A phase I and pharmacokinetic study of OSI-7904L, a liposomal thymidylate synthase inhibitor in combination with oxaliplatin in patients with advanced colorectal cancer.

Abstract

PURPOSE:

OSI-7904L is a liposomal formulation of a potent thymidylate synthase (TS) inhibitor. This phase I study evaluated the safety, tolerability and pharmacokinetics (PK) of OSI-7904L administered in combination with oxaliplatin every 21 days in patients with advanced colorectal carcinoma.

METHOD:

A 3+3 study design was utilized at predefined dose levels. Polymorphisms in the TS enhancer region and XPD enzyme were investigated as potential predictors of efficacy and toxicity.

RESULTS:

Fourteen patients received 76 cycles of treatment. At the highest dose level (OSI-7904L 9 mg/m(2), oxaliplatin 130 mg/m(2)) investigated, one of nine patients experienced dose-limiting toxicity of grade 3 oral mucositis with cycle 1 and five further patients required dose reductions. The toxicity profile of stomatitis, diarrhea, nausea, fatigue, sensory neuropathy and skin rash was consistent with that expected for a TS inhibitor/oxaliplatin combination regimen. PK analysis showed high interpatient variability with no detectable interaction between OSI-7904L and oxaliplatin. Partial radiological responses were documented in two patients.

CONCLUSIONS:

The recommended regimen for further investigation is OSI-7904L 9 mg/m(2) and oxaliplatin 130 mg/m(2).

• Authors: A R Clamp, P Schöffski, J W Valle, R H Wilson, S Marreaud, A-S Govaerts, M Debois, D Lacombe, C Twelves, J Chick, G C Jayson, EORTC New Drug Development Group
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 61 Issue 4 Pg. 579-85 (Apr 2008) ISSN: 0344-5704 [Print] Germany
• PMID: 17520255 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ((S)-2-(5-(1,2-dihydro-3-methyl-1-oxobenzo(f)-quinazoline-9-yl)methyl)amino-1-oxo-2-isoindolynyl)-glutaric acid
• Antineoplastic Agents
• Enzyme Inhibitors
• Glutarates
• Isoindoles
• Liposomes
• Organoplatinum Compounds
• Quinazolines
• Oxaliplatin
• Thymidylate Synthase

Topics

• Aged
• Antineoplastic Agents (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, pharmacokinetics, therapeutic use)
• Colorectal Neoplasms (drug therapy)
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (administration & dosage)
• Female
• Glutarates (administration & dosage)
• Humans
• Isoindoles (administration & dosage)
• Liposomes
• Male
• Middle Aged
• Organoplatinum Compounds (administration & dosage)
• Oxaliplatin
• Pharmacogenetics
• Polymorphism, Genetic
• Quinazolines (administration & dosage)
• Thymidylate Synthase (antagonists & inhibitors, genetics)