title: A phase I study of temozolomide and everolimus (RAD001) in patients with newly diagnosed and progressive glioblastoma either receiving or not receiving enzyme-inducing anticonvulsants: an NCIC CTG study.
abstract: OBJECTIVE
  This phase I trial was designed to determine the recommended phase II dose(s) of everolimus (RAD001) with temozolomide (TMZ) in patients with glioblastoma (GBM). Patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) and those not receiving EIAEDs (NEIAEDs) were studied separately.
  
  
  METHODS
  Enrollment was restricted to patients with proven GBM, either newly diagnosed or at first progression. Temozolomide was administered at a starting dose of 150 mg/m(2)/day for 5 days every 28 days, and everolimus was administered continuously at a starting dose of 2.5 mg orally on a daily schedule starting on day 2 of cycle 1 in 28-day cycles.
  
  
  RESULTS
  Thirteen patients receiving EIAEDs and 19 not receiving EIAEDs were enrolled and received 83 and 116 cycles respectively. Everolimus 10 mg daily plus TMZ 150 mg/m(2)/day for 5 days was declared the recommended phase II dose for the NEIAEDs cohort. In the EIAEDs group, doses were well tolerated without DLTs, and pharmacokinetic parameters indicated decreased everolimus exposure. Temozolomide pharmacokinetic parameters were unaffected by EIAEDs or everolimus. In the subset of 28 patients with measurable disease, 3 had partial responses (all NEIAEDs) and 16 had stable disease.
  
  
  CONCLUSIONS
  A dosage of 10 mg everolimus daily with TMZ 150 mg/m(2)/day for five consecutive days every 28 days in patients is the recommended dose for this regimen. Everolimus clearance is increased by EIAEDs, and patients receiving EIAEDs should be switched to NEIAEDs before starting this regimen.
authors.affiliation: University Health Network-Princess Margaret Hospital, 610 University Avenue, Suite 18-717, Toronto, ON, M5G 2M9, Canada. warren.mason@uhn.on.ca
authors.forename: Warren P
authors.initials: WP
authors.lastname: Mason
authors.forename: Mary
authors.initials: M
authors.lastname: Macneil
authors.forename: Petr
authors.initials: P
authors.lastname: Kavan
authors.forename: Jacob
authors.initials: J
authors.lastname: Easaw
authors.forename: David
authors.initials: D
authors.lastname: Macdonald
authors.forename: Brian
authors.initials: B
authors.lastname: Thiessen
authors.forename: Shweta
authors.initials: S
authors.lastname: Urva
authors.forename: Zarnie
authors.initials: Z
authors.lastname: Lwin
authors.forename: Lynn
authors.initials: L
authors.lastname: McIntosh
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Eisenhauer
mesh_terms: D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000008:administration & dosage*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics; D004338:Drug Combinations; D000068338:Everolimus; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics; D000077204:Temozolomide; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D000970:Antineoplastic Agents; D004338:Drug Combinations; D007166:Immunosuppressive Agents; D003606:Dacarbazine; D000068338:Everolimus; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D020123:Sirolimus; D000077204:Temozolomide