A Treatment Study Protocol for Participants 0-45 Years With Acute Lymphoblastic Leukaemia

Leukemia, Acute Lymphoblastic Clinical Trial

Official title:

ALLTogether1 - A Treatment Study Protocol of the ALLTogether Consortium for Children and Young Adults (0-45 Years of Age) With Newly Diagnosed Acute Lymphoblastic Leukaemia (ALL)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04307576
• Other study ID #: ALLTogether1
• Status: Recruiting
• Phase: Phase 3
• Start date: July 13, 2020
• Est. completion date: June 30, 2032

Study information

• Verified date: March 2024
• Source: Karolinska University Hospital
• Contact: Global Clinical Trial Manager ALLTogether1
• Phone: +46 8 524 800 00
• Email: karin.flood[@]ki.se
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

ALLTogether collects the experience of previously successful treatment of infants, children and young adults, with ALL from a number of well-renowned study groups into a new master protocol, which is both a comprehensive system for stratification and treatment of ALL in this age-group as well as the basis for several randomised and interventional trials included in the study-design.

Description:

ALLTogether is a European clinical treatment study for acute lymphoblastic leukaemia (ALL) in infants, children and young adults. The aims are to improve survival and quality of survival. In young people, ALL has excellent outcome with an overall survival of about 92% in children and 75% in young adults. Infants with BCP-ALL and KMT2A-rearrangements have a worse outcome and are treated according to separate protocols, but infants with KMT2A-germline and T-cell ALL have acceptable outcome on standard ALL therapy. However, patients still die of disease - from relapse because of under-treatment and a large fraction of patients are also over-treated: All patients risk treatment-related death and some suffer long-term side-effects or secondary cancer. To show improvement with such good survival, large populations are needed.

Study groups from Sweden, Norway, Iceland, Denmark, Finland, Estonia and Lithuania (NOPHO), the UK (UKALL), the Netherlands (DCOG), Germany (COALL), Belgium (BSPHO), Portugal (SHOP), Ireland (PHOAI), and France (SFCE), have designed a common treatment protocol.

The study has a complex clinical trial design with sub-protocols (the randomisations / intervention) connected to a master protocol. The master protocol consists of well established therapy-elements and in its design typical for current ALL therapy. The master protocol therapy is in the study design considered as standard of care (SOC) therapy for infants, children and young adults with ALL.

The study structure is defined by a master protocol onto which randomised and interventional sub-protocols as well as sub-studies may be added, run and stop in a modular fashion.

The randomisations / intervention may identify therapy that is less toxic, but equally efficacious for sub-groups of patients and innovative therapy that may reduce relapses and death from ALL. In the master protocol, improved risk-stratification is likely to increase survival and reduce unnecessary toxicity and the introduction of therapeutic drug monitoring (TDM) of Asparaginase activity will make the use of Asparaginase more rational and efficient and may thus improve overall outcomes.

The investigators hypothesise that patients stratified to the standard-risk group are over-treated. Therefore, it will be tested if the treatment can be safely reduced. In the R1 randomisation, patients will be randomised to receiving the Delayed Intensification (DI) phase of therapy with or without the anthracycline Doxorubicin.

A similar hypothesis of over-treatment will also be tested in patients stratified to the intermediate risk-low group. In the R2 randomisation patients will be randomly assigned to either removal of Doxorubicin during the DI phase or removal of Vincristine and Dexamethasone pulses during the maintenance phase or to the control group, which will be treated with Doxorubicin in DI as well as Vincristine and Dexamethasone pulses during maintenance. Patients will only be randomised once.

Randomisation R1 and R2 are only considered for children since adults have worse outcome and very poor survival after relapse, but the risk-stratification is likely to reduce the number of high-risk cases also in the adult-group.

Patients stratified as intermediate risk-high (IR-high) are identified as having an increased risk of relapse and thus a less favourable prognosis than the standard- and intermediate risk-low groups, but a more favourable prognosis than the high risk patients. The majority of all relapses in childhood ALL is expected to occur in the IR-high group. Following a relapse, only approximately 40% of the children can be successfully treated again and for adults the corresponding figure is less than 20 %, so preventing relapses is very important. New treatment options that improves the antileukaemic efficacy and which have an improved safety profile are urgently needed.

