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