Phase I trial of daily triapine in combination with cisplatin chemotherapy for advanced-stage malignancies

Charles A. Kunos, Edward Chu, Jan H. Beumer, Mario Sznol, S. Percy Ivy

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Purpose: Advanced-stage malignancies have increased deoxyribonucleotide demands in DNA replication and repair, making deoxyribonucleotide supply a potential exploitable target for therapy based on ribonucleotide reductase (RNR) inhibition. Methods: A dose-finding phase I trial was conducted of intravenous (i.v.) triapine, a small-molecule RNR inhibitor, and cisplatin chemotherapy in patients with advanced-stage solid tumor malignancies. Patients received dose-finding levels of i.v. triapine (48–96 mg/m2) and i.v. cisplatin (20–75 mg/m2) on 1 of 3 different schedules. The primary endpoint was to identify the maximum tolerated dose of a triapine–cisplatin combination. Secondary endpoints included the rate of triapine–cisplatin objective response and the pharmacokinetics and bioavailability of a single oral triapine dose. (Clinicaltrials.gov number, NCT00024323). Results: The MTD was 96 mg/m2 triapine daily days 1–4 and 75 mg/m2 cisplatin split over day 2 and day 3. Frequent grade 3 or 4 adverse events included fatigue, dyspnea, leukopenia, thrombocytopenia, and electrolyte abnormalities. No objective responses were observed; 5 (50%) of 10 patients treated at the MTD had stable disease. Pharmacokinetics indicated an oral triapine bioavailability of 88%. Conclusions: The triapine–cisplatin combination may be given safely in patients with advanced-stage solid tumor malignancies. On the basis of these results, a phase I trial adequately powered to evaluate oral triapine bioavailability in women with advanced-stage uterine cervix or vulvar cancers is underway.

Original languageEnglish (US)
Pages (from-to)201-207
Number of pages7
JournalCancer Chemotherapy and Pharmacology
Volume79
Issue number1
DOIs
StatePublished - Jan 1 2017
Externally publishedYes

Keywords

  • Advanced malignancies
  • Cisplatin
  • Dose-limiting toxicity
  • Maximum tolerated dose
  • Oral bioavailability
  • Phase I clinical trial
  • Triapine

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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