ID #672 A phase II study of continuous low dose panobinostat in paediatric patients with atypical teratoid rhabdoid tumours (ATRT).

Abstract Background Atypical Teratoid Rhabdoid Tumour (ATRT) is an aggressive central nervous system malignancy driven by loss of epigenetic regulation. The pan-histone deacetylase inhibitor panobinostat has demonstrated anti-tumour activity in pre-clinical models. Aims To establish final dosing, monitor toxicities and investigate the anti-tumour activity of continuous, low dose panobinostat in children with newly diagnosed or relapsed ATRT. Methods Following completion of institutional standard of care therapy, patients were enrolled and commenced on panobinostat at a dose of 10mg/m2/day. Toxicities were monitored and dose was adjusted accordingly. Acetylation status of histone H4 was measured to ensure biological drug activity. Results 12 children with an average age of 3.3 years (1–6 years) were enrolled. All were newly diagnosed and had received prior chemotherapy and 7/12 (58%) had received prior radiation therapy. 7/12 (58%) were in complete remission and 5/12 (42%) had stable disease at study entry. Average follow up time was 106.4 weeks (range: 5-124). Methylation subtypes were SHH (n = 8), TYR (n = 3) and MYC (n = 1). 133 adverse events occurred, 24 (18%) were grade III and 4 (3%) were grade IV. Haematological and gastrointestinal toxicities were the most common serious adverse event.Three patients had progressive disease on study, all in the first 6 months. The 24-month event-free survival was 75.0% (95%CI 40.8 – 91.2%) for the whole cohort, 80.0% (24.9 – 98%) for children with no prior radiation, and 66.7% (20.5 – 93.9%) for children younger than 36 months. Conclusions Treatment with low dose panobinostat was well tolerated. Although event-free survival appears encouraging, the favourable baseline characteristics of the cohort needs to be considered. A comparative analysis with a historical cohort with matched prognostic factors is currently in process to help elucidate this. Furthermore, small sample size limits conclusions about efficacy and further investigation with a larger-scale trial may be warranted.