Table 2.

Synthetic presentation of objectives and endpoints of the study for the staging, and different strata.

STAGING
Objectives
The primary objective is to determine whether centralized review of postoperative MRI can improve assessment of residual disease, increase the rate of complete resection compared to historical controls, and whether central neurosurgical and radiological review increase resection rates. Secondary objectives aim to evaluate second-look surgery rates as compared to historical controls.
Endpoint of the overall program
Primary endpoint is Gross Total Resection (GTR) rate.
Secondary endpoint is second-look surgery rate. Only descriptive statistics are produced for GTR rate and second-look surgery rate.
Stratum I	Stratum II	Stratum III
Objectives	Objectives	Objectives
The primary objective of the stratum I is to investigate whether PFS is improved in patients receiving 16-week chemotherapy (VEC + CDDP) after surgical resection and cRT compared to patients treated with surgical resection and cRT exclusively. Secondary objectives include assessment of overall survival (OS), neuroendocrine morbidity in each treatment arm, neuropsychological morbidity, quality of survival (QoS), and evaluation of safety in each treatment arm.	The primary objective is to compare the efficacy of the 2 postoperative chemotherapy schedules, VEC compared to VEC + HD-MTX in patients with incompletely resected ependymoma. Secondary objectives include safety and tolerability, evaluation of improvement in OS and PFS in patients who receive VEC + HD-MTX following surgical resection compared to those who receive VEC alone; to compare the neuroendocrine morbidity; to evaluate the neuropsychological morbidity; quality of survival in each treatment arm; to determine safety of 8 Gy boost radiotherapy in patients with residual disease after frontline chemotherapy and 59.4 Gy cRT.	For patients unable to receive radiation therapy, the primary objective is to evaluate the efficacy of adding the histone deacetylase inhibitor valproate to the standard chemotherapy regimen when compared to those that undergo chemotherapy alone. Secondary objectives include evaluation of OS and radiotherapy-free survival in patients in both groups; to evaluate neuroendocrine morbidity, neuropsychological morbidity, and QoS in each treatment arm; to determine the safety and tolerability of valproate combined to the standard chemotherapy in children not eligible to radiation therapy.
Endpoints	Endpoints	Endpoints
The primary endpoint is PFS calculated as the time from randomization to the date of event defined as progression or death due to any cause. Secondary endpoints included OS defined as the time from randomization to the date of death due to any cause, QoS, neuropsychological and neuroendocrine outcomes (late effects), short- and long-term safety. Efficacy is assessed using brain MRI performed within 6 weeks after the end of the radiotherapy for all patients, after cycle 2 and cycle 4 for patients with maintenance chemotherapy, then 3 months after the last radiological assessment for all patients. Ototoxicity must be evaluated at day 0 and before the 3rd cycle of CDDP. Tolerance is assessed continuously for all patients. Adverse events are assessed and graded according to the Common Terminology Criteria Adverse Events (CTCAE v4.03).	The primary endpoint is the number of treatment responders. Objective response to chemotherapy is measured based on SIOPE Neuro Imaging guidelines. Secondary endpoints include OS calculated as the time from randomization to the date of death due to any cause, PFS calculated as the time from randomization to the date of event defined as progression or death due to any cause, QoS, neuropsychological outcomes, neuroendocrine outcomes (Neuroendocrine late effects), short- and long-term safety Adverse events are assessed and graded according to the Common Terminology Criteria Adverse Events (CTCAE v4.03). Exploratory endpoints include toxicity monitoring in the subgroup receiving radiotherapy boost, and event-free survival (EFS) in patients receiving a radiotherapy boost.	The primary endpoint is PFS calculated as the time from randomization to the date of event defined as progression or death due to any cause. Secondary endpoints included OS defined from randomization to the date of death due to any cause; Radiotherapy-free survival rate; QoS; Neuropsychological outcomes; Neuroendocrine outcomes (late effects); Short- and long-term safety. Adverse events are assessed and graded according to the Common Terminology Criteria Adverse Events (CTCAE v4.03).