Phase I and pharmacokinetic study of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) using a single intravenous dose schedule

Lynn G Feun, Manuel Modiano, King Lee, John Mao, Angela Marini, Niramol Savaraj, Patricia Plezia, Bijan Almassian, Elizabeth Colacino, Jessica Fischer, Susan MacDonald

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Abstract

Purpose: To perform a phase I and pharmacokinetics study of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) a new ribonucleotide reductase inhibitor using a single intravenous (2-h) schedule every 4 weeks. 3-AP was given at a starting dose of 5 mg/m2 with escalation based on a modified Fibonacci scheme. Patients and methods: A total of 27 patients with advanced cancer were entered into the study. Doses of 3-AP ranged from 5 mg/m2 to 105 mg/m2. Blood and urine samples were collected and 3-AP was measured by HPLC. Results: A total of 46 courses were evaluable. One patient developed grade 4 thrombocytopenia at the lowest dose level, and one patient had grade 3 anemia. Two patients developed grade 3 coagulation abnormalities. The only other toxicities of more than grade 1 occurring in more than 10% of patients were fever and asthenia. No toxicities were observed at the highest dose level. Peak serum concentration of 3-AP increased linearly with dose. No tumor responses were observed in this heavily pretreated population, although eight patients had stabilization of their disease. Conclusions: Relevant tumor inhibitory concentrations were achieved without significant toxicity using doses up to 105 mg/m2 on this single intravenous dose schedule. Prolonged administration schedules and combinations with other cytotoxic agents, strategies predicted to have greater antitumor efficacy according to preclinical studies, are under investigation.

Original languageEnglish
Pages (from-to)223-229
Number of pages7
JournalCancer Chemotherapy and Pharmacology
Volume50
Issue number3
DOIs
StatePublished - Sep 23 2002

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Keywords

  • Pharmacokinetic
  • Phase I
  • Thiosemicarbazone

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Oncology

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