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

被引:0
|
作者
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
机构
[1] College of Medicine,Division of Medical Oncology, Department of Internal Medicine
[2] The Ohio State University and The Comprehensive Cancer Center,Pharmacoanalytical Shared Resources
[3] The Ohio State University and The Comprehensive Cancer Center,Center for Biostatistics
[4] The Ohio State University and The Comprehensive Cancer Center,Division of Pharmaceutics
[5] College of Pharmacy,Division of Hematology, Department of Internal Medicine
[6] The Ohio State University and The Comprehensive Cancer Center,undefined
[7] Cancer Therapeutics Evaluation Program,undefined
[8] National Cancer Institute,undefined
[9] City of Hope Comprehensive Cancer Center,undefined
[10] The Ohio State University and The Comprehensive Cancer Center,undefined
来源
Investigational New Drugs | 2013年 / 31卷
关键词
Triapine; Gemcitabine; Phase I; Clinical Trial;
D O I
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中图分类号
学科分类号
摘要
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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页码:685 / 695
页数:10
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