PURPOSE: Platinum-resistant oral cancer has a dismal outcome with limited treatment options. We conducted a phase I/II study to identify the optimal biologic dose (OBD) of methotrexate when given along with erlotinib and celecoxib and to assess the efficacy of this three-drug regimen in advanced oral cancer.
METHODS: Patients with platinum-resistant or early-failure squamous cell carcinoma of the oral cavity were eligible for this study. They were orally administered erlotinib 150 mg once per day, celecoxib 200 mg twice per day, and methotrexate per week. The primary end point of phase I was to determine the OBD of methotrexate, and that of phase II was to determine the 3-month progression-free survival. The OBD of methotrexate was determined on the basis of the clinical benefit rate at 2 months and circulating endothelial cell level at day 8, using a de-escalation model. Pharmacokinetic evaluation was performed during phase I. Phase II consisted of an expansion cohort of 76 patients.
RESULTS: Fifteen patients were recruited in phase I, and 9 mg/m2 methotrexate was identified as the OBD. A total of 91 patients were recruited, and the median follow-up was 6.8 months (range, 0 to 16.8 months). The 3-month progression-free survival rate was 71.1% (95% CI, 60.5% to 79.3%), the 6-month overall survival rate was 61.2% (95% CI, 49.2% to 67.8%), and the response rate was 42.9% (95% CI, 33.2% to 53.1%; n = 39). The mean Functional Assessment of Cancer Therapy-Head and Neck Trial Outcome Index score at day 8 was improved by 6.1 units (standard deviation, 13.6 units) and was maintained around this magnitude (P = .001).
CONCLUSION: Triple oral metronomic chemotherapy with erlotinib, methotrexate, and celecoxib is efficacious in platinum-refractory oral cavity cancers and represents a new therapeutic option in patients with poor prognosis.