title: A safety run-in and randomized phase 2 study of cilengitide combined with chemoradiation for newly diagnosed glioblastoma (NABTT 0306).
abstract: BACKGROUND
  Cilengitide is a selective integrin inhibitor that is well tolerated and has demonstrated biologic activity in patients with recurrent malignant glioma. The primary objectives of this randomized phase 2 trial were to determine the safety and efficacy of cilengitide when combined with radiation and temozolomide for patients with newly diagnosed glioblastoma multiforme and to select a dose for comparative clinical testing.
  
  
  METHODS
  In total, 112 patients were accrued. Eighteen patients received standard radiation and temozolomide with cilengitide in a safety run-in phase followed by a randomized phase 2 trial with 94 patients assigned to either a 500 mg dose group or 2000 mg dose group. The trial was designed to estimate overall survival benefit compared with a New Approaches to Brain Tumor Therapy (NABTT) Consortium internal historic control and data from the published European Organization for Research and Treatment of Cancer (EORTC) trial EORTC 26981.
  
  
  RESULTS
  Cilengitide at all doses studied was well tolerated with radiation and temozolomide. The median survival was 19.7 months for all patients, 17.4 months for the patients in the 500 mg dose group, 20.8 months for patients in the 2000 mg dose group, 30 months for patients who had methylated O6-methylguanine-DNA methyltransferase (MGMT) status, and 17.4 months for patients who had unmethylated MGMT status. For patients aged ≤70 years, the median survival and survival at 24 months was superior to what was observed in the EORTC trial (20.7 months vs 14.6 months and 41% vs 27%, respectively; P = .008).
  
  
  CONCLUSIONS
  Cilengitide was well tolerated when combined with standard chemoradiation and may improve survival for patients newly diagnosed with glioblastoma multiforme regardless of MGMT methylation status. The authors concluded that, from an efficacy and safety standpoint, future trials of this agent in this population should use the 2000 mg dose.
authors.affiliation: Brain Tumor Treatment and Research Program, University of Alabama at Birmingham, Birmingham, Alabama, USA. jfisher@jhmi.edu
authors.forename: L Burt
authors.initials: LB
authors.lastname: Nabors
authors.forename: Thomas
authors.initials: T
authors.lastname: Mikkelsen
authors.forename: Monika E
authors.initials: ME
authors.lastname: Hegi
authors.forename: Xiaubu
authors.initials: X
authors.lastname: Ye
authors.forename: Tracy
authors.initials: T
authors.lastname: Batchelor
authors.forename: Glenn
authors.initials: G
authors.lastname: Lesser
authors.forename: David
authors.initials: D
authors.lastname: Peereboom
authors.forename: Myrna R
authors.initials: MR
authors.lastname: Rosenfeld
authors.forename: Jeff
authors.initials: J
authors.lastname: Olsen
authors.forename: Steve
authors.initials: S
authors.lastname: Brem
authors.forename: Joy D
authors.initials: JD
authors.lastname: Fisher
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Grossman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000532:radiotherapy / Q000628:therapy*; D059248:Chemoradiotherapy; D003131:Combined Modality Therapy; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000378:metabolism*; D045643:DNA Repair Enzymes / Q000378:metabolism*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics / Q000532:radiotherapy / Q000628:therapy*; D006801:Humans; D016023:Integrins / Q000037:antagonists & inhibitors; D008297:Male; D008875:Middle Aged; D012910:Snake Venoms / Q000494:pharmacology / Q000627:therapeutic use*; D000077204:Temozolomide; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D055815:Young Adult
chemical_list: D018906:Antineoplastic Agents, Alkylating; D016023:Integrins; D012910:Snake Venoms; D025521:Tumor Suppressor Proteins; C422910:Cilengitide; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide