title: Phase I study of vinblastine and sirolimus in pediatric patients with recurrent or refractory solid tumors.
abstract: 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.
  
  
  METHODS
  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.
authors: Department of Paediatrics, University of Toronto and New Agent and Innovative Therapy Programme, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors: Daniel A
authors: DA
authors: Morgenstern
authors: Monia
authors: M
authors: Marzouki
authors: Ute
authors: U
authors: Bartels
authors: Meredith S
authors: MS
authors: Irwin
authors: Giselle L S
authors: GL
authors: Sholler
authors: Janet
authors: J
authors: Gammon
authors: Rosanna
authors: R
authors: Yankanah
authors: Bing
authors: B
authors: Wu
authors: Yvan
authors: Y
authors: Samson
authors: Sylvain
authors: S
authors: Baruchel
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D009369:Neoplasms / Q000188:drug therapy*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000097:blood; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D014747:Vinblastine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D042461:Vascular Endothelial Growth Factor A; D014747:Vinblastine; D040262:Receptors, Vascular Endothelial Growth Factor; D020123:Sirolimus
keywords: Phase I; anti-angiogenesis; mTOR; rapamycin; sirolimus; vinblastine