Gefitinib, Trastuzumab, and Docetaxel in Treating Patients With 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. Monoclonal antibodies such as trastuzumab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Drugs used in chemotherapy, such as docetaxel, work in different ways to stop tumor cells from dividing so they stop growing or die. Combining gefitinib and trastuzumab with docetaxel may kill more tumor cells. PURPOSE: This phase I/II trial is studying the best dose of docetaxel when given together with gefitinib and trastuzumab in treating patients with metastatic breast cancer.

Detailed Description
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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.

Official Title
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Phase I/II Trial of ZD1839 (Iressa®), Trastuzumab (Herceptin®), and Docetaxel (Taxotere®) in Patients With erbB-2 (HER-2) Overexpressing, Stage IV Breast Carcinoma

Conditions
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Breast Cancer

Intervention / Treatment
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* Biological: trastuzumab
* Drug: docetaxel
* Drug: gefitinib


Participation Criteria
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Eligibility Criteria
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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

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ZD1839, Trastuzumab and Docetaxel<br> | Biological: trastuzumab<br>* Cycle 1 loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks for subsequent cycles.<br>Drug: docetaxel<br>* 75 mg/m2 every three weeks, or 60 mg/m2 every three weeks depending on study findings<br>Drug: gefitinib<br>* 250 mg daily or 250 mg daily on days 2 through 14 depending on study findings<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With at Least One Dose Limiting Toxicity in Phase I | Dose Limiting Toxicity (DLT) defined as any treatment-related grade 3 or greater except for hematological toxicities which must be grade 4. Interstitial Lung Disease (ILD) related to treatment should be considered as a DLT regardless of the grade. | 4 weeks from start of treatment, up to 2 years | 
| Recommended Phase II Dose | The maximum tolerated dose (MTD): subjects received gefitinib 250 mg orally daily, trastuzumab 6 mg/kg intravenously every 3 weeks (after an initial dose of 8 mg/kg with cycle 1), and docetaxel 75 mg/m^2 intravenously every 3 weeks. This was to serve as the phase II dose if no dose-limiting toxicities (DLTs) occurred in the first three subjects. If one DLT occurred in the first three subjects, another three subjects where to be enrolled at this dose, whereas if two DLTs occurred in the first three subjects, the docetaxel dose was to be decreased to 60 mg/m^2. The study would then be continued only if no more than one patient had a DLT at this dose. Once the dose of docetaxel was established, all further subjects were to be treated at the phase II MTD dose. | 4 weeks from start of treatment, up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Estimated using the product-limit method of Kaplan and Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST), as a 20% increase in the sum of the longest diameter of target lesions, or the appearance of new lesions. | Until disease progression, up to 5 years. | 
| Objective Response Rate | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Objective Response Rate defined as percentage of patients achieving a Best Response of either CR or PR. | After 3 cycles of treatment, up to 2 years. | 
| Overall Survival | Estimated using the product-limit method of Kaplan and Meier. | Until death from any cause, up to 5 years. | 

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