OSI-774 IN PATIENTS WITH ORAL CAVITY OR OROPHARYNGEAL CANCER

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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. Novel therapeutics designed to target specific signaling pathways that contribute to the pathogenesis of malignancy have particular promise for improving survival for patients with cancer. Abnormalities of EGFR signal transduction are common in squamous cell carcinoma of the head and neck. Over expression of EGFR has been demonstrated in the majority (80-100%) of head and neck squamous cell carcinomas, and may be related to advanced T stage and presence of nodal disease. EGFR overexpression has also been shown to be a predictor of survival(1-3). Ligand binding to the epidermal growth factor receptor (EGFR) results in a cascade of signal transduction and subsequent promotion of cell replication(4). In vitro studies have shown that over expression of EGFR may lead to constitutive activity of signal transduction and dysregulated cell replication. The importance of EGFR signaling in HNSCC has been well demonstrated in vitro. Antisence oligonucleotides, monoclonal antibodies to EGFR and EGFR-specific tyrosine kinase inhibitors effect HNSCC proliferation (4,5). OSI-774 is a specific inhibitor of EGFR tyrosine kinase that has shown activity as a single agent in patients with advanced, drug-refractory head and neck cancer. OSI-774 has demonstrated synergy in vitro with conventional chemotherapy and radiation. This two-part phase I trial is designed to evaluate whether the addition of OSI-774 to primary radiation therapy and to concurrent chemo-radiotherapy will produce acceptable toxicities in patients with newly diagnosed HNSCC and to determine the recommended dose of daily OSI-774 in combination with these treatment modalities for subsequent phase II trials. The clinical trial is a phase I dose-finding study of OSI-774 in combination with radiation therapy (RT) and cisplatin in patients with newly diagnosed, locally advanced squamous cell cancers (SCC) of the oral cavity (OC) and oropharynx (OP). The study will be conducted in two sequential parts, Part A and B. Mechanistically, the clinical trial is a standard phase I dose escalation study in successive cohorts. In both Parts A and B, patients will receive single agent daily oral OSI-774 during a fourteen day induction "window" prior to start of concurrent chemoradiation. Part A will be a phase I dose finding study to maximum tolerated dose (MTD) of daily oral OSI-774 in combination with standard fractionation external beam radiation therapy in patients with stage II (T2N0) or stage III (T1-2N1) squamous cell carcinoma of the oropharynx (OP) and oral cavity (OC) (Group A). After the safety of the first dose level of OSI-774 and standard fractionation external beam radiation therapy has been determined in Part A, Part B will begin to enroll patients at that dose level. Part B will be a phase I dose finding study of the combination of daily oral OSI-774, low dose daily cisplatin chemotherapy (6 mg/m2/day) and concurrent standard fractionation external beam radiation therapy in patients with stage III (T3N0-1) or IV (T1-4N2-3M0, T4N0M0) squamous cell carcinoma of the OP and OC (Group B). Starting dose of OSI-774 will be 50 mg/day, or 33.3% of the recommended daily oral dose (150 mg/day) based on previous single agent Phase II trials. Patients will continue daily oral OSI-774 until unacceptable toxicity or disease progression for a maximum of two years. Dose escalations will occur in successive cohorts of 3-6 patients. Expected adverse events and appropriate dose modifications for OSI-774, and RT and cisplatin are described in the protocol. The maximally tolerated dose will be defined as the highest dose level of OSI-774 in combination with radiation therapy (Part A) or chemoradiation (Part B) that causes 1 of 6 or less patients to experience a dose limiting toxicity (as defined in the protocol). After the MTD has been defined, 6 additional patients will be enrolled at that dose level to better define toxicities. We expect the total number of patients treated with OSI-774 at the MTD in Parts A and B of the trial will be 24 and a total of 36 patients in all dose levels.