title: Phase I trial, pharmacokinetics, and pharmacodynamics of vandetanib and dasatinib in children with newly diagnosed diffuse intrinsic pontine glioma.
abstract: OBJECTIVE
  Testing of promising drug combinations is crucial in the treatment of diffuse intrinsic pontine glioma (DIPG). As the VEGF and platelet-derived growth factor (PDGF) pathways are critical in gliomas, we evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of vandetanib, a VEGFR-2 inhibitor, combined with dasatinib, a potent PDGFR inhibitor, during and after radiotherapy in children with newly diagnosed DIPG.
  
  
  METHODS
  Dasatinib was started concurrently with radiotherapy. Vandetanib was started 8 days later. We tested increasing doses of vandetanib (65 and 85 mg/m(2) once daily) and dasatinib (65 and 85 mg/m(2) twice daily). Dose-limiting toxicities were evaluated during the first 6 weeks of therapy. Plasma pharmacokinetics was obtained on days 8 and 42 ± 3 in all patients and concomitantly with cerebrospinal fluid (CSF) when possible. Inhibition of targets of dasatinib in peripheral blood mononuclear cells (PBMC) was evaluated.
  
  
  RESULTS
  Twenty-five patients were treated. Treatment was well tolerated. The median duration of treatment was 184 days. Diarrhea was the most significant toxicity. Three patients experienced substantial myelosuppression. The steady-state plasma pharmacokinetics of vandetanib was comparable with previous studies. Although the plasma exposure to dasatinib decreased from days 8 to 42, it remained similar to adult studies. CSF to plasma exposure of vandetanib and dasatinib were approximately 2% in 2 patients. Phosphorylated 70S6K decreased during therapy in PBMCs.
  
  
  CONCLUSIONS
  The MTD of vandetanib and dasatinib in combination was 65 mg/m(2) for each drug. Other studies are underway to test dasatinib and other PDGFR inhibitors alone or in combination for this deadly cancer.
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. alberto.broniscer@stjude.org
authors.forename: Alberto
authors.initials: A
authors.lastname: Broniscer
authors.forename: Sharyn D
authors.initials: SD
authors.lastname: Baker
authors.forename: Cynthia
authors.initials: C
authors.lastname: Wetmore
authors.forename: Atmaram S
authors.initials: AS
authors.lastname: Pai Panandiker
authors.forename: Jie
authors.initials: J
authors.lastname: Huang
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Davidoff
authors.forename: Arzu
authors.initials: A
authors.lastname: Onar-Thomas
authors.forename: John C
authors.initials: JC
authors.lastname: Panetta
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Chin
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Merchant
authors.forename: Justin N
authors.initials: JN
authors.lastname: Baker
authors.forename: Sue C
authors.initials: SC
authors.lastname: Kaste
authors.forename: Amar
authors.initials: A
authors.lastname: Gajjar
authors.forename: Clinton F
authors.initials: CF
authors.lastname: Stewart
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D020295:Brain Stem Neoplasms / Q000188:drug therapy* / Q000401:mortality; D002648:Child; D002675:Child, Preschool; D000069439:Dasatinib; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D008297:Male; D010880:Piperidines / Q000008:administration & dosage / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000008:administration & dosage / Q000493:pharmacokinetics; D011799:Quinazolines / Q000008:administration & dosage / Q000493:pharmacokinetics; D013844:Thiazoles / Q000008:administration & dosage / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D010880:Piperidines; D011743:Pyrimidines; D011799:Quinazolines; D013844:Thiazoles; D000069439:Dasatinib; C452423:vandetanib
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