title: Randomized phase 2 study of carboplatin and bevacizumab in recurrent glioblastoma.
abstract: BACKGROUND
  The optimal use of bevacizumab in recurrent glioblastoma (GBM), including the choice of monotherapy or combination therapy, remains uncertain. The purpose of this study was to compare combination therapy with bevacizumab monotherapy.
  
  
  METHODS
  This was a 2-part randomized phase 2 study. Eligibility criteria included recurrent GBM after radiotherapy and temozolomide, no other chemotherapy for GBM, and Eastern Cooperative Oncology Group performance status 0-2. The primary objective (Part 1) was to determine the effect of bevacizumab plus carboplatin versus bevacizumab monotherapy on progression-free survival (PFS) using modified Response Assessment in Neuro-Oncology criteria. Bevacizumab was given every 2 weeks, 10 mg/kg; and carboplatin every 4 weeks, (AUC 5). On progression, patients able to continue were randomized to continue or cease bevacizumab (Part 2). Secondary endpoints included objective radiological response rate (ORR), quality of life, toxicity, and overall survival (OS).
  
  
  RESULTS
  One hundred twenty-two patients (median age, 55y) were enrolled to Part 1 from 18 Australian sites. Median follow-up was 32 months, and median on-treatment time was 3.3 months. Median PFS was 3.5 months for each arm (hazard ratio [HR]: 0.92, 95% CI: 0.64-1.33, P = .66). ORR was 14% (combination) versus 6% (monotherapy) (P = .18). Median OS was 6.9 (combination) versus 7.5 months (monotherapy) (HR: 1.18, 95% CI: 0.82-1.69, P = .38). The incidence of bevacizumab-related adverse events was similar to prior literature, with no new toxicity signals. Toxicities were higher in the combination arm. Part 2 data (n = 48) will be reported separately.
  
  
  CONCLUSIONS
  Adding carboplatin resulted in more toxicity without additional clinical benefit. Clinical outcomes in patients with recurrent GBM treated with bevacizumab were inferior to those in previously reported studies.
  ACTRN12610000915055.
authors.affiliation: Royal Melbourne Hospital, Parkville, Australia (K.M.F, P.M.P, M.A.R.), National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia (J.S., C.S.B.B., E.H.B, K.S., A.L.); Sir Charles Gairdner Hospital, Nedlands, Australia (A.K.N); School of Medicine and Pharmacology, University of Western Australia, Crawley, Australia (A.K.N); Austin Health, Heidelberg, Australia (L.C., G.F.); Royal North Shore Hospital, St Leonards, Australia (H.W.); Prince of Wales Hospital, Randwick, Australia (E.J.H); University of New South Wales, Sydney, Australia (E.J.H); Monash Medical Centre, Clayton, Australia (R.F.); Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia (P.M.P., M.A.R., G.F.).
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Field
authors.affiliation: Royal Melbourne Hospital, Parkville, Australia (K.M.F, P.M.P, M.A.R.), National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia (J.S., C.S.B.B., E.H.B, K.S., A.L.); Sir Charles Gairdner Hospital, Nedlands, Australia (A.K.N); School of Medicine and Pharmacology, University of Western Australia, Crawley, Australia (A.K.N); Austin Health, Heidelberg, Australia (L.C., G.F.); Royal North Shore Hospital, St Leonards, Australia (H.W.); Prince of Wales Hospital, Randwick, Australia (E.J.H); University of New South Wales, Sydney, Australia (E.J.H); Monash Medical Centre, Clayton, Australia (R.F.); Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia (P.M.P., M.A.R., G.F.).
authors.forename: John
authors.initials: J
authors.lastname: Simes
authors.affiliation: Royal Melbourne Hospital, Parkville, Australia (K.M.F, P.M.P, M.A.R.), National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia (J.S., C.S.B.B., E.H.B, K.S., A.L.); Sir Charles Gairdner Hospital, Nedlands, Australia (A.K.N); School of Medicine and Pharmacology, University of Western Australia, Crawley, Australia (A.K.N); Austin Health, Heidelberg, Australia (L.C., G.F.); Royal North Shore Hospital, St Leonards, Australia (H.W.); Prince of Wales Hospital, Randwick, Australia (E.J.H); University of New South Wales, Sydney, Australia (E.J.H); Monash Medical Centre, Clayton, Australia (R.F.); Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia (P.M.P., M.A.R., G.F.).
