title: RADVAN: a randomised phase 2 trial of WBRT plus vandetanib for melanoma brain metastases - results and lessons learnt.
abstract: BACKGROUND
  Brain metastases occur in up to 75% of patients with advanced melanoma. Most are treated with whole-brain radiotherapy (WBRT), with limited effectiveness. Vandetanib, an inhibitor of vascular endothelial growth factor receptor, epidermal growth factor receptor and rearranged during transfection tyrosine kinases, is a potent radiosensitiser in xenograft models. We compared WBRT with WBRT plus vandetanib in the treatment of patients with melanoma brain metastases.
  
  
  METHODS
  In this double-blind, multi-centre, phase 2 trial patients with melanoma brain metastases were randomised to receive WBRT (30 Gy in 10 fractions) plus 3 weeks of concurrent vandetanib 100 mg once daily or placebo. The primary endpoint was progression-free survival in brain (PFS brain). The main study was preceded by a safety run-in phase to confirm tolerability of the combination. A post-hoc analysis and literature review considered barriers to recruiting patients with melanoma brain metastases to clinical trials.
  
  
  RESULTS
  Twenty-four patients were recruited, six to the safety phase and 18 to the randomised phase. The study closed early due to poor recruitment. Median PFS brain was 3.3 months (90% confidence interval (CI): 1.6-5.6) in the vandetanib group and 2.5 months (90% CI: 0.2-4.8) in the placebo group (P=0.34). Median overall survival (OS) was 4.6 months (90% CI: 1.6-6.3) and 2.5 months (90% CI: 0.2-7.2), respectively (P=0.54). The most frequent adverse events were fatigue, alopecia, confusion and nausea. The most common barrier to study recruitment was availability of alternative treatments.
  
  
  CONCLUSIONS
  The combination of WBRT plus vandetanib was well tolerated. Compared with WBRT alone, there was no significant improvement in PFS brain or OS, although we are unable to provide a definitive result due to poor accrual. A review of barriers to trial accrual identified several factors that affect study recruitment in this difficult disease area.
authors.affiliation: Department of Oncology, Oxford University Hospitals NHS Foundation Trust, Cancer and Haematology Centre, Churchill Hospital, Old Road, Oxford OX3 7LE, UK.
authors.forename: Avinash
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Botnar Research Centre, Windmill Road, Oxford OX3 7LD, UK.
authors.forename: Corran
authors.initials: C
authors.lastname: Roberts
authors.affiliation: Department of Oncology, Oxford University Hospitals NHS Foundation Trust, Cancer and Haematology Centre, Churchill Hospital, Old Road, Oxford OX3 7LE, UK.
authors.forename: Finn
authors.initials: F
authors.lastname: Tysoe
authors.affiliation: Oncology Clinical Trials Office, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Goff
authors.affiliation: Norfolk and Norwich University Hospitals NHS Foundation Trust, Colney Lane, Norwich NR4 7UY, UK.
authors.forename: Jenny
authors.initials: J
authors.lastname: Nobes
authors.affiliation: Sheffield Teaching Hospitals NHS Foundation Trust, Weston Park Hospital, Whitham Road, Sheffield S10 2SJ, UK.
authors.forename: James
authors.initials: J
authors.lastname: Lester
authors.affiliation: Clatterbridge Cancer Centre NHS Foundation Trust, Clatterbridge Road, Wirral CH63 4JY, UK.
authors.forename: Ernie
authors.initials: E
authors.lastname: Marshall
authors.affiliation: Mount Vernon Cancer Centre, Rickmansworth Road, Northwood, Middlesex HA6 2RN, UK.
authors.forename: Carie
authors.initials: C
authors.lastname: Corner
authors.affiliation: Barts Health NHS Trust, St. Bartholomew's Hospital, West Smithfield, London EC1A 7BE, UK.
authors.forename: Virginia
authors.initials: V
authors.lastname: Wolstenholme
authors.affiliation: Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Freeman Road, High Heaton, Newcastle upon Tyne NE7 7DN, UK.
authors.forename: Charles
authors.initials: C
authors.lastname: Kelly
authors.affiliation: Oncology Clinical Trials Office, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Adelyn
authors.initials: A
authors.lastname: Wise
authors.affiliation: Oncology Clinical Trials Office, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Linda
authors.initials: L
authors.lastname: Collins
authors.affiliation: Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Botnar Research Centre, Windmill Road, Oxford OX3 7LD, UK.
authors.forename: Sharon
authors.initials: S
authors.lastname: Love
authors.affiliation: Department of Oncology, Oxford University Hospitals NHS Foundation Trust, Cancer and Haematology Centre, Churchill Hospital, Old Road, Oxford OX3 7LE, UK.
authors.forename: Martha
authors.initials: M
authors.lastname: Woodward
authors.affiliation: Department of Oncology, Oxford University Hospitals NHS Foundation Trust, Cancer and Haematology Centre, Churchill Hospital, Old Road, Oxford OX3 7LE, UK.
authors.forename: Amanda
authors.initials: A
authors.lastname: Salisbury
authors.affiliation: Department of Oncology, Oxford University Hospitals NHS Foundation Trust, Cancer and Haematology Centre, Churchill Hospital, Old Road, Oxford OX3 7LE, UK.|Department of Oncology, NIHR Oxford Biomedical Research Centre, Churchill Hospital, Old Road, Oxford OX3 7LE, UK.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Middleton
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D003131:Combined Modality Therapy / Q000379:methods; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D008875:Middle Aged; D010880:Piperidines / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use; D011878:Radiotherapy / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D010880:Piperidines; D011799:Quinazolines; D011838:Radiation-Sensitizing Agents; C452423:vandetanib