International Cooperative Treatment Protocol for Children and Adolescents With Lymphoblastic Lymphoma

Official title

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

Overview

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)

Detailed 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.

Interventions

• 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)
• Drug 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 (Rand
• Drug Dexamethasone
  Part of the experimental therapy in Randomization R1 (Protocol Ia-Dexamethasone) and in Randomization R2 (Intensified Protocol M)
• Drug 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)
• Drug Doxorubicin
  Part of standard chemotherapy
• Drug Ifosfamide
  Part of the experimental therapy in Randomization R2 (Intensified Protocol M)
• Drug 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)
• Drug 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)
• Drug 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)
• Drug Prednisone
  Part of standard chemotherapy

Primary outcome measures

• Cumulative incidence of relapse with involvement of the CNS (CNS-relapse, pCICR) [Time frame: through study completion, maximal 7.25 years]
• Estimated probability of event-free survival (pEFS) [Time frame: through study completion, maximal 7.25 years]

Secondary outcome measures (7)

• Survival (pOS) [Time frame: through study completion, maximal 7.25 years]
• Frequency of treatment-related toxicity overall and in specific protocol elements, randomized arms and during follow up [Time frame: through study completion, maximal 7.25 years]
• Frequency of treatment-related mortality overall and in specific protocol elements, randomized arms and during follow up [Time frame: through study completion, maximal 7.25 years]
• Frequency of adverse events of interest and severe adverse events overall [Time frame: through study completion, maximal 7.25 years]
• Rate of evaluable patients for risk group stratification [Time frame: during recruitment]
• Cumulative incidence of relapses in association with molecular markers [Time frame: through study completion, maximal 7.25 years]
• Cumulative incidence of relapses in association with minimal residual disease results [Time frame: through study completion, maximal 7.25 years]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Germany · 55 centers

• Universitätsklinikum Aachen .Klinik für Kinder - und Jugendmedizin Hämatologie / Onkologie — Aachen
• Klinikum Augsburg ,Schwäbisches Kinderkrebszentrum. I. Klinik für Kinder und Jugendliche H — Augsburg
• HELIOS Klinikum Berlin-Buch, Kinderklinik, Pädiatrische Hämatologie und Onkologie — Berlin
• Charité Campus Virchow-Klinikum, Zentrum für Kinder- und Jugendmedizin- Abt. Hämatologie / — Berlin
• Evangelisches Krankenhaus Bielefeld GmbH, Klinik für Kinder- und Jugendmedizin, Hämatologi — Bielefeld
• Zentrum für Kinderheilkunde der Universität Bonn, Abt. Päd. Hämatologie / Onkologie — Bonn
• Städtisches Klinikum Braunschweig gGmbH, Zentrum für Kinder- und Jugendmedizin — Braunschweig
• Klinikum Bremen-Mitte gGmbH, Prof.-Hess-Kinderklinik,Pädiatrische Onkologie und Hämatologi — Bremen
• … and 47 more centers

Italy · 33 centers

Center list to be confirmed — check the primary protocol.

Spain · 30 centers

Center list to be confirmed — check the primary protocol.

France · 29 centers

• Service d'oncolologie, Hématologie pédiatrique. CHU Amiens, Avenue René Laënnec - SALOUEL — Amiens
• Pôle Femme Mère Enfant ; Unité d'Hématologie/Oncologie pédiatrique, CHU Angers — Angers
• Hématologie Oncologie pédiatrique, CHRU Besançon — Besançon
• Hôpital de Enfants, Unité Onco-Hématologie Pédiatrique, Groupe Hospitalier Pellegrin — Bordeaux
• Département de Pédiatrie et Génétique Médicale CHRU Morvan — Brest
• Unité d'hémato-immuno-oncologie pédiatrique. Centre Hospitalier Universitaire niveau 1 - b — Caen
• Unité Onco- Hématologie Pédiatrique CHU Estaing 1 place Lucie-Aubrac — Clermont-Ferrand
• Service Immuno-Hématologie Oncologie Pédiatrique — Dijon
• … and 21 more centers

Poland · 16 centers

Center list to be confirmed — check the primary protocol.