For IR-high patients Randomisation 3 (R3) is available. In R3 patients will be randomised to receive either:

1. the addition of two cycles of Inotuzumab ozogamicin (InO) - Besponsa®, before start of the maintenance phase. After these cycles, the patients randomised to the InO arm will receive maintenance for the same duration as in the control arm.

2. the addition of low dose 6-tioguanine (6TG) as an addition to the standard maintenance therapy.

3. standard maintenance therapy

Patients with ABL-class fusions in their leukaemic clone will, as a non-randomised experimental intervention, be treated with an addition of a tyrosine-kinase inhibitor during the induction phase (for patients <25 years) and from the consolidation phase (patients ≥25 years). This intervention may shift therapy for previously resistant cases to lower intensity treatment with the associated reduced morbidity and may also reduce the number of relapses in analogy with the results in Ph+ ALL. The reason for not performing a randomised comparison is the rarity of the aberration and also the diversity of ABL-class fusions, reducing statistical power for any comparison further. For this reason, the results of this intervention may be pooled with other study-groups trying similar approaches.

A new intervention is introduced for Down syndrome patients with CD19 positive ALL:

ALLTogether1 DS (NRI2). For Down syndrome-ALL patients who have end of Induction MRD detectable but <25% two conventional chemotherapy consolidation blocks will be replaced with two blocks of Blinatumomab.

For high-risk B-lineage patients, CAR-T therapy can be an alternative to high-risk blocks and stem-cell transplant, but in this case the intervention (CAR-T infusion) will be performed outside the ALLTogether1 study. However, the stratification-system in ALLTogether1 will define the population with a potential CAR-T indication.

ALLTogether1 also includes five sub-studies:

Efficacy and pharmacokinetics of Imatinib in ABL-class fusion positive ALL

Target population: All ABL-class patients enrolled in the ALLTogether study. Biomaterials to be collected at diagnosis, during TKI treatment, follow-up and relapse.

Aims

1. To determine the efficacy and dosing target of imatinib in the treatment of ABL-class leukemia

2. To find the best discriminative biomarkers for TKI response in ABL-class ALL

3. To determine the frequency of intrinsic (at diagnosis) and acquired TKI resistance (due to treatment), including backtracking of mutations using imatinib PK/PD findings during treatment

4. To find causes of TKI resistance in ABL-class patients

5. To describe the pharmacokinetics of Imatinib in TKI-treated patients

Objectives

1. To determine the percent of ABL-class patients who need to switch from IR-high to HR because of high MRD levels

2. To determine the effect of imatinib exposure on clinical outcome, including pharmacokinetic measurements of imatinib

3. To determine the molecular response to imatinib by monitoring fusion gene levels and mutational spectrum at diagnosis and during follow up

4. To determine whether the molecular response parameters reflect the Ig/TCR MRD or flow-MRD response or are a better predictor of therapy failure than Ig/TCR or flow-based MRD monitoring

5. To determine the phosphorylation status of ABL-class proteins and presence of TKI-resistance associated mutations in ABL genes prior to imatinib treatment and the emergence of such mutations during treatment with imatinib

6. To determine the presence of mutations in regulatory /other genes before and during imatinib treatment and functionally address the importance of these mutations in TKI resistance

7. To determine whether the efficacy of TKIs depends on the type of fusion gene

8. To describe inter- and intraindividual variations in imatinib PK (=trough levels) during therapy of ABL-class ALL

9. To describe associations between PK of imatinib and end-of-induction MRD (<25 yrs only) and end-of-consolidation MRD (all patients)

10. To describe associations between imatinib PK and relapse rates (overall, bone-marrow and CNS), event-free survival as well as overall survival;

11. To describe associations between imatinib PK and toxicities (including e.g. height z-scores at diagnosis and end of therapy, pancreatitis, treatment delays) with focus on those toxicities that are routinely monitored in ALLTogether.

Biomarkers to Reform Approaches to therapy-Induced Neurotoxicity (BRAIN)

Target population: All patients registered on ALLTogether1 aged ≥ 4 years at end of therapy (Arm A) and all patients registered on ALLTogether1 aged 4-21 years at start of therapy (Arm B) and without:

1. Pre-existing neurodevelopmental delay (e.g Trisomy 21) prior to diagnosis of ALL

2. Significant visual or motor impairment preventing use of a touch screen ipad

All centres are invited to enrol to arm A (Main BRAIN) of the study. Arm B (Longitudinal BRAIN) will be carried out in selected centres.

