{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T17:54:37Z","timestamp":1792691677150,"version":"4.5.0"},"reference-count":39,"publisher":"American Society of Clinical Oncology (ASCO)","issue":"9","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCO"],"published-print":{"date-parts":[[2004,5,1]]},"abstract":"<jats:sec><jats:title>Purpose<\/jats:title><jats:p> 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. <\/jats:p><\/jats:sec><jats:sec><jats:title>Patients and Methods<\/jats:title><jats:p> 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. <\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p> 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\/m<jats:sup>2<\/jats:sup>\/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\/m<jats:sup>2<\/jats:sup>\/d but administered every 2 weeks. At 120 mg\/m<jats:sup>2<\/jats:sup>\/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\/m<jats:sup>2<\/jats:sup>\/d every 2 weeks. Detailed pharmacokinetic studies demonstrated linear kinetics up to 160 mg\/m<jats:sup>2<\/jats:sup>, with substantial inter-patient variability. There was no correlation between dose and clearance (R<jats:sup>2<\/jats:sup> = 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. <\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p> The 96-hour infusion of 3-AP is safe and well tolerated at the recommended phase II doses. 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