Phase I Study of Vinblastine and Sirolimus in Pediatric Patients With Recurrent or Refractory Solid Tumors

作者：Morgenstern Daniel A; Marzouki Monia; Bartels Ute; Irwin Meredith S; Sholler Giselle L S; Gammon Janet; Yankanah Rosanna; Wu Bing; Samson Yvan; Baruchel Sylvain^*

来源：Pediatric Blood and Cancer, 2014, 61(1): 128-133.

DOI：10.1002/pbc.24656

• anti-angiogenesis
• mTOR
• Phase I
• rapamycin
• sirolimus
• vinblastine

BackgroundThe 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.
ProcedurePatients 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 10-15ng/ml, with weekly intravenous vinblastine (dose escalated 4-6mg/m(2)/dose according to 3+3 phase I design).
ResultsFourteen 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 (1.500.75ng/ml/mg vs. 2.25 +/- 1.07ng/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.
ConclusionsThe 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.

• 出版日期2014-1