title: Phase II study of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma.
abstract: OBJECTIVE
  Glioblastoma is an incurable solid tumor characterized by increased expression of vascular endothelial growth factor (VEGF). We performed a phase II study of cediranib in patients with recurrent glioblastoma.
  
  
  METHODS
  Cediranib, an oral pan-VEGF receptor tyrosine kinase inhibitor, was administered (45 mg/d) until progression or unacceptable toxicity to patients with recurrent glioblastoma. The primary end point was the proportion of patients alive and progression free at 6 months (APF6). We performed magnetic resonance imaging (MRI) and plasma and urinary biomarker evaluations at multiple time points.
  
  
  RESULTS
  Thirty-one patients with recurrent glioblastoma were accrued. APF6 after cediranib was 25.8%. Radiographic partial responses were observed by MRI in 17 (56.7%) of 30 evaluable patients using three-dimensional measurements and in eight (27%) of 30 evaluable patients using two-dimensional measurements. For the 15 patients who entered the study taking corticosteroids, the dose was reduced (n = 10) or discontinued (n = 5). Toxicities were manageable. Grade 3/4 toxicities included hypertension (four of 31; 12.9%); diarrhea (two of 31; 6.4%); and fatigue (six of 31; 19.4%). Fifteen (48.4%) of 31 patients required at least one dose reduction and 15 patients required temporary drug interruptions due to toxicity. Drug interruptions were not associated with outcome. Changes in plasma placental growth factor, basic fibroblast growth factor, matrix metalloproteinase (MMP) -2, soluble VEGF receptor 1, stromal cell-derived factor-1alpha, and soluble Tek/Tie2 receptor and in urinary MMP-9/neutrophil gelatinase-associated lipocalin activity after cediranib were associated with radiographic response or survival.
  
