PD, progressed after missing two or more consecutive radiological assessments or who died before disease progression were censored at the date of the last radiological assessment showing no progression.
Time to Response	From the date of first dose of study drug until disease progression or death; the median duration of treatment was 70 days, and the maximum was 660 days.	Time to response was defined as the time from the first date of enzalutamide treatment to initial CR or PR and was calculated for participants with a CR or PR.
Number of Participants With Treatment Emergent Adverse Events (TEAEs)	From the first dose date of study drug to 30 days after the last dose date of study drug or the start of subsequent treatment or date of death, whichever was first (Up to 3031 days)	An AE was defined as any untoward medical occurrence in a participant administered study drug/who underwent study procedures and did not necessarily have a causal relationship with treatment. Abnormalities identified during medical tests were defined as an AE if they induced clinical signs/symptoms, required active intervention, interruption or discontinuation of study medication, or were clinically significant to the investigator. An AE was defined as serious if any of the following resulted: Death, was life-threatening, persistent or significant disability/incapacity or substantial disruption of ability to conduct normal life functions, congenital anomaly/ birth defect, inpatient hospitalization/prolongation of hospitalization or other medically important event. TEAE was defined as an AE observed during the treatment emergent period, which is from first dose date of study drug to 30 days after last dose date or the start of subsequent treatment or date of death, whichever is first.

Trial Locations

Locations (39): Site CA15026
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Saskatoon, Saskatchewan, Canada
Site CA15001
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Quebec, Canada
Site IT39003
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Milan, Italy
Site ES34014
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Pozuelo de Alarcon, Madrid, Spain
Site ES34013
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Madrid, Spain
Site ES34010
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Barcelona, Spain
Site GB44003
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Edinburgh, United Kingdom
Site GB44013
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Manchester, United Kingdom
Site US10028
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Los Angeles, California, United States
Site US10081
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Chicago, Illinois, United States
Site CA15028
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Regina, Saskatchewan, Canada
Site CA15023
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Toronto, Ontario, Canada
Site BE32007
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Liege, Belgium
Site BE32016
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Bruxelles, Belgium
Site IT39005
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Meldola, Forli, Italy
Site IT39008
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Lecce, Italy
Site IT39002
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Milano, Italy
Site IT39001
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Sondrio, Italy
Site IT39021
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Udine, Italy
Site GB44001
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Nottingham, United Kingdom
Site CA15022
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Ottawa, Ontario, Canada
Site US10051
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Anaheim, California, United States
Site US10035
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San Francisco, California, United States
Site US10074
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Gainesville, Florida, United States
Site US10079
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Fort Myers, Florida, United States
Site US10070
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Boston, Massachusetts, United States
Site US10004
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Indianapolis, Indiana, United States
Site US10072
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Cincinnati, Ohio, United States
Site US10078
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Saint Louis, Missouri, United States
Site US10029
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Knoxville, Tennessee, United States
Site US10077
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Nashville, Tennessee, United States
Site BE32003
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Edegem, Antwerp, Belgium
Site US10082
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Houston, Texas, United States
Site US10076
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Fort Worth, Texas, United States
Site BE32013
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Brasschaat, Belgium
Site BE32001
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Charleroi, Belgium
Site BE32009
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Leuven, Belgium
Site US10048
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Pittsburgh, Pennsylvania, United States
Site US10042
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Nashville, Tennessee, United States