title: A phase I study of LY317615 (enzastaurin) and temozolomide in patients with gliomas (EORTC trial 26054).
abstract: We report a phase 1 study to examine the safety and recommended dose of the oral protein kinase C-beta inhibitor (anti-angiogenic) enzastaurin in combination with single-agent temozolomide. The study was conducted in patients with recurrent glioblastoma or newly diagnosed disease that was not treatable with standard (chemo)radiotherapy. Patients were treated with standard dose temozolomide (200 mg/m(2) for 5 days every 4 weeks) together with daily oral enzastaurin. Three dose levels of enzastaurin were investigated: 250 mg daily (OD), 500 mg OD, and 250 mg twice daily (BID). Dose-limiting toxicity was determined in the first 2 cycles, but treatment continued until limiting toxicity or disease progression was identified. Twenty-eight patients were enrolled. No dose-limiting toxicity was noted at 250 mg OD or 500 mg OD. However, at 250 mg BID, 2 dose-limiting episodes of thrombocytopenia were noted. The recommended dose for enzastaurin in combination with standard 4-weekly temozolomide is therefore 500 mg OD. The pharmacokinetics of enzastaurin in combination with temozolomide was evaluated. Temozolomide did not appear to effect enzastaurin exposures at the 250 mg or 500 mg OD dose levels.
authors.affiliation: Glasgow University/Beatson West of Scotland Cancer Centre, Glasgow, UK. roy.rampling@glasgow.ac.uk
authors.forename: Roy
authors.initials: R
authors.lastname: Rampling
authors.forename: Marc
authors.initials: M
authors.lastname: Sanson
authors.forename: Thiery
authors.initials: T
authors.lastname: Gorlia
authors.forename: Denis
authors.initials: D
authors.lastname: Lacombe
authors.forename: Christina
authors.initials: C
authors.lastname: Lai
authors.forename: Myriam
authors.initials: M
authors.lastname: Gharib
authors.forename: Walter
authors.initials: W
authors.lastname: Taal
authors.forename: Clemens
authors.initials: C
authors.lastname: Stoffregen
authors.forename: Rodney
authors.initials: R
authors.lastname: Decker
authors.forename: Martin J
authors.initials: MJ
authors.lastname: van den Bent
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000532:radiotherapy; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D000077204:Temozolomide; D055815:Young Adult
chemical_list: D007211:Indoles; D003606:Dacarbazine; C504878:enzastaurin; D000077204:Temozolomide