title: North Central Cancer Treatment Group Phase I trial N057K of everolimus (RAD001) and temozolomide in combination with radiation therapy in patients with newly diagnosed glioblastoma multiforme.
abstract: BACKGROUND
  The mammalian target of rapamycin (mTOR) functions within the PI3K/Akt signaling pathway as a critical modulator of cell survival. On the basis of promising preclinical data, the safety and tolerability of therapy with the mTOR inhibitor RAD001 in combination with radiation (RT) and temozolomide (TMZ) was evaluated in this Phase I study.
  
  
  METHODS
  All patients received weekly oral RAD001 in combination with standard chemoradiotherapy, followed by RAD001 in combination with standard adjuvant temozolomide. RAD001 was dose escalated in cohorts of 6 patients. Dose-limiting toxicities were defined during RAD001 combination therapy with TMZ/RT.
  
  
  RESULTS
  Eighteen patients were enrolled, with a median follow-up of 8.4 months. Combined therapy was well tolerated at all dose levels, with 1 patient on each dose level experiencing a dose-limiting toxicity: Grade 3 fatigue, Grade 4 hematologic toxicity, and Grade 4 liver dysfunction. Throughout therapy, there were no Grade 5 events, 3 patients experienced Grade 4 toxicities, and 6 patients had Grade 3 toxicities attributable to treatment. On the basis of these results, the recommended Phase II dosage currently being tested is RAD001 70 mg/week in combination with standard chemoradiotherapy. Fluorodeoxyglucose (FDG) positron emission tomography scans also were obtained at baseline and after the second RAD001 dose before the initiation of TMZ/RT; the change in FDG uptake between scans was calculated for each patient. Fourteen patients had stable metabolic disease, and 4 patients had a partial metabolic response.
  
  
  CONCLUSIONS
  RAD001 in combination with RT/TMZ and adjuvant TMZ was reasonably well tolerated. Changes in tumor metabolism can be detected by FDG positron emission tomography in a subset of patients within days of initiating RAD001 therapy.
authors.affiliation: Mayo Clinic Rochester, Rochester, MN 55905, USA. sarkaria.jann@mayo.edu
authors.forename: Jann N
authors.initials: JN
authors.lastname: Sarkaria
authors.forename: Evanthia
authors.initials: E
authors.lastname: Galanis
authors.forename: Wenting
authors.initials: W
authors.lastname: Wu
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Peller
authors.forename: Caterina
authors.initials: C
authors.lastname: Giannini
authors.forename: Paul D
authors.initials: PD
authors.lastname: Brown
authors.forename: Joon H
authors.initials: JH
authors.lastname: Uhm
authors.forename: Steven
authors.initials: S
authors.lastname: McGraw
authors.forename: Kurt A
authors.initials: KA
authors.lastname: Jaeckle
authors.forename: Jan C
authors.initials: JC
authors.lastname: Buckner
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000532:radiotherapy*; D003131:Combined Modality Therapy / Q000009:adverse effects / Q000379:methods; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D000068338:Everolimus; D005260:Female; D019788:Fluorodeoxyglucose F18; D005500:Follow-Up Studies; D005909:Glioblastoma / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000532:radiotherapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D000077204:Temozolomide
chemical_list: D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D003606:Dacarbazine; D000068338:Everolimus; D020123:Sirolimus; D000077204:Temozolomide