authors.forename: Anna K
authors.initials: AK
authors.lastname: Nowak
authors.affiliation: Royal Melbourne Hospital, Parkville, Australia (K.M.F, P.M.P, M.A.R.), National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia (J.S., C.S.B.B., E.H.B, K.S., A.L.); Sir Charles Gairdner Hospital, Nedlands, Australia (A.K.N); School of Medicine and Pharmacology, University of Western Australia, Crawley, Australia (A.K.N); Austin Health, Heidelberg, Australia (L.C., G.F.); Royal North Shore Hospital, St Leonards, Australia (H.W.); Prince of Wales Hospital, Randwick, Australia (E.J.H); University of New South Wales, Sydney, Australia (E.J.H); Monash Medical Centre, Clayton, Australia (R.F.); Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia (P.M.P., M.A.R., G.F.).
authors.forename: Lawrence
authors.initials: L
authors.lastname: Cher
authors.affiliation: Royal Melbourne Hospital, Parkville, Australia (K.M.F, P.M.P, M.A.R.), National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia (J.S., C.S.B.B., E.H.B, K.S., A.L.); Sir Charles Gairdner Hospital, Nedlands, Australia (A.K.N); School of Medicine and Pharmacology, University of Western Australia, Crawley, Australia (A.K.N); Austin Health, Heidelberg, Australia (L.C., G.F.); Royal North Shore Hospital, St Leonards, Australia (H.W.); Prince of Wales Hospital, Randwick, Australia (E.J.H); University of New South Wales, Sydney, Australia (E.J.H); Monash Medical Centre, Clayton, Australia (R.F.); Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia (P.M.P., M.A.R., G.F.).
authors.forename: Helen
authors.initials: H
authors.lastname: Wheeler
authors.affiliation: Royal Melbourne Hospital, Parkville, Australia (K.M.F, P.M.P, M.A.R.), National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia (J.S., C.S.B.B., E.H.B, K.S., A.L.); Sir Charles Gairdner Hospital, Nedlands, Australia (A.K.N); School of Medicine and Pharmacology, University of Western Australia, Crawley, Australia (A.K.N); Austin Health, Heidelberg, Australia (L.C., G.F.); Royal North Shore Hospital, St Leonards, Australia (H.W.); Prince of Wales Hospital, Randwick, Australia (E.J.H); University of New South Wales, Sydney, Australia (E.J.H); Monash Medical Centre, Clayton, Australia (R.F.); Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia (P.M.P., M.A.R., G.F.).
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Hovey
authors.affiliation: Royal Melbourne Hospital, Parkville, Australia (K.M.F, P.M.P, M.A.R.), National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia (J.S., C.S.B.B., E.H.B, K.S., A.L.); Sir Charles Gairdner Hospital, Nedlands, Australia (A.K.N); School of Medicine and Pharmacology, University of Western Australia, Crawley, Australia (A.K.N); Austin Health, Heidelberg, Australia (L.C., G.F.); Royal North Shore Hospital, St Leonards, Australia (H.W.); Prince of Wales Hospital, Randwick, Australia (E.J.H); University of New South Wales, Sydney, Australia (E.J.H); Monash Medical Centre, Clayton, Australia (R.F.); Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia (P.M.P., M.A.R., G.F.).
authors.forename: Christopher S B
authors.initials: CS
authors.lastname: Brown
authors.affiliation: Royal Melbourne Hospital, Parkville, Australia (K.M.F, P.M.P, M.A.R.), National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia (J.S., C.S.B.B., E.H.B, K.S., A.L.); Sir Charles Gairdner Hospital, Nedlands, Australia (A.K.N); School of Medicine and Pharmacology, University of Western Australia, Crawley, Australia (A.K.N); Austin Health, Heidelberg, Australia (L.C., G.F.); Royal North Shore Hospital, St Leonards, Australia (H.W.); Prince of Wales Hospital, Randwick, Australia (E.J.H); University of New South Wales, Sydney, Australia (E.J.H); Monash Medical Centre, Clayton, Australia (R.F.); Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia (P.M.P., M.A.R., G.F.).
authors.forename: Elizabeth H
authors.initials: EH
authors.lastname: Barnes
authors.affiliation: Royal Melbourne Hospital, Parkville, Australia (K.M.F, P.M.P, M.A.R.), National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia (J.S., C.S.B.B., E.H.B, K.S., A.L.); Sir Charles Gairdner Hospital, Nedlands, Australia (A.K.N); School of Medicine and Pharmacology, University of Western Australia, Crawley, Australia (A.K.N); Austin Health, Heidelberg, Australia (L.C., G.F.); Royal North Shore Hospital, St Leonards, Australia (H.W.); Prince of Wales Hospital, Randwick, Australia (E.J.H); University of New South Wales, Sydney, Australia (E.J.H); Monash Medical Centre, Clayton, Australia (R.F.); Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia (P.M.P., M.A.R., G.F.).
