Phase I and Pharmacokinetic Study of Triapine, a Potent Ribonucleotide Reductase Inhibitor, Administered Daily for Five Days in Patients with Advanced Solid Tumors

• Published in: Clinical cancer research 2003-09, Vol.9 (11), p.4092-4100
• Main Authors: MURREN, John, MODIANO, Manuel, CLAIRMONT, Caroline, LAMBERT, Paula, SAVARAJ, Niramol, DOYLE, Terry, SZNOL, Mario
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - blood; Antineoplastic Agents - toxicity; Asthenia - chemically induced; Biological and medical sciences; Chemotherapy; Dose-Response Relationship, Drug; Drug Administration Schedule; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - blood; Enzyme Inhibitors - toxicity; Female; Humans; Male; Medical sciences; Metabolic Clearance Rate; Middle Aged; Neoplasms - drug therapy; Neoplasms - pathology; Pharmacology. Drug treatments; Pyridines - administration & dosage; Pyridines - blood; Pyridines - toxicity; Ribonucleotide Reductases - antagonists & inhibitors; Thiosemicarbazones - administration & dosage; Thiosemicarbazones - blood; Thiosemicarbazones - toxicity
• ISSN: 1078-0432; 1557-3265

Purpose: A Phase I study in patients with advanced cancer was conducted to determine the safety, pharmacokinetics, and maximum tolerated dose of Triapine, a new, potent small-molecule inhibitor of ribonucleotide reductase. Experimental Design: Triapine was administered by 2-h i.v. infusion daily for 5 days. Courses were repeated every 4 weeks. The starting dose was 5 mg/m 2 /day, but was reduced to 2 mg/m 2 /day after the first patient developed a hepatic adverse event. The dose was subsequently escalated using a modified Fibonacci scheme in cohorts of 3–6 patients. After the 12 mg/m 2 /day dose level, the study design was amended to permit 100% dose escalation in single-patient cohorts until the first episode of a drug-related grade 2 adverse event or dose-limiting toxicity (DLT). On reaching a dose of 96 mg/m 2 /day, the study was amended to determine the safety and tolerability of the 96-mg/m 2 dose administered daily for 5 days every 2 weeks in an expanded cohort of patients. Results: A total of 32 patients received treatment. During the dose escalation phase of the study, grade 2–4 drug-related adverse events were first observed at a dose of 96 mg/m 2 /day. Grade 3–4 leukopenia was the primary toxicity observed among four patients treated at this dose, which occurred in the week after treatment and resolved to grade 1 or lower by day 15. Fifteen patients were subsequently treated at the 96-mg/m 2 dose, daily for 5 days, with courses repeated every 2 weeks. The most common nonhematological toxicities for the latter schedule were asthenia, fever, nausea and vomiting, mucositis, decreased serum bicarbonate, and hyperbilirubinemia, and were predominantly grade 1–2 in severity and rapidly reversible. Hematological toxicity on the every-other-week schedule consisted of leukopenia (grade 4 in 93% in at least one course) and anemia (grade 2 in 71%, grade 3 in 22%). Thrombocytopenia was less common and was grade 3–4 in severity in only 22%. Triapine showed linear pharmacokinetic behavior although interpatient variability was relatively high. Peak concentrations at the 96-mg/m 2 /day dose averaged 8 μ m , and the mean elimination T 1/2 ranged from 35 min to 3 h, with a median value of ∼1 h. Cumulative urinary recovery averaged 1–3% of the administered dose, suggesting that the elimination of Triapine was primarily through metabolism. No partial or complete responses were observed. Conclusions: Triapine administered at a dose of 96 mg/m 2 by 2-h i.v. infusion da