Switzerland · 9 centers

Center list to be confirmed — check the primary protocol.

Belgium · 8 centers

• Hôpital Universitaire des Enfants Reine Fabiola (ULB), Pédiatrie hémato-oncologie — Brussels
• University Hospital Brussels, Pediatrische oncologie — Brussels
• Cliniques Universitaires Saint-Luc (UCL), Hématologie et oncologie pédiatrique — Brussels
• UZ Antwerpen Kinderhemato-oncologie — Edegem
• University Hospital Gent Pediatrische hemato-oncologie — Ghent
• University Hospitals Leuven, Kinderhemato-oncologie — Leuven
• CHR Citadelle Hémato - oncologie pédiatrique — Liège
• CHR Citadelle Hémato - oncologie pédiatrique — Montegnée

Hungary · 6 centers

Center list to be confirmed — check the primary protocol.

Israel · 6 centers

Center list to be confirmed — check the primary protocol.

Sweden · 6 centers

Center list to be confirmed — check the primary protocol.

Austria · 5 centers

• Univ.Klinik für Kinder- und Jugendheilkunde Graz, Klin. Abteilung für pädiatrische Hämato- — Graz
• Univ.Klinik für Kinder- und Jugendheilkunde Innsbruck, Universitätsklinik für Pädiatrie I — Innsbruck
• Kepler Universitätsklinikum, Med Campus IV / Onkologie — Linz
• LKH Salzburg, Universitätsklinik für Kinder- und Jugendheilkunde, Kinderonkologie — Salzburg
• St. Anna Kinderspital — Vienna

Finland · 5 centers

• Helsinki University Hospital, Department of Pediatric Hematology and Oncology — Helsinki
• Kuopio University Hospital, Department of Pediatric Hematology and Oncology — Kuopio
• University Hospital of Oulu, Paediatric Haematology and Oncology — Oulu
• Tampere University Hospital, Paediatric Haematology and Oncology — Tampere
• Turku University Hospital, Paediatric and Adolescent Haematology and Oncology — Turku

Denmark · 4 centers

• University Hospital Aalborg, Nord, Department of Pediatrics — Aalborg
• Aarhus University Hospital, Department of Pediatrics — Aarhus
• Børneonkologisk afsnit 5054, BørneUngeKlinikken, Juliane Marie Centret, Rigshospitalet — Copenhagen
• H.C. Andersens Children Hospital, Odense University Hospital — Odense

Norway · 3 centers

Center list to be confirmed — check the primary protocol.

Portugal · 3 centers

Center list to be confirmed — check the primary protocol.

Slovakia · 3 centers

Center list to be confirmed — check the primary protocol.

Czechia · 2 centers

• Dept. of Pediatric Oncology, University Hospital Brno and Faculty of Medicine, Masaryk Uni — Brno
• Dept. of Pediatric Hematology and Oncology. University Hospital Motol and 2nd Medical Scho — Prague

Russia · 2 centers

Center list to be confirmed — check the primary protocol.

China · 1 center

• Hong Kong Children's Hospital — Hong Kong

Ireland · 1 center

Center list to be confirmed — check the primary protocol.

Netherlands · 1 center

Center list to be confirmed — check the primary protocol.

Publications

• Khanam T, Sandmann S, Seggewiss J, Ruether C, Zimmermann M, Norvil AB, Bartenhagen C, Randau G, Mueller S, Herbrueggen H, Hoffmann P, Herms S, Wei L, Woeste M, Wuensch C, Gowher H, Oschlies I, Klapper W, Woessmann W, Dugas M, Burkhardt B. Integrative genomic analysis of pediatric T-cell lymphoblastic lymphoma reveals candidates of clinical significance. Blood. 2021 Apr 29;137(17):2347-2359. doi: 1 PMID 33152759

Identifiers

NCT: NCT04043494 · UKM17_0023 · 2017-001691-39

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