A phase I study of a fixed dose of cisplatin with increasing doses of raltitrexed (Tomudex®) in the treatment of patients with locally advanced or metastatic squamous cell carcinoma of the head and neck

Purpose: A phase I trial of raltitrexed in combination with cisplatin in patients with locally advanced or metastatic squamous cell carcinoma of the head and neck (SCCHN). Patients and methods: Eligible patients had locally advanced or metastatic SCCHN. Cohorts of patients were treated with escalating doses of raltitrexed (2.0 mg/m(2) to 3.5 mg/m(2)) as a 15-minute intravenous infusion immediately followed by cisplatin (80 mg/m(2)) administered over four hours every three weeks to determine the maximum tolerated dose (MTD). Results: A total of 17 patients was administered 60 courses of an escalating dose of raltitrexed. Starting dose of cisplatin was initially 100 mg/m(2) in the first three patients treated at the first dose level. Due to cisplatin-induced nephrotoxicity expressed as a creatinine clearance decrease by more than 50%, the cisplatin dose was reduced to 80 mg/m(2) for all subsequent treatment cycles. Dose-limiting toxicity was observed at raltitrexed dose of 3.5 mg/m(2) in two out of five patients. Dose-limiting grade 4 (CTC) neutropenia, grade 4 diarrhoea, grade 3 lethargy and elevation of transaminases and bilirubine was seen in these two patients. One patient treated at the level of the MTD, died 23 days after the first cycle with unresolved gastro-intestinal toxicity. In all other dose levels toxicity was very limited. The recommended dose for further study was raltitrexed 3.0 mg/m(2) in combination with cisplatin 80 mg/m(2). In 15 evaluable patients, we observed 9 WHO objective responses (1 complete and 8 partial). At the recommended dose level 3 partial responses were observed in five evaluable patients. Conclusion: The regimen of raltitrexed 3.0 mg/m(2) followed by cisplatin 80 mg/m(2) on day 1, every three weeks has manageable toxicity and these doses are recommended for phase II evaluation. Results indicate that this combination is active for the treatment of patients with locally advanced or metastatic SCCHN. Recently, a phase II study has been started.