CRUK/12/036: SIOP Intracranial Ependymoma II; An International clinical trial for the diagnosis and treatment of children, adolescent and young adults with intracranial ependymoma

Background The clinical management of ependymoma in childhood to young adults is complex and the clinico-bio-pathological correlates of outcome remain poorly understood. Overall the prognosis remains poor and at relapse is dismal. Over half of the patients may ultimately die from the disease and those that survive face serious long-term sequelae.

This ongoing trial seeks to test 6 key hypotheses all aimed at improving outcomes. Aims To test the hypotheses that: 1.

There will be an improvement in patients who receive chemotherapy following complete surgical resection and radiotherapy compared to those that undergo complete surgical resection and radiotherapy alone (Stratum I). 2.

The addition of high dose methotrexate to standard of care chemotherapy (VEC) improves Progression Free and Overall Survival in patients with tumour residuum on imaging after surgery (randomised Phase II) and evaluate the role of ‘second look’ surgery in improving outcomes (Stratum II) 3.

Adding valproic acid (VPA) as a histone deacetylase inhibitor to primary chemotherapy strategy improves Progression Free and Overall Survival a randomised Phase II study (Stratum III). 4.

Conformal radiotherapy does not adversely affect neurocognitive outcomes in very young children with ependymoma - secondary endpoint 5.

Key molecular events in paediatric ependymoma pathogenesis are predictive of clinical behaviour and will allow future treatment stratification ( Precision Medicine)- exploratory endpoint and 6.

To determine the toxicity, feasibility and efficacy of an 8 Gy boost in patients with residual disease (Stratum II) [A Phase I Study] Methods The original proposal was to recruit a minimum of 480 patients under 22-years of age throughout Europe to 3 main study arms (Strata I-III) depending on age, tumour location and extent of surgical resection.

Central review was established to verify allocation to study arm.

Prospective biological studies were planned to interrogate the underlying biology and define Biomarkers for future treatment stratification.

The neuropsychological and quality of life of survivors is being rigorously assessed through a novel ’core’ and ‘core plus’ strategy developed and published during this trial.

Projected Endpoints Following full and final recruitment, this trial will set a new standard of care for completely resected ependymoma, confirm optimal chemotherapy and surgical strategy for incompletely resected ependymoma, determine safety feasibility and efficacy of 8 Gy radiotherapy boost, define optimal primary chemotherapy strategies and identify key biomarkers for future trial stratification.

Projected recruitment of required patients to provide required statistical power will be complete by 31-May-2025.