  
  CONCLUSIONS
  Cediranib monotherapy for recurrent glioblastoma is associated with encouraging proportions of radiographic response, 6-month progression-free survival, and a steroid-sparing effect with manageable toxicity. We identified early changes in circulating molecules as potential biomarkers of response to cediranib. The efficacy of cediranib and the predictive value of these candidate biomarkers will be explored in prospective trials.
authors.affiliation: Stephen E. and Catherine Pappas Center for Neuro-Oncology, Yawkey 9E, Massachusetts General Hospital Cancer Center, 55 Fruit St, Boston, MA 02114, USA. tbatchelor@partners.org
authors.forename: Tracy T
authors.initials: TT
authors.lastname: Batchelor
authors.forename: Dan G
authors.initials: DG
authors.lastname: Duda
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: di Tomaso
authors.forename: Marek
authors.initials: M
authors.lastname: Ancukiewicz
authors.forename: Scott R
authors.initials: SR
authors.lastname: Plotkin
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Gerstner
authors.forename: April F
authors.initials: AF
authors.lastname: Eichler
authors.forename: Jan
authors.initials: J
authors.lastname: Drappatz
authors.forename: Fred H
authors.initials: FH
authors.lastname: Hochberg
authors.forename: Thomas
authors.initials: T
authors.lastname: Benner
authors.forename: David N
authors.initials: DN
authors.lastname: Louis
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Cohen
authors.forename: Houng
authors.initials: H
authors.lastname: Chea
authors.forename: Alexis
authors.initials: A
authors.lastname: Exarhopoulos
authors.forename: Jay S
authors.initials: JS
authors.lastname: Loeffler
authors.forename: Marsha A
authors.initials: MA
authors.lastname: Moses
authors.forename: Percy
authors.initials: P
authors.lastname: Ivy
authors.forename: A Gregory
authors.initials: AG
authors.lastname: Sorensen
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Wen
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood; D001932:Brain Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D005909:Glioblastoma / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D011799:Quinazolines / Q000009:adverse effects / Q000627:therapeutic use*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D055815:Young Adult; D007211:Indoles
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D040262:Receptors, Vascular Endothelial Growth Factor; C500926:cediranib; D007211:Indoles
references.citation: Cancer Cell. 2009 Mar 3;15(3):232-9
references.pmid: 19249681
references.citation: J Clin Oncol. 2009 May 20;27(15):2542-52
references.pmid: 19332720
references.citation: J Clin Oncol. 2006 Jan 10;24(2):217-27
references.pmid: 16365183
references.citation: J Clin Oncol. 2009 Feb 10;27(5):740-5
references.pmid: 19114704
references.citation: Cancer Res. 2009 Jul 1;69(13):5296-300
references.pmid: 19549889
references.citation: J Clin Oncol. 2009 Jun 20;27(18):3027-35
references.pmid: 19470923
references.citation: Cancer Res. 2005 May 15;65(10):4389-400
references.pmid: 15899831
references.citation: J Clin Oncol. 2006 Jan 1;24(1):16-24
references.pmid: 16330672
references.citation: Nature. 1992 Oct 29;359(6398):843-5
references.pmid: 1279431
references.citation: Nat Rev Clin Oncol. 2009 Jun;6(6):327-38
references.pmid: 19483739
references.citation: Nat Clin Pract Oncol. 2008 Nov;5(11):634-44
references.pmid: 18711427
references.citation: Clin Cancer Res. 2007 Feb 15;13(4):1253-9
references.pmid: 17317837
references.citation: J Clin Oncol. 1999 Aug;17(8):2572-8
references.pmid: 10561324
references.citation: J Clin Oncol. 2009 Oct 1;27(28):4733-40
references.pmid: 19720927
references.citation: Nat Protoc. 2007;2(4):805-10
references.pmid: 17446880
references.citation: Int J Radiat Oncol Biol Phys. 1994 Jun 15;29(3):427-31
references.pmid: 8005794
references.citation: Cancer Cell. 2004 Dec;6(6):553-63
references.pmid: 15607960
references.citation: Clin Cancer Res. 2008 Mar 1;14(5):1407-12
references.pmid: 18316562
references.citation: Cancer Res. 2009 Oct 15;69(20):7905-10
references.pmid: 19826039
references.citation: J Clin Oncol. 2007 Jul 20;25(21):3045-54
references.pmid: 17634482
references.citation: J Clin Oncol. 2008 Apr 10;26(11):1810-6
references.pmid: 18347007
references.citation: Clin Cancer Res. 2008 Oct 15;14(20):6610-7
references.pmid: 18927302
references.citation: Cancer Cell. 2007 Jan;11(1):83-95
references.pmid: 17222792
references.citation: J Clin Oncol. 1990 Jul;8(7):1277-80
references.pmid: 2358840
references.citation: Science. 2005 Jan 7;307(5706):58-62
references.pmid: 15637262
references.citation: Exp Toxicol Pathol. 1995 May;47(2-3):89-94
references.pmid: 7580112
references.citation: Ann Oncol. 2005 Apr;16(4):558-65
references.pmid: 15705616
references.citation: J Nucl Med. 1992 Dec;33(12):2133-7
references.pmid: 1334136
references.citation: Nature. 1994 Feb 10;367(6463):576-9
references.pmid: 8107827
references.citation: Clin Cancer Res. 2007 May 1;13(9):2643-50
references.pmid: 17473195
references.citation: Cancer Cell. 2009 Mar 3;15(3):220-31
references.pmid: 19249680
references.citation: Neurosurgery. 2007 Jun;60(6):E1148-9; discussion E1149
references.pmid: 17538362
references.citation: Nat Clin Pract Oncol. 2006 Jan;3(1):24-40
references.pmid: 16407877
references.citation: Neuro Oncol. 2007 Jan;9(1):29-38
references.pmid: 17108063
references.citation: Neuro Oncol. 2010 May;12(5):466-72
references.pmid: 20406897
references.citation: Int J Cancer. 1999 Feb 19;84(1):10-8
references.pmid: 9988225
references.citation: Cancer Res. 1995 Mar 1;55(5):1189-93
references.pmid: 7532545
references.citation: Nat Rev Neurosci. 2007 Aug;8(8):610-22
references.pmid: 17643088
references.citation: Science. 1999 Jun 18;284(5422):1994-8
references.pmid: 10373119
references.citation: Clin Cancer Res. 2008 Apr 15;14(8):2378-86
references.pmid: 18413828