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


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/m(2)/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(2)/d but administered every 2 weeks. At 120 mg/m(2)/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/m(2), with substantial inter-patient variability. There was no correlation between dose and clearance (R(2) = 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.


CONCLUSIONS
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.
Wadler
Scott
S
Albert Einstein College of Medicine and the Albert Einstein Comprehensive Cancer Center, Bronx, NY, USA.
Makower
Della
D
Clairmont
Caroline
C
Lambert
Paula
P
Fehn
Karen
K
Sznol
Mario
M
D000328:Adult; D000368:Aged; D001247:Asthenia / Q000139:chemically induced; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D006932:Hyperbilirubinemia / Q000139:chemically induced; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011446:Prospective Studies; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D012307:Risk Factors; D013882:Thiosemicarbazones / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D014511:Uremia / Q000139:chemically induced
D004791:Enzyme Inhibitors; D011725:Pyridines; D013882:Thiosemicarbazones; C078157:3-aminopyridine-2-carboxaldehyde thiosemicarbazone