Phase I and pharmacological study of CI-980, a novel synthetic antimicrotubule agent.
CI-980 (NSC 613862) is one of a novel class of 1,2-dihydropyrido[3, 4-b]pyrazines that inhibits tubulin polymerization, presumably by binding to the colchicine binding site of tubulin. In a Phase I and pharmacological study, 16 patients with advanced solid neoplasms were treated with CI-980 on a continuous 72-h infusion schedule at doses ranging from 3.0-5.4 mg/m2/day every 3 weeks. High rates of central nervous system (CNS) toxicity and neutropenia occurred in both minimally and heavily pretreated patients who were treated with CI-980 doses above 3.75 mg/m2/day, which is the maximum tolerated dose and the recommended dose for additional evaluations. CNS effects, characterized by neurocortical, mood, and cerebellar manifestations, were generally observed toward the end of the infusion and immediately posttreatment and usually resolved within 48 h after the completion of treatment. Toxicity was mild to modest at the 3.75 mg/m2/day dose level. Neither clinical nor pharmacological risk factors that may predispose patients to the development of CNS effects were evident. Although no objective antineoplastic activity was observed in this Phase I study, CI-980 steady-state plasma concentrations achieved at the recommended dose of 3.75 mg/m2/day (mean +/- SE, 5.74 +/- 0.54 nM) approached and exceeded concentrations that have been associated with significant activity in preclinical studies, indicating that additional disease-directed evaluations of CI-980 may be warranted.
Rowinsky
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EK
The Johns Hopkins Oncology Center, Baltimore, Maryland 21287-8934, USA. erowinsk@ctrc.fs.saci.org
Long
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GS
Noe
D A
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Grochow
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Bowling
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MK
Sartorius
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Donehower
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RC
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D002219:Carbamates / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D002493:Central Nervous System Diseases / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D013921:Thrombocytopenia / Q000139:chemically induced
D000970:Antineoplastic Agents; D002219:Carbamates; D011719:Pyrazines; D011725:Pyridines; C072383:canertinib dihydrochloride