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

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Abstract
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.

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