The best overall response rate as assessed by the independent review committee was 36% (95% confidence interval: 20, 55) and was significantly greater (= 0.002) than the protocol-specified threshold of 15% at the one-sided 5% level. There were no unexpected safety concerns. Grade 3 or 4 4 adverse events were experienced by nearly all patients (32, 97%). No adverse events were fatal. Conclusions The demonstrated efficacy and safety of cetuximab in combination with cisplatin and 5-fluorouracil for the first-line treatment of Japanese patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck justify the further use of this combination treatment in this patient population (ClinicalTrials.gov number, “type”:”clinical-trial”,”attrs”:”text”:”NCT00971932″,”term_id”:”NCT00971932″NCT00971932). = 0.04]. The addition of cetuximab to chemotherapy also prolonged the median PFS time (from 3.3 to 5 5.6 months; hazard ratio for progression, 0.54, 95% CI: 0.43, 0.67; 0.001) and increased the best ORR (from 20 to 36%; odds ratio 2.33, 95% CI: 1.50, 3.60, 0.001). The use of cetuximab plus platinum/5-FU for the first-line treatment of R/M SCCHN is now recommended by a group of European cancer societies (9) and the USA-based National Comprehensive Cancer Network (NCCN) Practice Guidelines Piperine (1-Piperoylpiperidine) (10). In Japan, cetuximab has not yet been approved for use in head and neck cancers. In other respects, however, the treatment options for R/M SCCHN are not substantially different from those in Europe and the USA. Cisplatin is the mainstay of treatment, and the combination of cisplatin and 5-FU is the most frequently used chemotherapy regimen (11). The dose of cisplatin used in combination with 5-FU at an interval of 3 or 4 4 weeks is commonly lower in Japan (cisplatin 75C100 mg/m2 on day 1 plus 5-FU 600C1000 mg/m2/day for 4C5 days) than in many Western countries (11,12), in keeping with observations from the treatment of different types of cancer, including head and neck cancers, that Japanese patients are generally not able to tolerate the doses of chemotherapy approved for use in Western patients (13,14). However, others have reported that the incidence of high-grade toxicity associated with standard doses of chemotherapy used in Western patients is not substantially higher in Japanese patients (15,16). The use of cetuximab in combination with radiotherapy for patients with locally advanced SCCHN showed significant benefits over radiotherapy alone in a Phase III trial in Western patients (17), and the efficacy and safety of Piperine (1-Piperoylpiperidine) cetuximab plus radiotherapy has since been demonstrated in a Phase II trial in Japanese patients (18). The primary objective of the current trial was to assess the antitumor activity of cetuximab when given in combination with cisplatin and 5-FU for the first-line treatment of R/M SCCHN in Japanese patients. Of note, cisplatin was used at a dose of 100 mg/m2 in line with the dose used in the EXTREME trial. Secondary objectives included the assessment of safety, pharmacokinetic (PK) parameters, biomarkers, pharmacogenomics and the immunogenicity of cetuximab in Japanese patients. This paper reports the efficacy, safety and PK results. PATIENTS AND METHODS Patient eligibility criteria and treatment regimens were consistent with those used in the EXTREME trial (8). Piperine (1-Piperoylpiperidine) Patient Selection Japanese adults with histologically or cytologically confirmed R/M SCCHN, unsuitable for Piperine (1-Piperoylpiperidine) local therapy, with at least one bidimensionally measurable [computed tomography (CT) scan or magnetic resonance imaging (MRI)] lesion and confirmed expression of EGFR by immunohistochemistry (IHC) were eligible for entry to the trial. The exclusion criteria included nasopharyngeal carcinoma, prior systemic chemotherapy (except as part of multimodal therapy completed 6 months before the trial Piperine (1-Piperoylpiperidine) entry), surgery or irradiation within 4 weeks of trial entry, current or prior cardiac or pulmonary disease, high risk of uncontrolled arrhythmia or cardiac insufficiency and active infection. A written informed consent was provided by all patients taking part in the trial, and additional consent was provided by those also taking part in PK and biomarker analyses. Trial Design This was an open-label, single-arm, multicenter, Phase II trial conducted in Tbp Japan. Patients received weekly cetuximab (week 1, 400 mg/m2; subsequent weeks, 250 mg/m2) plus three-weekly cycles of cisplatin (100 mg/m2, day 1) and 5-FU (1000 mg/m2/day, 24-h infusion, day 1C4). Patients could switch to carboplatin (AUC5 on day 1 of each cycle) in the event of non-hematologic toxicities to.