International Cooperative Treatment Protocol for Children and Adolescents With Lymphoblastic Lymphoma

Lymphoblastic Lymphoma, Childhood Clinical Trial

— LBL 2018  

Official title:

LBL 2018 - International Cooperative Treatment Protocol for Children and Adolescents With Lymphoblastic Lymphoma

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04043494
• Other study ID #: UKM17_0023
• Secondary ID: 2017-001691-39
• Status: Recruiting
• Phase: Phase 3
• Start date: August 23, 2019
• Est. completion date: November 22, 2027

Study information

• Verified date: November 2022
• Source: University Hospital Muenster
• Contact: Birgit Burkhardt, Prof. Dr. Dr.
• Phone: +49 251 83 55696
• Email: LBL2018[@]ukmuenster.de
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Primary objectives: - Randomization R1, all patients eligible: To examine, whether the cumulative incidence of relapses with involvement of the CNS (CNS relapse, pCICR) can be decreased by a modified induction therapy including dexamethasone (experimental arm) instead of prednisone (standard arm) - Randomization R2, only patients with high risk LBL eligible: to examine, whether the probability of event-free survival (pEFS) in these patients can be improved by receiving an intensified treatment arm versus a standard treatment arm (as used in the EURO-LB 02)

Description:

The trial LBL 2018 is a collaborative prospective, multi-national, multi-center, randomized clinical trial for the treatment of children and adolescents with newly diagnosed lymphoblastic lymphoma. The LBL 2018 trial will be open for the qualified centers of following participating study Groups (core study cohort): AIEOP (Italy), BFM (Austria, Czech Republic, Germany, Switzerland), BSPHO (Belgium), CoALL (Germany), DCOG (The Netherlands), NOPHO (Denmark, Finland, Norway, Sweden), PPLLSG (Poland), SEHOP (Spain) and SFCE (France). HKPHOSG (Hong Kong), HPOG (Hungary), ISPHO (Israel), NSPHO (Moscow), SHOP (Portugal) and SPS (Slovak Republic) start patient recruitment into the extended study cohort (without randomization). Over the trial period study groups may switch from the extended study cohort to the core study cohort. Primary objectives: - Randomization R1, all patients eligible: To examine, whether the cumulative incidence of relapses with involvement of the CNS (CNS relapse, pCICR) can be decreased by a modified induction therapy including dexamethasone (experimental arm) instead of prednisone (standard arm) - Randomization R2, only patients with high risk LBL eligible: to examine, whether the probability of event-free survival (pEFS) in these patients can be improved by receiving an intensified treatment arm versus a standard treatment arm (as used in the EURO-LB 02) Patients are stratified into 3 different risk groups according to CNS status, immunophenotype, genetic markers and stage of disease at diagnosis: high risk group (HR), standard risk group I/II (SR I/II) and standard risk group (SR). Patients in the risk groups SR I/II and SR are randomized (R1) in two arms after a cytoreductive prephase with prednisone. Patients in standard arm receive the standard induction phase with prednisone. Patients in the experimental arm receive an induction phase with dexamethasone instead of prednisone. In SR group, induction phase is followed by the consolidation phase, the non-HR extra-compartment phase with HD-MTX (high-dose methotrexate), the reintensification phase and the maintenance therapy for the total therapy duration of 24 months. In SR I/II group, patients receive no reintensification phase. The Induction phase is followed by the consolidation phase, the non-HR extra-compartment phase and the maintenance therapy for the total therapy duration of 24 months. Patients in the HR group are eligible for randomization (R1) as outlined above. In addition high risk patients are eligible for second randomization (R2) at the end of induction phase. In the standard arm, HR-patients receive the consolidation phase and the non-HR extra-compartment phase. In the experimental arm, HR-patients receive a consolidation phase including two additional doses of PEG asparaginase and the HR-intensified extra-compartment phase consisting of two high risk courses alternating with two HD-MTX courses. Either phase is followed by the reintensification phase and the maintenance therapy for the total therapy duration of 24 months. Patients with involvement of the CNS (CNS positive) are stratified to the high risk group (HR) and are eligible for both randomizations (R1 and R2). Additionally, patients with CNS involvement (CNS positive) receive intensified intrathecal therapy. Intrathecal therapy consists of TIT (triple intrathecal therapy) after diagnosis of CNS involvement. TIT is administered twice weekly until clearance of blasts in the cerebrospinal fluid is achieved. Further intrathecal therapy is provided at the same points of time as for patients without CNS involvement, but TIT instead of MTX IT. In addition, patients receive four additional doses of TIT during maintenance. Cranial irradiation is omitted for patients with CNS involvement.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 683
• Est. completion date: November 22, 2027
• Est. primary completion date: November 22, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 18 Years

