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Clinical Therapy Trials—Drug |
Department of Neurosurgery, University of California, San Francisco, San Francisco, CA 94143 (M.D.P., K.R.L., S.C., E.B., N.B., M.M., A.K., J.R., M.S.P., A.F.); and Department of Pharmacokinetic and Pharmacodynamic Sciences (D.K.) and Product Portfolio Management (S.K.K.), Genentech, Inc., South San Francisco, CA 94080; USA
2 Address correspondence to Michael Prados, Department of Neurosurgery, University of California, San Francisco, 400 Parnassus Avenue, Room A808, San Francisco, CA 94143-0372 (pradosm{at}neurosurg.ucsf.edu).
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.
Key Words: EGFR • enzyme-inducing antiepileptic drugs • erlotinib • glioma • recurrent • temozolomide
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