Docetaxel and Trastuzumab With or Without Carboplatin in Treating Women With HER2-Positive Breast Cancer

OBJECTIVES:

• Compare the time to disease progression in women with HER2-positive stage IIIB, IIIC, or IV breast cancer treated with docetaxel and trastuzumab (Herceptin) with or without carboplatin.
• Compare the response rate and duration of overall response in patients treated with these regimens.
• Compare the overall survival of patients treated with these regimens.
• Compare rate of clinical benefit, defined as complete response, partial response, or stable disease for more than 24 weeks, in patients treated with these regimens.
• Compare the toxicity of these regimens in these patients.
• Determine pathologic and molecular markers for predicting efficacy of these regimens in these patients.
• Determine genetic and biochemical markers for predicting risk of cardiac dysfunction and later cardiac events in patients receiving these regimens.
• Determine whether peripheral levels of shed HER2 extracellular domain constitute a prognostic and/or predictive factor of time to progression and survival of patients receiving these regimens.

OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified according to prior adjuvant and/or neoadjuvant chemotherapy (none vs with taxanes vs without taxanes) and participating center. Patients are randomized to 1 of 2 treatment arms.

• Arm I:

• Course 1: Patients receive trastuzumab (Herceptin) IV over 30-90 minutes on days 1, 8, and 15. Patients receive docetaxel IV over 1 hour and carboplatin IV over 30-60 minutes on day 2.
• Courses 2 and all subsequent courses: Patients receive docetaxel IV over 1 hour and carboplatin IV over 30-60 minutes on day 1 and trastuzumab IV over 30 minutes on days 1, 8, and 15.
• Arm II: Patients receive docetaxel and trastuzumab as in arm I. In both arms, treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity. After completion of 8 courses, patients continue to receive trastuzumab IV over 30 minutes every 21 days in the absence of disease progression.

Patients are followed every 2 months for 3 years.

PROJECTED ACCRUAL: A total of 250 patients (125 per treatment arm) will be accrued for this study within 18 months.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed adenocarcinoma of the breast

• Stage IIIB, IIIC, or IV
• HER2-positive
• Measurable or evaluable disease

• Patients with osteolytic bone lesions as only site of disease must have at least 2 lytic sites confirmed by bone x-ray, MRI, or CT scan
• None of the following are eligible as only manifestation of metastatic disease:

• Blastic bone metastases
• Mixed bone metastases
• Lymphangitic carcinomatosis
• Ascites
• Pleural/pericardial effusion
• Lymphangitis cutis/pulmonis
• Inflammatory breast disease
• Abdominal masses not confirmed and followed by imaging techniques
• Cystic lesions
• No prior or known concurrent clinical manifestation of brain or leptomeningeal involvement
• Hormone receptor status:

• Not specified

PATIENT CHARACTERISTICS:

Age

• 18 to 75

Sex

• Female

Menopausal status

• Pre- or post-menopausal

Performance status

• Karnofsky 60-100%

Life expectancy

• Not specified

Hematopoietic

• Neutrophil count at least 2,000/mm3
• Platelet count at least 100,000/mm3
• Hemoglobin at least 10 g/dL

Hepatic

• Bilirubin no greater than upper limit of normal (ULN)
• AST and ALT no greater than 5 times ULN
• Alkaline phosphatase no greater than 5 times ULN (unless due to bone metastases or any nonmalignant bone disease and in absence of liver disorders)
• AST and/or ALT greater than 1.5 times ULN AND alkaline phosphatase greater than 2.5 times ULN ineligible

Renal

• Creatinine no greater than 2 mg/dL
• Creatinine clearance at least 60 mL/min

Cardiovascular

• LVEF normal by MUGA or echocardiogram
• No myocardial infarction within the past year
• No unstable angina pectoris
• No documentation of congestive heart failure
• No concurrent grade 3 or 4 cardiovascular arrhythmia
• No poorly controlled hypertension (i.e., diastolic pressure greater than 100 mmHg)

Pulmonary

• No severe dyspnea due to complications of advanced malignancy
• No respiratory insufficiency requiring supplemental oxygen

Other

• No significant neurologic or psychiatric disorders (e.g., psychotic disorders, dementia, or seizures) that would preclude study
• No pre-existing sensory or motor neuropathy grade 2 or greater
• No other serious illness or medical condition
• No active uncontrolled infection
• No active peptic ulcer disease
• No unstable diabetes mellitus
• No other prior or concurrent malignancy except for:

• Curatively treated nonmelanoma skin cancer
• Carcinoma in situ of the cervix
• Other curatively treated cancer and disease free for at least 10 years
• No known allergic reactions to study drugs
• No contraindications for the use of corticosteroids
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy

• See Chemotherapy
• No prior trastuzumab (Herceptin) for locally advanced or metastatic disease
• Prior trastuzumab-containing regimen (except with taxane) as adjuvant or neoadjuvant therapy allowed provided relapse occurred at least 6 months after therapy

Chemotherapy

• No prior chemotherapy for locally advanced or metastatic disease or local recurrence
• No prior chemotherapy with anthracycline or anthracenedione regimens with cumulative doses of more than 360 mg/m2 of doxorubicin, 720 mg/m2 of epirubicin, or 72 mg/m2 of mitoxantrone
• No prior platinum-containing regimen as adjuvant or neoadjuvant chemotherapy
• At least 4 weeks since prior anthracyclines or anthracenediones
• Prior taxanes as adjuvant or neoadjuvant chemotherapy allowed provided relapse occurred at least 6 months after therapy
• Prior taxane with trastuzumab as adjuvant or neoadjuvant chemotherapy allowed provided relapse occurred at least 12 months after therapy
• No concurrent amifostine

Endocrine therapy

• Prior hormonal therapy in the adjuvant or metastatic setting allowed provided patient has progressive disease and therapy has stopped before study entry
• Concurrent chronic corticosteroids allowed if initiated more than 6 months before study entry and at a low dose (no greater than 20 mg methylprednisolone or equivalent)
• No concurrent raloxifene, tamoxifen, or other selective estrogen receptor modulators
• No concurrent hormonal therapy

Radiotherapy

• No prior radiotherapy to study lesion unless clear progression
• At least 4 weeks since prior radiotherapy (unless radiotherapy involved only a single field to treat a single metastatic bone lesion)
• Concurrent radiotherapy for palliative treatment allowed

Surgery

• Not specified

Other

• Recovered from prior antitumor therapy
• At least 30 days since prior experimental drugs
• No other concurrent experimental drugs
• No other concurrent anticancer therapy
• No concurrent bisphosphonates if osteolytic bone metastases are only site of disease

• If receiving concurrent bisphosphonates other than for bone metastases only, must have been started at least 3 months before study entry
• No concurrent primary prophylactic antibiotics
• No concurrent cardioprotectors (e.g., dexrazoxane)