Phase I dose-escalating study of biweekly fixed-dose rate gemcitabine plus pemetrexed in patients with advanced solid tumors.

ABSTRACT

PURPOSE: To determine the maximum tolerated dose (MTD) and the recommended phase II dose and to identify the dose-limiting toxicities (DLTs) of gemcitabine, administered by fixed-dose rate (FDR) infusion, combined with the antifolate agent pemetrexed in patients with advanced solid tumors. METHODS: Eligible patients were entered into this open label, phase I trial. Using a 3 + 3 dose escalation design, patients received intravenous pemetrexed 300-800 mg/m(2) followed by FDR gemcitabine 900-1,500 mg/m(2) at 10 mg/m(2)/min on Day 1 every 2 weeks. All patients received folic acid and vitamin B(12) supplementation. Patients continued until DLT or disease progression. RESULTS: A total of 33 patients were treated at 7 dose levels with a total of 230 cycles (median 4 cycles; mean 7 cycles; range 1-35 cycles). The MTD of the combination was pemetrexed 800 mg/m(2) and gemcitabine 1,500 mg/m(2) over 150 min. DLTs were febrile neutropenia and grade 3 renal failure. Of the 28 patients evaluable for response, 3 patients experienced a partial response (10.7%) and 13 patients had stable disease (46.4%); the disease control rate was 57.1%. CONCLUSIONS: The recommended phase II dose for biweekly pemetrexed with FDR gemcitabine is 800 mg/m(2) and 1,200 mg/m(2) × 120 min, respectively. This regimen allows good dose intensity of both drugs to be administered on a simple schedule with an excellent tolerability profile. This regimen showed moderate activity in a diverse phase I population, possibly greater than either single agent. Further assessment of the combination in a phase II setting is suggested.