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)