Journal of Neuro-Oncology

, Volume 96, Issue 2, pp 219–230

Phase 2 trial of erlotinib plus sirolimus in adults with recurrent glioblastoma

  • David A. Reardon
  • Annick Desjardins
  • James J. Vredenburgh
  • Sridharan Gururangan
  • Allan H. Friedman
  • James E. HerndonII
  • Jennifer Marcello
  • Julie A. Norfleet
  • Roger E. McLendon
  • John H. Sampson
  • Henry S. Friedman
Clinical Study - Patient Study

DOI: 10.1007/s11060-009-9950-0

Cite this article as:
Reardon, D.A., Desjardins, A., Vredenburgh, J.J. et al. J Neurooncol (2010) 96: 219. doi:10.1007/s11060-009-9950-0

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).

Keywords

Malignant gliomaEGFRmTORErlotinibSirolimus

Abbreviations list

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

Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • David A. Reardon
    • 1
    • 2
    • 6
  • Annick Desjardins
    • 4
  • James J. Vredenburgh
    • 4
  • Sridharan Gururangan
    • 1
    • 2
  • Allan H. Friedman
    • 1
  • James E. HerndonII
    • 5
  • Jennifer Marcello
    • 5
  • Julie A. Norfleet
    • 1
  • Roger E. McLendon
    • 3
  • John H. Sampson
    • 1
  • Henry S. Friedman
    • 1
    • 2
  1. 1.Department of SurgeryDuke University Medical CenterDurhamUSA
  2. 2.Department of PediatricsDuke University Medical CenterDurhamUSA
  3. 3.Department of PathologyDuke University Medical CenterDurhamUSA
  4. 4.Department of MedicineDuke University Medical CenterDurhamUSA
  5. 5.Cancer Center BiostatisticsDuke University Medical CenterDurhamUSA
  6. 6.The Preston Robert Tisch Brain Tumor Center at DukeDuke University Medical CenterDurhamUSA