Background: Cetuximab in combination with platinum and 5FU has become a standard in first-line treatment of patients (pts) with R/M SCCHN. Cetuximab and taxane combinations have shown promising activity. This multicenter phase II study evaluates the efficacy and safety of cetuximab, docetaxel and cisplatin combination (TPEx) as first-line treatment in pts with R/M SCCHN. Methods: Pts were required to have WHO PS 0-1, no prior systemic therapy for R/M SCCHN, cumulative dose of cisplatin less than 300 mg/m² and no prior anti-EGFR therapy. Pts received docetaxel 75 mg/m² day 1, cisplatin 75 mg/m² day 1 and cetuximab (400 mg/m² on day 1 of cycle 1 then 250 mg/m² weekly), repeated every 21 days x 4 cycles then followed by cetuximab 500 mg/m² every 2 weeks as maintenance therapy until disease progression or unacceptable toxicity. G-CSF support with lenograstim 150 microgr./m²/day was delivered after each cycle of chemotherapy. Response was assessed every 6 weeks, according to RECIST. The primary endpoint was objective response rate (ORR) at 12 weeks. Secondary endpoints were safety, best overall response, progression-free survival, overall survival and biomarkers. A Simon two-stage design was used with OR in more than 9/30 pts needed before continuing accrual to the final 54 pts. Results: 51 pts have been enrolled to date and 33 pts could be evaluated for primary endpoint: all male, median age 55 years (48-68), 50% metastatic. ORR at 12 weeks was 48.5%. Partial response, stable disease and progression were respectively found in 16 pts (PR 48.5%), 15 pts (SD 45.5%) and 2 pts (PD 6%). There were 18 pts (54.5%) with PR as best response. Treatment related toxicities included G4 neutropenia (n=3). Grade 3 events were skin rash (n=5), hypersensitivity (n=3), mucositis (n=1), fatigue (n=1) and febrile neutropenia (n=1). Alopecia was common. No death was related to study treatment. Conclusions: Preliminary efficacy analysis based on response rate demonstrates that TPEx regimen has encouraging activity as first-line treatment in pts with R/M SCCHN. Toxicity is manageable with G-CSF support. Trial accrual continues up to 54 pts.