Phase I, pharmacokinetic and biological correlative study of OSI-7904L, a novel liposomal thymidylate synthase inhibitor, and cisplatin in patients with solid tumors

Alejandro D. Ricart, Jordan D. Berlin, Kyriakos P. Papadopoulos, Samira Syed, Daniel W. Drolet, Charlotte Quaratino-Baker, Julie Horan, Jon Chick, Wendy Vermeulen, Anthony W. Tolcher, Eric K. Rowinsky, Mace L. Rothenberg

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Purpose:To evaluate the safety and describe the pharmacokinetic profile of OSI-7904L, a novel liposomal thymidylate synthase inhibitor, in combination with cisplatin (CDDP) in adults with advanced solid tumors. Experimental Design:CDDP was administered as a 2-h intravenous infusion followed by OSI-7904L intravenously over 30 min, both given every 3 weeks. Doses of each drug were escalated in separate cohorts of patients. Five dose levels of CDDP/OSI-7904L were explored:60/6, 60/9, 60/12, 60/7.5, and 75/7.5 mg/m 2. Pharmacokinetic samples, baseline plasma homocysteine, and genotype polymorphisms were evaluated. Results:Twenty-seven patients were treated with 101 total courses of CDDP/OSI-7904L. Dose-limiting toxicity was observed in 2 patients in the CDDP/OSI-7904L 60/12 mg/m 2 cohort. One patient experienced rash, stomatitis, dehydration, renal failure, hyperbilirubinemia, and fatal neutropenic sepsis, whereas the other patient experienced grade 3 nausea, vomiting, and ileus. Therefore, the CDDP/OSI-7904L 60/9 mg/m 2 cohort was expanded, with 2 of 6 patients reporting significant fatigue. Other toxicities were mild or moderate. Intermediate dose levels of 60/7.5 and 75/7.5 mg/m 2 were evaluated, and the latter was identified as the recommended dose for phase II studies. No major pharmacokinetic interactions between CDDP and OSI-7904L were observed. Three patients had partial responses (gastric adenocarcinoma and heavily pretreated breast cancer). There was no significant relationship between baseline homocysteine and toxicity. Conclusions:The recommended doses for CDDP and OSI-7904L administered once every 3 weeks are 75 and 7.5 mg/m 2, respectively. Pharmacokinetic interaction between the agents was not apparent. Preliminary clinical activity was observed in breast and gastric cancer.

Original languageEnglish (US)
Pages (from-to)7947-7955
Number of pages9
JournalClinical Cancer Research
Volume14
Issue number23
DOIs
StatePublished - Dec 1 2008

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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