title: Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial.
abstract: BACKGROUND
  Treatment options for recurrent glioblastoma are scarce, with second-line chemotherapy showing only modest activity against the tumour. Despite the absence of well controlled trials, bevacizumab is widely used in the treatment of recurrent glioblastoma. Nonetheless, whether the high response rates reported after treatment with this drug translate into an overall survival benefit remains unclear. We report the results of the first randomised controlled phase 2 trial of bevacizumab in recurrent glioblastoma.
  
  
  METHODS
  The BELOB trial was an open-label, three-group, multicentre phase 2 study undertaken in 14 hospitals in the Netherlands. Adult patients (≥18 years of age) with a first recurrence of a glioblastoma after temozolomide chemoradiotherapy were randomly allocated by a web-based program to treatment with oral lomustine 110 mg/m(2) once every 6 weeks, intravenous bevacizumab 10 mg/kg once every 2 weeks, or combination treatment with lomustine 110 mg/m(2) every 6 weeks and bevacizumab 10 mg/kg every 2 weeks. Randomisation of patients was stratified with a minimisation procedure, in which the stratification factors were centre, Eastern Cooperative Oncology Group performance status, and age. The primary outcome was overall survival at 9 months, analysed by intention to treat. A safety analysis was planned after the first ten patients completed two cycles of 6 weeks in the combination treatment group. This trial is registered with the Nederlands Trial Register (www.trialregister.nl, number NTR1929).
  
  
  RESULTS
  Between Dec 11, 2009, and Nov 10, 2011, 153 patients were enrolled. The preplanned safety analysis was done after eight patients had been treated, because of haematological adverse events (three patients had grade 3 thrombocytopenia and two had grade 4 thrombocytopenia) which reduced bevacizumab dose intensity; the lomustine dose in the combination treatment group was thereafter reduced to 90 mg/m(2). Thus, in addition to the eight patients who were randomly assigned to receive bevacizumab plus lomustine 110 mg/m(2), 51 patients were assigned to receive bevacizumab alone, 47 to receive lomustine alone, and 47 to receive bevacizumab plus lomustine 90 mg/m(2). Of these patients, 50 in the bevacizumab alone group, 46 in the lomustine alone group, and 44 in the bevacizumab and lomustine 90 mg/m(2) group were eligible for analyses. 9-month overall survival was 43% (95% CI 29-57) in the lomustine group, 38% (25-51) in the bevacizumab group, 59% (43-72) in the bevacizumab and lomustine 90 mg/m(2) group, 87% (39-98) in the bevacizumab and lomustine 110 mg/m(2) group, and 63% (49-75) for the combined bevacizumab and lomustine groups. After the reduction in lomustine dose in the combination group, the combined treatment was well tolerated. The most frequent grade 3 or worse toxicities were hypertension (13 [26%] of 50 patients in the bevacizumab group, three [7%] of 46 in the lomustine group, and 11 [25%] of 44 in the bevacizumab and lomustine 90 mg/m(2) group), fatigue (two [4%], four [9%], and eight [18%]), and infections (three [6%], two [4%], and five [11%]). At the time of this analysis, 144/148 (97%) of patients had died and three (2%) were still on treatment.
  
  
  CONCLUSIONS
  The combination of bevacizumab and lomustine met prespecified criteria for assessment of this treatment in further phase 3 studies. However, the results in the bevacizumab alone group do not justify further studies of this treatment.
  