Eligibility

Inclusion criteria:

• newly diagnosed lymphoblastic lymphoma
• age <18 years
• patient enrolled in a participating center
• written informed consent of patient (>14 years of age or according to local law and regulation) and parents to trial participation and transfer and processing of data
• willingness of patients and the investigator/pathologist to provide adequate slides/blocks for reference (molecular) pathology and international pathology panel and/or fresh or fresh frozen samples for genetic risk group stratification if these samples are available after standard diagnostic procedures.

Exclusion criteria:

• lymphoblastic lymphoma as secondary malignancy
• non-lymphoma related relevant medical, psychiatric or social conditions incompatible with trial treatment, including among others
• prior organ transplant
• severe immunodeficiency
• demyelinating Charcot-Marie Tooth syndrome
• serious acute or chronic infections, such as HIV, VZV and tuberculosis
• urinary tract infection, cystitis, urinary outflow obstruction, severe renal impairment (creatinine clearance less than 20 ml/min)
• severe hepatic impairment (bilirubin >3 times ULN, transaminases >10 times ULN)
• myocardial insufficiency, severe arrhythmias
• ulcers of the oral cavity and known active gastrointestinal ulcer disease
• known hypersensitivity to any IMP and to any excipient (listed in section 6.1 of the respective SmPC)
• steroid pre-treatment with = 1 mg/kg/d for more than two weeks during the last month before diagnosis
• vaccination with live vaccines within 2 weeks before start of protocol treatment
• treatment started according to another protocol or pre-treatment with cytostatic drugs
• participation in another clinical trial that interferes with the protocol, except NHL-BFM Registry 2012 and trials with different endpoints, involving aspects of supportive treatment, which can run parallel to LBL 2018 without influencing the outcome of this trial (e.g. trials on antiemetics, antibiotics, strategies for psychosocial support)
• evidence of pregnancy or lactation period
• sexually active adolescents not willing to use highly effective contraceptive method (pearl index < 1) until 12 months after end of cytostatic therapy

Related Conditions & MeSH terms

• Lymphoblastic Lymphoma, Childhood
• Lymphoma
• Lymphoma, Non-Hodgkin
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

Drug:
• Cyclophosphamide
Part of standard chemotherapy and included in the experimental treatment phase protocol Ib* (Randomization 2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)
• Cytarabine
No involvement of CNS: Part of standard chemotherapy and included in the experimental treatment phase protocol Ib* (Randomization 2) and in the experimental treatment phase Intensified Protocol M (Randomization R2). Involvement of CNS: Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1), in the experimental treatment phase Protocol Ib* (Randomization R2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)
• Dexamethasone
Part of the experimental therapy in Randomization R1 (Protocol Ia-Dexamethasone) and in Randomization R2 (Intensified Protocol M)
• Daunorubicin
Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1), in the experimental treatment phase Protocol Ib* (Randomization R2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)
• Doxorubicin
Part of standard chemotherapy
• Ifosfamide
Part of the experimental therapy in Randomization R2 (Intensified Protocol M)
• 6-Mercaptopurine
Part of standard chemotherapy and included in the experimental treatment phase protocol Ib* (Randomization 2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)
• Methotrexate
Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1), in the experimental treatment phase Protocol Ib* (Randomization R2) and in the experimental treatment phase Intensified Protocol M (Randomization R2)
• PEG asparaginase
Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1) and in the experimental treatment phase Protocol Ib* (Randomization R2)
• Prednisone
Part of standard chemotherapy
• Prednisolone
No involvement of CNS: Part of standard chemotherapy. Involvement of CNS: Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1), in the experimental treatment phase Protocol Ib* (Randomization R2) and in the experimental treatment phase Intensified Protocol M (Randomization R2
• Thioguanine
Part of standard chemotherapy
• Vincristine
Part of standard chemotherapy and included in the experimental treatment phase Protocol Ia-Dexamethasone (Randomization R1) and in the experimental treatment phase Intensified Protocol M (Randomization R2)
• Vindesine
Part of the experimental therapy in Randomization R2 (Intensified Protocol M)

Locations

Country	Name	City	State
Austria	Univ.Klinik für Kinder- und Jugendheilkunde Graz, Klin. Abteilung für pädiatrische Hämato-Onkologie	Graz
Austria	Univ.Klinik für Kinder- und Jugendheilkunde Innsbruck, Universitätsklinik für Pädiatrie I	Innsbruck
Austria	Kepler Universitätsklinikum, Med Campus IV / Onkologie	Linz
Austria	LKH Salzburg, Universitätsklinik für Kinder- und Jugendheilkunde, Kinderonkologie	Salzburg
Austria	St. Anna Kinderspital	Wien
Belgium	Cliniques Universitaires Saint-Luc (UCL), Hématologie et oncologie pédiatrique	Brussel
Belgium	University Hospital Brussels, Pediatrische oncologie	Brussel
Belgium	Hôpital Universitaire des Enfants Reine Fabiola (ULB), Pédiatrie hémato-oncologie	Brussels
Belgium	UZ Antwerpen Kinderhemato-oncologie	Edegem
Belgium	University Hospital Gent Pediatrische hemato-oncologie	Gent
Belgium	University Hospitals Leuven, Kinderhemato-oncologie	Leuven
Belgium	CHR Citadelle Hémato - oncologie pédiatrique	Liège
Belgium	CHR Citadelle Hémato - oncologie pédiatrique	Montegnée
China	Hong Kong Children's Hospital	Hong Kong
Czechia	Dept. of Pediatric Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University Cernopolni	Brno
Czechia	Dept. of Pediatric Hematology and Oncology. University Hospital Motol and 2nd Medical School, Charles University	Praha
Denmark	University Hospital Aalborg, Nord, Department of Pediatrics	Aalborg
Denmark	Aarhus University Hospital, Department of Pediatrics	Aarhus
Denmark	Børneonkologisk afsnit 5054, BørneUngeKlinikken, Juliane Marie Centret, Rigshospitalet	Kobenhavn
Denmark	H.C. Andersens Children Hospital, Odense University Hospital	Odense
Finland	Helsinki University Hospital, Department of Pediatric Hematology and Oncology	Helsinki
Finland	Kuopio University Hospital, Department of Pediatric Hematology and Oncology	Kuopio
Finland	University Hospital of Oulu, Paediatric Haematology and Oncology	Oulu
Finland	Tampere University Hospital, Paediatric Haematology and Oncology	Tampere
Finland	Turku University Hospital, Paediatric and Adolescent Haematology and Oncology	Turku
France	Service d'oncolologie, Hématologie pédiatrique. CHU Amiens, Avenue René Laënnec - SALOUEL	Amiens
France	Pôle Femme Mère Enfant ; Unité d'Hématologie/Oncologie pédiatrique, CHU Angers	Angers
France	Hématologie Oncologie pédiatrique, CHRU Besançon	Besançon
France	Hôpital de Enfants, Unité Onco-Hématologie Pédiatrique, Groupe Hospitalier Pellegrin	Bordeaux
France	Département de Pédiatrie et Génétique Médicale CHRU Morvan	Brest
France	Unité d'hémato-immuno-oncologie pédiatrique. Centre Hospitalier Universitaire niveau 1 - bâtiment FEH	Caen
France	Unité Onco- Hématologie Pédiatrique CHU Estaing 1 place Lucie-Aubrac	Clermont-Ferrand
France	Service Immuno-Hématologie Oncologie Pédiatrique	Dijon
France	Service onco hématologie pédiatrique CHU de Grenoble site Nord - Hôpital Couple enfant	Grenoble
France	Unité d'hématologie pédiatrique CHRU de Lille - Hôpital Jeanne de Flandre	Lille
France	Service d'Hématologie - Oncologie pédiatrique CHU Limoges - Hôpital de la mère et de l'enfant	Limoges
France	Service d'immuno-hématologie pédiatrique et de transplantation de moelle osseuse, CHU de Lyon HCL - GH Est-Institut d'hématologie et d'oncologie pédiatrique IHOP	Lyon
France	Service de Pédiatrie et hématologie pédiatrique, CHU de Marseille - Hôpital de la Timone	Marseille
France	UAM Hématologie et Oncologie Pédiatrique, CHU de Montpellier - Hôpital Arnaud de Villeneuve	Montpellier
France	Service d'hématologie et oncologie pédiatriques, Hôpital enfant-adolescent, CHU NANTES	Nantes
France	Service d'hémato-oncologie pédiatrique CHU NICE - Hôpital l'Archet 2	Nice
France	Service d' hémato-immunologie CHU Paris - Hôpital Robert Debré	Paris
France	service d'oncologie pédiatrique, institut Curie	Paris
France	Service Hémato-immuno- oncologie- CHU PARIS Armand Trousseau	Paris
