Phase I and pharmacokinetic study of the ribonucleotide reductase inhibitor, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, administered by 96-hour intravenous continuous infusion

Scott Wadler, Della F. Makower, Caroline Clainmont, Paula Lambert, Karen Fehn, Mario Sznol

Research output: Contribution to journalArticle

110 Citations (Scopus)

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/m 2/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.

Original languageEnglish (US)
Pages (from-to)1553-1563
Number of pages11
JournalJournal of Clinical Oncology
Volume22
Issue number9
DOIs
StatePublished - 2004
Externally publishedYes

Fingerprint

Ribonucleotide Reductases
Intravenous Infusions
Pharmacokinetics
Hyperbilirubinemia
Appointments and Schedules
Azotemia
Asthenia
Maximum Tolerated Dose
3-aminopyridine-2-carboxaldehyde thiosemicarbazone
Tumor Biomarkers
Acidosis
Neutropenia
Nausea
Vomiting
Neoplasms
Biomarkers
Kidney
Liver

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Phase I and pharmacokinetic study of the ribonucleotide reductase inhibitor, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, administered by 96-hour intravenous continuous infusion. / Wadler, Scott; Makower, Della F.; Clainmont, Caroline; Lambert, Paula; Fehn, Karen; Sznol, Mario.

In: Journal of Clinical Oncology, Vol. 22, No. 9, 2004, p. 1553-1563.

Research output: Contribution to journalArticle

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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/m 2/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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AU - Fehn, Karen

AU - Sznol, Mario

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