Publikationsdatum:
2012-08-02
Beschreibung:
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/m 2 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/m 2 (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. Content Type Journal Article Category PHASE I STUDIES Pages 1-11 DOI 10.1007/s10637-012-9863-1 Authors Amir Mortazavi, 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 Yonghua Ling, Pharmacoanalytical Shared Resources, The Ohio State University and The Comprehensive Cancer Center, Columbus, OH 43210, USA Ludmila Katherine Martin, 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 Lai Wei, Center for Biostatistics, The Ohio State University and The Comprehensive Cancer Center, Columbus, OH 43210, USA Mitch A. Phelps, Division of Pharmaceutics, College of Pharmacy, The Ohio State University and The Comprehensive Cancer Center, Columbus, OH 43210, USA Zhongfa Liu, Division of Pharmaceutics, College of Pharmacy, The Ohio State University and The Comprehensive Cancer Center, Columbus, OH 43210, USA Erica J. Harper, 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 S. Percy Ivy, Cancer Therapeutics Evaluation Program, National Cancer Institute, Rockville, MD 20852, USA Xin Wu, 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 Bing-Sen Zhou, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA Xiyong Liu, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA Deidre Deam, 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 J. Paul Monk, 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 William J. Hicks, 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 Yun Yen, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA Gregory A. Otterson, 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 Michael R. Grever, Division of Hematology, Department of Internal Medicine, The Ohio State University and The Comprehensive Cancer Center, Columbus, OH 43210, USA Tanios Bekaii-Saab, 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 Journal Investigational New Drugs Online ISSN 1573-0646 Print ISSN 0167-6997
Print ISSN:
0167-6997
Digitale ISSN:
1573-0646
Thema:
Chemie und Pharmazie
,
Medizin
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