Phase 1 study of cetuximab in combination with 5-fluorouracil, cisplatin, and radiotherapy in patients with locally advanced anal canal carcinoma.

Background: This study sought to determine the feasibility and recommended phase 2 dose (RP2D) of the combination of cetuximab with chemoradiotherapy based on 5-fluorouracil (5-FU) and cisplatin (CP) in locally advanced anal canal carcinoma.

Methods: Cetuximab was administered on days 1, 8, 15, 29, 36, 43, and 50 (400 mg/m(2) initial dose, then 250 mg/m(2) /week) concurrent with total dose radiation of 55 to 59 Gy, both starting on day 1. Escalating doses of 5-FU (96-hour infusion) and CP (2-hour infusion), both on days 1 and 29, were administered according to the following design: starting dose level (0) 5-FU/CP = 800/60 mg/m(2) /day and up to dose level (+2) 5-FU/CP = 1000/80 mg/m(2) /day.

Results: Dose-limiting toxicity (DLT) events (uncontrolled diarrhea or febrile neutropenia) occurred in 3 of 14 assessable patients receiving escalated dose of 5-FU/CP, with 1 in dose level (0) and 2 in dose level (+2). The RP2D was 5-FU/CP = 800/80 mg/m(2) /day. Because of unexpected non-DLT treatment-related grade 3 (G3) adverse events (AEs) such as thrombosis/embolism, syncope, and infection occurring in ≥ 20% of patients, a safety expansion cohort with an additional 9 patients was investigated with the RP2D. The most frequent G3/G4 AEs evaluated in 23 patients were radiation dermatitis (12 patients), diarrhea (10 patients), thrombosis/embolism (6 patients), and infection (5 patients). The study was closed due to these severe AEs, although no G5 AEs occurred. Twenty of 21 patients (95%) achieved pathological complete response at primary tumor. With a median follow-up of 43.4 months, the 3-year locoregional control rate was 64.2%.

Conclusions: Cetuximab could not be integrated with chemoradiotherapy-cisplatin-based therapy due to the high toxicity rate. However, efficacy is encouraging and further investigation of an epidermal growth factor receptor-targeted agent (other than cetuximab) concurrent with chemoradiation should be pursued.