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Investigational New Drugs
Published in: Investigational New Drugs 3/2013

01-06-2013 | PHASE I STUDIES

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

Authors: Amir Mortazavi, Yonghua Ling, Ludmila Katherine Martin, Lai Wei, Mitch A. Phelps, Zhongfa Liu, Erica J. Harper, S. Percy Ivy, Xin Wu, Bing-Sen Zhou, Xiyong Liu, Deidre Deam, J. Paul Monk, William J. Hicks, Yun Yen, Gregory A. Otterson, Michael R. Grever, Tanios Bekaii-Saab

Published in: Investigational New Drugs | Issue 3/2013

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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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Metadata
Title
A phase I study of prolonged infusion of triapine in combination with fixed dose rate gemcitabine in patients with advanced solid tumors
Authors
Amir Mortazavi
Yonghua Ling
Ludmila Katherine Martin
Lai Wei
Mitch A. Phelps
Zhongfa Liu
Erica J. Harper
S. Percy Ivy
Xin Wu
Bing-Sen Zhou
Xiyong Liu
Deidre Deam
J. Paul Monk
William J. Hicks
Yun Yen
Gregory A. Otterson
Michael R. Grever
Tanios Bekaii-Saab
Publication date
01-06-2013
Publisher
Springer US
Published in
Investigational New Drugs / Issue 3/2013
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI
https://doi.org/10.1007/s10637-012-9863-1

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