A phase I/II study of radiation therapy, paclitaxel poliglumex, and cetuximab in locally advanced head and neck cancer.

Abstract

e16047 Background: In patients with locally advanced head and neck cancer (LA-HNC), radiotherapy (RT) + cisplatin showed survival benefit over RT alone, but with significant toxicity. The addition of cetuximab to RT demonstrated survival benefit without increased RT-related toxicity. Paclitaxel poliglumex (PPX) is a novel conjugate consisting of paclitaxel linked to a biodegradable, water-soluble polymer of glutamic acid. PPX has a radiation enhancement factor of ≈8 and improved curability in a murine carcinoma model. In a phase I study of PPX + RT in esophageal cancer, no dose-limiting toxicities (DLTs) occurred at PPX doses up to 70 mg/m2/week and an encouraging rate of pathological CRs was observed. This phase I/II study addresses the combined use of intensity modulated RT (IMRT), PPX, and cetuximab in patients with LA-HNC. Methods: Eligible patients had untreated stage III or IV squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx; ECOG PS 0-1; and adequate bone marrow function. In the phase I portion, patients received cetuximab 400 mg/m2 day 1 and 250 mg/m2 days 8, 15, 22, 29, 36, 43, and 50. PPX was administered at 40 mg/m2 days 8, 15, 22, 29, 36, 43, and 50 for Cohort 1 (n = 3) then escalated or decreased for Cohorts 2-5 (3 patients each) until the maximum tolerated dose (MTD) was established. IMRT began on day 8 and consisted of 69.96 Gy delivered in 2.12 Gy daily fractions. In the phase II portion, patients received PPX at the MTD + cetuximab and IMRT at the phase I dose and schedule. Results: In total, 14 patients were treated (9 phase I, 5 phase II). The PPX MTD was determined to be 40 mg/m2. The majority of adverse events (AEs) were grade 1/2 and consistent with known toxicities of individual agents. The most common grade 3 AEs were mucositis (n = 8), radiation dermatitis (n = 4), and cetuximab rash (n = 3). Of 13 patients evaluable for response, 9 had CR and 4 had PR. After a median 17-month follow up, the local control rate was 11/11 and the median survival was 20 months. Two patients with stage IVC disease were excluded for local control and survival analysis. Conclusions: The combination of IMRT, PPX, and cetuximab is tolerable and shows promising clinical activity in patients with LA-HNC.