Pemetrexed: single-agent and combination phase I study overview

Pemetrexed is a novel folic acid antimetabolite that exerts its activity by the inhibition of multiple enzyme targets. It has been evaluated in a series of phase I clinical trials that explored different administration schedules. The schedule that has been carried forward into phase II trials involves the administration of pemetrexed as a 10-minute intravenous infusion every 21 days with no standard pretreatment with folic acid or vitamin B(12). When given in this manner, the dose-limiting toxicities were neutropenia and thrombocytopenia. Other toxicities included mucositis, rash, and fatigue. The recommended phase II dose was 600 mg/m(2) administered intravenous every 21 days, although this was subsequently modified to 500 mg/m(2) when several early patients experienced toxicities requiring dose reduction in phase II studies. On the basis of preclinical studies suggesting additive or synergistic effects, pemetrexed has also been evaluated in phase I studies in combination with several other agents including cisplatin, carboplatin, oxaliplatin, irinotecan, the taxanes, and anthracyclines. Encouraging anticancer activity has been observed in many of these studies.