Related Experiment Video
Updated: May 8, 2026
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
Phase I study of vinblastine and sirolimus in pediatric patients with recurrent or refractory solid tumors
Daniel A Morgenstern1, Monia Marzouki, Ute Bartels
1Department of Paediatrics, University of Toronto and New Agent and Innovative Therapy Programme, The Hospital for Sick Children, Toronto, Ontario, Canada.
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.
Insights
This study found that combining a mammalian target of rapamycin (mTOR) inhibitor with vinblastine is safe for pediatric patients with advanced solid tumors. The treatment showed anti-angiogenic effects and led to clinical responses, warranting further investigation.
Area of Science:
- Pediatric Oncology
- Pharmacology
- Cancer Biology
Background:
- Neuroblastoma xenografts show inhibited growth with vinblastine and mammalian target of rapamycin (mTOR) inhibitor sirolimus.
- This combination exhibits pro-apoptotic and anti-angiogenic mechanisms.
- A phase I study was conducted to assess the safety and toxicity of this combination in pediatric patients with advanced solid tumors.
Purpose of the Study:
- To evaluate the safety and toxicity of combining vinblastine with an mTOR inhibitor (sirolimus) in pediatric patients.
- To explore the anti-angiogenic effects of this combination therapy.
- To identify potential clinical responses in advanced solid tumors.
Main Methods:
- Eligible patients were ≤21 years old with recurrent/refractory solid tumors.
- Sirolimus was administered orally or via nasogastric (NG) tube, with dose adjustments for target trough concentration (10-15 ng/ml).
- Vinblastine was given intravenously weekly, with dose escalation (4-6 mg/m(2)/dose) following a 3+3 phase I design.
Main Results:
- Fourteen patients were enrolled; 12 were evaluable for toxicity. One patient experienced dose-limiting mucositis at the highest vinblastine dose.
- Myelosuppression was the most frequent toxicity. Lower sirolimus concentrations were observed with NG tube administration.
- A significant reduction in soluble vascular endothelial growth factor receptor 2 (sVEGFR2) was noted, indicating inhibition of angiogenesis. One partial response and three cases of stable disease (>3 months) were observed.
Conclusions:
- The combination of an mTOR inhibitor and vinblastine is safe for extended continuous administration in pediatric patients.
- This regimen reduces circulating angiogenic factor VEGFR2, suggesting anti-angiogenic activity.
- Clinical responses were observed, supporting further investigation with agents like temsirolimus.
Related Concept Videos
02:56Treatment Resistant Cancers
01:23Pharmacokinetics in Pediatric Patients: Overview and Drug Absorption
01:24Pharmacokinetics in Pediatric Patients: Drug Metabolism