A dose escalation trial for the combination of erlotinib and sirolimus for recurrent malignant gliomas

Phioanh Leia Nghiemphu,David A Reardon,Timothy Cloughesy,Albert Lai,Richard M Green

doi:10.1007/s11060-012-0960-y

Abstract

In order to achieve higher dosages than previously used in clinical trials, we conducted a phase I trial to determine the maximum tolerated dose (MTD) for the combination of erlotinib and sirolimus for the treatments of recurrent malignant gliomas. Patients with pathologically proven World Health Organization (WHO) grade III glioma and grade IV glioblastoma and radiographically proven tumor recurrence were eligible for this study. Treatments included once daily erlotinib, which was given alone for the first 7 days of treatments, then in combination with once daily sirolimus. Sirolimus was given with a loading dose on day 8 followed by a maintenance dose starting on day 9. Dose-limiting toxicity (DLT) was determined over the first 28 days of treatments, and the MTD was determined in a 3 + 3 classic study design. 19 patients were enrolled, and 13 patients were eligible for MTD determination. The MTD was determined to be 150 mg daily for erlotinib and 5 mg daily (after a 15 mg loading dose) for sirolimus. The DLTs included rash and mucositis (despite maximal medical managements), hypophosphatemia, altered mental status, and neutropenia. The combination of erlotinib and sirolimus is difficult to tolerate at dosages higher than previously reported in phase II trials.

Highlights

In order to achieve higher dosages than previously used in clinical trials, we conducted a phase I trial to determine the maximum tolerated dose (MTD) for the combination of erlotinib and sirolimus for the treatments of recurrent malignant gliomas
Looking at tumor response to erlotinib or gefitinib, Mellinghoff et al [15] found that EGFRvIII sensitize tumors to epidermal growth factor receptor (EGFR) kinase inhibitors, and loss of the phosphotase tensin homologue of ten (PTEN) tumor suppressor would impair the response to such inhibitors
In tumor tissues of subjects given erlotinib or gefitinib for the treatment of recurrent GBM, EGFRvIII/PTEN protein coexpression was significantly associated with clinical response

Summary

Introduction

In order to achieve higher dosages than previously used in clinical trials, we conducted a phase I trial to determine the maximum tolerated dose (MTD) for the combination of erlotinib and sirolimus for the treatments of recurrent malignant gliomas. In the most aggressive type, grade IV glioblastoma (GBM), almost 90 % of patients will have tumor progression by 2 years after the standard treatments of radiation therapy combined with temozolomide chemotherapy [2]. There have been several trials of EGFR inhibitors in GBM, mainly using small molecular ATP-competitive tyrosine kinase inhibitors Several phase II trials of EGFR inhibitors such as erlotinib or gefitinib have demonstrated limited effectiveness of these agents for gliomas[14]. In tumor tissues of subjects given erlotinib or gefitinib for the treatment of recurrent GBM, EGFRvIII/PTEN protein coexpression was significantly associated with clinical response. Treatments targeting the PI3K pathway using mTOR-C1 inhibitors, the rapalogues, have not been successful as monotherapy for recurrent GBM, either, and may lead to increase activation via loss of negative feedback and reactivation of the pathway via AKT [16]

Methods

Results

Conclusion