This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Murren, J. Articles by Sznol, M. Search for Related Content PubMed PubMed Citation Articles by Murren, J. Articles by Sznol, M.

Phase I and Pharmacokinetic Study of Triapine, a Potent Ribonucleotide Reductase Inhibitor, Administered Daily for Five Days in Patients with Advanced Solid Tumors¹

Yale-New Haven Cancer Center, New Haven, Connecticut 06520 [J. M.]; Arizona Clinical Research Center, Tucson, Arizona 85712 [M. M.]; Veterans’ Administration Medical Center, Miami, Florida 33125 [N. S.]; and Vion Pharmaceuticals, Inc, New Haven, Connecticut 06511 [C. C., P. L., T. D., M. S.]

Purpose: A Phase I study in patients with advanced cancer was conducted to determine the safety, pharmacokinetics, and maximum tolerated dose of Triapine, a new, potent small-molecule inhibitor of ribonucleotide reductase.

Experimental Design: Triapine was administered by 2-h i.v. infusion daily for 5 days. Courses were repeated every 4 weeks. The starting dose was 5 mg/m²/day, but was reduced to 2 mg/m²/day after the first patient developed a hepatic adverse event. The dose was subsequently escalated using a modified Fibonacci scheme in cohorts of 3–6 patients. After the 12 mg/m²/day dose level, the study design was amended to permit 100% dose escalation in single-patient cohorts until the first episode of a drug-related grade 2 adverse event or dose-limiting toxicity (DLT). On reaching a dose of 96 mg/m²/day, the study was amended to determine the safety and tolerability of the 96-mg/m² dose administered daily for 5 days every 2 weeks in an expanded cohort of patients.

Results: A total of 32 patients received treatment. During the dose escalation phase of the study, grade 2–4 drug-related adverse events were first observed at a dose of 96 mg/m²/day. Grade 3–4 leukopenia was the primary toxicity observed among four patients treated at this dose, which occurred in the week after treatment and resolved to grade 1 or lower by day 15. Fifteen patients were subsequently treated at the 96-mg/m² dose, daily for 5 days, with courses repeated every 2 weeks. The most common nonhematological toxicities for the latter schedule were asthenia, fever, nausea and vomiting, mucositis, decreased serum bicarbonate, and hyperbilirubinemia, and were predominantly grade 1–2 in severity and rapidly reversible. Hematological toxicity on the every-other-week schedule consisted of leukopenia (grade 4 in 93% in at least one course) and anemia (grade 2 in 71%, grade 3 in 22%). Thrombocytopenia was less common and was grade 3–4 in severity in only 22%. Triapine showed linear pharmacokinetic behavior although interpatient variability was relatively high. Peak concentrations at the 96-mg/m²/day dose averaged 8 µM, and the mean elimination T_1/2 ranged from 35 min to 3 h, with a median value of 1 h. Cumulative urinary recovery averaged 1–3% of the administered dose, suggesting that the elimination of Triapine was primarily through metabolism. No partial or complete responses were observed.

Conclusions: Triapine administered at a dose of 96 mg/m² by 2-h i.v. infusion daily for 5 days on an every-other-week schedule demonstrates an acceptable safety profile. Serum concentrations that surpass in vitro tumor growth-inhibitory concentrations are achieved for brief periods of time each day and are sufficient to produce myelosuppression, the expected consequence of ribonucleotide reductase inhibition. Phase II trials are indicated but will proceed with a daily-for-4-days schedule to reduce the incidence of grade 4 leukopenia. The safety profile also supports the initiation of Phase I combination trials with other anticancer agents.

This article has been cited by other articles:

				J. D. Heidel, J. Y.-C. Liu, Y. Yen, B. Zhou, B. S.E. Heale, J. J. Rossi, D. W. Bartlett, and M. E. Davis Potent siRNA Inhibitors of Ribonucleotide Reductase Subunit RRM2 Reduce Cell Proliferation In vitro and In vivo Clin. Cancer Res., April 1, 2007; 13(7): 2207 - 2215. [Abstract] [Full Text] [PDF]

				Y. Yu, J. Wong, D. B. Lovejoy, D. S. Kalinowski, and D. R. Richardson Chelators at the Cancer Coalface: Desferrioxamine to Triapine and Beyond Clin. Cancer Res., December 1, 2006; 12(23): 6876 - 6883. [Abstract] [Full Text] [PDF]

				C. A. Barker, W. E. Burgan, D. J. Carter, D. Cerna, D. Gius, M. G. Hollingshead, K. Camphausen, and P. J. Tofilon In vitro and In vivo Radiosensitization Induced by the Ribonucleotide Reductase Inhibitor Triapine (3-Aminopyridine-2-Carboxaldehyde-Thiosemicarbazone). Clin. Cancer Res., May 1, 2006; 12(9): 2912 - 2918. [Abstract] [Full Text] [PDF]

				A. B. Alvero, W. Chen, A. C. Sartorelli, P. Schwartz, T. Rutherford, and G. Mor Triapine (3-aninopyridine-2-carboxaldehyde thiosemicarbazone) Induces Apoptosis in Ovarian Cancer Cells Reproductive Sciences, February 1, 2006; 13(2): 145 - 152. [Abstract] [PDF]

				Z.-G. Jiang, X.-C. M. Lu, V. Nelson, X. Yang, W. Pan, R.-w. Chen, M. S. Lebowitz, B. Almassian, F. C. Tortella, R. O. Brady, et al. A multifunctional cytoprotective agent that reduces neurodegeneration after ischemia PNAS, January 31, 2006; 103(5): 1581 - 1586. [Abstract] [Full Text] [PDF]

				S. Wadler, D. Makower, C. Clairmont, P. Lambert, K. Fehn, and M. Sznol Phase I and Pharmacokinetic Study of the Ribonucleotide Reductase Inhibitor, 3-Aminopyridine-2-Carboxaldehyde Thiosemicarbazone, Administered by 96-Hour Intravenous Continuous Infusion J. Clin. Oncol., May 1, 2004; 22(9): 1553 - 1563. [Abstract] [Full Text] [PDF]