title: A Multicenter, Phase II, Randomized, Noncomparative Clinical Trial of Radiation and Temozolomide with or without Vandetanib in Newly Diagnosed Glioblastoma Patients.
abstract: OBJECTIVE
  Vandetanib, a tyrosine kinase inhibitor of KDR (VEGFR2), EGFR, and RET, may enhance sensitivity to chemotherapy and radiation. We conducted a randomized, noncomparative, phase II study of radiation (RT) and temozolomide with or without vandetanib in patients with newly diagnosed glioblastoma (GBM).
  
  
  METHODS
  We planned to randomize a total of 114 newly diagnosed GBM patients in a ratio of 2:1 to standard RT and temozolomide with (76 patients) or without (38 patients) vandetanib 100 mg daily. Patients with age ≥ 18 years, Karnofsky performance status (KPS) ≥ 60, and not on enzyme-inducing antiepileptics were eligible. Primary endpoint was median overall survival (OS) from the date of randomization. Secondary endpoints included median progression-free survival (PFS), 12-month PFS, and safety. Correlative studies included pharmacokinetics as well as tissue and serum biomarker analysis.
  
  
  RESULTS
  The study was terminated early for futility based on the results of an interim analysis. We enrolled 106 patients (36 in the RT/temozolomide arm and 70 in the vandetanib/RT/temozolomide arm). Median OS was 15.9 months [95% confidence interval (CI), 11.0-22.5 months] in the RT/temozolomide arm and 16.6 months (95% CI, 14.9-20.1 months) in the vandetanib/RT/temozolomide (log-rank P = 0.75).
  
  
  CONCLUSIONS
  The addition of vandetanib at a dose of 100 mg daily to standard chemoradiation in patients with newly diagnosed GBM or gliosarcoma was associated with potential pharmacodynamic biomarker changes and was reasonably well tolerated. However, the regimen did not significantly prolong OS compared with the parallel control arm, leading to early termination of the study.
authors.affiliation: Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.
authors.forename: Eudocia Q
authors.initials: EQ
authors.lastname: Lee
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kaley
authors.affiliation: Harvard Medical School, Boston, Massachusetts. Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Dan G
authors.initials: DG
authors.lastname: Duda
authors.affiliation: University of Virginia, Charlottesville, Virginia.
authors.forename: David
authors.initials: D
authors.lastname: Schiff
authors.affiliation: New York-Presbyterian Hospital/Columbia University Medical Center, New York, New York.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Lassman
authors.affiliation: Harvard Medical School, Boston, Massachusetts. Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: Eric T
authors.initials: ET
authors.lastname: Wong
authors.affiliation: Henry Ford Hospital, Detroit, Michigan.
authors.forename: Tom
authors.initials: T
authors.lastname: Mikkelsen
authors.affiliation: University of Virginia, Charlottesville, Virginia.
authors.forename: Benjamin W
authors.initials: BW
authors.lastname: Purow
authors.affiliation: Harvard Medical School, Boston, Massachusetts. Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Alona
authors.initials: A
authors.lastname: Muzikansky
authors.affiliation: Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Marek
authors.initials: M
authors.lastname: Ancukiewicz
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Jason T
authors.initials: JT
authors.lastname: Huse
authors.affiliation: Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.
authors.forename: Shakti
authors.initials: S
authors.lastname: Ramkissoon
authors.affiliation: University of Pittsburgh Medical Center, Cancer Centers, Pittsburgh, Pennsylvania.
authors.forename: Jan
authors.initials: J
authors.lastname: Drappatz
authors.affiliation: Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Norden
authors.affiliation: Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.
authors.forename: Rameen
authors.initials: R
authors.lastname: Beroukhim
authors.affiliation: Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Weiss
authors.affiliation: Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Alexander
authors.affiliation: Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts.
authors.forename: Christine S
authors.initials: CS
authors.lastname: McCluskey
authors.affiliation: Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts.
authors.forename: Mary
authors.initials: M
authors.lastname: Gerard
authors.affiliation: Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts.
authors.forename: Katrina H
authors.initials: KH
authors.lastname: Smith
authors.affiliation: Harvard Medical School, Boston, Massachusetts. Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
authors.affiliation: Harvard Medical School, Boston, Massachusetts. Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Tracy T
authors.initials: TT
authors.lastname: Batchelor
authors.affiliation: Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.
authors.forename: Keith L
authors.initials: KL
authors.lastname: Ligon
authors.affiliation: Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts. Patrick_Wen@dfci.harvard.edu.
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Wen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003131:Combined Modality Therapy; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D018572:Disease-Free Survival; D005260:Female; D005909:Glioblastoma / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D053208:Kaplan-Meier Estimate; D017567:Karnofsky Performance Status; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000008:administration & dosage* / Q000009:adverse effects; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects; D000077204:Temozolomide; D016896:Treatment Outcome
chemical_list: D010880:Piperidines; D011799:Quinazolines; D003606:Dacarbazine; D000077204:Temozolomide; C452423:vandetanib