Gefitinib, Trastuzumab, and Docetaxel in Treating Patients With Metastatic Breast Cancer

OBJECTIVES:

Primary

• Determine the safety and efficacy of gefitinib, trastuzumab (Herceptin®), and docetaxel, in terms of time to disease progression, in patients with HER2/neu-overexpressing metastatic adenocarcinoma of the breast.

Secondary

• Determine the objective tumor response rate in patients treated with this regimen.
• Correlate expression and/or degree of phosphorylation of epidermal growth factor receptor, HER2/neu, c-fos, Akt, ERK½, P13K, p53, p21, and p27 with outcome in patients treated with this regimen.

OUTLINE: This is a phase I, multicenter, dose-escalation study of docetaxel followed by a phase II study. Patients are stratified according to trastuzumab (Herceptin®)-naive vs trastuzumab-failure.

• Phase I: Patients receive oral gefitinib once daily on days 2-14. Patients also receive trastuzumab* IV over 30-90 minutes and docetaxel IV over 1 hour on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

NOTE: *Trastuzumab is given at a higher dose (loading dose) in course 1 and then at a lower dose in subsequent courses.

Cohorts of 3-6 patients receive docetaxel at dose level 1. If no dose-limiting toxicity (DLT) is observed in the first cohort of 3 patients, the dose of docetaxel remains the same. If 1 DLT is observed in the first cohort of 3 patients, 3 additional patients are added (for a total of 6 patients) to dose level 1. If no further DLTs are observed at dose level 1, the dose of docetaxel remains the same. If 2 of 3 or 2 of 6 patients experience DLT at dose level 1, the dose of docetaxel is considered above the maximum tolerated dose (MTD) and is subsequently reduced. If 2 of 3 or 2 of 6 patients experience DLT at the reduced dose of docetaxel, the study is stopped.

• Phase II: Patients receive docetaxel at the MTD and gefitinib and trastuzumab as in phase I.

Patients are followed for survival.

PROJECTED ACCRUAL: A total of 3-76 patients will be accrued for this study within 26 months.

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the breast

• Metastatic disease
• HER-2/neu overexpression (3+ by immunohistochemistry OR 2+ by fluorescence in situ hybridization)
• Measurable or evaluable disease
• Hormone receptor status:

• Not specified

PATIENT CHARACTERISTICS:

Age

• 18 and over

Sex

• Male or female

Menopausal status

• Not specified

Performance status

• ECOG 0-2

Life expectancy

• Not specified

Hematopoietic

• Absolute granulocyte count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3

Hepatic

• AST and ALT < 2.5 times upper limit of normal (ULN) (5.0 times ULN in the presence of liver metastases)
• Bilirubin < 1.5 times ULN
• No unstable or uncompensated hepatic disease

Renal

• Creatinine < 1.6 mg/dL
• No unstable or uncompensated renal disease

Cardiovascular

• LVEF > 45% by echocardiogram or MUGA
• No prior New York Heart Association class I-IV heart disease
• No prolonged PR interval or atrioventricular block on ECG
• No unstable or uncompensated cardiac disease

Pulmonary

• No unstable or uncompensated respiratory disease
• No clinically active interstitial lung disease

• Patients who are asymptomatic and have chronic stable radiographic changes are allowed

Immunologic

• No autoimmune disorders
• No conditions of immunosuppression
• No severe hypersensitivity to taxane or gefitinib or any of its excipients

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No other prior or concurrent malignancy within the past 5 years except basal cell carcinoma or carcinoma in situ of the cervix
• No other severe or uncontrolled systemic disease
• No other acute or chronic medical condition that would preclude study participation
• No other significant clinical disorder or laboratory finding that would preclude study participation
• No psychiatric illness that would preclude study compliance

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Prior adjuvant trastuzumab (Herceptin®) allowed if > 6 months elapsed before disease recurrence
• No prior trastuzumab for metastatic breast cancer
• No prior monoclonal antibodies directed at the epidermal growth factor receptor (EGFR)

Chemotherapy

• Prior adjuvant chemotherapy (or as first-line therapy for metastatic breast cancer) allowed
• Prior adjuvant taxane allowed if completed > 6 months before diagnosis of metastatic breast cancer
• No prior docetaxel for metastatic breast cancer

Endocrine therapy

• Prior adjuvant hormonal therapy (or as first-line therapy for metastatic breast cancer) allowed
• No concurrent hormonal therapy

• Concurrent steroids allowed provided dose is stable

Radiotherapy

• Not specified

Surgery

• Fully recovered from prior oncologic or other major surgery
• No concurrent surgery within 7 days of gefitinib administration

Other

• Recovered from prior anticancer therapy (alopecia allowed)
• More than 30 days since prior non-approved drug or investigational agent
• No other prior EGFR-directed therapy (i.e., tyrosine kinase inhibitors)
• No concurrent use of any of the following medications:

• Phenytoin
• Carbamazepine
• Barbiturates
• Rifampin
• Hypericum perforatum (St. John's wort)
• No other concurrent anticancer therapy
• No concurrent cardioprotective drugs
• No concurrent oral retinoids
• Concurrent participation in the City of Hope indium-labeled trastuzumab imaging study allowed