Phase I study of vinblastine and sirolimus in pediatric patients with recurrent or refractory solid tumors

Background The combination of vinblastine and mammalian target of rapamycin (mTOR) inhibitor sirolimus inhibits the growth of neuroblastoma xenografts through pro‐apoptotic and anti‐angiogenic mechanisms. This phase I study aimed to explore the safety and toxicity of this combination in pediatric patients with advanced solid tumors. Procedure Patients ≤21 years of age with recurrent/refractory solid tumors (including CNS) were eligible. Sirolimus was administered daily by mouth or nasogastric (NG) tube, with doses adjusted to achieve a target trough concentration of 10–15 ng/ml, with weekly intravenous vinblastine (dose escalated 4–6 mg/m 2 /dose according to 3 + 3 phase I design). Results Fourteen patients were enrolled (median age 8.7 years; range 2.3–19) of whom 12 were evaluable for toxicity and 11 for response. One patient experienced a dose‐limiting toxicity (grade 3 mucositis) at the highest vinblastine dose level. Myelosuppression was the most common toxicity. Dose‐adjusted sirolimus trough concentrations were significantly lower in patients receiving drug via NG tube (1.50 ± 0.75 ng/ml/mg vs. 2.25 ± 1.07 ng/ml/mg for oral administration). Correlative biomarker analysis demonstrated a significant reduction in serum concentration of soluble vascular endothelial growth factor receptor (sVEGFR2) at 28 days compared to baseline consistent with inhibition of angiogenesis. One patient had a partial response and three had stable disease for more than 3 months. Conclusions The combination of mTOR inhibitor and vinblastine given over an extended continuous schedule is safe, associated with a reduction in circulating angiogenic factor (CAF) VEGFR2 and resulted in clinical responses. Future studies using the intravenously administered mTOR inhibitor temsirolimus are planned. Pediatr Blood Cancer 2014;61:128–133. © 2013 Wiley Periodicals, Inc.