A Study to Evaluate the Efficacy and Safety of Herceptin® (Trastuzumab) in Combination With Arimidex® (Anastrozole) an Aromatase Inhibitor Compared to Arimidex® Alone in Patients With Metastatic Breast Cancer

Study Overview
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Brief Summary
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This 2 arm study assessed the safety and efficacy of adding intravenous trastuzumab (Herceptin®) to daily oral anastrozole (Arimidex®) tablets as first- and second-line treatment in postmenopausal patients with human epidermal growth factor receptor-2 (HER2) overexpressing metastatic breast cancer (ER+ve and/or PR+ve). Patients were randomized to receive either anastrazole 1 mg per os (po) daily, or anastrazole 1 mg po daily + a loading dose of Herceptin® 4 mg/kg intravenous (iv) followed by weekly doses of Herceptin® 2 mg/kg iv. The anticipated time on study treatment was until disease progression, and the target sample size was 100-500 individuals.

Official Title
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A Randomized, Open-label Study of the Effect of Herceptin Plus Arimidex Compared With Arimidex Alone on Progression-free Survival in Patients With HER2-positive and Hormone-receptor Positive Metastatic Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: trastuzumab (Herceptin®)
* Drug: anastrazole (Arimidex®)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: postmenopausal women; metastatic breast cancer suitable for endocrine therapy; positive hormone receptor status; Human epidermal growth factor receptor 2 (HER2) overexpression. Exclusion Criteria: patients on hormone replacement therapy; previous chemotherapy for metastatic disease; uncontrolled cardiac disease and history of cardiac failure.

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: trastuzumab + anastrozole<br>Trastuzumab 4 mg/kg loading dose intravenous (iv) over 90 minutes, followed by weekly doses of 2 mg/kg iv over 30 minutes plus 1 mg oral dose of anastrozole every day for 24 Months in the Main phase and in the Extension Phase. | Drug: trastuzumab (Herceptin®)<br>* 4mg/kg iv loading dose, followed by 2mg/kg iv weekly<br>* Other names: Herceptin®;Drug: anastrazole (Arimidex®)<br>* 1 mg tablet taken orally daily<br>* Other names: Arimidex®;|
| Active Comparator: anastrozole<br>1 mg oral dose of anastrozole every day for 24 Months in the Main phase. In the Extension Phase participants could cross-over to also receive trastuzumab 4 mg/kg initial loading dose intravenous (iv) over 90 minutes, followed by weekly doses of 2 mg/kg iv over 30 minutes. | Drug: anastrazole (Arimidex®)<br>* 1 mg tablet taken orally daily<br>* Other names: Arimidex®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS was assessed by the investigator based on World Health Organization (WHO) criteria using radiographic tumor evaluations. Disease progression was defined as the appearance of any new lesion not previously identified or an estimated increase of 25% or more in existent bidimensionally or unidimensionally measurable lesions or progression of an existing non-measurable lesion. For bidimensionally measurable malignant lesions with an area of at least 2.0 centimeters squared (cm^2) an increase of 1.0 cm^2 was required and for unidimensionally measurable lesions of 1.0 cm or less an increase of 0.5 cm was required. PFS was defined as the number of days between date of randomization and date of documented disease progression or date of death. Kaplan Meier estimates of PFS are presented. | 24 Months, End of Study (Up to 5 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Clinical Benefit | Clinical Benefit was defined as stable disease for ≥ six months or complete response or partial response. | 24 Months, End of Study (Up to 5 years) | 
| Duration of Response at 24 Months | Duration of response was defined as the number of days from the day complete response or partial response was first noted to the day of progression of disease, death or last follow-up. | 24 Months | 
| Time to Response at 24 Months | Time to response was defined as the number of days from the day of randomization to the day complete response or partial response was first noted. | 24 Months | 
| Overall Survival at 24 Months | Overall Survival is defined as the number of days from randomization to death. | 24 Months | 
| Percentage of Participants With Two-Year Survival |  | 24 Months | 
| Percentage of Participants With Overall Tumor Response at 24 Months | Tumor Response levels were determined by the investigator and an Independent Response Evaluation Committee and Reconciled. Overall Response was defined as either complete response or partial response. | 24 Months | 
| Percentage of Participants With Best Tumor Response at 24 Months | Tumor Response levels were determined by the investigator and an Independent Response Evaluation Committee and Reconciled. Best Response was defined as the best response a patient achieves in the study. | 24 Months | 
| Percentage of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status at Final Visit Compared to Baseline | Participants rated their performance status using the ECOG Questionnaire on the following scale: 0=Fully active, perform all pre-disease activities without restriction; 1=Restricted in physically strenuous activity but ambulatory, carry out work of a light or sedentary nature; 2=Ambulatory, capable of self-care, unable to carry out any work activities, up and about more than >50% of waking hours; 3=Capable of limited self-care, confined to bed or chair >50% of waking hours; 4=Completely disabled, not capable of any self-care, totally confined to bed or chair; 5=Dead. The percentage of participants in the following categories: Improved: Score decrease from baseline. Unchanged: Score the same as baseline. Worse: Score increase from baseline. | Baseline, Final Visit (Up to 24 Months) | 
| Duration of Response at End of Study | Duration of response was defined as the number of days from the day complete response or partial response was first noted to the day of progression of disease, death or last follow-up. | End of Study (Up to 5 years) | 
| Time to Response at End of Study | Time to response was defined as the number of days from the day of randomization to the day complete response or partial response was first noted. | End of Study (Up to 5 years) | 
| Percentage of Participants With Overall Tumor Response at End of Study | Tumor Response levels were determined by the investigator and an Independent Response Evaluation Committee and Reconciled. Overall Response was defined as either complete response or partial response. | End of Study (Up to 5 years) | 
| Percentage of Participants With Best Tumor Response at End of Study | Tumor Response levels were determined by the investigator and an Independent Response Evaluation Committee and Reconciled. Best Response was defined as the best response a patient achieves in the study. | End of Study (Up to 5 years) | 
| Number of Participants With Adverse Events | Number of participants with adverse events as a measure for safety as assessed by the collection of adverse events, laboratory tests for Hematology and Serum Chemistry, clinical assessments and cardiac monitoring. | Throughout the Study (Up to 5 years) |