A Study of Herceptin (Trastuzumab) in Combination Chemotherapy in Women With Locally Advanced Breast Cancer

Study Overview
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Brief Summary
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This study will assess the efficacy and safety of adding Herceptin to a paclitaxel-containing regimen followed by cyclophosphamide/methotrexate/fluorouracil (CMF) chemotherapy in women with locally advanced breast cancer and HER2/c-erbB-2 gene amplification. In a parallel observational study patients with HER2-negative disease will receive the same chemotherapy without Herceptin.

Official Title
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A Randomized, Open-label Study of the Effect of Paclitaxel, Doxorubicin, and CMF Neoadjuvant Chemotherapy, With and Without Herceptin, on Tumor Response in Women With HER2-positive Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Trastuzumab
* Drug: Doxorubicin
* Drug: Paclitaxel
* Drug: CMF


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: female patients, >=18 years of age, with locally advanced breast cancer. Exclusion Criteria: previous therapy for any invasive malignancy.

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: HER-2+ Trastuzumab, Doxorubicin/Paclitaxel/CMF<br>Participants with HER2 proto-oncogene positive breast cancer (HER2+) were treated with trastuzumab 8 milligrams per kilogram (mg/kg), intravenous (IV), on Day 1 of Cycle 1, followed by 6 mg/kg, IV, on Day 1 of Cycle 2 to up a maximum of Cycle 17. Participants also received doxorubicin 60 mg/ square meter (m^2), IV, and paclitaxel 150 mg/m^2, IV, on Day 1 of Cycles 1 through 3. Followed by paclitaxel 175 mg/m^2, IV, alone on Day 1 of Cycles 4 through 7. Participants also received CMF: cyclophosphamide 600 mg/m^2, IV; methotrexate 40 mg/m^2, IV; and 5-fluorouracil 600 mg/m^2, IV, on Day 1 of Cycles 8 through 10. | Drug: Trastuzumab<br>* 8mg/kg IV on Day 1 of Cycle 1, followed by 6 mg/kg on Day 1 of Cycle 2 up a maximum of Cycle 17<br>* Other names: Herceptin;Drug: Doxorubicin<br>* 60 mg/m2 IV on Day 1 of Cycles 1 through 3<br>Drug: Paclitaxel<br>* 150 mg/m2 IV on Day 1 of Cycles 1 through 3, followed by 175 mg/m2 IV on Day 1 of Cycles 4 through 7<br>Drug: CMF<br>* CMF: Cyclophosphamide (600 mg/m2 IV bolus), methotrexate (40 mg/m2 IV bolus), 5-fluorouracil (600 mg/m2 IV bolus) on Day 1 of Cycles 8 through 10<br>|
| Active Comparator: HER-2+ Doxorubicin/Paclitaxel/CMF<br>Participants with HER2 proto-oncogene positive breast cancer were treated with doxorubicin 60 mg/m^2, IV, and paclitaxel 150 mg/m^2, IV, on Day 1 of Cycles 1 through 3. Followed by paclitaxel 175 mg/m^2, IV, alone on Day 1 of Cycles 4 through 7. Participants also received CMF on Day 1 of Cycle 8 through 10. | Drug: Doxorubicin<br>* 60 mg/m2 IV on Day 1 of Cycles 1 through 3<br>Drug: Paclitaxel<br>* 150 mg/m2 IV on Day 1 of Cycles 1 through 3, followed by 175 mg/m2 IV on Day 1 of Cycles 4 through 7<br>Drug: CMF<br>* CMF: Cyclophosphamide (600 mg/m2 IV bolus), methotrexate (40 mg/m2 IV bolus), 5-fluorouracil (600 mg/m2 IV bolus) on Day 1 of Cycles 8 through 10<br>|
| Active Comparator: HER-2- Doxorubicin/Paclitaxel/CMF<br>Participants with HER2 proto-oncogene negative breast cancer were treated with doxorubicin 60 mg/m^2, IV, and paclitaxel 150 mg/m^2, IV, on Day 1 of Cycles 1 through 3. Followed by paclitaxel 175 mg/m^2, IV, alone on Day 1 of Cycles 4 through 7. Participants also received CMF on Day 1 of Cycle 8 through 10. | Drug: Doxorubicin<br>* 60 mg/m2 IV on Day 1 of Cycles 1 through 3<br>Drug: Paclitaxel<br>* 150 mg/m2 IV on Day 1 of Cycles 1 through 3, followed by 175 mg/m2 IV on Day 1 of Cycles 4 through 7<br>Drug: CMF<br>* CMF: Cyclophosphamide (600 mg/m2 IV bolus), methotrexate (40 mg/m2 IV bolus), 5-fluorouracil (600 mg/m2 IV bolus) on Day 1 of Cycles 8 through 10<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-Free Survival (EFS) - Percentage of Participants With an Event | EFS was defined as the time between randomization and date of documented occurrence of disease recurrence or progression (local, regional, distant or contralateral) or death due to any cause. | Baseline (BL), Presurgery: Day 1 (Cycles 1-7) and Days 1 and 8 (Cycles 8-10); Postsurgery: Day 1 (Cycles 1-17); every 6 months up to 60 months after last dose of study drug; yearly thereafter | 
