title: Phase I trial of daily triapine in combination with cisplatin chemotherapy for advanced-stage malignancies.
abstract: OBJECTIVE
  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/m2triapine daily days 1-4 and 75 mg/m2cisplatin 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.
authors.affiliation: Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA. charles.kunos@nih.gov.|Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, MSC 9739, Rockville, MD, 20892-9760, USA. charles.kunos@nih.gov.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Kunos
authors.affiliation: University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Chu
authors.affiliation: University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.|University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA.
authors.forename: Jan H
authors.initials: JH
authors.lastname: Beumer
authors.affiliation: Yale University School of Medicine and Yale Cancer Center, New Haven, CT, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Sznol
authors.affiliation: Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA.
authors.forename: S Percy
authors.initials: SP
authors.lastname: Ivy
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy*; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*; D013882:Thiosemicarbazones / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D011725:Pyridines; D013882:Thiosemicarbazones; C078157:3-aminopyridine-2-carboxaldehyde thiosemicarbazone; D012264:Ribonucleotide Reductases; D002945:Cisplatin
keywords: Advanced malignancies; Cisplatin; Dose-limiting toxicity; Maximum tolerated dose; Oral bioavailability; Phase I clinical trial; Triapine