Phase I evaluation of oral and intravenous vinorelbine in pediatric cancer patients: a report from the Children's Oncology Group.

PURPOSE Vinorelbine (Navelbine) is an orally absorbable Vinca with broad antitumor activity. It differs from other Vinca in that it is structurally modified on the catharanthine nucleus and has differential actions on tubulin that render it less neurotoxic than other compounds in this class. We conducted a phase I study of vinorelbine given the activity of Vinca alkaloids in many pediatric tumors. EXPERIMENTAL DESIGN We evaluated the safety and pharmacokinetics of oral and i.v. vinorelbine administered weekly x 6 in children (age, 2-17 years) with different tumors. Patients with disease involvement in the bone marrow were eligible but were stratified and dose-escalated separately. Oral vinorelbine (week 1) was administered as liquid-filled gelatin capsules at thrice the i.v. dose. Intravenous vinorelbine doses of 24 to 37.5 mg/m(2) were administered on weeks 2 to 6. RESULTS The dose-limiting toxicity in patients without marrow involvement was reversible neutropenia. Common nonhematologic toxicities included < or = grade 2 nausea/vomiting and increased hepatic transaminases. A higher mean i.v. Cl(TB) was observed (1.75 +/- 1.0 L/h/kg) compared with adult reports, with a mean t(1/2B) of 16.5 +/- 9.7 hours. Mean oral bioavailability was 28.5 +/- 22.5%. The apparent oral clearance (12.1 +/- 13.0 L/h/kg) and volume of distribution (69.4 +/- 30.6 L/kg) were substantially higher than in adults given similar oral doses. CONCLUSIONS The maximum tolerated dose in children without bone marrow involvement was 30 mg/m(2), similar to that reported in adults, with myelosuppression being the dose-limiting toxicity. Higher plasma clearance resulted in lower area under the plasma concentration-time curves at a given dose compared with that reported in adults.