OBJECTIVES:

• Determine the response rate, duration of response, and time to progression in patients with metastatic breast cancer that overexpresses HER2-neu treated with trastuzumab (Herceptin) and gefitinib .
• Determine the phase II dose of gefitinib when given in combination with trastuzumab in these patients.
• Determine the toxicity of this regimen in these patients.
• Determine the 3- and 6-month progression-free survival of patients treated with this regimen.
• Correlate response rates with plasma levels of circulating HER2 and tumor levels of epidermal growth factor receptor, activated HER2, and HER2 receptors, as measured by immunohistochemistry and/or fluorescent in situ hybridization (FISH), in patients treated with this regimen.

OUTLINE: This is a multicenter, dose-escalation study of gefitinib. The phase I portion of this study was open in only 5 ECOG institutions. The phase I portion has been completed, and the study is being opened in all ECOG-affiliated institutions.

• Phase I (completed): Patients receive trastuzumab (Herceptin) IV over 30-90 minutes once weekly and oral gefitinib once daily beginning on day 1.

Cohorts of 3-6 patients receive escalating doses of gefitinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Once the MTD is established, additional patients are accrued to the phase II portion of the study and are treated at that dose.

• Phase II: Patients receive oral gefitinib once daily (at the MTD established in phase I) and trastuzumab IV weekly until week 24, at which time trastuzumab is given every 3 weeks (with daily gefitinib) until disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every 3 months until 2 years from study entry.

PROJECTED ACCRUAL: A total of 3-12 patients will be accrued for the phase I portion of this study. The phase I portion of this study has been completed. A total of 34-132 patients (15-46 previously treated with chemotherapy but not trastuzumab [Herceptin] in the metastatic setting; 19-86 not previously treated with chemotherapy or trastuzumab in the metastatic setting) will be accrued for the phase II portion of this study.

DISEASE CHARACTERISTICS:

• Histologically confirmed metastatic adenocarcinoma of the breast

  • Patients may have had or not had standard first-line chemotherapy for the treatment of metastatic disease
• Overexpression of HER2-neu (HER2 3+ by immunohistochemistry or gene amplification as measured by fluorescent in situ hybridization)
• Measurable disease
• Patients with no prior adjuvant chemotherapy may have failed or not failed first-line chemotherapy for metastatic disease

• No more than 2 prior systemic chemotherapy regimens for metastatic disease

  • Relapse while receiving or within 6 months of completion of adjuvant chemotherapy is considered failure of 1 regimen for metastatic disease

• No untreated brain metastases or brain metastases undergoing radiotherapy

  • Previously treated brain metastasis that has responded to radiotherapy and/or surgery allowed if not sole site of measurable 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:

• Granulocyte count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3

Hepatic:

• Bilirubin no greater than 1.5 times upper limit of normal (ULN)
• AST and ALT no greater than 3 times ULN (5 times ULN if liver metastases is present)
• INR no greater than 1.5 times ULN
• PT and PTT no greater than 1.5 times ULN

Renal:

• Creatinine no greater than 1.5 mg/dL
• No more than trace blood or protein in urine

Cardiovascular:

• LVEF ≥ 50% by MUGA scan
• No prior New York Heart Association class I-IV heart disease
• No PR prolongation or atrioventricular block on ECG

Other:

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception (preferably nonhormonal)
• Random blood sugar less than 2.5 times ULN
• No other malignancy within the past 5 years except curatively treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
• No other acute or chronic medical or psychiatric condition or laboratory abnormality that would preclude study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• No prior trastuzumab (Herceptin)
• No other concurrent immunologic therapy

Chemotherapy:

• See Disease Characteristics
• Recovered from prior cytotoxic chemotherapy
• No prior cumulative dose of doxorubicin more than 360 mg/m^2
• No concurrent chemotherapy

Endocrine therapy:

• At least 2 weeks since prior hormonal therapy
• No concurrent hormonal therapy, including tamoxifen
• No concurrent dexamethasone, progesterone, or glucocorticoids

Radiotherapy:

• See Disease Characteristics
• At least 2 weeks since prior radiotherapy
• No prior radiotherapy to target lesions or only site of measurable disease
• No concurrent radiotherapy

Surgery:

• See Disease Characteristics
• No prior organ allograft

Other:

• No prior gefitinib
• No prior immunosuppressive therapy
• At least 2 weeks since prior cytotoxic drugs
• No concurrent carbamazepine, ethosuximide, griseofulvin, nafcillin, nelfinavir mesylate, nevirapine, oxcarbazepine, phenobarbital, phenylbutazone, phenytoin, primidone, rifabutin, rifampin, rofecoxib, Hypericum perforatum (St. John's Wort), sulfadimidine, sulfinpyrazone, troglitazone, or grapefruit juice
• No other concurrent investigational agents
• No concurrent topical eye agents
• Concurrent bisphosphonates allowed for hypercalcemia and/or prophylaxis of bone metastases