Abstract
Multitargeted antifolate (MTA, LY231514) is a novel antifolate antimetabolite, with antitumor activity via inhibition of thymidylate synthase, glycinamide formyl transferase, and dihydrofolate reductase. Three dosing schedules have been investigated in the phase I setting: daily x5 every 21 days, weekly x4 every 42 days, and once every 21 days. The maximum tolerated doses on these schedules were 4.0 mg/m2, 30 mg/m2, and 600 mg/m2, respectively. The major dose-limiting toxicity seen on all schedules was neutropenia, with a greater degree of reversible liver biochemistry disturbances observed on the daily x5 schedule. Given that toxicities were manageable and reversible, the antitumor activity exhibited, and the convenience of an every-21-day dosing schedule, this schedule was selected for phase II evaluation.
Publication types
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Research Support, Non-U.S. Gov't
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Review
MeSH terms
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Antimetabolites, Antineoplastic / administration & dosage
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Antimetabolites, Antineoplastic / pharmacokinetics
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Antimetabolites, Antineoplastic / therapeutic use*
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Clinical Trials, Phase I as Topic
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Drug Administration Schedule
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Enzyme Inhibitors / administration & dosage
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Enzyme Inhibitors / pharmacokinetics
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Enzyme Inhibitors / therapeutic use*
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Folic Acid Antagonists / administration & dosage
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Folic Acid Antagonists / pharmacokinetics
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Folic Acid Antagonists / therapeutic use*
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Glutamates / administration & dosage
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Glutamates / pharmacokinetics
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Glutamates / therapeutic use*
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Guanine / administration & dosage
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Guanine / analogs & derivatives*
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Guanine / pharmacokinetics
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Guanine / therapeutic use
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Humans
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Pemetrexed
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Thymidylate Synthase / antagonists & inhibitors*
Substances
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Antimetabolites, Antineoplastic
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Enzyme Inhibitors
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Folic Acid Antagonists
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Glutamates
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Pemetrexed
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Guanine
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Thymidylate Synthase