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

Purpose: A phase I trial of raltitrexed in combination with cisplatin in pa tients with locally advanced or metastatic squamous cell carcinoma of the h ead and neck (SCCHN). Patients and methods: Eligible patients had locally advanced or metastatic SCCHN. Cohorts of patients were treated with escalating doses of raltitrexe d (2.0 mg/m(2) to 3.5 mg/m(2)) as a 15-minute intravenous infusion immediat ely followed by cisplatin (80 mg/m(2)) administered over four hours every t hree weeks to determine the maximum tolerated dose (MTD). Results: A total of 17 patients was administered 60 courses of an escalatin g 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 cispla tin-induced nephrotoxicity expressed as a creatinine clearance decrease by more than 50%, the cisplatin dose was reduced to 80 mg/m(2) for all subsequ ent treatment cycles. Dose-limiting toxicity was observed at raltitrexed do se 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 transamin ases 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 ga stro-intestinal toxicity. In all other dose levels toxicity was very limite d. The recommended dose for further study was raltitrexed 3.0 mg/m(2) in co mbination with cisplatin 80 mg/m(2). In 15 evaluable patients, we observed 9 WHO objective responses (1 complete and 8 partial). At the recommended do se 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 dose s are recommended for phase II evaluation. Results indicate that this combi nation is active for the treatment of patients with locally advanced or met astatic SCCHN. Recently, a phase II study has been started.