title: Phase II trial of continuous low-dose temozolomide for patients with recurrent malignant glioma.
abstract: BACKGROUND
  In this phase II trial, we investigated the efficacy of a metronomic temozolomide schedule in the treatment of recurrent malignant gliomas (MGs).
  
  
  METHODS
  Eligible patients received daily temozolomide (50 mg/m2) continuously until progression. The primary endpoint was progression-free survival rate at 6 months in the glioblastoma cohort (N = 37). In an exploratory analysis, 10 additional recurrent grade III MG patients were enrolled. Correlative studies included evaluation of 76 frequent mutations in glioblastoma (iPLEX assay, Sequenom) aiming at establishing the frequency of potentially "drugable" mutations in patients entering recurrent MG clinical trials.
  
  
  RESULTS
  Among glioblastoma patients, median age was 56 y; median Karnofsky performance score (KPS) was 80; 62% of patients had been treated for ≥2 recurrences, including 49% of patients having failed bevacizumab. Treatment was well tolerated; clinical benefit (complete response + partial response + stable disease) was seen in 10 (36%) patients. Progression-free survival rate at 6 months was 19% and median overall survival was 7 months. Patients with previous bevacizumab exposure survived significantly less than bevacizumab-naive patients (median overall survival: 4.3 mo vs 13 mo; hazard ratio = 3.2; P = .001), but those patients had lower KPS (P = .04) and higher number of recurrences (P < .0001). Mutations were found in 13 of the 38 MGs tested, including mutations of EGFR (N = 10), IDH1 (N = 5), and ERBB2 (N = 1).
  
  
  CONCLUSIONS
  In spite of a heavily pretreated population, including nearly half of patients having failed bevacizumab, the primary endpoint was met, suggesting that this regimen deserves further investigation. Results in bevacizumab-naive patients seemed particularly favorable, while results in bevacizumab-failing patients highlight the need to develop further treatment strategies for advanced MG. Clinical trials.gov identifier NCT00498927 (available at http://clinicaltrials.gov/ct2/show/NCT00498927).
authors.affiliation: Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. omuroa@mskcc.org
authors.forename: Antonio
authors.initials: A
authors.lastname: Omuro
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Chan
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Abrey
authors.forename: Mustafa
authors.initials: M
authors.lastname: Khasraw
authors.forename: Anne S
authors.initials: AS
authors.lastname: Reiner
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kaley
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Deangelis
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Lassman
authors.forename: Craig P
authors.initials: CP
authors.lastname: Nolan
authors.forename: Igor T
authors.initials: IT
authors.lastname: Gavrilovic
authors.forename: Adilia
authors.initials: A
authors.lastname: Hormigo
authors.forename: Cynthia
authors.initials: C
authors.lastname: Salvant
authors.forename: Adriana
authors.initials: A
authors.lastname: Heguy
authors.forename: Andrew
authors.initials: A
authors.lastname: Kaufman
authors.forename: Jason T
authors.initials: JT
authors.lastname: Huse
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Panageas
authors.forename: Andreas F
authors.initials: AF
authors.lastname: Hottinger
authors.forename: Ingo
authors.initials: I
authors.lastname: Mellinghoff
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D005910:Glioma / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000401:mortality; D011379:Prognosis; D011446:Prospective Studies; D015996:Survival Rate; D000077204:Temozolomide
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D000077204:Temozolomide