France	Service Oncologie-Hématologie pédiatrique CHU de Poitiers	Poitiers
France	Service d'Hémato-Oncologie Pédiatrique- American Hospital	Reims
France	Pôle pédiatrie Hémato-cancérologie pédiatrique- CHU RENNES - Hôpital sud	Rennes
France	Service d'Hemato-Oncologie Pediatrique CHU Rouen	Rouen
France	service d'oncologie pédiatrique, hopital Félix Guyon	Saint-Denis
France	Pôle mère enfant-Unité Hématologie - Oncologie pédiatrique - CHU Hôpital NORD	Saint-Priest-en-Jarez
France	Service d'Onco-Hematologie Pediatrique CHU STRASBOURG -Hôpital de Hautepierre	Strasbourg
France	Service Pédiatrie - Hématologie Immunologie Oncologie - CHU Toulouse	Toulouse
France	Service d'hémato-oncologie pédiatrique- CHU de Nancy - Hôpital de Brabois Enfant	Vandœuvre-lès-Nancy
France	Dépt de Pédiatrie Gustave Roussy	Villejuif
Germany	Universitätsklinikum Aachen .Klinik für Kinder - und Jugendmedizin Hämatologie / Onkologie	Aachen
Germany	Klinikum Augsburg ,Schwäbisches Kinderkrebszentrum. I. Klinik für Kinder und Jugendliche Hämatologie / Onkologie	Augsburg
Germany	Charité Campus Virchow-Klinikum, Zentrum für Kinder- und Jugendmedizin- Abt. Hämatologie / Onkologie	Berlin
Germany	HELIOS Klinikum Berlin-Buch, Kinderklinik, Pädiatrische Hämatologie und Onkologie	Berlin
Germany	Evangelisches Krankenhaus Bielefeld GmbH, Klinik für Kinder- und Jugendmedizin, Hämatologie und Onkologie	Bielefeld
Germany	Zentrum für Kinderheilkunde der Universität Bonn, Abt. Päd. Hämatologie / Onkologie	Bonn
Germany	Städtisches Klinikum Braunschweig gGmbH, Zentrum für Kinder- und Jugendmedizin	Braunschweig
Germany	Klinikum Bremen-Mitte gGmbH, Prof.-Hess-Kinderklinik,Pädiatrische Onkologie und Hämatologie	Bremen
Germany	Klinikum Chemnitz gGmbH, Klinik für Kinder- und Jugendmedizin, Päd. Hämatologie und Onkologie	Chemnitz
Germany	Carl-Thiem-Klinikum, Kinderklinik, Station 5e	Cottbus
Germany	Vestische Kinderklinik, Universität Witten / Herdecke	Datteln
Germany	Klinikum Dortmund gGmbH, Klinik für Kinder- und Jugendmedizin, Station K1, Abt. Päd. Onkologie / Hämatologie	Dortmund
Germany	Universitätsklinik Carl Gustav Carus der TU Dresden, Klinik für Kinder- und Jugendmedizin	Dresden
Germany	Universitätsklinikum Düsseldorf, Zentrum für Kinder- und Jugendmedizin, Klinik für Päd. Hämatologie und Onkologie	Düsseldorf
Germany	HELIOS Klinikum Erfurt GmbH, Klinik für Kinder- und Jugendmedizin, Päd. Onkologie / Hämatologie	Erfurt
Germany	Universitätsklinikum Erlangen, Klinik für Kinder- und Jugendmedizin, Pädiatrische Onkologie / Hämatologie	Erlangen
Germany	Universitätsklinikum Essen, Zentrum für Kinder- und Jugendmedizin, Hämatologie / Onkologie	Essen
Germany	Universitätsklinikum Frankfurt, Klinik für Kinder- und Jugendmedizin, Pädiatrische Hämatologie und Onkologie	Frankfurt
Germany	Universitätsklinikum Freiburg, Zentrum für Kinder- und Jugendmedizin, Klinik IV: Päd. Hämatologie und Onkologie	Freiburg
Germany	Universitätsklinikum Gießen und Marburg, Standort Gießen, Zentrum für Kinderhämatologie und -onkologie	Gießen
Germany	Georg-August-Universität Universitäts-Kinderklinik, Pädiatrie I	Göttingen
Germany	Universitätsklinikum Greifswald KdöR, Klinik und Poliklinik für Kinder- und Jugendmedizin, Abt. Pädiatrische Onkologie und Hämatologie	Greifswald
Germany	Universitätsklinikum Halle (Saale), Klinik für Kinder- und Jugendmedizin, Pädiatrische Hämatologie / Onkologie	Halle
Germany	Universitätsklinikum Hamburg Eppendorf, Zentrum für Kinder- und Jugendmedizin, Abt. Pädiatrische Hämatologie und Onkologie	Hamburg
Germany	Medizinische Hochschule Hannover, Kinderheilkunde, Päd. Hämatologie / Onkologie	Hannover
Germany	Universitäts-Kinderklinik Heidelberg, Abt. Hämatologie / Onkologie	Heidelberg
Germany	Gemeinschaftskrankenhaus Herdecke, Kinder- und Jugendmedizin, Päd. Hämatologie / Onkologie	Herdecke
