title: Phase I trial of aflibercept (VEGF trap) with radiation therapy and concomitant and adjuvant temozolomide in patients with high-grade gliomas.
abstract: Anti-vascular endothelial growth factor (VEGF) therapy has shown promise in the treatment of high-grade gliomas (HGG). Aflibercept is a recombinant human fusion protein that acts as a soluble decoy receptor for VEGF-A, VEGF-B and placental growth factor, depleting circulating levels of these growth factors. The Adult Brain Tumor Consortium conducted a phase I trial of aflibercept and temozolomide (TMZ) in patients with newly diagnosed HGG with 2 dose levels and a 3+3 design. Three arms using aflibercept were examined; with radiation and concomitant temozolomide; with adjuvant temozolomide using the 5/28 regimen; and with adjuvant temozolomide using the 21/28 day regimen. Fifty-nine patients were enrolled, 21 in arm 1, 20 in arm 2 and 18 in arm 3. Median age was 56 years (24-69); median KPS 90 (60-100). The maximum tolerated dose (MTD) of aflibercept for all 3 arms was 4 mg/kg every 2 weeks. Dose limiting toxicities at the MTD were: Arm 1: 0/21 patients; Arm 2: 2/20 patients (G3 deep vein thrombosis, G4 neutropenia; Arm 3: 3/18 patients) (G4 biopsy-confirmed thrombotic microangiopathy, G3 rash, G4 thrombocytopenia). The median number of cycles of aflibercept was 5 (range, 1-16). All patients stopped treatment; 28 (47%) for disease progression, 21 (36%) for toxicities, 8 (14%) for other reasons, and 2 (3%) patients completed the full treatment course. This study met its primary endpoint and the MTD of aflibercept with radiation and concomitant and adjuvant temozolomide is 4 mg/kg every 2 weeks.
authors.affiliation: Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, 450 Brookline Avenue, Boston, MA, 02215, USA.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Nayak
authors.affiliation: Department of Neuro-Oncology, M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: John
authors.initials: J
authors.lastname: de Groot
authors.affiliation: Department of Neuro-Oncology, M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Wefel
authors.affiliation: Neuro-Oncology Program, The Ronald Reagan UCLA Medical Center, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Cloughesy
authors.affiliation: University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Lieberman
authors.affiliation: Division of Neuro-Oncology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Chang
authors.affiliation: Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Omuro
authors.affiliation: University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Drappatz
authors.affiliation: Pappas Center For Neuro-Oncology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Tracy T
authors.initials: TT
authors.lastname: Batchelor
authors.affiliation: Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: DeAngelis
authors.affiliation: Department of Neuro-Oncology, M.D. Anderson Cancer Center, Houston, TX, USA.|Neuro-oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Gilbert
authors.affiliation: Department of Neuro-Oncology, M.D. Anderson Cancer Center, Houston, TX, USA.|Department of Pathology, Toronto General Hospital/Princess Margaret Cancer Center, Toronto, ON, Canada.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Aldape
authors.affiliation: Department of Neuro-Oncology, M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Alfred W K
authors.initials: AW
authors.lastname: Yung
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
authors.forename: Joy
authors.initials: J
authors.lastname: Fisher
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
authors.forename: Xiaobu
authors.initials: X
authors.lastname: Ye
authors.affiliation: Investigational Drug Branch, Cancer Therapeutics Evaluation Program, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Alice
authors.initials: A
authors.lastname: Chen
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
authors.forename: Stuart
authors.initials: S
authors.lastname: Grossman
authors.affiliation: Division of Neuro-Oncology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Prados
authors.affiliation: Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, 450 Brookline Avenue, Boston, MA, 02215, USA. patrick_wen@dfci.harvard.edu.
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Wen
mesh_terms: D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000532:radiotherapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D040262:Receptors, Vascular Endothelial Growth Factor / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D000077204:Temozolomide; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; C533178:aflibercept; D003606:Dacarbazine; D040262:Receptors, Vascular Endothelial Growth Factor; D000077204:Temozolomide
keywords: Aflibercept; Dose-dense; Newly diagnosed glioblastoma; Temozolomide; VEGF trap