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 journalArticle

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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

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Thymidylate Synthase
Cisplatin
Pharmacokinetics
Neoplasms
Homocysteine
Breast Neoplasms
Stomatitis
Hyperbilirubinemia
((S)-2-(5-(1,2-dihydro-3-methyl-1-oxobenzo(f)-quinazoline-9-yl)methyl)amino-1-oxo-2-isoindolynyl)-glutaric acid
Ileus
Exanthema
Dehydration
Intravenous Infusions
Nausea
Stomach Neoplasms
Vomiting
Renal Insufficiency
Fatigue
Sepsis
Stomach

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Phase I, pharmacokinetic and biological correlative study of OSI-7904L, a novel liposomal thymidylate synthase inhibitor, and cisplatin in patients with solid tumors. / Ricart, Alejandro D.; Berlin, Jordan D.; Papadopoulos, Kyriakos P.; Syed, Samira; Drolet, Daniel W.; Quaratino-Baker, Charlotte; Horan, Julie; Chick, Jon; Vermeulen, Wendy; Tolcher, Anthony W.; Rowinsky, Eric K.; Rothenberg, Mace L.

In: Clinical Cancer Research, Vol. 14, No. 23, 01.12.2008, p. 7947-7955.

Research output: Contribution to journalArticle

Ricart, AD, Berlin, JD, Papadopoulos, KP, Syed, S, Drolet, DW, Quaratino-Baker, C, Horan, J, Chick, J, Vermeulen, W, Tolcher, AW, Rowinsky, EK & Rothenberg, ML 2008, 'Phase I, pharmacokinetic and biological correlative study of OSI-7904L, a novel liposomal thymidylate synthase inhibitor, and cisplatin in patients with solid tumors', Clinical Cancer Research, vol. 14, no. 23, pp. 7947-7955. https://doi.org/10.1158/1078-0432.CCR-08-0864
Ricart, Alejandro D. ; Berlin, Jordan D. ; Papadopoulos, Kyriakos P. ; Syed, Samira ; Drolet, Daniel W. ; Quaratino-Baker, Charlotte ; Horan, Julie ; Chick, Jon ; Vermeulen, Wendy ; Tolcher, Anthony W. ; Rowinsky, Eric K. ; Rothenberg, Mace L. / Phase I, pharmacokinetic and biological correlative study of OSI-7904L, a novel liposomal thymidylate synthase inhibitor, and cisplatin in patients with solid tumors. In: Clinical Cancer Research. 2008 ; Vol. 14, No. 23. pp. 7947-7955.
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T1 - Phase I, pharmacokinetic and biological correlative study of OSI-7904L, a novel liposomal thymidylate synthase inhibitor, and cisplatin in patients with solid tumors

AU - Ricart, Alejandro D.

AU - Berlin, Jordan D.

AU - Papadopoulos, Kyriakos P.

AU - Syed, Samira

AU - Drolet, Daniel W.

AU - Quaratino-Baker, Charlotte

AU - Horan, Julie

AU - Chick, Jon

AU - Vermeulen, Wendy

AU - Tolcher, Anthony W.

AU - Rowinsky, Eric K.

AU - Rothenberg, Mace L.

PY - 2008/12/1

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N2 - 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.

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