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SIOP Ependymoma II Protocol V3.1 22 April 2020 Clean Ependymoma Program II FINAL Protocol Version 3. 1 April 22 th , 2020 An international clinical program for the diagnosis and treatment of children, adolescents and young adults with ependymoma Final Version 3.1_ April 22 nd , 2020 Sponsor: Centre Léon Bérard Sponsor Protocol Number: ET-13-002 EudraCT Number: 2013-002766-39 VHP number: VHP358 (VHP201385) Page | 1 CONFIDENTIAL Ependymoma Program II FINAL Protocol Version 3. 1 April 22 th , 2020 SIGNATURE PAGE SIOP EPENDYMOMA II – An international Clinical Program for the diagnosis and treatment of children, adolescents and young adults with ependymoma Protocol version 3.1 dated April 22 nd , 2020 This protocol has been approved by: Name: Dr David PEROL Trial Role: Medical and scientific coordinator Signature: _______________________________ Date: 22-Apr-2020 This protocol describes the SIOP Ependymoma Program II and provides information about procedures for patients taking part in this trial. The protocol should not be used as a guide for treatment of patients not taking part in the SIOP Ependymoma Program II. CONFIDENTIALITY NOTE: This trial protocol is the property of the authoring Coordinating Investigators and is protected by copyright. The content of the trial protocol and the case report forms is confidential and oral or written disclosure to any uninvolved / third parties (without previous written agreement by one of the international or national coordinating investigators) is prohibited. Page | 2 CONFIDENTIAL Ependymoma Program II FINAL Protocol Version 3. 1 April 22 th , 2020 AMENDMENTS The following amendments and/or administrative changes have been made to this protocol since the implementation of the first approved version. Protocol Amendment Date of Type of version Summary of main modifications number amendment amendment number 1 August 21st 2.0 Substantial ° Inclusion and exclusion criteria 2014 amendment ° Objectives ° Guidelines regarding dose modification of IMPs ° Guidelines regarding dose of IMPs to be administered (stratum 3) ° Volume of IMP administration (Methotrexate and Carboplatin) ° Hydration guidelines regarding Cisplatin administration ° Radiotherapy guidelines ° Supportive treatments & Concomitant medications ° MRI time point ° Assessment of Response to Treatment ° Hearing – PTA Dose Modification ° Endocrine evaluation ° Biological material needed for BIOMECA studies ° Planned interim analysis and stopping rules (Stratum 2) ° Adverse Events reporting ° Withdrawal from trial treatment ° Withdrawal of consent to data collection ° Valproate PK/PD studies 2 3.0 Substantial ° Update of the study rationale amendment ° Study design (staging mandatory for all patients) ° Rearrangement of selection criteria ° Update of the WHO classification ° Inclusion of relapsing patients ° Addition of examinations (BARS, audiograms) ° Valproic acid administration schedule ° Update of the pharmacovigilance section ° Update of the Integrated BIOMECA study ° Precisions on timing of study examinations 3 3.1 Non- ° Change of Principal Investigator Coordinator substantial ° Recruitment period extended amendment ° Addition of Greece ° Contact updates Page | 3 CONFIDENTIAL Ependymoma Program II FINAL Protocol Version 3. 1 April 22 th , 2020 FLOW SHEETS OF TREATMENTS Pre -Operative MRI + Surgery FIRST STEP Staging Phase Study entry Post-Operative MRI + CSF Central review of imaging and pathology Confirm diagnosis Evaluate need of second look surgery Patients ≥ 12 months Patients ≥ 12 months Patients < 12 months Patients not included in with no measurable residue with measurable and patients not eligible to one of the interventional inoperable residue receive RT studies Randomized phase III trial to evaluate the efficacy of post Randomized frontline Randomized phase II Observational study radiation maintenance phase II chemotherapy chemotherapy study: chemotherapy study and exploration of Alternated myelosuppressive (VEC CDDP for 16 weeks) the efficacy of a boost of and non myelosuppressive radiotherapy chemotherapy +/- HDACi (Valproate) Stratum 1 Stratum 2 Stratum 3 SECOND STEP Interventional or observational Phase Page | 4 CONFIDENTIAL Ependymoma Program II FINAL Protocol Version 3. 1 April 22 th , 2020 FLOW SHEETS OF PATIENTS INCLUSION MRI Surgery Entry in staging phase 1st Consent Central review of imaging and pathology: Confirm diagnosis and evaluate second look surgery 2nd Consent Residual / operable 2nd Consent Stratum 1 Absence of residual disease Second look surgery Inoperable residue Stratum 2 < 12 months or Age ≥ 12 months not eligible for radiotherapy Age ≥ 12 months and eligible for radiotherapy and e ligible for radiotherapy 2nd Consent Stratum 3 Page | 5 CONFIDENTIAL Ependymoma Program II FINAL Protocol Version 3. 