This phase II trial confirmed the tolerability of the MTD (8 mg/m2
/dose) of ixabepilone from the pediatric phase I trial (17
) on a daily ×5 d schedule in children and adolescents. The DLT rate in the 12 patients older than 18 years was 33%, which would have exceeded the acceptable rate on the phase I trial, consistent with the lower MTD (6 mg/m2
/dose) in adults on this dosing schedule. The toxicity profile in children and
adults was similar to that in the previously reported clinical trials(12
). Myelosuppression was the predominant toxicity, and peripheral neuropathy was minimal on this dosing schedule. Cumulative toxicity could not be evaluated, because of the small number of patients who received more than 2 treatment cycles. Ixabepilone was inactive in the six solid tumor strata evaluated. Incongruity in the result of this study and the pediatric xenograft model data may be due to a number of factors. The dosing schedule used in the pediatric xenograft models (11
), in which tumor regressions were observed, differed from the dosing schedule used on this phase II trial raising the question if responses might have been observed on the every 4 days × 3 doses schedule evaluated in the pediatric xenograft model. However, the MTDs and activity observed on the 3 dosing schedules in adults (40 mg/m2
as a single dose, 30 mg/m2
divided into 5 daily doses, and 60–75 mg/m2
divided into 3 weekly doses) do not indicate that the drug’s effects are schedule-dependent. Moreover, we studied a dose and schedule that had greater dose intensity than that utilized in adult trials, rendering it unlikely that efficacy would be observed on alternative short duration schedules. The relationship of schedule of ixabepilone (daily × 5 days dosing versus q21 day dosing) to response was explored in a randomized phase II trial of ixabepilone in NSCLC. While the toxicity profile differed with more serious and frequent toxicities (mucositis, neutropenia) occurring in the q21 day schedule, the response rates were similar in both groups (reviewed in 22
). Finally, as the pediatric xenograft testing was initiated after the pediatric phase I study established a MTD of ixabepilone using the daily × 5 days schedule (11
), it would not have been easily feasible to evaluate a different dosing schedule in the pediatric phase II trial.
We specifically did not utilize less well established criteria for clinical efficacy, such as prolonged stable disease, as a primary endpoint, as the myelosuppression resulting from ixabepilone would not justify diminishing the dose intensity of more active agents currently utilized in the treatment of childhood solid tumors.
The vinca alkaloids, which bind to tubulin and block microtubule formation and were clinically developed several decades ago, are active against a broad spectrum of childhood cancers. However, despite their activity against a broad variety of cancers in adults, the taxanes (7
) and now apparently the epothilones, have minimal activity in childhood cancers. This disparity between the activity of microtubule stabilizing agents in adult and childhood cancers may reflect biologic differences in the cancers occurring in the two age groups. Alternatively, the lack of antitumor activity observed in this phase II trial may reflect the more heavily pretreated patient population. While further development of ixabepilone in children with solid tumors is not planned, a cohort of children with advanced, refractory leukemia continues on study.