title: RTOG 0913: a phase 1 study of daily everolimus (RAD001) in combination with radiation therapy and temozolomide in patients with newly diagnosed glioblastoma.
abstract: OBJECTIVE
  To determine the safety of the mammalian target of rapamycin inhibitor everolimus (RAD001) administered daily with concurrent radiation and temozolomide in newly diagnosed glioblastoma patients.
  
  
  METHODS
  Everolimus was administered daily with concurrent radiation (60 Gy in 30 fractions) and temozolomide (75 mg/m(2) per day). Everolimus was escalated from 2.5 mg/d (dose level 1) to 5 mg/d (dose level 2) to 10 mg/d (dose level 3). Adjuvant temozolomide was delivered at 150 to 200 mg/m(2) on days 1 to 5, every 28 days, for up to 12 cycles, with concurrent everolimus at the previously established daily dose of 10 mg/d. Dose escalation continued if a dose level produced dose-limiting toxicities (DLTs) in fewer than 3 of the first 6 evaluable patients.
  
  
  RESULTS
  Between October 28, 2010, and July 2, 2012, the Radiation Therapy Oncology Group 0913 protocol initially registered a total of 35 patients, with 25 patients successfully meeting enrollment criteria receiving the drug and evaluable for toxicity. Everolimus was successfully escalated to the predetermined maximum tolerated dose of 10 mg/d. Two of the first 6 eligible patients had a DLT at each dose level. DLTs included gait disturbance, febrile neutropenia, rash, fatigue, thrombocytopenia, hypoxia, ear pain, headache, and mucositis. Other common toxicities were grade 1 or 2 hypercholesterolemia and hypertriglyceridemia. At the time of analysis, there was 1 death reported, which was attributed to tumor progression.
  
  
  CONCLUSIONS
  Daily oral everolimus (10 mg) combined with both concurrent radiation and temozolomide followed by adjuvant temozolomide is well tolerated, with an acceptable toxicity profile. A randomized phase 2 clinical trial with mandatory correlative biomarker analysis is currently under way, designed to both determine the efficacy of this regimen and identify molecular determinants of response.
authors.affiliation: Department of Radiation Oncology, Experimental Therapeutics and Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center, Tampa, Florida, USA. prakash.chinnaiyan@moffitt.org
authors.forename: Prakash
authors.initials: P
authors.lastname: Chinnaiyan
authors.forename: Minhee
authors.initials: M
authors.lastname: Won
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Wen
authors.forename: Amyn M
authors.initials: AM
authors.lastname: Rojiani
authors.forename: Merideth
authors.initials: M
authors.lastname: Wendland
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Dipetrillo
authors.forename: Benjamin W
authors.initials: BW
authors.lastname: Corn
authors.forename: Minesh P
authors.initials: MP
authors.lastname: Mehta
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001932:Brain Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D017024:Chemotherapy, Adjuvant; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D019583:Dose Fractionation, Radiation; D000068338:Everolimus; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D000077204:Temozolomide
chemical_list: D003606:Dacarbazine; D000068338:Everolimus; D020123:Sirolimus; D000077204:Temozolomide