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. Mechanistic studies have identified a pathogenetic role for over-expression of transforming growth factor-a (TGF-a) and its tyrosine kinase receptor epidermal growth factor receptor (EGFR) in squamous cell carcinoma of the head and neck. In response to ligand, EGFR results in the recruitment of Stat proteins (signal transducer and activators of transcription), which play an important role in cell growth and proliferation; these events can be antagonized in vitro by antisense Stat 3 or EGFR. It has been demonstrated that TGF-a and EGFR expression in tissue sections obtained from primary head and neck tumors is associated with adverse outcomes. There is abundant preclinical and clinical data to support the use of EGFR as a therapeutic target in many epithelial tumors and squamous cell carcinoma of the head and neck in particular. These data indicate that blocking the function of this important cellular survival factor may enhance the effects of chemotherapy and/or radiation induced tumor regression. There are preliminary results that OSI-774 may be active in a wide variety of tumors which express EGFR. Since squamous cell carcinoma of the head and neck abundantly over-expresses the EGFR and can be readily biopsied, this disease provides an ideal tumor model in which to investigate both the clinical and biological effects of EGFR inhibition. On the basis of the above preclinical and clinical rationale we are exploring a concurrent combined modality treatment approach with daily oral dosing of OSI-774 and weekly low-dose docetaxel with concurrent radiation in patients with newly diagnosed regionally advanced squamous cell carcinoma of the head and neck. The goals of this study are to: 1) determine the maximum tolerated dose and toxicity of the combination of EGFR inhibitor (OSI-774), docetaxel and radiation; 2) determine the effect of treatment and dose of treatment on biologic correlates in tumor tissue and or surrounding mucosa; 3) determine the pharmacokinetic profile of OSI-774 alone and in combination with docetaxel; 4) determine the overall and complete response rate of this combination; 5) determine overall, disease free and progression free survival of this combination. This is a dose escalation, dose finding phase I study. Treatment will be administered on an outpatient basis with the exception that patients will be admitted to the GCRC for 24 hours on day -3 for week 1, day 5 of week 2 and day 3 of week 5 for pharmacokinetics. OSI-774 is an oral drug taken daily for two weeks. It is then given in combination with weekly docetaxel and radiation for an additional seven weeks. All patients will be required to have biopsies of their tumor three times throughout the trial. After the completion of the first nine weeks, patients will go to a planned neck dissection. Following surgery the patients will resume the OSI-774 for two years.
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