title: Talampanel with standard radiation and temozolomide in patients with newly diagnosed glioblastoma: a multicenter phase II trial.
abstract: OBJECTIVE
  Recent data suggest that the glutamatergic system is important in the proliferation and migration of glioblastoma. Talampanel is a well-tolerated, oral alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor blocker that could be beneficial in this disease.
  
  
  METHODS
  This trial was designed to estimate overall survival in adults with newly diagnosed glioblastoma treated with talampanel in addition to standard radiation (RT) and temozolomide (TMZ). A secondary purpose was to evaluate talampanel toxicity in this setting. Talampanel was initiated with RT + TMZ and discontinued for toxicity or disease progression. Survival was compared with historical controls.
  
  
  RESULTS
  Seventy-two patients were enrolled from December 2005 to July 2006. Their median age was 60 years (range, 37 to 85 years, with 17% > 70 years), median Karnofsky performance score was 90 (range, 70 to 100), and 77% had a debulking procedure. With a median follow-up time of 18 months, 55 patients (76%) have died, yielding a median survival time of 18.3 months (95% CI, 14.6 to 22.5 months). When the 60 patients who were 18 to 70 years old were compared with the European Organisation for Research and Treatment of Cancer (EORTC) RT + TMZ data, the median survival (20.3 v 14.6 months, respectively) and percentage of patients surviving at 24 months (41.7% v 26.5%, respectively; P = .02) seemed superior. The percentage of patients methylated at O(6)-methylguanine-DNA methyltransferase was lower than on the EORTC study (29% v 43%, respectively). Talampanel was well tolerated and did not increase the known hematologic or nonhematologic toxicities of TMZ.
  
  
  CONCLUSIONS
  Talampanel can be added to RT + TMZ without significant additional toxicity. The encouraging survival results in methylated and unmethylated patients suggest that blocking AMPA receptors may be a useful strategy in newly diagnosed glioblastoma.
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1550 Orleans St, Baltimore, MD 21231, USA. grossman@jhmi.edu
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Grossman
authors.forename: Xiaobu
authors.initials: X
authors.lastname: Ye
authors.forename: Marc
authors.initials: M
authors.lastname: Chamberlain
authors.forename: Tom
authors.initials: T
authors.lastname: Mikkelsen
authors.forename: Tracy
authors.initials: T
authors.lastname: Batchelor
authors.forename: Serena
authors.initials: S
authors.lastname: Desideri
authors.forename: Steven
authors.initials: S
authors.lastname: Piantadosi
authors.forename: Joy
authors.initials: J
authors.lastname: Fisher
authors.forename: Howard A
authors.initials: HA
authors.lastname: Fine
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001569:Benzodiazepines / Q000008:administration & dosage; D001932:Brain Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality / Q000532:radiotherapy* / Q000601:surgery; D016371:Cranial Irradiation; D019175:DNA Methylation; D015254:DNA Modification Methylases; D045643:DNA Repair Enzymes; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018691:Excitatory Amino Acid Antagonists; D005260:Female; D005909:Glioblastoma / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality / Q000532:radiotherapy* / Q000601:surgery; D006801:Humans; D053208:Kaplan-Meier Estimate; D017567:Karnofsky Performance Status; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D018714:Radiotherapy, Adjuvant; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors; D018570:Risk Assessment; D000077204:Temozolomide; D013997:Time Factors; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins; D014481:United States
chemical_list: D018906:Antineoplastic Agents, Alkylating; D018691:Excitatory Amino Acid Antagonists; D018091:Receptors, AMPA; D025521:Tumor Suppressor Proteins; D001569:Benzodiazepines; D003606:Dacarbazine; C085266:talampanel; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide