Phase I/II study of erlotinib and temsirolimus for patients with recurrent malignant gliomas: North American Brain Tumor Consortium trial 04-02
Open Access
- 26 January 2014
- journal article
- research article
- Published by Oxford University Press (OUP) in Neuro-Oncology
- Vol. 16 (4), 567-578
- https://doi.org/10.1093/neuonc/not247
Abstract
Inhibition of epidermal growth factor receptor (EGFR) and the mechanistic target of rapamycin (mTOR) may have synergistic antitumor effects in high-grade glioma patients. We conducted a phase I/II study of the EGFR inhibitor erlotinib (150 mg/day) and the mTOR inhibitor temsirolimus. Patients initially received temsirolimus 50 mg weekly, and the dose adjusted based on toxicities. In the phase II component, the primary endpoint was 6-month progression-free survival (PFS6) among glioblastoma patients. Twenty-two patients enrolled in phase I, 47 in phase II. Twelve phase I patients treated at the maximum tolerated dosage were included in the phase II cohort for analysis. The maximum tolerated dosage was 15 mg temsirolimus weekly with erlotinib 150 mg daily. Dose-limiting toxicities were rash and mucositis. Among 42 evaluable glioblastoma patients, 12 (29%) achieved stable disease, but there were no responses, and PFS6 was 13%. Among 16 anaplastic glioma patients, 1 (6%) achieved complete response, 1 (6%) partial response, and 2 (12.5%) stable disease, with PFS6 of 8%. Tumor levels of both drugs were low, and posttreatment tissue in 3 patients showed no reduction in the mTOR target phosphorylated (phospho-)S6S235/236 but possible compensatory increase in phospho-AktS473. Presence of EGFR variant III, phospho-EGFR, and EGFR amplification did not correlate with survival, but patients with elevated phospho–extracellular signal-regulated kinase or reduced phosphatase and tensin homolog protein expression had decreased progression-free survival at 4 months. Because of increased toxicity, the maximum tolerated dosage of temsirolimus in combination with erlotinib proved lower than expected. Insufficient tumor drug levels and redundant signaling pathways may partly explain the minimal antitumor activity noted.This publication has 48 references indexed in Scilit:
- Current clinical development of PI3K pathway inhibitors in glioblastomaNeuro-Oncology, 2012
- Differential Sensitivity of Glioma- versus Lung Cancer–Specific EGFR Mutations to EGFR Kinase InhibitorsCancer Discovery, 2012
- Emerging insights into the molecular and cellular basis of glioblastomaGenes & Development, 2012
- Safety and efficacy of erlotinib in first-relapse glioblastoma: a phase II open-label studyNeuro-Oncology, 2010
- A phase II trial of erlotinib in patients with recurrent malignant gliomas and nonprogressive glioblastoma multiforme postradiation therapyNeuro-Oncology, 2009
- Phase 2 trial of erlotinib plus sirolimus in adults with recurrent glioblastomaJournal of Neuro-Oncology, 2009
- Integrated genomic profiling of endometrial carcinoma associates aggressive tumors with indicators of PI3 kinase activationProceedings of the National Academy of Sciences of the United States of America, 2009
- Antitumor activity of the rapamycin analog CCI-779 in human primitive neuroectodermal tumor/medulloblastoma models as single agent and in combination chemotherapy.2001
- Diversity and frequency of epidermal growth factor receptor mutations in human glioblastomas.2000
- Mutation of the PTEN (MMAC1) tumor suppressor gene in a subset of glioblastomas but not in meningiomas with loss of chromosome arm 10q.1998