Gefitinib, Trastuzumab, and Docetaxel in Treating Patients With Metastatic Breast Cancer
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.
|Breast Cancer||Biological: trastuzumab Drug: docetaxel Drug: gefitinib||Phase 1 Phase 2|
|Study Design:||Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase I/II Trial of ZD1839 (Iressa®), Trastuzumab (Herceptin®), and Docetaxel (Taxotere®) in Patients With erbB-2 (HER-2) Overexpressing, Stage IV Breast Carcinoma|
- Number of Participants With at Least One Dose Limiting Toxicity in Phase I [ Time Frame: 4 weeks from start of treatment, up to 2 years ]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.
- Recommended Phase II Dose [ Time Frame: 4 weeks from start of treatment, up to 2 years ]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.
- Progression-free Survival [ Time Frame: Until disease progression, up to 5 years. ]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.
- Objective Response Rate [ Time Frame: After 3 cycles of treatment, up to 2 years. ]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.
- Overall Survival [ Time Frame: Until death from any cause, up to 5 years. ]Estimated using the product-limit method of Kaplan and Meier.
|Study Start Date:||January 2004|
|Study Completion Date:||August 2015|
|Primary Completion Date:||August 2015 (Final data collection date for primary outcome measure)|
|Experimental: ZD1839, Trastuzumab and Docetaxel||
Cycle 1 loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks for subsequent cycles.Drug: docetaxel
75 mg/m2 every three weeks, or 60 mg/m2 every three weeks depending on study findingsDrug: gefitinib
250 mg daily or 250 mg daily on days 2 through 14 depending on study findings
- 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.
- 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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00086957
|United States, California|
|Tower Cancer Research Foundation|
|Beverly Hills, California, United States, 90211-1850|
|City of Hope Comprehensive Cancer Center|
|Duarte, California, United States, 91010-3000|
|Hematology Oncology Consultants-Hemet|
|Hemet, California, United States, 92543|
|Breastlink Medical Group, Incorporated at Long Beach Memorial Medical Center|
|Long Beach, California, United States, 90806|
|USC/Norris Comprehensive Cancer Center and Hospital|
|Los Angeles, California, United States, 90089-9181|
|City of Hope Medical Group|
|Pasadena, California, United States, 91105|
|Principal Investigator:||George Somlo, MD||City of Hope Medical Center|