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

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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.

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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.

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Authors and Affiliations

  1. Neuro-Oncology Division, Neurological Institute of New York, Columbia University College of Physicians and Surgeons, 710 West 168th Street, 9th Floor, NI 9-017, New York, NY, 10032, USA

    Yazmin Odia, Fabio M. Iwamoto & Teri N. Kreisl

  2. University of Vermont Medical Center, 89 South Williams Street, Burlington, VT, 05401, USA

    Argirios Moustakas

  3. Mallinckrodt Institute of Radiology, Washington University School of Medicine, Campus Box 8131, 510 S. Kingshighway Blvd., Saint Louis, MO, 63110, USA

    Tyler J. Fraum

  4. University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD, 21201, USA

    Carlos A. Salgado

  5. Center for Cancer Research, National Cancer Institute, Building 37, Room 1142, Bethesda, MD, 20892, USA

    Aiguo Li

  6. Federal Drug Administration, 10903 New Hampshire Ave, Bldg WO22 Rm 2331, Silver Spring, MD, 20993, USA

    Joohee Sul

  7. Department of Radiology, National Institutes of Health Clinical Center, Building 10, Clinical Center 10 Center Drive, MSC 1074, Bethesda, MD, 20892, USA

    John A. Butman

  8. Division of Neuro-Oncology, Director of the Brain Tumor Center, New York-Presbyterian Hospital/Weill Cornell Medical Center, 1305 York Avenue, 9th Floor, New York, NY, 10021, USA

    Howard A. Fine

Authors
  1. Yazmin Odia
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  2. Fabio M. Iwamoto
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  5. Carlos A. Salgado
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  6. Aiguo Li
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  7. Teri N. Kreisl
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  10. Howard A. Fine
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Correspondence to Yazmin Odia.

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11060_2015_2020_MOESM1_ESM.tif

Supplementary material 1 (TIFF 11487 kb).Figure S1: Progression and Overall Survival Relative to Response at 96 Hours for Glioblastoma and Anaplastic Glioma Cohorts

Supplementary material 2 (DOC 168 kb)

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Odia, Y., Iwamoto, F.M., Moustakas, A. et al. A phase II trial of enzastaurin (LY317615) in combination with bevacizumab in adults with recurrent malignant gliomas. J Neurooncol 127, 127–135 (2016). https://doi.org/10.1007/s11060-015-2020-x

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  • DOI: https://doi.org/10.1007/s11060-015-2020-x

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