A Phase 2, Multi-Center Trial of ZD1839 (IRESSA) in Combination With Docetaxel as First-Line Treatment in Patients With Advanced Breast Cancer
Patients with advanced breast cancer continue to have an extremely poor prognosis with an
average life expectancy of approximately 2 years. Novel treatments designed to exploit
biologic properties of the tumor are urgently required as a means to improve the outcome for
the large numbers of patients who relapse after receiving optimal chemotherapy treatments.
Overexpresssion of EGFR and/or TGF-alpha is frequent in human breast cancer and has been
correlated in many cases with poor prognostic features. Inhibition of the EGFR pathway has
been proposed as a potential therapeutic modality in advanced breast cancer. The
antiproliferative activity of ZD 1839 in combination with cytotoxic drugs, such as
docetaxel was evaluated in breast cancer cell lines ZR-75-1 and MCF-10A ras that coexpress
EGFR and TGF-alpha. Combination treatment demonstrated dose dependent supra-additive growth
inhibition and markedly enhanced apoptotic cell death.
Although taxanes bind to the microtubular network in cells that is essential for mitotic and
interphase cellular functions, the mechanism by which these agents induce cell death is not
entirely clear. Docetaxel has also shown dose-dependent anti-angiogenic activity. Thus,
the mechanism(s) of anti-tumor activity of docetaxel remain unclear and combinations of
signal transduction pathway inhibition and/or anti-angiogenesis may provide potentiation of
concurrent ZD 1839 and docetaxel therapy.
This phase 2 trial is designed to prospectively investigate the efficacy and safetey of
combination therapy with ZD 1839 and docetaxel in patients with metastatic breast cancer.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To estimate the clinical benefit rate of the combination of ZD 1839 and docetaxel; clinical benefit measured by clinical response, pathologic response, and stable disease (SD greater than or equal to 24 weeks)
Norman Wolmark, MD
NSABP Foundation, Inc.
United States: Food and Drug Administration
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