authors.forename: Kate
authors.initials: K
authors.lastname: Sawkins
authors.affiliation: Royal Melbourne Hospital, Parkville, Australia (K.M.F, P.M.P, M.A.R.), National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia (J.S., C.S.B.B., E.H.B, K.S., A.L.); Sir Charles Gairdner Hospital, Nedlands, Australia (A.K.N); School of Medicine and Pharmacology, University of Western Australia, Crawley, Australia (A.K.N); Austin Health, Heidelberg, Australia (L.C., G.F.); Royal North Shore Hospital, St Leonards, Australia (H.W.); Prince of Wales Hospital, Randwick, Australia (E.J.H); University of New South Wales, Sydney, Australia (E.J.H); Monash Medical Centre, Clayton, Australia (R.F.); Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia (P.M.P., M.A.R., G.F.).
authors.forename: Ann
authors.initials: A
authors.lastname: Livingstone
authors.affiliation: Royal Melbourne Hospital, Parkville, Australia (K.M.F, P.M.P, M.A.R.), National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia (J.S., C.S.B.B., E.H.B, K.S., A.L.); Sir Charles Gairdner Hospital, Nedlands, Australia (A.K.N); School of Medicine and Pharmacology, University of Western Australia, Crawley, Australia (A.K.N); Austin Health, Heidelberg, Australia (L.C., G.F.); Royal North Shore Hospital, St Leonards, Australia (H.W.); Prince of Wales Hospital, Randwick, Australia (E.J.H); University of New South Wales, Sydney, Australia (E.J.H); Monash Medical Centre, Clayton, Australia (R.F.); Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia (P.M.P., M.A.R., G.F.).
authors.forename: Ron
authors.initials: R
authors.lastname: Freilich
authors.affiliation: Royal Melbourne Hospital, Parkville, Australia (K.M.F, P.M.P, M.A.R.), National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia (J.S., C.S.B.B., E.H.B, K.S., A.L.); Sir Charles Gairdner Hospital, Nedlands, Australia (A.K.N); School of Medicine and Pharmacology, University of Western Australia, Crawley, Australia (A.K.N); Austin Health, Heidelberg, Australia (L.C., G.F.); Royal North Shore Hospital, St Leonards, Australia (H.W.); Prince of Wales Hospital, Randwick, Australia (E.J.H); University of New South Wales, Sydney, Australia (E.J.H); Monash Medical Centre, Clayton, Australia (R.F.); Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia (P.M.P., M.A.R., G.F.).
authors.forename: Pramit M
authors.initials: PM
authors.lastname: Phal
authors.affiliation: Royal Melbourne Hospital, Parkville, Australia (K.M.F, P.M.P, M.A.R.), National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia (J.S., C.S.B.B., E.H.B, K.S., A.L.); Sir Charles Gairdner Hospital, Nedlands, Australia (A.K.N); School of Medicine and Pharmacology, University of Western Australia, Crawley, Australia (A.K.N); Austin Health, Heidelberg, Australia (L.C., G.F.); Royal North Shore Hospital, St Leonards, Australia (H.W.); Prince of Wales Hospital, Randwick, Australia (E.J.H); University of New South Wales, Sydney, Australia (E.J.H); Monash Medical Centre, Clayton, Australia (R.F.); Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia (P.M.P., M.A.R., G.F.).
authors.forename: Greg
authors.initials: G
authors.lastname: Fitt
authors.affiliation: Royal Melbourne Hospital, Parkville, Australia (K.M.F, P.M.P, M.A.R.), National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia (J.S., C.S.B.B., E.H.B, K.S., A.L.); Sir Charles Gairdner Hospital, Nedlands, Australia (A.K.N); School of Medicine and Pharmacology, University of Western Australia, Crawley, Australia (A.K.N); Austin Health, Heidelberg, Australia (L.C., G.F.); Royal North Shore Hospital, St Leonards, Australia (H.W.); Prince of Wales Hospital, Randwick, Australia (E.J.H); University of New South Wales, Sydney, Australia (E.J.H); Monash Medical Centre, Clayton, Australia (R.F.); Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia (P.M.P., M.A.R., G.F.).
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rosenthal
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage / Q000009:adverse effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects; D018572:Disease-Free Survival; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D016016:Proportional Hazards Models
chemical_list: D000068258:Bevacizumab; D016190:Carboplatin
keywords: bevacizumab; carboplatin; glioblastoma