Abstract
We evaluated the anti-tumor activity and safety of erlotinib, a receptor tyrosine kinase inhibitor of the epidermal growth factor receptor, plus sirolimus, an inhibitor of the mammalian target of rapamycin, among patients with recurrent glioblastoma (GBM) in a phase 2, open-label, single-arm trial. Thirty-two patients received daily erlotinib and sirolimus. The doses of erlotinib and sirolimus were 150 mg and 5 mg for patients not on concurrent CYP3A-inducing anti-epileptics (EIAEDS), and 450 mg and 10 mg for patients on EIAEDS. Evaluations were performed every two months. The primary endpoint was 6-month progression-free survival and secondary endpoints included safety and overall survival. Archival tumor samples were assessed for EGFR, EGFRvIII, PTEN, pAKT and pS6. Enrolled patients were heavily pre-treated including 53% who had received three or more prior chemotherapy agents and 28% who had received prior bevacizumab therapy. The most common grade ≥2 adverse events were rash (59%), mucositis (34%) and diarrhea (31%). Grade 3 or higher events were rare. Best radiographic response included stable disease in 15 patients (47%); no patients achieved either a CR or PR. The estimated 6-month progression-free survival was 3.1% for all patients. Progression-free survival was better for patients not on EIAEDs (P = 0.03). Tumor markers failed to show an association with PFS except for increased pAKT expression which achieved borderline significance (P = 0.045). Although neither rash nor diarrhea had an association with outcome, hyperlipidemia was associated with longer PFS (P = 0.029). Erlotinib plus sirolimus was well tolerated but had negligible activity among unselected recurrent GBM patients. (ClinicalTrials.gov number: NCT0062243).
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Abbreviations
- ANC:
-
Absolute neutrophil count
- AST:
-
Aspartate aminotransferase
- BBB:
-
Blood-brain barrier
- BUN:
-
Blood urea nitrogen
- CBC:
-
Complete blood count
- CI:
-
Confidence intervals
- CNS:
-
Central nervous system
- CR:
-
Complete response
- CTC:
-
Common Toxicity Criteria
- CYP:
-
Cytochrome p450
- DLT:
-
Dose-limiting toxicity
- EGFR:
-
Epidermal growth factor receptor
- EIAEDs:
-
Enzyme-inducing antieptileptic drugs
- EGFR:
-
Epidermal growth factor receptor
- GBM:
-
Glioblastoma multiforme
- GS:
-
Gliosarcoma
- IRB:
-
Institutional review board
- ITT:
-
Intent-to treat
- KPS:
-
Karnofsky performance status
- MG:
-
Malignant glioma
- MTD:
-
Maximum-tolerated dose
- mTOR:
-
Mammalian target of rapamycin
- NCI:
-
National Cancer Institute
- NE:
-
Non-estimable
- pAKT:
-
Phosphorylated akt murine thymomoa viral oncogene homologue 1
- PD:
-
Progressive disease
- PFS:
-
Progression-free survival
- P-gp:
-
p-glycoprotein
- pMAPK:
-
Phosphorylated mitogen activated protein kinase
- PR:
-
Partial response
- pS-6:
-
Phosphorylated S-6 ribosomal protein
- PTEN:
-
Phosphatase and tensin homologue
- SD:
-
Stable disease
- TKI:
-
Tyrosine kinase inhibitor
- VEGF:
-
Vascular endothelial growth factor
- XRT:
-
External beam radiotherapy
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This work was supported by NIH Grants NS20023 and CA11898; NIH Grant MO1 RR 30, GCRC Program, NCRR; and NCI SPORE 1 P20 CA096890
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Reardon, D.A., Desjardins, A., Vredenburgh, J.J. et al. Phase 2 trial of erlotinib plus sirolimus in adults with recurrent glioblastoma. J Neurooncol 96, 219–230 (2010). https://doi.org/10.1007/s11060-009-9950-0
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DOI: https://doi.org/10.1007/s11060-009-9950-0