Chemoprevention of Head and Neck Cancer with Celecoxib and Erlotinib: Results of a Phase 1b and Pharmacokinetic Study
Mené sur 12 patients présentant des lésions pré-cancéreuses de stade avancé de la tête et du cou (durée médiane de suivi : 36 mois), cet essai de phase IB évalue la dose tolérable, la toxicité et le taux de réponse histologique globale associés à un traitement combinant célécoxib et erlotinib pour prévenir la progression de la maladie vers un cancer
Epidermal growth factor receptor (EGFR) and cyclooxygenase 2 inhibitors synergistically inhibit head and neck squamous cell carcinoma tumorigenesis in preclinical studies. We conducted a phase I and pharmacokinetic study with the erlotinib and celecoxib combination in patients with advanced premalignant lesions. 36 subjects with oral leukoplakia, mild, moderate, or severe dysplasia, or carcinoma in situ were screened for study participation; 12 consented and received therapy for a median of 5.38 months. Erlotinib was escalated following a standard 3+3 design at 50, 75, and 100mg orally daily and celecoxib was fixed at 400mg twice daily for 6 months. Biopsy of lesions and cytobrush of normal mucosa were performed at baseline, 3, 6 and 12 months. Erlotinib pharmacokinetics were analyzed in 10 subjects. The maximum tolerated dose of erlotinib with celecoxib 400mg BID was 50mg per day with skin rash being the main observed toxicity. Overall histologic response rate was 63% (complete response 43%, partial response 14%, stable disease 29%, disease progression 14%). With median follow-up of 36 months, mean time to progression to higher-grade dysplasia or carcinoma was 25.4 months. Downregulation of EGFR and p-ERK in follow-up biopsies correlated with response to treatment. Larger average erlotinib V/F (~308L) and CL/F (8.3L/hr) compared to previous studies may be related to relatively large average bodyweights. Average erlotinib t1/2 was 25.6hr. Encouraging responses to the celecoxib and erlotinib combination correlated with EGFR pathway inhibition. Although erlotinib-related rash was the main limitation to dose escalation, the intervention was well tolerated.