Journal of Neuro-Oncology

, Volume 127, Issue 1, pp 127–135 | Cite as

A phase II trial of enzastaurin (LY317615) in combination with bevacizumab in adults with recurrent malignant gliomas

  • Yazmin Odia
  • Fabio M. Iwamoto
  • Argirios Moustakas
  • Tyler J. Fraum
  • Carlos A. Salgado
  • Aiguo Li
  • Teri N. Kreisl
  • Joohee Sul
  • John A. Butman
  • Howard A. Fine
Clinical Study
First Online:
Received:
Accepted:

Abstract

We evaluated the efficacy of combination enzastaurin (LY317615) and bevacizumab for recurrent malignant gliomas and explored serologic correlates. We enrolled 81 patients with glioblastomas (GBM, n = 40) and anaplastic gliomas (AG, n = 41). Patients received enzastaurin as a loading dose of 1125 mg, followed by 500 or 875 mg daily for patients on non-enzyme-inducing or enzyme-inducing antiepileptics, respectively. Patients received bevacizumab 10 mg/kg intravenously biweekly. Clinical evaluations were repeated every 4 weeks. Magnetic resonance imaging was obtained at baseline and every 8 weeks from treatment onset. Phosphorylated glycogen synthase kinase (GSK)-3 levels from peripheral blood mononuclear cells (PBMCs) were checked with each MRI. Median overall survival was 7.5 and 12.4 months for glioblastomas and anaplastic glioma cohorts, with median progression-free survivals of 2.0 and 4.4 months, respectively. Of GBM patients, 3/40 (7.5 %) were not evaluable, while 8/37 (22 %) had partial or complete response and 20/37 (54 %) had stable disease for 2+ months. Of the 39 evaluable AG patients, 18 (46 %) had an objective response, and 16 (41 %) had stable disease for 2+ months. The most common grade 3+ toxicities were lymphopenia (15 %), hypophosphatemia (8.8 %) and thrombotic events (7.5 %). Two (2.5 %) GBM patients died suddenly; another death (1.3 %) occurred from intractable seizures. Phosphorylated GSK-3 levels from PBMCs did not correlate with treatment response. A minimally important improvement in health-related quality of life was self-reported in 7–9/24 (29.2–37.5 %). Early response based on Levin criteria was significantly associated with significantly longer progression free survival for glioblastomas. Enzastaurin (LY317615) in combination with bevacizumab for recurrent malignant gliomas is well-tolerated, with response and progression-free survival similar to bevacizumab monotherapy.

Keywords

Enzastaurin Bevacizumab Trial Glioma Glioblastoma 
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Notes

Acknowledgments

The National Cancer Institute (NCI) Intramural Research Program provided grant funding for this trial [NCT00586508]. Enzastaurin (LY317615) and additional funds were provided by Eli Lilly via a Cooperative Research and Development Agreement (CRADA) with the NCI. A portion of these data was previously presented at the Society for Neuro-Oncology in November 2011, in Garden Grove, California.

Funding

National Cancer Institute Intramural Research Program.

Compliance with ethical standards

Conflicts of Interest

Authors have no conflicts of interest to declare.

Supplementary material

11060_2015_2020_MOESM1_ESM.tif (11.2 mb)
Supplementary material 1 (TIFF 11487 kb).Figure S1: Progression and Overall Survival Relative to Response at 96 Hours for Glioblastoma and Anaplastic Glioma Cohorts
11060_2015_2020_MOESM2_ESM.doc (168 kb)
Supplementary material 2 (DOC 168 kb)

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Copyright information

© Springer Science+Business Media New York (outside the USA) 2015

Authors and Affiliations

  • Yazmin Odia
    • 1
  • Fabio M. Iwamoto
    • 1
  • Argirios Moustakas
    • 2
  • Tyler J. Fraum
    • 3
  • Carlos A. Salgado
    • 4
  • Aiguo Li
    • 5
  • Teri N. Kreisl
    • 1
  • Joohee Sul
    • 6
  • John A. Butman
    • 7
  • Howard A. Fine
    • 8
  1. 1.Neuro-Oncology Division, Neurological Institute of New YorkColumbia University College of Physicians and SurgeonsNew YorkUSA
  2. 2.University of Vermont Medical CenterBurlingtonUSA
  3. 3.Mallinckrodt Institute of RadiologyWashington University School of MedicineSaint LouisUSA
  4. 4.University of Maryland School of MedicineBaltimoreUSA
  5. 5.Center for Cancer ResearchNational Cancer InstituteBethesdaUSA
  6. 6.Federal Drug AdministrationSilver SpringUSA
  7. 7.Department of RadiologyNational Institutes of Health Clinical CenterBethesdaUSA
  8. 8.Division of Neuro-Oncology, Director of the Brain Tumor CenterNew York-Presbyterian Hospital/Weill Cornell Medical CenterNew YorkUSA

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