Phase 1 study of erlotinib HCl alone and combined with temozolomide in patients with stable or recurrent malignant glioma1

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.

The Role of Myosin II in Glioma Invasion of the Brain

“…Because glioma invasion remains a vexing problem that limits all current brain tumor therapies, many of these components have been investigated as targets for the development of anti-invasive treatments. However, clinical trials with agents that target these invasive elements have not demonstrated broad-scale or durable responses (Steward and Thomas, 2000;Mamelak et al, 2006;Prados et al, 2006;Nabors et al, 2007). There thus remains a pressing need to identify other anti-invasive strategies, and addressing this will require a detailed understanding of how glioma cells migrate within the brain.…”

PTEN signaling in brain: neuropathology and tumorigenesis

“…EGFR is amplified, mutated or both in a number of neoplasms including glioblastoma. Furthermore, a subset of patients responds favorably when treated with small molecule inhibitors of the receptor, such as erlotinib or gefitinib (Rich et al, 2004;Prados et al, 2006). Many patients, however, do not respond to treatment and a recent study suggested that poor response in GBM patients was associated with PTENdeficient tumors (Mellinghoff et al, 2005).…”

Targeting HER proteins in cancer therapy and the role of the non-target HER3

“…Barriers to effective drug biodistribution in the CNS compartment make this disease more challenging for systemic therapy modalities. But there is evidence from phase I studies that HER family TKIs are active in the treatment of this disease (Prados et al, 2006). Molecular determinants of treatment response have been studied in patients with GBM.…”