Phase I study of vinblastine and temsirolimus in pediatric patients with recurrent or refractory solid tumors: Canadian Cancer Trials Group Study IND.218.

Combining mammalian target of rapamycin (mTOR) inhibitors and vinca alkaloids has shown therapeutic synergy in xenograft models of pediatric cancers. This phase I study assessed safety and toxicity of temsirolimus in combination with vinblastine in children.
Procedure: Patients ≥ 1 and ≤ 18 years with recurrent/refractory solid or CNS tumors were eligible. Vinblastine (4 mg/m ² ) and temsirolimus (15 mg/m ² ) were administered i.v. weekly, with planned dose escalation of vinblastine using a rolling six phase I design. Pharmacokinetic and pharmacodynamic data were collected.
Results: Seven patients with median age 12 years (range, 8-18 years) were enrolled; all were evaluable for toxicity and six for response. At dose level 1, four of six patients developed grade 3 mucositis, of which one met duration criteria for dose-limiting toxicity (DLT). Four patients required dose omissions for grade 3 or 4 hematologic toxicity, including one prolonged neutropenia DLT. A subsequent patient was enrolled on dose level -2 (temsirolimus 10 mg/m ² , vinblastine 4 mg/m ² ) with no protocol-related toxicity > grade 1, except grade 2 neutropenia. Two serious adverse events (SAE) occurred-an allergic reaction to temsirolimus (grade 2) and an intracranial hemorrhage in a CNS tumor patient (grade 3)-unlikely related to study therapy. Soluble VEGFR2 was reduced at cycle 1, day 36 in keeping with inhibition of angiogenesis. Four patients achieved prolonged stable disease for a median of 5.0 months (range, 3.1-8.3 months).
Conclusion: The combination of weekly temsirolimus (15 mg/m ² ) and vinblastine (4 mg/m ² ) exceeds the maximum tolerated dose in children, with frequent oral mucositis and hematologic toxicity.
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