Children and adolescents tolerated ixabepilone at doses of up to 8 mg/m2
/d administered on a daily for 5 consecutive days schedule repeated every 21 days. The DLTs in two of three patients at the 10-mg/m2
/d dose level were neutropenia and fatigue. One of the six patients receiving 8 mg/m2
/d experienced a variety of grade 3 DLTs (GI, neuropathy, myalgia, fever, and neutropenia). Neutropenia was the most consistent dose-related toxicity observed on the study, and neutropenia was more severe than thrombocytopenia, as we previously observed with docetaxel in children.24,25
Hepatic and GI toxicities were common but mild (grade 1) in most patients and not clearly dose related. Neuropathy, myalgia, and arthralgia were not prominent and not cumulative in the few patients who received multiple treatment cycles.
This pediatric phase I trial was designed to allow for direct comparison of results in children and adults receiving ixabepilone on the daily for 5 days schedule. The phase I trial in adults performed at the NCI used an accelerated dose-escalation design with initial dose-escalation increments of 100% (1.5, 3, and 6 mg/m2
The accelerated escalation was halted at the third dose level because toxicity data from concurrent phase I trials indicated that the third dose level was close to the MTD. The starting dose for our pediatric trial was selected as one dose level below the MTD (3 mg/m2
/d), and the dose levels of 6 and 8 mg/m2
/d were also included. We added an intermediate dose level (4.5 mg/m2
/d) between the starting dose and the adult MTD and a 10 mg/m2
/d dose level. The traditional method of determining dose levels for a pediatric phase I trial using 80% of the adult MTD as a starting dose and escalating in 33% increments would have yielded dose levels of 4.8, 6.5, 8.5, and 11.3 mg/m2
Neutropenia was the primary DLT in adults at 8 mg/m2/d and was also dose limiting at 10 mg/m2/d on our trial, which used the same definition of dose-limiting neutropenia. An attempt was made in the adult study to re-escalate to the 8 mg/m2/d dose level by adding filgrastim to shorten the duration of neutropenia, but two of six patients experienced dose-limiting neutropenia. Children and adolescents tolerated a 33% higher dose of ixabepilone on the daily for 5 days schedule than adults.
Pharmacokinetic sampling times, the ixabepilone assay method, and the derivation of pharmacokinetic parameters were identical for the adult and pediatric trials. The pharmacokinetic parameters were similar in children and adults (), but there seemed to be more variability in the pediatric population. The coefficients of variation for ixabepilone clearance in adults and children were 31% and 52%, respectively. Although the mean clearance of ixabepilone in children was 18% higher than in adults, more rapid elimination does not seem to fully account for the 33% higher tolerable dose in children.
Table 4. Comparison of Pharmacokinetic Parameters in Children and Adults11 Receiving Ixabepilone on the Daily for 5 Days Schedule
The half-life in children estimated from the 24- and 48-hour plasma concentrations after the fifth dose exceeded 24 hours, consistent with the half-life of more than 30 hours reported in adults on the less frequent administration schedules.5,6
Despite the long terminal half-life, there was minimal accumulation of drug over the 5-day treatment course. Trough concentrations at the 8 mg/m2
/d dose level increased from 4.5 ng/mL on day 2 to 7.9 ng/mL on day 6, but there was no impact on end of infusion (peak) concentrations, which were 114 ng/mL on day 1 and 94 ng/mL on day 5.
The activity of ixabepilone at the 8 mg/m2
/d dose on the daily for 5 days schedule in childhood solid tumors is being assessed in a phase II trial within the Children's Oncology Group based on the safety and tolerability data from this trial and preclinical activity in xenograft models of rhabdomyosarcoma, neuroblastoma, and Wilms' tumor.4
We are also studying the tolerability of the 8 mg/m2
/d dose daily for 5 days in children with relapsed leukemia.