A phase I trial of erlotinib in patients with nonprogressive glioblastoma multiforme postradiation therapy, and recurrent malignant gliomas and meningiomas.

The objective of this phase I study was to determine the maximal tolerated dose (MTD) of erlotinib in patients with recurrent malignant gliomas (MGs) or recurrent meningiomas on enzyme-inducing antiepileptic drugs (EIAEDs). Dose escalation was by a standard 3 x 3 design. The initial starting dose of erlotinib was 150 mg daily. If no dose-limiting toxicity (DLT) was observed, then dose escalation occurs as follows: 200 mg/day, 275 mg/day, and then increased in 125 mg increments until the MTD was reached. The MTD was defined as the dose where < or = 1 of 6 patients experienced a DLT and the dose above had 2 or more DLTs. The MTD was 650 mg/day; the observed DLTs were grade 3 rash in 2 patients at 775 mg/day. Pharmacokinetic analysis showed a significant influence of EIAEDs on the metabolism of erlotinib when compared with our phase II data published separately. Primary toxicities were rash and diarrhea. The MTD of erlotinib in patients receiving EIAEDs is substantially higher than the standard dose of 150 mg. This has important implications for further development of this drug in the treatment of MG as well as the optimal management of patients with other malignancies such as NSCLC who are on enzyme-inducing drugs.

[1]  J. Raizer,et al.  Erratum: Molecular study of malignant gliomas treated with epidermal growth factor receptor inhibitors: Tissue analysis from North American Brain Tumor Consortium Trials 01-03 and 00-01 (Clinical Cancer Research (November 1, 2005) 11 (7841-7850)) , 2006 .

[2]  A. Sehgal,et al.  Molecular changes during the genesis of human gliomas. , 1998, Seminars in surgical oncology.

[3]  B. Lum,et al.  Effect of food on the pharmacokinetics of erlotinib, an orally active epidermal growth factor receptor tyrosine-kinase inhibitor, in healthy individuals , 2008, Anti-cancer drugs.

[4]  W. Cavenee,et al.  A mutant epidermal growth factor receptor common in human glioma confers enhanced tumorigenicity. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[5]  Koji Yoshimoto,et al.  Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. , 2005, The New England journal of medicine.

[6]  O. Bogler,et al.  A common mutant epidermal growth factor receptor confers enhanced tumorigenicity on human glioblastoma cells by increasing proliferation and reducing apoptosis. , 1996, Cancer research.

[7]  Susan Chang,et al.  Phase 1 study of erlotinib HCl alone and combined with temozolomide in patients with stable or recurrent malignant glioma. , 2006, Neuro-oncology.

[8]  B. Lum,et al.  The effects of CYP3A4 inhibition on erlotinib pharmacokinetics: computer-based simulation (SimCYP™) predicts in vivo metabolic inhibition , 2007, European Journal of Clinical Pharmacology.

[9]  K. Umezawa,et al.  Preferential inhibition of glioblastoma cells with wild-type epidermal growth factor receptors by a novel tyrosine kinase inhibitor ethyl-2,5-dihydroxycinnamate. , 1997, Oncology research.

[10]  N. Nathoo,et al.  EPIDERMAL GROWTH FACTOR RECEPTOR ANTAGONISTS: NOVEL THERAPY FOR THE TREATMENT OF HIGH-GRADE GLIOMAS , 2004, Neurosurgery.

[11]  T. Cascino,et al.  Response criteria for phase II studies of supratentorial malignant glioma. , 1990, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  Susan M. Chang,et al.  Molecular Study of Malignant Gliomas Treated with Epidermal Growth Factor Receptor Inhibitors: Tissue Analysis from North American Brain Tumor Consortium Trials 01-03 and 00-01 , 2005, Clinical Cancer Research.

[13]  S. Piantadosi,et al.  Preirradiation paclitaxel in glioblastoma multiforme: efficacy, pharmacology, and drug interactions. New Approaches to Brain Tumor Therapy Central Nervous System Consortium. , 1997, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  D. Bigner,et al.  Molecular pathogenesis of malignant gliomas. , 1999, Current opinion in oncology.

[15]  Howard A. Fine,et al.  Phase I/II Study of Imatinib Mesylate for Recurrent Malignant Gliomas: North American Brain Tumor Consortium Study 99-08 , 2006, Clinical Cancer Research.

[16]  Martin J. van den Bent,et al.  Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. , 2005, The New England journal of medicine.

[17]  A. Scott,et al.  Growth suppression of intracranial xenografted glioblastomas overexpressing mutant epidermal growth factor receptors by systemic administration of monoclonal antibody (mAb) 806, a novel monoclonal antibody directed to the receptor. , 2001, Cancer research.