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

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

Abstract

PURPOSE:

This phase I trial evaluated intraperitoneal (IP) pemetrexed, cisplatin, and paclitaxel in optimally debulked ovarian cancer.

EXPERIMENTAL DESIGN:

Dose escalation of d1 IP pemetrexed accrued 3 patients to each of 5 dose levels (60mg/m2 to 1000mg/m2), along with d2 IP cisplatin (75mg/m2), and d8 IP paclitaxel (60mg/m2). The goals were to determine maximum tolerated dose (MTD), 18-month progression-free survival (PFS), and pharmacokinetics (PK) of IP pemetrexed.

RESULTS:

Cycles, given every 21d, had an 80% 6-cycle completion rate. There was minimal grade 3 toxicity in the first 4 dose levels and remarkably an almost complete absence of peripheral neuropathy and alopecia. At the highest dose level, 2 of 3 patients experienced greater than or equal to grade 3 and dose-limiting toxicity (DLT)(hematologic, infection, gastrointestinal). There was a PK advantage for IP pemetrexed with a IP:plasma area under the concentration-time-curve ratio of 13-fold. Neither analysis of PK nor homocysteine levels explains the unexpected severity of toxicity in those 2 patients. Based on plasma C24 h levels, the 42 cycles at greater than or equal to 500mg/m2 IP pemetrexed without DLT, the MTD appears to be 500mg/m2. Median PFS is 30.1 months; 18-month PFS is 78.6% (median follow-up 22.4 months).

CONCLUSIONS:

This IP 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 IP pemetrexed at 500mg/m2. The favorable toxicity profile at doses less than 1000mg/m2, which needs to be confirmed, appears to compare well with standard combination intravenous/IP platinum/taxane chemotherapy in this disease.