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

  • Clinical Trial Report
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

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.

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Acknowledgements

The authors acknowledge posthumously John Murren, MD, of the Yale Cancer Center who served as principal investigator for this trial prior to his death in 2005. The authors would like to thank the clinical research staff of the Yale Cancer Center and of the Arizona Clinical Research Center for their hard work and efforts to support this clinical trial. Finally, the authors would also like to thank the patients and their family members for being involved in this clinical trial. Support: Grant UM1-CA186690 (NCI-CTEP). This project used the UPCI Cancer Pharmacokinetics and Pharmacodynamics Facility (CPPF) and was supported in part by award P30-CA47904.

Funding

This study was funded by Vion Pharmaceuticals, Incorporated (Contract Number CLI-021).

Author information

Authors and Affiliations

  1. Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA

    Charles A. Kunos & S. Percy Ivy

  2. University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Edward Chu & Jan H. Beumer

  3. Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    Jan H. Beumer

  4. University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA

    Jan H. Beumer

  5. Yale University School of Medicine and Yale Cancer Center, New Haven, CT, USA

    Mario Sznol

  6. 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 A. Kunos

Authors
  1. Charles A. Kunos
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Corresponding author

Correspondence to Charles A. Kunos.

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The authors declare that they have no conflict of interests.

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Kunos, C.A., Chu, E., Beumer, J.H. et al. Phase I trial of daily triapine in combination with cisplatin chemotherapy for advanced-stage malignancies. Cancer Chemother Pharmacol 79, 201–207 (2017). https://doi.org/10.1007/s00280-016-3200-x

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  • DOI: https://doi.org/10.1007/s00280-016-3200-x

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