title: A phase II trial of enzastaurin (LY317615) in combination with bevacizumab in adults with recurrent malignant gliomas.
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.
authors.affiliation: 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. yo2240@cumc.columbia.edu.
authors.forename: Yazmin
authors.initials: Y
authors.lastname: Odia
authors.affiliation: 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.
authors.forename: Fabio M
authors.initials: FM
authors.lastname: Iwamoto
authors.affiliation: University of Vermont Medical Center, 89 South Williams Street, Burlington, VT, 05401, USA.
authors.forename: Argirios
authors.initials: A
authors.lastname: Moustakas
authors.affiliation: Mallinckrodt Institute of Radiology, Washington University School of Medicine, Campus Box 8131, 510 S. Kingshighway Blvd., Saint Louis, MO, 63110, USA.
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Fraum
authors.affiliation: University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD, 21201, USA.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Salgado
authors.affiliation: Center for Cancer Research, National Cancer Institute, Building 37, Room 1142, Bethesda, MD, 20892, USA.
authors.forename: Aiguo
authors.initials: A
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Teri N
authors.initials: TN
authors.lastname: Kreisl
authors.affiliation: Federal Drug Administration, 10903 New Hampshire Ave, Bldg WO22 Rm 2331, Silver Spring, MD, 20993, USA.
authors.forename: Joohee
authors.initials: J
authors.lastname: Sul
authors.affiliation: Department of Radiology, National Institutes of Health Clinical Center, Building 10, Clinical Center 10 Center Drive, MSC 1074, Bethesda, MD, 20892, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Butman
authors.affiliation: 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.
authors.forename: Howard A
authors.initials: HA
authors.lastname: Fine
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D011788:Quality of Life; D015996:Survival Rate
chemical_list: D007211:Indoles; D000068258:Bevacizumab; D038362:Glycogen Synthase Kinase 3; C504878:enzastaurin
keywords: Bevacizumab; Enzastaurin; Glioblastoma; Glioma; Trial