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Cancer Chemother Pharmacol. 2017 Jan;79(1):201-207. doi: 10.1007/s00280-016-3200-x. Epub 2016 Nov 22.

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

Author information

1
Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA. charles.kunos@nih.gov.
2
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.
3
University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
4
Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
5
University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA.
6
Yale University School of Medicine and Yale Cancer Center, New Haven, CT, USA.
7
Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA.

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.

KEYWORDS:

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

PMID:
27878356
PMCID:
PMC5226891
DOI:
10.1007/s00280-016-3200-x
[Indexed for MEDLINE]
Free PMC Article

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