title: Phase 1 trial of dasatinib plus erlotinib in adults with recurrent malignant glioma.
abstract: To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of dasatinib, an inhibitor of the Src family kinase proteins, with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, among recurrent malignant glioma patients. Once daily dasatinib was escalated in successive cohorts while erlotinib was administered daily at established doses based on concurrent CYP3A-inducing anticonvulsant (EIAEDS) use. Dasatinib pharmacokinetic analyzes were performed. Forty-seven patients enrolled including 37 (79 %) with grade IV and 10 (21 %) with grade III malignant glioma. Thirty patients (64 %) were at ≥second recurrence, while 27 (57 %) had received prior bevacizumab. The dasatinib MTD was 180 mg when combined with either 150 mg of erlotinib for patients not on EIAEDs, or 450 mg of erlotinib for patients on EIAEDs. The most common DLTs were diarrhea and fatigue, while most adverse events were grade 2. Pharmacokinetic data suggests that dasatinib exposure increased with increased dasatinib dose and concurrent erlotinib administration, while concurrent EIAED use diminished dasatinib exposure. No radiographic responses were observed, and only one patient (2 %) remained progression-free at 6 months. We demonstrate that dasatinib plus erlotinib can be safely co-administered on a continuous, daily dosing schedule with erlotinib, and established the recommended dose level of this combination.
authors.affiliation: Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. David_Reardon@DFCI.HARVARD.EDU
authors.forename: David A
authors.initials: DA
authors.lastname: Reardon
authors.forename: James J
authors.initials: JJ
authors.lastname: Vredenburgh
authors.forename: Annick
authors.initials: A
authors.lastname: Desjardins
authors.forename: Katherine B
authors.initials: KB
authors.lastname: Peters
authors.forename: Sith
authors.initials: S
authors.lastname: Sathornsumetee
authors.forename: Stevie
authors.initials: S
authors.lastname: Threatt
authors.forename: John H
authors.initials: JH
authors.lastname: Sampson
authors.forename: James E
authors.initials: JE
authors.lastname: Herndon
authors.forename: April
authors.initials: A
authors.lastname: Coan
authors.forename: Frances
authors.initials: F
authors.lastname: McSherry
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Rich
authors.forename: Roger E
authors.initials: RE
authors.lastname: McLendon
authors.forename: Steven
authors.initials: S
authors.lastname: Zhang
authors.forename: Henry S
authors.initials: HS
authors.lastname: Friedman
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000401:mortality; D000069439:Dasatinib; D000069347:Erlotinib Hydrochloride; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis* / Q000401:mortality / Q000517:prevention & control*; D011379:Prognosis; D011743:Pyrimidines / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage; D013844:Thiazoles / Q000008:administration & dosage; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D011743:Pyrimidines; D011799:Quinazolines; D013844:Thiazoles; D000069347:Erlotinib Hydrochloride; D000069439:Dasatinib