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A phase I study of prolonged infusion of triapine in combination with fixed dose rate gemcitabine in patients with advanced solid tumors

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Summary

Purpose Prolonged exposure of cancer cells to triapine, an inhibitor of ribonucleotide reductase, followed by gemcitabine enhances gemcitabine activity in vitro. Fixed-dose-rate gemcitabine (FDR-G) has improved efficacy compared to standard-dose. We conducted a phase I trial to determine the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of prolonged triapine infusion followed by FDR-G. Experimental Design Triapine was given as a 24-hour infusion, immediately followed by FDR-G (1000 mg/m2 over 100-minute). Initially, this combination was administered days 1 and 8 of a 21-day cycle (Arm A, triapine starting dose 120 mg); but because of myelosuppression, it was changed to days 1 and 15 of a 28-day cycle (Arm B, starting dose of triapine 75 mg). Triapine steady-state concentrations (Css) and circulating ribonucleotide reductase M2-subunit (RRM2) were measured. Results Thirty-six patients were enrolled. The MTD was determined to be triapine 90 mg (24-hour infusion) immediately followed by gemcitabine 1000 mg/m2 (100-minute infusion), every 2 weeks of a 4-week cycle. DLTs included grade 4 thrombocytopenia, leukopenia and neutropenia. The treatment was well tolerated with fatigue, nausea/vomiting, fever, transaminitis, and cytopenias being the most common toxicities. Among 30 evaluable patients, 1 had a partial response and 15 had stable disease. Triapine PK was similar, although more variable, compared to previous studies using doses normalized to body-surface-area. Steady decline in circulating levels of RRM2 may correlate with outcome. Conclusions This combination was well tolerated and showed evidence of preliminary activity in this heavily pretreated patient population, including prior gemcitabine failure.

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Acknowledgements

We thank all the patients who participated in this trial, as well as the Clinical Trials Office personnel, James Cancer Hospital inpatient nurses and enrolling physicians, for their help in completion of this study. This study was supported by the National Institutes of Health, National Cancer Institute, Bethesda, U.S.A. (NCI Protocol # 7043).

Grant Support

This study was supported by the U01 Grant through National Institutes of Health (Grant # U01 CA076576).

Disclosure of Potential Conflict of Interest

There are no potential conflicts of interest among the authors of this article. This article has been seen, read, and agreed on in its content by all designated authors. This article has not been submitted or published elsewhere.

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Authors and Affiliations

  1. Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University and The Comprehensive Cancer Center, A454 Starling-Loving Hall, 320 West 10th Ave, Columbus, OH, 43210, USA

    Amir Mortazavi, Ludmila Katherine Martin, Erica J. Harper, Xin Wu, Deidre Deam, J. Paul Monk, William J. Hicks, Gregory A. Otterson & Tanios Bekaii-Saab

  2. Pharmacoanalytical Shared Resources, The Ohio State University and The Comprehensive Cancer Center, Columbus, OH, 43210, USA

    Yonghua Ling, Mitch A. Phelps & Zhongfa Liu

  3. Center for Biostatistics, The Ohio State University and The Comprehensive Cancer Center, Columbus, OH, 43210, USA

    Lai Wei

  4. Division of Pharmaceutics, College of Pharmacy, The Ohio State University and The Comprehensive Cancer Center, Columbus, OH, 43210, USA

    Mitch A. Phelps & Zhongfa Liu

  5. Cancer Therapeutics Evaluation Program, National Cancer Institute, Rockville, MD, 20852, USA

    S. Percy Ivy

  6. City of Hope Comprehensive Cancer Center, Duarte, CA, 91010, USA

    Bing-Sen Zhou, Xiyong Liu & Yun Yen

  7. Division of Hematology, Department of Internal Medicine, The Ohio State University and The Comprehensive Cancer Center, Columbus, OH, 43210, USA

    Michael R. Grever

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  1. Amir Mortazavi
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  2. Yonghua Ling
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  18. Tanios Bekaii-Saab
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Correspondence to Tanios Bekaii-Saab.

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Table 1S

Response to treatment (DOC 73 kb)

Table 2S

Summary of changes in hRRM2a expression (DOC 93 kb)

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Mortazavi, A., Ling, Y., Martin, L.K. et al. A phase I study of prolonged infusion of triapine in combination with fixed dose rate gemcitabine in patients with advanced solid tumors. Invest New Drugs 31, 685–695 (2013). https://doi.org/10.1007/s10637-012-9863-1

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