Cancer Therapy: Clinical Phase I Trial of Intraperitoneal Pemetrexed, Cisplatin, and Paclitaxel in Optimally Debulked Ovarian Cancer

Purpose: This phase I trial evaluated intraperitoneal (i.p.) pemetrexed, cisplatin, and paclitaxel in optimally debulked ovarian cancer. ExperimentalDesign:Dose escalation of day 1 i.p. pemetrexed accrued three patients to eachof five dose levels (60–1,000 mg/m), along with day 2 i.p. cisplatin (75 mg/m) and day 8 i.p. paclitaxel (60 mg/m). The goals were to determine maximum tolerated dose (MTD), 18-month progression-free survival (PFS), and pharmacokinetics of i.p. pemetrexed. Results: Cycles, given every 21 days, had an 80% 6-cycle completion rate. There was minimal grade III toxicity in the first 4 dose levels and remarkably an almost complete absence of peripheral neuropathy and alopecia. At the highest dose level, two of three patients experienced grade III and dose-limiting toxicity (DLT; hematologic, infection, gastrointestinal). There was a pharmacokinetic advantage for i.p. pemetrexed with an intraperitoneal:plasma area under the concentration–time curve ratio of 13-fold.Neither analysis of pharmacokinetic nor homocysteine levels explains the unexpected severity of toxicity in those two patients. On the basis of plasma C24h levels, the 42 cycles at 500 mg/m i.p. pemetrexed without DLT, the MTD appears to be 500 mg/m. Median PFS is 30.1 months; 18-month PFS is 78.6% (median follow-up 22.4