Combination Chemotherapy With Trastuzumab in Treating Women With Metastatic Breast Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy such as cyclophosphamide, methotrexate, and fluorouracil use different ways to stop tumor cells from dividing so they stop growing or die. Monoclonal antibodies, such as trastuzumab, can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Combining chemotherapy with trastuzumab may kill more tumor cells. PURPOSE: Phase II trial to study the effectiveness of combining combination chemotherapy with trastuzumab in treating women who have metastatic breast cancer.

Detailed Description
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OBJECTIVES: Compare the incidence of clinical heart failure in women with c-erbB2-positive metastatic breast cancer treated with cyclophosphamide, methotrexate, and fluorouracil in combination with trastuzumab (Herceptin®). Compare the therapeutic activity of this regimen, in terms of objective response rate, in these patients. Compare the duration of response and time to progression in patients treated with this regimen. Compare the toxic effects of this regimen in these patients. OUTLINE: This is a multicenter study. Patients receive CMF comprising cyclophosphamide orally on days 1-14 or IV on days 1 and 8 and methotrexate IV and fluorouracil IV on days 1 and 8. Patients also receive trastuzumab (Herceptin®) IV over 30-90 minutes once weekly beginning on day 1. Treatment repeats every 4 weeks for 8 courses. Patients then receive trastuzumab once every 3 weeks in the absence of disease progression, unacceptable toxicity, or patient refusal. Patients are followed every 8 weeks until documentation of disease progression or initiation of a new anticancer therapy. Patients developing disease progression are followed every 12 weeks. PROJECTED ACCRUAL: A total of 66 patients will be accrued for this study within 2 years.

Official Title
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A Randomized Phase II Study Of CMF Alone And In Combination With Anti c-erbB2 Antibody (Herceptin) In Women With c-erbB2 Positive Metastatic Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Biological: trastuzumab
* Drug: CMF regimen
* Drug: cyclophosphamide
* Drug: fluorouracil
* Drug: methotrexate


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed metastatic breast cancer c-erbB2 positive (3+ overexpression by the HercepTest™ method) in the primary tumor or metastatic site At least 1 unidimensionally measurable target lesion At least 20 mm by conventional techniques OR At least 10 mm by spiral CT scan Lesions that have been irradiated in the preceding 3 months cannot be used as target lesions unless they have appeared or clearly progressed since prior irradiation No bone lesions as the only target lesions No contralateral breast cancer that is c-erbB2-positive or c-erbB2-negative/unknown, with status determined on a metastatic site No CNS metastases CT scan of brain and CSF cytology are required if neurologic symptoms are present Hormone receptor status: Any estrogen or progesterone receptor status PATIENT CHARACTERISTICS: Age: 18 and over Sex: Female Menopausal status: Any status Performance status: ECOG 0-2 Life expectancy: Not specified Hematopoietic: Neutrophil count at least 1,500/mm^3 Platelet count at least 100,000/mm^3 Hepatic: Bilirubin no greater than 1.25 times upper limit of normal (ULN) Transaminases less than 2.5 times ULN (5 times ULN if liver metastases present) Renal: For patients age 18 to 69: Creatinine no greater than ULN For patients age 70 and over: Creatinine clearance normal Cardiovascular: LVEF normal by MUGA or echocardiogram No clinical heart failure Pulmonary: No malignancy-associated dyspnea at rest No requirement for supportive oxygen therapy Other: Not pregnant or nursing No other prior or concurrent malignancy within the past 5 years except adequately treated carcinoma in situ of the cervix or basal cell skin cancer No psychological, familial, sociological, or geographical condition that would preclude compliance with study therapy and follow-up schedule PRIOR CONCURRENT THERAPY: Biologic therapy: No prior anti-c-erbB2 antibody, including trastuzumab (Herceptin®) No other concurrent biologic therapy Chemotherapy: No more than 1 prior chemotherapy regimen for metastatic breast cancer Prior combination of cyclophosphamide, methotrexate, and fluorouracil (CMF) allowed in the adjuvant or metastatic setting only if the disease-free interval after completion of CMF was at least 12 months Prior anthracyclines and/or taxanes allowed At least 4 weeks since prior anthracyclines No prior cumulative dose of doxorubicin more than 360 mg/m^2 No prior cumulative dose of epirubicin more than 720 mg/m^2 No prior cumulative dose of mitoxantrone more than 90 mg/m^2 No other concurrent chemotherapy Endocrine therapy: More than 2 weeks since prior hormonal therapy in the adjuvant or metastatic setting No concurrent hormonal therapy Radiotherapy: See Disease Characteristics No concurrent radiotherapy Surgery: Not specified Other: No other concurrent anticancer therapy or investigational drugs No concurrent bisphosphonates started after study enrollment except for hypercalcemia

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: CMF + Herceptin<br> | Biological: trastuzumab<br> <br> Drug: CMF regimen<br> <br> Drug: cyclophosphamide<br> <br> Drug: fluorouracil<br> <br> Drug: methotrexate<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical heart failure rate measured by New York Heart Association classification, LVEF, and ECG |  | from registration | 
| Response rate by RECIST |  | from registration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of response by RECIST |  | from registration | 
| Time to progression |  | from registration | 
| Toxicity measured by CTC v2.0 |  | from registration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage IV breast cancer, recurrent breast cancer