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

Setsuko K Chambers, Hsiao-Hui 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

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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

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Pemetrexed
Ovarian Neoplasms
Disease-Free Survival
Maximum Tolerated Dose
Pharmacokinetics
Alopecia
Homocysteine
Peripheral Nervous System Diseases
Paclitaxel
Platinum
Cisplatin
TP protocol
Research Design
Drug Therapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Phase I trial of intraperitoneal pemetrexed, cisplatin, and paclitaxel in optimally debulked ovarian cancer. / Chambers, Setsuko K; Chow, Hsiao-Hui; Janicek, Mike F.; Cragun, Janiel M.; Hatch, Kenneth D; Cui, Haiyan; Laughren, Cynthia; Clouser, Mary C.; Cohen, Janice L.; Wright, Heather M.; Shahin, Nisreen Abu; Alberts, David S.

In: Clinical Cancer Research, Vol. 18, No. 9, 01.05.2012, p. 2668-2678.

Research output: Contribution to journalArticle

Chambers, Setsuko K ; Chow, Hsiao-Hui ; Janicek, Mike F. ; Cragun, Janiel M. ; Hatch, Kenneth D ; Cui, Haiyan ; Laughren, Cynthia ; Clouser, Mary C. ; Cohen, Janice L. ; Wright, Heather M. ; Shahin, Nisreen Abu ; Alberts, David S. / Phase I trial of intraperitoneal pemetrexed, cisplatin, and paclitaxel in optimally debulked ovarian cancer. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 9. pp. 2668-2678.
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T1 - Phase I trial of intraperitoneal pemetrexed, cisplatin, and paclitaxel in optimally debulked ovarian cancer

AU - Chambers, Setsuko K

AU - Chow, Hsiao-Hui

AU - Janicek, Mike F.

AU - Cragun, Janiel M.

AU - Hatch, Kenneth D

AU - Cui, Haiyan

AU - Laughren, Cynthia

AU - Clouser, Mary C.

AU - Cohen, Janice L.

AU - Wright, Heather M.

AU - Shahin, Nisreen Abu

AU - Alberts, David S

PY - 2012/5/1

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N2 - 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.

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