Journal Article

RADVAN: a randomised phase 2 trial of WBRT plus vandetanib for melanoma brain metastases – results and lessons learnt

Wolstenholme, Virginia, Nobes, Jenny, Salisbury, Amanda, Woodward, Martha, Tysoe, Finn, Marshall, Ernie, Kelly, Charles, Goff, Matthew, Love, Sharon, Corner, Carie, Roberts, Corran, Wise, Adelyn, Lester, James, Collins, Linda, Gupta, Avinash, Middleton, Mark R

2016

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 692/699/67/1922 / 692/699/67/322 / 692/700/565/1436 / 692/700/565/485 / Adult / Aged / Aged, 80 and over / Antineoplastic Agents - therapeutic use / Biomedical and Life Sciences / Biomedicine / Brain - drug effects / Brain - pathology / Brain - radiation effects / Brain Neoplasms - drug therapy / Brain Neoplasms - pathology / Brain Neoplasms - radiotherapy / Brain research / Cancer Research / Clinical Study / Clinical trials / Combined Modality Therapy - methods / Disease-Free Survival / Double-Blind Method / Drug Resistance / Effectiveness / Epidemiology / Epidermal growth factor / Female / Hospitals / Humans / Male / Medical research / Melanoma / Melanoma - drug therapy / Melanoma - pathology / Melanoma - radiotherapy / Metastasis / Middle Aged / Molecular Medicine / Oncology / Piperidines - therapeutic use / Quinazolines - therapeutic use / Radiation therapy / Radiation-Sensitizing Agents - therapeutic use / Radiotherapy - methods / Recruitment / Vascular endothelial growth factor