title: REBECA: a phase I study of bevacizumab and whole-brain radiation therapy for the treatment of brain metastasis from solid tumours.
abstract: BACKGROUND
  Brain metastases (BMs) are associated with a poor prognosis. Standard treatment comprises whole-brain radiation therapy (WBRT). As neo-angiogenesis is crucial in BM growth, combining angiogenesis inhibitors such as bevacizumab with radiotherapy is of interest. We aimed to identify the optimal regimen of bevacizumab combined with WBRT for BM for phase II evaluation and provide preliminary efficacy data.
  
  
  METHODS
  In this multicentre single-arm phase I study with a 3 + 3 dose-escalation design, patients with unresectable BM from solid tumours received three cycles of bevacizumab at escalating doses [5, 10 and 15 mg/kg every 2 weeks at dose levels (DL) 0, 1 and 2, respectively] and WBRT (30 Gy/15 fractions/3 weeks) administered from day 15. DL3 consisted of bevacizumab 15 mg/kg with WBRT from day 15 in 30 Gy/10 fractions/2 weeks. Safety was evaluated using NCI-CTCAE version 3. BM response (RECIST 1.1) was assessed by magnetic resonance imaging at 6 weeks and 3 months after WBRT.
  
  
  RESULTS
  Nineteen patients were treated, of whom 13 had breast cancer. There were no DLTs. Grade 1-2 in-field and out-field toxicities occurred for five and nine patients across all DLs, respectively, including three and six patients (including one patient with both, so eight patients overall) of nine patients in DL3. One patient experienced BM progression during treatment (DL0). At the 3-month post-treatment assessment, 10 patients showed a BM response: one of three treated at DL0, one of three at DL1, two of three at DL2 and six of seven at DL3, including one complete response. BM progression occurred in five patients, resulting in two deaths. The remaining patient died from extracranial disease progression.
  
  
  CONCLUSIONS
  Bevacizumab combined with WBRT appears to be a tolerable treatment of BM. DL3 warrants further efficacy evaluation based on the favourable safety/efficacy balance. ClinicalTrials.gov Identifier: NCT01332929.
authors.affiliation: Department of Oncology. Electronic address: c.levy@baclesse.unicancer.fr.
authors.forename: C
authors.initials: C
authors.lastname: Lévy
authors.affiliation: Department of Oncology.
authors.forename: D
authors.initials: D
authors.lastname: Allouache
authors.affiliation: Department of Radiology, Centre François Baclesse, Caen; Department of GIP Cyceron, Caen.
authors.forename: J
authors.initials: J
authors.lastname: Lacroix
authors.affiliation: Department of Clinical Research, Centre François Baclesse, Caen.
authors.forename: A E
authors.initials: AE
authors.lastname: Dugué
authors.affiliation: Department of Oncology.
authors.forename: S
authors.initials: S
authors.lastname: Supiot
authors.affiliation: Department of Oncology.
authors.forename: M
authors.initials: M
authors.lastname: Campone
authors.affiliation: Department of Radiotherapy, Institut de Cancérologie de l'Ouest René Gauducheau, Nantes-Saint Herblain, Caen.
authors.forename: M
authors.initials: M
authors.lastname: Mahe
authors.affiliation: Department of Radiology, Centre François Baclesse, Caen.
authors.forename: S
authors.initials: S
authors.lastname: Kichou
authors.affiliation: Department of Oncology.
authors.forename: M
authors.initials: M
authors.lastname: Leheurteur
authors.affiliation: Department of Radiotherapy, Centre Henri Becquerel, Rouen.
authors.forename: C
authors.initials: C
authors.lastname: Hanzen
authors.affiliation: Department of Oncology.
authors.forename: V
authors.initials: V
authors.lastname: Dieras
authors.affiliation: Department of Radiotherapy, Institut Curie, Paris.
authors.forename: Y
authors.initials: Y
authors.lastname: Kirova
authors.affiliation: Department of Radiotherapy, Institut Curie, Paris.
authors.forename: F
authors.initials: F
authors.lastname: Campana
authors.affiliation: Department of Oncology.
authors.forename: E
authors.initials: E
authors.lastname: Le Rhun
authors.affiliation: Department of Radiotherapy, Centre Oscar Lambret, Lille.
authors.forename: L
authors.initials: L
authors.lastname: Gras
authors.affiliation: Department of Oncology.
authors.forename: T
authors.initials: T
authors.lastname: Bachelot
authors.affiliation: Department of Radiotherapy, Centre Léon Bérard, Lyon.
authors.forename: M-P
authors.initials: MP
authors.lastname: Sunyach
authors.affiliation: Department of Oncology.
authors.forename: I
authors.initials: I
authors.lastname: Hrab
authors.affiliation: Department of Radiotherapy, Centre François Baclesse, Caen.
authors.forename: J
authors.initials: J
authors.lastname: Geffrelot
authors.affiliation: Department of Oncology; Department of Clinical Research, Centre François Baclesse, Caen.
authors.forename: K
authors.initials: K
authors.lastname: Gunzer
authors.affiliation: Department of GIP Cyceron, Caen; Department of Radiology, Centre Hospitalier Universitaire, Caen.
authors.forename: J-M
authors.initials: JM
authors.lastname: Constans
authors.affiliation: Department of Clinical Research, Centre François Baclesse, Caen.
authors.forename: J-M
authors.initials: JM
authors.lastname: Grellard
authors.affiliation: Department of Clinical Research, Centre François Baclesse, Caen.
authors.forename: B
authors.initials: B
authors.lastname: Clarisse
authors.affiliation: Department of Biostatistics, Institut Curie/Inserm U900, Paris, France.
authors.forename: X
authors.initials: X
authors.lastname: Paoletti
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000627:therapeutic use*; D000068258:Bevacizumab; D001921:Brain / Q000528:radiation effects; D001932:Brain Neoplasms / Q000188:drug therapy / Q000532:radiotherapy / Q000556:secondary*; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab
keywords: anti-angiogenic; bevacizumab; brain metastasis; cranial radiotherapy; phase 1