Phase I trial of intraperitoneal pemetrexed, cisplatin, and paclitaxel in optimally debulked ovarian cancer

Setsuko K. Chambers, H. H.Sherry Chow, Mike F. Janicek, Janiel M. Cragun, Kenneth D. Hatch, Haiyan Cui, Cynthia Laughren, Mary C. Clouser, Janice L. Cohen, Heather M. Wright, Nisreen Abu Shahin, David S. Alberts

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Purpose: This phase I trial evaluated intraperitoneal (i.p.) pemetrexed, cisplatin, and paclitaxel in optimally debulked ovarian cancer. Experimental Design: Dose escalation of day 1 i.p. pemetrexed accrued three patients to each of five dose levels (60-1,000 mg/m 2), along with day 2 i.p. cisplatin (75 mg/m 2) and day 8 i.p. paclitaxel (60 mg/m 2). 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 2 i.p. pemetrexed without DLT, the MTD appears to be 500 mg/m 2. Median PFS is 30.1 months; 18-month PFS is 78.6% (median follow-up 22.4 months). Conclusions: This i.p.-only regimen in front-line ovarian cancer is feasible with PFS in line with recent literature. We suggest phase II trials of this regimen in this population with i.p. pemetrexed at 500 mg/m 2. The favorable toxicity profile at doses <1,000 mg/m 2, which needs to be confirmed, appears to compare well with standard combination i.v./i.p. platinum/taxane chemotherapy in this disease.

Original languageEnglish (US)
Pages (from-to)2668-2678
Number of pages11
JournalClinical Cancer Research
Volume18
Issue number9
DOIs
StatePublished - May 1 2012

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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