PH I STUDY OF EGFR AND HER2 BLOCKADE W/ OSI-774, TRASTUZUMAB AND PACLITAXEL

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. OBJECTIVES: 1. To determine the safety, and the quantitative and qualitative toxicities of combined erbB1 and erbB2 (EGFR and HER2) inhibition with OSI-774 administered continuously once daily by the oral route, in combination with intravenous Trastuzumab and paclitaxel administered on Days 1, 8, and 15 or Days 1, 8, 15, and 22 in patients with advanced cancer. 2. To determine the maximum tolerated doses and dose-limiting toxicities of these schedules. 3. To investigate relevant pharmacokinetic interactions between these agents. 4. To document the preliminary antitumor activity of dual erbB1 and erbB2 inhibition with continuous oral OSI-774 in combination with weekly intravenous Trastuzumab and Paclitaxel. RESEARCH PLAN AND METHODS: This is an open-label, dose-escalation, non-randomized, single center Phase I study of OSI-774 in combination with Trastuzumab and Paclitaxel in patients with advanced carcinoma. Adult patients with histologically confirmed HER2 positive (+ to +++) metastatic solid tumors that have a high likelihood of expressing EGFR with no effective standard treatment options will be enrolled. It is anticipated that up to 40 eligible patients will be enrolled in this Phase I trial, with enrollment of about 20 patients anticipated for the GCRC. OSI-774 dose levels will range from 25 mg/day to 150 mg/day. Trastuzumab will be dosed at 2 mg/kg. Paclitaxel dose levels will range from 60 mg/m2/week to 90 mg/m2/week. Paclitaxel will be administered first. Trastuzumab will follow 30 minutes after the completion of the paclitaxel infusion. OSI-774 will always be administered last. A course of treatment will be considered to be complete 28 days following the start of administration of treatment. Following the initial course, adjustments of OSI-774 dose are allowed based on patient tolerance. Patients will be allowed to receive multiple courses. The treatment will continue until development of progressive disease, intolerable toxicity, or the patient decides to discontinue therapy. CLINICAL RELEVANCE: OSI-774 is an orally active potent and selective inhibitor of the EGFR tyrosine kinase. In an in vitro enzyme assay, it inhibited the human EGFR tyrosine kinase and reduced the EGFR autophosphorylation in intact tumor cells and an IC50 of 20 nm (i.e., HN5 human head and neck carcinoma and A431 squamous epidermoid carcinoma xenografts in athymic mice).