RATIONALE: Gefitinib may stop the growth of tumor cells by blocking the enzymes necessary
for their growth. Hormone therapy using tamoxifen may fight breast cancer by blocking the
use of estrogen by the tumor cells. Combining gefitinib with tamoxifen may be effective in
killing tumor cells that have become resistant (stopped responding) to tamoxifen.
PURPOSE: This randomized phase II trial is studying how well giving gefitinib together with
tamoxifen works compared to gefitinib alone in treating patients with metastatic breast
cancer that has stopped responding to tamoxifen.
- Compare the rate of clinical benefit in patients with tamoxifen-resistant breast cancer
treated with gefitinib with or without tamoxifen.
- Determine the toxic effects of these regimens in these patients.
- Determine whether changes in fludeoxyglucose F 18 uptake by positron emission
tomography scan and changes in plasma DNA levels are indicators of an early response to
gefitinib in these patients.
- Determine the pharmacokinetics of these regimens in these patients.
OUTLINE: This is a randomized, double-blind, placebo-controlled study. Patients are
stratified according to population (intent-to-treat population comprising all patients who
receive 1 dose of treatment vs a subset of the intent-to-treat population, excluding
patients with nonmeasurable/evaluable only disease). Patients are randomized to 1 of 2
- Arm I: Patients receive oral tamoxifen once daily. Beginning 14 days after the start of
tamoxifen, patients receive oral gefitinib once daily.
- Arm II: Patients receive oral placebo once daily. Beginning 14 days after the start of
placebo, patients receive oral gefitinib as in arm I.
In both arms, treatment continues for 26 weeks in the absence of disease progression or
Patients are followed for 6 months.
PROJECTED ACCRUAL: A total of 46 patients (23 per treatment arm) will be accrued for this
study within 23 months.
- Histologically confirmed breast cancer
- Metastatic disease
- Initial clinical benefit from tamoxifen for metastatic disease, defined by 1 of the
- Stable disease for 24 weeks or longer
- Objective tumor response
- Documentation of clinical progression on tamoxifen within the past 6 weeks
- Hormone receptor status:
- Estrogen or progesterone receptor positive on most recently analyzed biopsy
- 18 and over
- Not specified
- Not specified
- ECOG 0-2
- At least 6 months
- Absolute neutrophil count ≥ 1,500/mm^3
- Platelet count ≥ 100,000/mm^3
- AST ≤ 1.5 times upper limit of normal (ULN)
- Bilirubin ≤ 1.5 times ULN
- Creatinine ≤ 1.5 times ULN OR
- Creatinine clearance ≥ 50 mL/min
- No clinically active interstitial lung disease
- Patients with asymptomatic chronic stable radiographic changes are eligible
- Not pregnant or nursing
- Fertile patients must use effective contraception
- No known hypersensitivity to gefitinib
- No other malignancy within the past 5 years except basal cell carcinoma or carcinoma
in situ of the cervix
PRIOR CONCURRENT THERAPY:
- No concurrent trastuzumab (Herceptin®)
- No concurrent cytotoxic chemotherapy
- See Disease Characteristics
- At least 2 weeks since other prior tamoxifen
- No concurrent hormone replacement therapy
- No other concurrent antiestrogens, including raloxifene
- No concurrent aromatase inhibitors
- No concurrent megestrol
- Concurrent systemic steroids for reasons other than skin toxicity allowed provided
the steroids were initiated before study entry AND dose remains stable
- Concurrent palliative radiotherapy as short-term treatment for symptomatic bone
metastases allowed provided other evaluable sites of disease are present AND
treatment lasts no more than 14 days
- Recovered from prior oncologic or other major surgery
- No concurrent surgery during and for 7 days after study treatment
- No concurrent ophthalmic surgery
- Recovered from all prior therapy (except alopecia)
- More than 30 days since prior investigational drugs
- No other concurrent investigational agents
- No concurrent administration of any of the following:
- Hypericum perforatum (St. John's wort)
- Systemic retinoids
- CYP3A4 inhibitors (e.g., itraconazole)
- Drugs that cause significant sustained elevation in gastric pH ≥ 5