title: EORTC 26083 phase I/II trial of dasatinib in combination with CCNU in patients with recurrent glioblastoma.
abstract: The treatment of patients with recurrent glioblastoma remains a major oncologic problem, with median survival after progression of 7-9 months. To determine the maximum tolerated dose and dose-limiting toxicity (DLT), the combination of dasatinib and cyclonexyl-chloroethyl-nitrosourea (CCNU) was investigated in this setting. The study was designed as multicenter, randomized phase II trial, preceded by a lead-in safety phase. The safety component reported here, which also investigated pharmacokinetics and preliminary clinical activity, required expansion and is therefore considered a phase I part to establish a recommended dosing regimen of the combination of CCNU (90-110 mg/m(2)) and dasatinib (100-200 mg daily). Overall, 28 patients were screened, and 26 patients were enrolled. Five dose levels were explored. DLTs, mainly myelosuppression, occurred in 10 patients. Grade 3 or 4 neutropenia was recorded in 7 patients (26.9%) and thrombocytopenia in 11 patients (42.3%). No significant effect of CCNU coadministration on dasatinib pharmacokinetics was found. Median progression-free survival (PFS) was 1.35 months (95% confidence interval: 1.2-1.4) and 6-month PFS was 7.7%. In this phase I study of recurrent glioblastoma patients, the combination of CCNU and dasatinib showed significant hematological toxicities and led to suboptimal exposure to both agents.
authors.affiliation: Department of Medical Oncology, Bellaria-Maggiore Hospital, Azienda USL of Bologna, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Franceschi
authors.forename: Roger
authors.initials: R
authors.lastname: Stupp
authors.forename: Martin J
authors.initials: MJ
authors.lastname: van den Bent
authors.forename: Carla
authors.initials: C
authors.lastname: van Herpen
authors.forename: Florence
authors.initials: F
authors.lastname: Laigle Donadey
authors.forename: Thierry
authors.initials: T
authors.lastname: Gorlia
authors.forename: Monika
authors.initials: M
authors.lastname: Hegi
authors.forename: Benoit
authors.initials: B
authors.lastname: Lhermitte
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Strauss
authors.forename: Anouk
authors.initials: A
authors.lastname: Allgeier
authors.forename: Denis
authors.initials: D
authors.lastname: Lacombe
authors.forename: Alba A
authors.initials: AA
authors.lastname: Brandes
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001932:Brain Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D000069439:Dasatinib; D018572:Disease-Free Survival; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D006801:Humans; D008130:Lomustine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D011743:Pyrimidines; D013844:Thiazoles; D008130:Lomustine; D000069439:Dasatinib