title: Phase 1 study of erlotinib HCl alone and combined with temozolomide in patients with stable or recurrent malignant glioma.
abstract: The purpose of this study was to define the maximum tolerated dose of erlotinib and characterize its pharmaco-kinetics and safety profile, alone and with temozolomide, with and without enzyme-inducing antiepileptic drugs (EIAEDs), in patients with malignant gliomas. Patients with stable or progressive malignant primary glioma received erlotinib alone or combined with temozolomide in this dose-escalation study. In each treatment group, patients were stratified by coadministration of EIAEDs. Erlotinib was started at 100 mg orally once daily as a 28-day treatment cycle, with dose escalation by 50 mg/day up to 500 mg/day. Temozolomide was administered at 150 mg/m2 for five consecutive days every 28 days, with dose escalation up to 200 mg/m2 at the second cycle. Eightythree patients were evaluated. Rash, fatigue, and diarrhea were the most common adverse events and were generally mild to moderate. The recommended phase 2 dose of erlotinib is 200 mg/day for patients with glioblastoma multiforme who are not receiving an EIAED, 450 mg/day for those receiving temozolomide plus erlotinib with an EIAED, and at least 500 mg/day for those receiving erlotinib alone with an EIAED. Of the 57 patients evaluable for response, eight had a partial response (PR). Six of the 57 patients had a progression-free survival of longer than six months, including four patients with a PR. Coadministration of EIAEDs reduced exposure to erlotinib as compared with administration of erlotinib alone (33%-71% reduction). There was a modest pharmacokinetic interaction between erlotinib and temozolomide. The favorable tolerability profile and evidence of antitumor activity indicate that further investigation of erlotinib is warranted.
authors.affiliation: Department of Neurosurgery, University of California, San Francisco, CA 94143-0372, USA. pradosm@neurosurg.ucsf.edu
authors.forename: Michael D
authors.initials: MD
authors.lastname: Prados
authors.forename: Kathleen R
authors.initials: KR
authors.lastname: Lamborn
authors.forename: Susan
authors.initials: S
authors.lastname: Chang
authors.forename: Eric
authors.initials: E
authors.lastname: Burton
authors.forename: Nicholas
authors.initials: N
authors.lastname: Butowski
authors.forename: Mary
authors.initials: M
authors.lastname: Malec
authors.forename: Ami
authors.initials: A
authors.lastname: Kapadia
authors.forename: Jane
authors.initials: J
authors.lastname: Rabbitt
authors.forename: Margaretta S
authors.initials: MS
authors.lastname: Page
authors.forename: Ann
authors.initials: A
authors.lastname: Fedoroff
authors.forename: Dong
authors.initials: D
authors.lastname: Xie
authors.forename: Sean K
authors.initials: SK
authors.lastname: Kelley
mesh_terms: D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects*; D001932:Brain Neoplasms / Q000188:drug therapy*; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D000069347:Erlotinib Hydrochloride; D005260:Female; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000077204:Temozolomide; D016896:Treatment Outcome
chemical_list: D000927:Anticonvulsants; D011799:Quinazolines; D003606:Dacarbazine; D000069347:Erlotinib Hydrochloride; D000077204:Temozolomide