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Phase I and Pharmacokinetic Study of the Ribonucleotide Reductase Inhibitor, 3-Aminopyridine-2-Carboxaldehyde Thiosemicarbazone, Administered by 96-Hour Intravenous Continuous Infusion

From the Albert Einstein College of Medicine and the Albert Einstein Comprehensive Cancer Center, Bronx, NY; and Vion Pharmaceuticals, Inc, New Haven, CT.

Address reprint requests to Scott Wadler, MD, Division of Hematology and Oncology, C 606, Weill Medical College of Cornell University, 1300 York Ave, New York, NY 10021

PURPOSE: 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP; Triapine; Vion Pharmaceuticals Inc, New Haven, CT) is a potent inhibitor of ribonucleotide reductase, with activity in preclinical tumor model systems. A phase I trial was initiated to determine the dose-limiting toxicities, maximum-tolerated dose, and pharmacokinetics of a 96-hour intravenous (IV) continuous infusion in patients with advanced cancer.

PATIENTS AND METHODS: Initially, courses were administered every 3 weeks, using an accelerated titration design. Subsequently, courses were administered every 2 weeks, and the dose was escalated in cohorts of three to six patients.

RESULTS: Twenty-one patients were enrolled, seven on the every-3-week schedule and 14 on the every-other-week schedule. Three of six patients at 160 mg/m²/d developed dose-limiting toxicities including neutropenia, hyperbilirubinemia, and nausea or vomiting. Based on these initial results, the dose for 3-AP was re-escalated beginning at 80 mg/m²/d but administered every 2 weeks. At 120 mg/m²/d, three of seven patients had dose-limiting but reversible asthenia, hyperbilirubinemia, and azotemia or acidosis; however, in the case of renal and hepatic adverse events, the events were related to pre-existing borderline abnormal organ function. Therefore, the recommended phase II dose for 3-AP administered by 96-hour IV infusion is 120 mg/m²/d every 2 weeks. Detailed pharmacokinetic studies demonstrated linear kinetics up to 160 mg/m², with substantial inter-patient variability. There was no correlation between dose and clearance (R² = 0.0137). There were no objective responses, but there was prolonged stabilization of disease or decreases in serum tumor markers associated with stable disease in four patients.

CONCLUSION: The 96-hour infusion of 3-AP is safe and well tolerated at the recommended phase II doses. Phase II trials of Triapine are ongoing.

Supported by Vion Pharmaceuticals, Inc, and by Cancer Center Support Grant CA 13330 from the National Cancer Institute of the National Institutes of Health.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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