TY - JOUR
T1 - Phase I trial of daily triapine in combination with cisplatin chemotherapy for advanced-stage malignancies
AU - Kunos, Charles A.
AU - Chu, Edward
AU - Beumer, Jan H.
AU - Sznol, Mario
AU - Ivy, S. Percy
N1 - Funding Information:
This study was funded by Vion Pharmaceuticals, Incorporated (Contract Number CLI-021).
Funding Information:
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.
Publisher Copyright:
© 2016, Springer-Verlag Berlin Heidelberg (outside the USA).
PY - 2017/1/1
Y1 - 2017/1/1
N2 - 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.
AB - 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.
KW - Advanced malignancies
KW - Cisplatin
KW - Dose-limiting toxicity
KW - Maximum tolerated dose
KW - Oral bioavailability
KW - Phase I clinical trial
KW - Triapine
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U2 - 10.1007/s00280-016-3200-x
DO - 10.1007/s00280-016-3200-x
M3 - Article
C2 - 27878356
AN - SCOPUS:84996483051
SN - 0344-5704
VL - 79
SP - 201
EP - 207
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 1
ER -
