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

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

Official Title
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A Phase 2, Multicenter, Open-label Study to Assess the Efficacy and Safety of Enzalutamide With Trastuzumab in Subjects With HER2+ AR+ Metastatic or Locally Advanced Breast Cancer

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

Intervention / Treatment
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* Drug: Enzalutamide
* Drug: Trastuzumab


Participation Criteria
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Eligibility Criteria
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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.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Enzalutamide + Trastuzumab<br>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. | Drug: Enzalutamide<br>* Capsules for oral administration<br>* Other names: Xtandi;Drug: Trastuzumab<br>* Intravenous infusion (IV) or subcutaneous injection if it is standard of care within a country<br>* Other names: Herceptin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Benefit Rate (CBR) | 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. | Tumor assessments were performed every 8 weeks through week 49, and then every 12 weeks thereafter until disease progression, initiation of new therapy or withdrawal of consent. The median duration of treatment was 70 days, and the maximum was 660 days. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate at Week 24 | 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. | 24 weeks | 
| Best Overall Response Rate | 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. | Tumor assessments were performed every 8 weeks through week 49, and then every 12 weeks thereafter until disease progression, initiation of new therapy or withdrawal of consent. The median duration of treatment was 70 days, and the maximum was 660 days. | 
| Progression-free Survival | 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. | From the date of first dose of study drug to the data cut-off date of 28 February 2017; the median duration of treatment was 70 days, and the maximum was 660 days. | 
| Time to Progression | 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. | From the date of first dose of study drug to the data cut-off date of 28 February 2017; the median duration of treatment was 70 days, and the maximum was 660 days. | 
| Duration of Response | 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. | Tumor assessments were performed every 8 weeks through week 49, and then every 12 weeks thereafter until disease progression, initiation of new therapy or withdrawal of consent. The median duration of treatment was 70 days, and the maximum was 660 days. | 
| Time to Response | 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. | From the date of first dose of study drug to the data cut-off date of 28 February 2017; the median duration of treatment was 70 days, and the maximum was 660 days. | 
| Number of Participants With Adverse Events (AEs) | An AE was defined as any untoward medical occurrence in a patient administered study drug or who underwent study procedures and did not necessarily have a causal relationship with treatment. An abnormality identified during a medical test was defined as an AE only if the abnormality induced clinical signs or symptoms, required active intervention, required interruption or discontinuation of study medication, or was clinically significant in the opinion of the investigator. An AE was defined as serious if it resulted in any of the following outcomes: Death Was life-threatening Persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions Congenital anomaly, or birth defect Inpatient hospitalization or prolongation of hospitalization Other medically important event. Drug-related AEs were those assessed by the investigator as AEs whose relationship to the to the study drugs could not be ruled out. | 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; median duration of treatment was 70 days, and the maximum was 660 days. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Enzalutamide, Trastuzumab, Breast cancer, HER2, Androgen receptor positive, Xtandi