  
  BACKGROUND
  Roche Nederland and KWF Kankerbestrijding.
authors.affiliation: Department of Neuro-oncology, Erasmus MC Cancer Institute, Rotterdam, Netherlands.
authors.forename: Walter
authors.initials: W
authors.lastname: Taal
authors.affiliation: Department of Medical Oncology, Medical Center Haaglanden, The Hague, Netherlands.
authors.forename: Hendrika M
authors.initials: HM
authors.lastname: Oosterkamp
authors.affiliation: Department of Medical Oncology, University Medical Center Groningen, Groningen, Netherlands.
authors.forename: Annemiek M E
authors.initials: AM
authors.lastname: Walenkamp
authors.affiliation: Department of Pathology, Erasmus MC Cancer Institute, Rotterdam, Netherlands.
authors.forename: Hendrikus J
authors.initials: HJ
authors.lastname: Dubbink
authors.affiliation: Department of Oncology, St Elisabeth Ziekenhuis, Tilburg, Netherlands.
authors.forename: Laurens V
authors.initials: LV
authors.lastname: Beerepoot
authors.affiliation: Department of Neurology, Catharina Hospital Eindhoven, Netherlands.
authors.forename: Monique C J
authors.initials: MC
authors.lastname: Hanse
authors.affiliation: Department of Oncology, VU University Medical Center, Amsterdam, Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Buter
authors.affiliation: Department of Internal Medicine, Isala Kliniek, Zwolle, Netherlands.
authors.forename: Aafke H
authors.initials: AH
authors.lastname: Honkoop
authors.affiliation: Department of Neurology, Rijnstate, Arnhem, Netherlands.
authors.forename: Dolf
authors.initials: D
authors.lastname: Boerman
authors.affiliation: Department of Medical Oncology, University Medical Centre Utrecht, Utrecht, Netherlands.
authors.forename: Filip Y F
authors.initials: FY
authors.lastname: de Vos
authors.affiliation: Department of Pathology, Erasmus MC Cancer Institute, Rotterdam, Netherlands.
authors.forename: Winand N M
authors.initials: WN
authors.lastname: Dinjens
authors.affiliation: Department of Neurology, University Medical Center Groningen, Groningen, Netherlands.
authors.forename: Roelien H
authors.initials: RH
authors.lastname: Enting
authors.affiliation: Department of Neurology, Medical Center Haaglanden, The Hague, Netherlands.
authors.forename: Martin J B
authors.initials: MJ
authors.lastname: Taphoorn
authors.affiliation: Department of Oncology, Atrium MC Parkstad, Heerlen, Netherlands.
authors.forename: Franchette W P J
authors.initials: FW
authors.lastname: van den Berkmortel
authors.affiliation: Department of Oncology, Maastricht Universitair Medisch Centrum, Netherlands.
authors.forename: Rob L H
authors.initials: RL
authors.lastname: Jansen
authors.affiliation: Department of Neuro-oncology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands.
authors.forename: Dieta
authors.initials: D
authors.lastname: Brandsma
authors.affiliation: Department of Neuro-oncology, Erasmus MC Cancer Institute, Rotterdam, Netherlands.
authors.forename: Jacoline E C
authors.initials: JE
authors.lastname: Bromberg
authors.affiliation: Department of Neuro-oncology, Erasmus MC Cancer Institute, Rotterdam, Netherlands.
authors.forename: Irene
authors.initials: I
authors.lastname: van Heuvel
authors.affiliation: Clinical Trial Centre, Erasmus MC Cancer Institute, Rotterdam, Netherlands.
authors.forename: René M
authors.initials: RM
authors.lastname: Vernhout
authors.affiliation: Clinical Trial Centre, Erasmus MC Cancer Institute, Rotterdam, Netherlands.
authors.forename: Bronno
authors.initials: B
authors.lastname: van der Holt
authors.affiliation: Department of Neuro-oncology, Erasmus MC Cancer Institute, Rotterdam, Netherlands. Electronic address: m.vandenbent@erasmusmc.nl.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: van den Bent
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects; D000068258:Bevacizumab; D001932:Brain Neoplasms / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D005909:Glioblastoma / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007262:Infusions, Intravenous; D008130:Lomustine / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D009367:Neoplasm Staging; D016019:Survival Analysis; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D004338:Drug Combinations; D000068258:Bevacizumab; D008130:Lomustine