1017O - Preclinical Rational, Safety, and Preliminary Efficacy Results of Weekly Everolimus, Carboplatin and Paclitaxel as An Induction Therapy for Patients with Unresectable Locally Advanced Head & Neck Squamous Cell Carcinoma (CAPRA): A GERCOR-IRC Phase I/II Study

Abstract

ABSTRACT Background PI3K/mTOR is a survival pathway that was shown activated in 57-81% of patients (pts) with head & neck squamous cell carcinoma (HNSCC) and might drive resistance to cytotoxics. Methods We have previously shown synergistic cell-cycle dependent effects between rapamycin/everolimus and carboplatin, or paclitaxel in HNSCC cells (Aissat 2008). Based on this preclinical translational rationale, a two-step phase I/II trial was designed using 9 consecutive weekly (w) cycles of oral everolimus combined with carboplatin (AUC2) and paclitaxel (60mg/m2) followed by chemoradiotherapy in pts with untreated locally advanced HNSCC. Results A total of 27 pts with stage IV HNSCC (median age 58, range 46-84; ECOG 0-2) have been enrolled in this phase I/II study (42 pts scheduled for the phase II). Among the 7 pts enrolled in the everolimus dose escalation phase I step, 6 pts were evaluable for safety (3pts at 30 mg/w and 3pts at 50 mg/w). No dose-limiting toxicity (defined during the first 4 weeks of treatment) was reported. Transient asymptomatic grade 3 neutropenia (3 pts), anemia (3 pts), and thrombocytopenia (1 pt) were observed. The most frequently reported adverse events were mild to moderate asthenia, skin toxicity, and alopecia. The recommended dose of everolimus for the phase II step was 50 mg/w. So far, among pts treated in the phase I/II, 11/13 objective responses (1CR, 10 PR, 2SD) were observed in evaluable pts. Interestingly, several major responses (ranging -60 to -80% by RECIST) were observed in large necrotic primary tumors and lymph nodes of >6cm diameters. Preliminary genetic analysis of tumors showed neither KRAS, BRAF, PI3KCA, nor EGFR mutations in tumors responding to this combination. Conclusions Weekly 50 mg everolimus combined with carboplatin and paclitaxel was well tolerated with no DLT, allowing repeated cycles. Major clinical responses in pts with bulky, locally advanced and necrotic diseases deserve further evaluation of this combination in pts with HNSCC. Updated results will be presented at meeting. Disclosure S. Faivre: Novartis, honorarium, compensated E. Raymond: Novartis, honorarium, compensated K. Slimane: Novartis, employment, compensated All other authors have declared no conflicts of interest.