This proposal, the Clinical Program of a Breast Cancer Treatment Group, requests funding through a Cooperative Agreement with the National Cancer Institute. We have produced monoclonal antibodies (MAbs), against the EGF receptor (EGFR), that block activation of receptor tyrosine kinase and inhibit the growth of tumors expressing the receptor. We consider these MAbs to be pharmacologic antagonists of receptor mediated signal transduction pathways, although they also may have the capacity to activate immune antitumor mechanisms. In a series of experiments in vivo we have observed that combined treatments with anti-EGFR MAbs plus either doxorubicin or paclitaxel have a major antitumor effect, resulting in the disappearance of well-established tumor xenografts that cannot be eradicated by any other known therapy. Human clinical trials with murine anti-EGFR MAbs, conducted by our group, have shown that the administration of single doses of the mMAbs is safe and that we can achieve plasma levels of the muMAbs sufficient to saturate receptors. Based on these pre-clinical and clinical data we plan to conduct a series of Phase I and II clinical trials with the human:murine chimeric version of MAb 225 (HC MAb 225). Our goal is to determine the safety, feasibility, and noncomparative efficacy of multiple doses of MAb and of chemotherapy plus MAb in the treatment of patients with metastatic breast cancers expressing high levels of EGFR. The description of efficacy will be based on experience with patients who have received no prior chemotherapy for their advanced disease. Simultaneously, we will obtain pharmacokinetic data and tissue biopsies to study potential mechanisms of action. Should these clinical trials demonstrate the safety, feasibility, and reasonable activity of these treatments, we plan to design prospective, randomized trials of chemotherapy with and without MAb, in order to determine the comparative efficacy of the combination. Such randomized comparisons cannot proceed in the absence of the research proposed in this application.
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