Germany	Universitätskliniken für Kinder- und Jugendmedizin, Päd. Hämatologie und Onkologie, Geb. 9	Homburg
Germany	Universitätsklinikum Jena, Klinik für Kinder- und Jugendmedizin	Jena
Germany	Städtisches Klinikum Karlsruhe gGmbH, Kinderklinik, Station S 24	Karlsruhe
Germany	Klinikum Kassel Gesundheit Nordhessen Holding AG, Klinik für pädiatrische Hämatologie und Onkologie	Kassel
Germany	Universitätsklinikum Schleswig Holstein Campus Kiel, Klinik für Allgemeine Pädiatrie, Päd. Onkologie / Hämatologie	Kiel
Germany	Gemeinschaftsklinikum Mittelrhein Kemperhof, Klinik für Kinder- und Jugendmedizin, Pädiatrische Hämatologie und Onkologie	Koblenz
Germany	Klinikum der Universität zu Köln, Klinik für Kinder- und Jugendmedizin, Abt. Kinderonkologie und -hämatologie	Köln
Germany	HELIOS Klinikum Krefeld, Zentrum für Kinder- und Jugendmedizin, Päd. Hämatologie/Onkologie	Krefeld
Germany	Universitätsklinikum Leipzig, Klinik für Kinder und Jugendliche, Abt. Päd. Hämatologie / Onkologie	Leipzig
Germany	Universitätsklinikum Schleswig Holstein Campus Lübeck, Klinik für Kinder- und Jugendmedizin, Hämatologie und Onkologie	Lübeck
Germany	Universitätsklinikum Magdeburg A. ö. R., Kinderklinik, Päd. Hämatologie / Onkologie	Magdeburg
Germany	Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Zentrum für Kinder- und Jugendmedizin, Pädiatrische Hämatologie / Onkologie	Mainz
Germany	Klinikum Mannheim gGmbH, Universitäts-Kinderklinik, Päd. Onkologie /Hämatologie	Manheim
Germany	Johannes Wesling Klinikum Minden, Klinik für Kinder- und Jugendmedizin, Päd. Hämatologie / Onkologie, Station E 22	Minden
Germany	Klinikum der LMU, Dr. von Haunersches Kinderspital, Pädiatrische Hämatologie / Onkologie	München
Germany	Klinikum Schwabing, Kinderklinik der TU Päd. Hämatologie / Onkologie, Station 24d	München
Germany	Universitätsklinikum Münster, Klinik für Kinder- und Jugendmedizin, Abt. Pädiatrische Hämatologie und Onkologie	Münster
Germany	Diakonie Neuendettelsau, Kliniken Hallerwiese / Cnopf'sche Kinderklinik, Pädiatrische Hämatologie /Onkologie	Nürnberg
Germany	Klinikum Oldenburg AöR, Zentrum für Kinder- und Jugendmedizin, Abt. Hämatologie / Onkologie	Oldenburg
Germany	Universitätsklinikum Regensburg, Klinik für Kinder- und Jugendmedizin, Abt. Päd. Hämatologie, Onkologie, SZT	Regensburg
Germany	Universitätsklinikum Rostock, Kinder- und Jugendklinik, Päd. Hämatologie und Onkologie	Rostock
Germany	Asklepios Klinik St. Augustin GmbH, Kinder- und Jugendmedizin, Kinder-Hämatologie und Onkologie	Sankt Augustin
Germany	HELIOS Kliniken Schwerin GmbH, Klinik für Kinder- und Jugendmedizin, Station A1	Schwerin
Germany	Klinikum Stuttgart, Olgahospital Zentrum für Kinder- und Jugendmedizin Pädiatrie 5 (Onkologie, Hämatologie, Immunologie)	Stuttgart
Germany	Klinikum Mutterhaus der Borromäerinnen gGmbH, Pädiatrische Abteilung	Trier
Germany	Universitätsklinik Tübingen, Klinik für Kinderheilkunde und Jugendmedizin, Päd. Hämatologie / Onkologie	Tübingen
Germany	Universitätsklinikum Ulm, Klinik für Kinder- und Jugendmedizin, Päd. Hämatologie und Onkologie	Ulm
Germany	Universitätskinderklinik Würzburg, Päd. Onkologie und Hämatologie	Würzburg
Hungary	2nd Dep. of Pediatrics, Semmelweis Univ	Budapest
Hungary	Heim Pal Children Hospital	Budapest
Hungary	Dep. of Pediatrics, Univ. of Debrecen	Debrecen
Hungary	Children's Treating Center, Miskolc	Miskolc
Hungary	Dep. of Pediatrics, University of Pecs	Pécs
Hungary	Dep. of Pediatrics, Univ. of Szeged	Szeged
Ireland	Our Lady's Children's Hospital Crumlin	Dublin
Israel	Children's Hospital at Soroka Medical Center	Be'er Sheva
Israel	Ruth Rappaport Children's Hospital, Rambam Medical Center	Haifa
Israel	Children's Hospital at Hadassah, Ein Kerem Medical Center	Jerusalem
Israel	Schneider Children's hospital, Rabin Medical Center	Petah tikva
Israel	Edmond and Lily Safra Children's Hospital, Sheba Medical Center	Ramat Gan
