Phase II randomized trial of radiotherapy (RT), cetuximab (E), and pemetrexed (Pem) with or without bevacizumab (B) in locally advanced squamous cell carcinoma of the head and neck (SCCHN).

TPS264 Background: RT and E, an anti-EGFR monoclonal antibody, has emerged as a standard nonsurgical therapy for stage III/IV SCCHN. Pem, a multitargeted antifolate that inhibits several enzymes of the folate pathway (thymidylate synthetase, dihydrofolate reductase, and other) has attributed promising results in SCCHN. We previously established the recommend doses of Pem in combination with RT plus E in SCCHN (ASCO 2008; A2540). The combination of Pem plus B has produced promising results in a phase II trial in recurrent or metastatic SCCHN (ASCO 2008; A6069). Upregulation of VEGF has been associated with E resistance, thus, adding B to the RT plus PemE regimen may enhance antitumor activity. Methods: Eligible patients have previously untreated stage III/IV SCCHN of the oropharynx, larynx or hypopharynx, ECOG performance status (PS) 0-1, no history of bleeding and not receiving therapeutic anticoagulation, and adequate laboratory parameters. Patients are randomized after stratification by stage, site, and PS to receive either: A) RT 2Gy/day to 70 Gy, E 250 mg/m2 weekly, after a loading dose of 400 mg/m2 1 week prior starting RT, and Pem 500 mg/m2 every 21 days × 3 cycles (PemE), or B) the same regimen plus B 15 mg/kg every 21 days × 3 cycles during RT (B-PemE) followed by B maintenance × 8 cycles (24 weeks). All patients receive folic acid and B12, and antibiotic prophylaxis with cycles 2 and 3. Placement of prophylactic gastrostomy tube is strongly recommended. The primary endpoint is the progression-free survival (PFS) at 2 years. We target a 2-year PFS of 64% assuming 46% as historical control. 40 patients will be accrued per arm. Secondary objectives include local PFS, distant PFS, overall survival, toxicities, and quality-of-life. 14 pts have been enrolled in this ongoing trial (6 in arm A; 8 in arm B). No significant financial relationships to disclose.