Phase I trial of pemetrexed (P) in combination with cetuximab (C) and concurrent radiotherapy (RT) in patients (pts) with head and neck cancer (HNC)

Abstract

16516 Background: P is a multitargeted antifolate that has demonstrated activity in HNC and radiosensitizing properties in animal models. C is a chimeric IgG1 monoclonal antibody directed against the epidermal growth factor receptor that has increased the survival of pts with stage III/IV HNC when added to RT. We conducted a phase I study to evaluate the dose-limiting toxicities (DLT) and maximum tolerated dose of P when combined with standard RT and C. Methods: Pts with high-risk HNC were enrolled and evaluated separately in 2 cohorts: pts with no prior head and neck RT (cohort A) and previously irradiated pts (cohort B). A loading dose of C 400 mg/m2 was given intravenously 7 days prior to starting RT followed by 250 mg/m2 weekly throughout RT. RT was given 2 Gy/day to a total dose of 70 Gy (cohort A) or 60–66 Gy (cohort B). P was administered intravenously on days 1 and 22 (and day 43 if >60 Gy was delivered) according to the following design: Starting dose level (0)-350 mg/m2, dose level (-1)-200 mg/m2, dose level (+1)-500 mg/m2. Additional pts could be treated at a lower dose level while other pts were being evaluated at a higher dose level. Results: 18 pts have been enrolled (A: 14; B:4). 2 pts in cohort A were not evaluable and replaced (1 pt was noncompliant due to transportation issues and 1 pt had sudden death attributable to aspiration). Histological types: squamous cell (13), undifferentiated (1), medullary thyroid (1), adenoid cystic (1), and adenosquamous carcinomas (2). In cohort A, 2 DLT (both neutropenic fever with ANC <500) occurred: 1/6 at dose level 0 and 1/6 at dose level -1. In cohort B, no DLT has occurred: 0/3 pts at dose level 0 and 0/1 pts at dose level +1. There were no grade (G) 4 non- hematologic toxicities. Other serious toxicities included: neutropenic fever (NF) with ANC <1000 (n=1), G 3/4 neutropenia (n=3/n=4), G 3 dysphagia (n=5), G 3 dermatitis (n=3), G 3 mucositis (n=4), G 3 fatigue (n=1), and G 3 anemia (n=1). Due to the development of 3 cases of NF in cohort A the protocol was amended and prophylactic antibiotics were added. Conclusions: The addition of P to RT and C was feasible in pts with or without a history prior RT. Neutropenia and in-field toxicities were predominant but manageable. Pts are currently being treated at dose level +1 (P 500 mg/m2). No significant financial relationships to disclose.