Israel	Dana Children's Hospital, Tel-Aviv Sourasky Medical Center	Tel Aviv
Italy	Clinica Pediatrica, Centro Regionale Oncoematologia Pediatrica- Ospedale dei Bambini "G. Salesi"	Ancona
Italy	Dipartimento Biomedicina Età Evolutiva- U.O. Pediatrica I Policlinico	Bari
Italy	Dipartimento Pediatrico degli OO.RR. di Bergamo	Bergamo
Italy	Dipartimento di Scienze Pediatriche Mediche Chirurgiche Ospedale Sant'Orsola Malpighi	Bologna
Italy	Clinica Pediatrica Ospedale Civile	Brescia
Italy	Istituto di Clinica Pediatrica- Ospedale Regionale Microcitemie	Cagliari
Italy	Divisione Ematologia - Oncologia Pediatrica, Clinica Pediatrica	Catania
Italy	U. O. di Pediatria- Azienda Ospedaliera Annunziata	Cosenza
Italy	Dipartimento di Medicina Clinica e Sperimentale Sezione di Pediatria - Università di Ferrara	Ferrara
Italy	Unità Autonoma di Oncoematologia Pediatrica, Dipartimento Pediatria - Azienda "A.Meyer"	Firenze
Italy	Dipartimento di Ematologia e Oncologia Pediatrica Istituto " G. Gaslini"	Genova
Italy	Divisione di Oncologia Pediatrica Ist. Nazionale Studio e Cura Tumori	Milano
Italy	U.O. di Ematologia, Oncologia e Trapianto-Azienda Policlinico di Modena	Modena
Italy	Clinica Pediatrica Ospedale S. Gerardo Via Donizetti	Monza
Italy	S.C. Ematologia Oncologica- Ospedale "Pausilipon"	Napoli
Italy	Clinica di Oncoematologia Pediatrica- Azienda Ospedaliera-Università di Padova	Padova
Italy	Oncoematologia Pediatrica- Ospedale dei Bambini G. di Cristina	Palermo
Italy	U.O. di Pediatria e Oncoematologia Pediatrica. Az. Osp. di Parma	Parma
Italy	Oncoematologia Pediatrica IRCCS, Policlinico San Matteo Piazzale Golgi	Pavia
Italy	Dipartimento di Ematologia -Ospedale Civile	Pescara
Italy	U.O. Pediatria Ospedale Infermi- Azienda USL Rimini	Rimini
Italy	Divisione di Ematologia Pediatrica- Ospedale "Bambino Gesù". Istituto di Ricerca Scientifica	Roma
Italy	Sezione Ematologia- Dipart. Biotecnico Cellulare ed Ematologia- Università "La Sapienza"	Roma
Italy	Divisione di Pediatria- Ospedale "Casa Sollievo della Sofferenza"	San Giovanni Rotondo
Italy	Oncologia Pediatrica,- Ospedale "R. Silvestrini"	San Sisto
Italy	Dip. Scienze Pediatriche e dell'Adolescenza Ospedale Infantile Regina Margherita	Torino
Italy	U.O. Emato-Oncologia Pediatrica- Università degli studi di Trieste-Ospedale Infantile Burlo Garofolo	Trieste
Italy	U.O. Oncoematologia Pediatrica- Policlinico "G.B. Rossi"	Verona
Netherlands	Princess Maxima Centre for Pediatric Oncology	Utrecht
Norway	Haukeland University Hospital in Bergen	Bergen
Norway	University Hospital Northern Norway	Tromsø
Norway	St Olavs Hospital in Trondheim	Trondheim
Poland	Department of Pediatric Oncology and Hematology, Medical University of Bialystok	Bialystok
Poland	Department of Pediatric Hematology and Oncology, Nicolaus Copernicus University	Bydgoszcz
Poland	Department of Pediatric Hematology and Oncology, Center of Pediatrics and Oncology in Chorzów	Chorzów
Poland	Department of Pediatrics, Hematology, Oncology and Endocrinology, Medical University of Gdansk	Gdansk
Poland	Department of Pediatric Oncology and Hematology, Center of Pediatrics in Kielce	Kielce
Poland	Department of Pediatric Oncology/Hematology, Institute of Pediatrics, Medical College Jagiellonian University	Kraków
Poland	Department of Pediatrics, Oncology, Hematology and Diabetology, Institute of Pediatrics, Medical University of Lodz	Lódz
Poland	Department of Pediatric Hematology, Oncology and Transplantology, Medical University of Lublin	Lublin
Poland	Department of Pediatric Oncology and Hematology, Provincial Specialist Children's Hospital	Olsztyn
Poland	Department of Pediatric Oncology, Hematology and Transplantology, Poznan University of Medical Sciences	Poznan
Poland	Department of Paediatric Oncology and Haematology, University of Rzeszów, Department of Pediatrics	Rzeszów
