PMID- 23956145
OWN - NLM
STAT- MEDLINE
DCOM- 20140107
LR  - 20131113
IS  - 1545-5017 (Electronic)
IS  - 1545-5009 (Linking)
VI  - 61
IP  - 1
DP  - 2014 Jan
TI  - Phase I study of vinblastine and sirolimus in pediatric patients with recurrent 
      or refractory solid tumors.
PG  - 128-33
LID - 10.1002/pbc.24656 [doi]
AB  - 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.
CI  - (c) 2013 Wiley Periodicals, Inc.
FAU - Morgenstern, Daniel A
AU  - Morgenstern DA
AD  - Department of Paediatrics, University of Toronto and New Agent and Innovative 
      Therapy Programme, The Hospital for Sick Children, Toronto, Ontario, Canada.
FAU - Marzouki, Monia
AU  - Marzouki M
FAU - Bartels, Ute
AU  - Bartels U
FAU - Irwin, Meredith S
AU  - Irwin MS
FAU - Sholler, Giselle L S
AU  - Sholler GL
FAU - Gammon, Janet
AU  - Gammon J
FAU - Yankanah, Rosanna
AU  - Yankanah R
FAU - Wu, Bing
AU  - Wu B
FAU - Samson, Yvan
AU  - Samson Y
FAU - Baruchel, Sylvain
AU  - Baruchel S
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
DEP - 20130817
PL  - United States
TA  - Pediatr Blood Cancer
JT  - Pediatric blood & cancer
JID - 101186624
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 5V9KLZ54CY (Vinblastine)
RN  - EC 2.7.10.1 (Receptors, Vascular Endothelial Growth Factor)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adolescent
MH  - Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics/*therapeutic use
MH  - Child
MH  - Child, Preschool
MH  - Dose-Response Relationship, Drug
MH  - Drug Resistance, Neoplasm/drug effects
MH  - Female
MH  - Humans
MH  - Male
MH  - Maximum Tolerated Dose
MH  - Neoplasm Recurrence, Local/drug therapy
MH  - Neoplasms/*drug therapy
MH  - Receptors, Vascular Endothelial Growth Factor/blood
MH  - Sirolimus/administration & dosage/adverse effects/pharmacokinetics
MH  - Vascular Endothelial Growth Factor A/blood
MH  - Vinblastine/administration & dosage/adverse effects/pharmacokinetics
MH  - Young Adult
OTO - NOTNLM
OT  - Phase I
OT  - anti-angiogenesis
OT  - mTOR
OT  - rapamycin
OT  - sirolimus
OT  - vinblastine
EDAT- 2013/08/21 06:00
MHDA- 2014/01/08 06:00
CRDT- 2013/08/20 06:00
PHST- 2013/04/02 00:00 [received]
PHST- 2013/05/23 00:00 [accepted]
PHST- 2013/08/20 06:00 [entrez]
PHST- 2013/08/21 06:00 [pubmed]
PHST- 2014/01/08 06:00 [medline]
AID - 10.1002/pbc.24656 [doi]
PST - ppublish
SO  - Pediatr Blood Cancer. 2014 Jan;61(1):128-33. doi: 10.1002/pbc.24656. Epub 2013 
      Aug 17.