| Event-Free Survival | The median time, in months, between randomization and date of documented occurrence of an EFS event. | BL, Presurgery: Day 1 (Cycles 1-7) and Days 1 and 8 (Cycles 8-10); Postsurgery: Day 1 (Cycles 1-17); every 6 months up to 60 months after last dose of study drug; yearly thereafter | 
| Percentage of Participants Event Free at 1 Year |  | BL, Presurgery: Day 1 (Cycles 1-7) and Days 1 and 8 (Cycles 8-10); Postsurgery: Day 1 (Cycles 1-17); every 6 months up to 60 months after last dose of study drug; yearly thereafter | 
| Percentage of Participants Event Free at 2 Years |  | BL, Presurgery: Day 1 (Cycles 1-7) and Days 1 and 8 (Cycles 8-10); Postsurgery: Day 1 (Cycles 1-17); every 6 months up to 60 months after last dose of study drug; yearly thereafter | 
| Percentage of Participants Event Free at 3 Years |  | BL, Presurgery: Day 1 (Cycles 1-7) and Days 1 and 8 (Cycles 8-10); Postsurgery: Day 1 (Cycles 1-17); every 6 months up to 60 months after last dose of study drug; yearly thereafter | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Breast Pathological Complete Response (bpCR) | bpCR was defined as an absence of any invasive cancer cell of the primary tumor at the time of major surgery after neoadjuvant chemotherapy with and without trastuzumab. | BL, Day 1 of Cycles 1-10 (pre-surgery) | 
| Percentage of Participants With Total Pathological Complete Response (tpCR) | tpCR was defined as a determination of bpCR and an absence of positive axillary nodes on pathology. | BL, Day 1 of Cycles 1-10 (pre-surgery) | 
| Percentage of Participants Achieving Either Complete Response (CR) or Partial Response (PR) According to Modified Response Evaluation Criteria in Solid Tumors (RECIST) Criteria | Assessments were made based on objective tumor measurements of the lesions as recorded in the case report form. In inflammatory cancer, progressive disease (PD) was defined as progression of any of the 2 signs of breast edema and erythema. In non-inflammatory cancer, PD was concluded if either the investigator judged the participant as having progressed at any time prior to surgery, or there was at least a 20% increase in the sum of target lesions (TLs), any new lesion, or clear progression of any nontarget lesion (NTLs). Clear progression of any NTL was defined as at least a 20% increase in the sum of NTLs compared to BL. PR was defined as at least a 30% decrease from BL in the sum of the longest diameter of TLs. CR was defined as no PD as assessed by the investigator and complete disappearance of all lesions. | BL, Presurgery: Day 1 of Cycles 1-10 | 
| Overall Survival (OS) - Percentage of Participants With an Event | OS was defined as the time from the date of randomization to the date of the death due to any cause. | BL, Presurgery: Day 1 (Cycles 1-7) and Days 1 and 8 (Cycles 8-10); Postsurgery: Day 1 (Cycles 1-17); every 6 months up to 60 months after last dose of study drug; yearly thereafter | 
| Overall Survival | OS was defined as the time from the date of randomization to the date of the death due to any cause. | BL, Presurgery: Day 1 (Cycles 1-7) and Days 1 and 8 (Cycles 8-10); Postsurgery: Day 1 (Cycles 1-17); every 6 months up to 60 months after last dose of study drug; yearly thereafter | 
| Percentage of Participants Surviving at 1 Year |  | BL, Presurgery: Day 1 (Cycles 1-7) and Days 1 and 8 (Cycles 8-10); Postsurgery: Day 1 (Cycles 1-17); every 6 months up to 60 months after last dose of study drug; yearly thereafter | 
| Percentage of Participants Surviving at 2 Years |  | BL, Presurgery: Day 1 (Cycles 1-7) and Days 1 and 8 (Cycles 8-10); Postsurgery: Day 1 (Cycles 1-17); every 6 months up to 60 months after last dose of study drug; yearly thereafter | 
| Percentage of Participants Surviving at 3 Years |  | BL, Presurgery: Day 1 (Cycles 1-7) and Days 1 and 8 (Cycles 8-10); Postsurgery: Day 1 (Cycles 1-17); every 6 months up to 60 months after last dose of study drug; yearly thereafter |