Poland	Department of Pediatrics, Children Hematology nad Oncology, Pomeranian Medical University	Szczecin
Poland	Department of Pediatric Oncology, Children's Memorial Health Institute	Warsaw
Poland	Department of Pediatrics, Hematology and Oncology, Medical University of Warsaw	Warsaw
Poland	Department of Bone Marrow Transplantation, Children Oncology and Hematology, Wroclaw Medical University	Wroclaw
Poland	Department of Pediatric Hematology and Oncology, Silesian Medical University in Katowice	Zabrze
Portugal	Centro Hospitalar e Universitário de Coimbra	Coimbra
Portugal	Instituto Português de Oncologia - Francisco Gentil - Libosa	Lisboa
Portugal	Instituto Português de Oncologia - Francisco Gentil - Porto	Porto
Russian Federation	Oncological center of regional Children's Hospital	Ekaterinburg
Russian Federation	National Center for Pediatric Hematology, Oncology and Immunology Moscow	Moscow
Slovakia	Department of pediatric oncology and hematology, Children´s Faculty Hospital	Banská Bystrica
Slovakia	Department of pediatric hematology and oncology, National Institute of Children's Diseases	Bratislava
Slovakia	Department of pediatric hematology and oncology, Children´s University Hospital	Košice
Spain	Hospital General Universitario de Alicante	Alicante
Spain	Hospital Universitario Torrecárdenas	Almería
Spain	Hospital Materno-Infantil de Badajoz	Badajoz
Spain	Hospital Universitario Cruces	Baracaldo
Spain	Hospital de la Santa Creu i Sant Pau	Barcelona
Spain	Hospital Universitari Vall d'Hebron	Barcelona
Spain	Hospital Universitario Donostia	Donostia
Spain	Hospital Sant Joan de Déu	Esplugues De Llobregat
Spain	Hospital Universitario Virgen de las Nieves	Granada
Spain	Complejo Hospitalario Universitario Insular Materno Infantil	Las Palmas De Gran Canaria
Spain	Hospital General Universitario Gregorio Marañón	Madrid
Spain	Hospital Infantil Universitario Niño Jesús	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Regional Universitario de Málaga	Málaga
Spain	Hospital Clínico Universitario Virgen de la Arrixaca	Murcia
Spain	Hospital Universitario Central de Asturias	Oviedo
Spain	Hospital Universitari Son Espases	Palma De Mallorca
Spain	Hospital Virgen del Camino	Pamplona
Spain	Complejo Hospitalario Universitario de Vigo	Pontevedra
Spain	Hospital Universitario Nuestra Señora de Candelaria	Santa Cruz De Tenerife
Spain	Hospital Universitario Marqués de Valdecilla	Santander
Spain	Hospital Clínico Universitario de Santiago	Santiago De Compostela
Spain	Hospital Universitario Virgen del Rocío	Sevilla
Spain	Hospital Universitario Virgen Macarena	Sevilla
Spain	Hospital Virgen de la Salud	Toledo
Spain	Hospital Clínico Universitario de Valencia	Valencia
Spain	Hospital Universitari i Politècnic La Fe	Valencia
Spain	Hospital Clínico Universitario de Valladolid	Valladolid
Spain	Hospital Universitario Miguel Servet	Zaragoza
Sweden	Barncancercentrum, Drottning Silvias Barn och Ungdomssjukhus, Sahlgrenska Universitetssjukhuset	Göteborg
Sweden	Barnonkologiska enheten, Barn och Ungdomsmedicinska kliniken, Universitetssjukhuset i Linköping	Linköping
Sweden	Barnonkologi, Skåne Universitetssjukhus	Lund
Sweden	Barncanceravdelningen Astrid Lindgrens Barnsjukhus, Nya Karolinska Universitetssjukhuset	Stockholm
Sweden	Barnonkologiska avdelningen, Barn 3, Norrlands Universitetssjukhus	Umeå
Sweden	Barnavdelningen för blod- och tumörsjukdomar 95A, Akademiska sjukhuset	Uppsala
Switzerland	Kantonsspital Aarau	Aarau
Switzerland	Universitäts-Kinderspital beider Basel (UKBB)	Basel
Switzerland	Ospedale San Giovanni	Bellinzona
Switzerland	Inselspital Bern, University of Bern	Bern
Switzerland	HUG Hôpitaux Universitaires de Genève	Geneva
Switzerland	CHUV - Centre Hospitalier Universitaire Vaudois	Lausanne
Switzerland	Luzerner Kantonspital - Kinderspital Luzern	Luzern
Switzerland	Ostschweizer Kinderspital	Sankt Gallen
Switzerland	Universitäts-Kinderspital Zürich	Zürich