1 April 22 th , 2020 STRATUM 1 Patients with no measurable residual disease (R0-1-2), WHO Grade II-III ependymoma No metastasis Age > 12 months and < 22 years Adequate bone marrow, renal and liver function. Randomisation Conformal RT 59.4 Gy (children < 18 months or with risk factors (*): 54 Gy) Daily fraction 1.8 Gy, 5 fractions/week Observation Maintenance CT (**) WEEK 1 => WEEK 6 => WEEK 11=> WEEK 16 D1: Vincristine (VCR) 1.5 mg/m² D1-D3 : Etoposide (VP16) 100 mg/m² D1: Cyclophosphamide 3000 mg/m² WEEK 4 => WEEK 9=> WEEK 14 D1: Cisplatin (CDDP) 80 mg/m² D1: Vincristine (VCR) 1.5 mg/m² (*) multiple surgeries (more than 2) or poor neurological status. (**) dose adaptation for children less than 10 kg Page | 6 CONFIDENTIAL Ependymoma Program II FINAL Protocol Version 3. 1 April 22 th , 2020 STRATUM 2 Patients with measurable inoperable residual disease (R3-R4), WHO Grade II-III ependymoma No metastasis Age > 12 months and < 22 years Adequate bone marrow, renal and liver function Randomisation VEC -HD -MTX (**) VEC (**) WEEK 1=> WEEK 4=> WEEK 7 WEEK 1=> WEEK 4=> WEEK 7 VEC-MTX VEC D1: Vincristine (VCR) 1.5 mg/m² D1: Vincristine (VCR) 1.5 mg/m² D1-D3: Etoposide (VP16) 100 mg/m² D1-D3: Etoposide (VP16) 100 mg/m² D1: Cyclophosphamide: 3000 mg/m² D1: Cyclophosphamide 3000 mg/m² WEEK 3=> WEEK 6=> WEEK 9 D1: Methotrexate at 8000 mg/m 2 as a 24 hour infusion. MRI with central r eview 2nd look surgery if possible No residual Residual disease disease Conformal RT 59.4 Gy (children < 18 months or with risk factors (*): 54 Gy) Daily fraction of 1.8 Gy, 5 fractions/week Boost of RT of 8 Gy to residue (Daily fraction of 4 Gy: 2 fractions) Maintenance CT (if no prior progression under VEC) (**) WEEK 1 => WEEK 6 => WEEK 11 => WEEK 16 D1: Vincristine (VCR) 1.5 mg/m² D1-D3 : Etoposide (VP16) 100 mg/m² D1: Cyclophosphamide: 3000 mg/m² WEEK 4 => WEEK 9 => WEEK 14 D1: Cisplatin (CDDP) 80 mg/m² D1:Vincristine (VCR) 1.5 mg/m² (*) multiple surgeries (more than 2) or poor neurological status. (**) dose adaptation for children less than 10 kg Page | 7 CONFIDENTIAL Ependymoma Program II FINAL Protocol Version 3. 1 April 22 th , 2020 STRATUM 3 Children < 12 months or those not eligible to receive radiotherapy Adequate bone marrow, renal and liver function and ammonia Randomisation STANDARD CHEMOTHERAPY STANDARD CHEMOTHERAPY + HDACi = valproate Maintenance HDACi Treatment for one year period If no progression during frontline chemotherapy CHEMO +/- HDACi (**) CYCLE N° 1 2 3 4 5 6 7 Vincristine - Carboplatin D1 D 57 D113 D169 D225 D281 D337 Vincristine - Methotrexate D15 D71 D127 D183 D239 D295 D351 Vincristine - Cyclophosphamide D29 D85 D141 D197 D253 D309 D365 Cisplatin 2-day D43 D99 D154 D211 D267 D323 D379 Continuous infusion 44 100 155 212 268 324 380 +/- Valproate (*) Initial dose: 30 mg /kg/day for two weeks in 2 divided doses (15mg/Kg/b.d.). Increasing weekly up to 40->50->60 mg /kg/day in 2 divided doses until serum target level achieved. If therapeutic levels of 100-150 µg/ml are not achieved when giving 60 mg /kg/day administer in three divided doses (20mg/kg/dose b.d.). If therapeutic level is still not achieved increase to higher total daily dose in 5 mg/kg/day increments that is 65 mg /kg/day then 70 mg /kg/day (23.3mg/kg/dose t.d.s) in 3 divided doses. Dosing schedule (***) Dose for infants Dose for infants Dose for infants over 12 months 6 to 12 months less than 6 months Vincristine 1.5 mg/m² x 1 1.125 mg/m² x 1 0.75 mg/m² x 1 (Maximum dose: 2mg) Carboplatin 550 mg/m²x 1 412.5 mg/m² x 1 275 mg/m² x 1 Methotrexate 8000 mg/m² x 1 6000 mg/m² x 1 4000 mg/ m² x 1 Cyclophosphamide 1500 mg/m² x 1 1125 mg/m² x 1 750 mg/m² x 1 Cisplatin 40 mg/m² x 2 30 mg/m² x 2 20 mg/m² x 2 Valproate * (BID) 30 mg/kg/day* 30 mg/kg/day* 30 mg/kg/day* * Initial dosing then according to monitoring **If residual disease please consider for further surgery at each reassessment point. *** For patients aged: • 12 months and over: full surface-area-based dose of chemotherapy • 6-11 months: 75% of the surface-area-based dose of chemotherapy • Under 6 months: 50% of the surface-area –based dose of chemotherapy Page | 8 CONFIDENTIAL Ependymoma Program II FINAL Protocol Version 3. 1 April 22 th , 2020 TRIAL COORDINATION OVERALL SIOP EPENDYMOMA II PROGRAM Coordinating Dr Pierre LEBLOND investigator Institut d’Hématologie et d’Oncologie Pédiatrique 1 place Joseph Renaut 69673 Lyon Cedex, France Phone: +33 4 69 16 65 71 Fax: +33 4 78 78 27 09 Email: [email protected] Stratum 1 Phase III study for patients with no measurable residual disease ≥ 12 months of age Chief investigator / Dr Pierre LEBLOND Cécile DALBAN Chief statistician Institut d’Hématologie et d’Oncologie Direction de la Recherche Clinique et de Pédiatrique l’Innovation 1 place Joseph Renaut Centre Léon Bérard 69673 Lyon Cedex,
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