Gefitinib With or Without Tamoxifen in Treating Patients With Tamoxifen-Resistant Metastatic Breast Cancer

Study Overview
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Brief Summary
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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.

Detailed Description
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OBJECTIVES: Primary Compare the rate of clinical benefit in patients with tamoxifen-resistant breast cancer treated with gefitinib with or without tamoxifen. Secondary 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 treatment arms. 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 unacceptable toxicity. 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.

Official Title
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ZD1839 (IRESSA) In Tamoxifen-Resistant Metastatic Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: gefitinib
* Drug: tamoxifen citrate
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed breast cancer Metastatic disease Initial clinical benefit from tamoxifen for metastatic disease, defined by 1 of the following: 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 PATIENT CHARACTERISTICS: Age 18 and over Sex Not specified Menopausal status Not specified Performance status ECOG 0-2 Life expectancy At least 6 months Hematopoietic Absolute neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Hepatic AST ≤ 1.5 times upper limit of normal (ULN) Bilirubin ≤ 1.5 times ULN Renal Creatinine ≤ 1.5 times ULN OR Creatinine clearance ≥ 50 mL/min Pulmonary No clinically active interstitial lung disease Patients with asymptomatic chronic stable radiographic changes are eligible Other 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: Biologic therapy No concurrent trastuzumab (Herceptin®) Chemotherapy No concurrent cytotoxic chemotherapy Endocrine therapy 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 Radiotherapy 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 Surgery Recovered from prior oncologic or other major surgery No concurrent surgery during and for 7 days after study treatment No concurrent ophthalmic surgery Other 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: Phenytoin Carbamazepine Barbiturates Rifampin Phenobarbital Hypericum perforatum (St. John's wort) Systemic retinoids CYP3A4 inhibitors (e.g., itraconazole) Drugs that cause significant sustained elevation in gastric pH ≥ 5

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Tamoxifen<br>Tamoxifen 20 mg po once daily | Drug: gefitinib<br>* 250 mg po once daily<br>* Other names: ZD1839, Iressa;Drug: tamoxifen citrate<br>* 20 mg po once daily<br>* Other names: Nolvadex;|
| Placebo Comparator: Placebo<br>Placebo comparator one tablet po once daily | Drug: gefitinib<br>* 250 mg po once daily<br>* Other names: ZD1839, Iressa;Drug: Placebo<br>* One pill po once daily<br>* Other names: Sugar pill;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical benefit rate (complete response, partial response, and stable disease) for 26 weeks |  | 26 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent breast cancer, stage IV breast cancer