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital Muenster	Deutsche Krebshilfe e.V., Bonn (Germany)

Countries where clinical trial is conducted

Austria,  Belgium,  China,  Czechia,  Denmark,  Finland,  France,  Germany,  Hungary,  Ireland,  Israel,  Italy,  Netherlands,  Norway,  Poland,  Portugal,  Russian Federation,  Slovakia,  Spain,  Sweden,  Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Cumulative incidence of relapse with involvement of the CNS (CNS-relapse, pCICR)	The time to relapse is defined as the time from randomization to the first relapse or the date of last follow-up. Other events (non-response, progressive disease, relapse, second malignancy or death before and in CR) will be taken into account as competing events.	through study completion, maximal 7.25 years
Primary	Estimated probability of event-free survival (pEFS)	The pEFS is defined as the time from randomization to the first event (non-response, progressive disease, relapse, second malignancy or death from any cause) or date of last follow-up.	through study completion, maximal 7.25 years
Secondary	Survival (pOS)	Survival (pOS) is defined as time from diagnosis to death due to any cause or to the date of last contact for patients alive	through study completion, maximal 7.25 years
Secondary	Frequency of treatment-related toxicity overall and in specific protocol elements, randomized arms and during follow up		through study completion, maximal 7.25 years
Secondary	Frequency of treatment-related mortality overall and in specific protocol elements, randomized arms and during follow up		through study completion, maximal 7.25 years
Secondary	Frequency of adverse events of interest and severe adverse events overall		through study completion, maximal 7.25 years
Secondary	Rate of evaluable patients for risk group stratification		during recruitment
Secondary	Cumulative incidence of relapses in association with molecular markers		through study completion, maximal 7.25 years
Secondary	Cumulative incidence of relapses in association with minimal residual disease results		through study completion, maximal 7.25 years