Aims

1. To implement universal screening of all children for adverse neurocognitive outcomes at the end of treatment using a validated user-friendly computer software programme (CogState) and compare neurocognitive outcomes by treatment allocation (Arm A).

2. To identify risk factors for adverse outcomes including whether acute neurotoxic events are associated with poor performance on cognitive tests at end of therapy compared to patients without acute neurotoxicity (Arm A).

3. To examine changes in neurocognitive performance over time and the risk/protective factors associated with differences in outcome, such as demographic, clinical, and physical/psychosocial factors (Arm B).

Primary end-point

a. Proportion of children with a z-score <1.5 on detection and/or identification CogState tasks in each treatment arm at the end of ALL therapy. A z-score < 1.5 correlates with moderate cognitive impairment at a level that may require additional support.

Secondary and exploratory end-points

1. Association between CogState scores at end of treatment and overt neurotoxic episodes as recorded on the trial adverse event database.

2. Association between Cogstate scores and clinical and demographic variables - age, sex, ethnicity, CNS status.

3. Proportion of children with scores <1.5SD for one card learning (learning), one back (working memory) and Groton's maze (executive function) on different treatment arms.

4. Association between CogState scores and patient reported outcome measures/Quality of life measurements collected as part of the main ALLTogether1 trial.

5. Changes in neurocognitive scores over time, including CogState and BRIEF-2/BRIEF-A scores.

6. Association between neurocognitive scores over time and interactions with demographic variables (age, sex), clinical variables (treatment arm, neurotoxicity), social-emotional and physical functioning (SDQ, PedsQL 4.0 Generic; PedsQL 3.0 Fatigue), and family factors (MEES; PedsQL FIM)

Association between asparaginase activity levels and outcome

Target population: All patients included in the ALLTogether1 protocol are eligible for participation.

Primary aim

To study the association between asparaginase activity levels and outcome (MRD, relapse, survival)

Secondary aims

1. To evaluate the association between asparaginase activity levels and toxicities, such as pancreatitis, infections and deep venous thrombosis (DVT)

2. To evaluate the association between asparaginase activity levels and hepatotoxicity in a subset of patients

CSF-Flow

Target population: All patients included in the ALLTogether1 protocol are eligible for participation

Aims

1. To use cerebrospinal fluid (CSF) flow cytometry (FCM) to improve the accuracy of diagnostic tests for CNS leukaemia compared to conventional CSF cytology. An associated objective will be to develop a recommended protocol for CSF flow cytometry with external quality assessment to ensure uniformity of measurement across the ALLTogether consortium.

2. To investigate whether negative FCM identifies a group of children at very low risk of CNS relapse, suitable for testing de-escalation of CNS-directed therapy in future trials.

3. To investigate whether positive FCM can identify children at increased risk of CNS relapse and whether patients with persistent positivity (FCM positive at day 15 onwards) might benefit from studies testing escalated CNS-directed therapy or a switch to more intensive treatment arms.

4. To collect matching CSF supernatant for studies comparing CSF FCM with soluble biomarkers (e.g. metabolic, cell-free DNA, proteomic and microRNA).

Maintenance therapy pharmacokinetics/-dynamics study

Target population: All patients included in the ALLTogether1 protocol are eligible for participation. For IR-high patients participating in the randomised InO- and TEAM sub-protocols, the monitoring of 6-mercaptopurine (6MP)/Methotrexate (MTX) metabolites at three months intervals is mandatory.

Aims and specific objectives

1. To map pharmacokinetics of 6MP and MTX during maintenance therapy in all patients in the ALLTogether protocol.

2. To associate metabolite profiles with TPMT and NUDT15 variants, as routinely analysed in ALLTogether.

3. To explore the association of event-free survival with DNA-TG and other 6MP/MTX metabolites.

4. To explore the association between risk of second cancers with DNA-TG and other 6MP/MTX metabolites.

5. To explore the association of risk of invasive infections with DNA-TG and other 6MP/MTX metabolites.

6. To explore the association of risk of osteonecrosis with DNA-TG and other 6MP/MTX metabolites.

7. To explore the association of sinusoidal obstruction syndrome with DNA-TG and other 6MP/MTX metabolites.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 6430
• Est. completion date: June 30, 2032
• Est. primary completion date: June 30, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 0 Years to 45 Years

Eligibility

Inclusion Criteria:

• Patients newly diagnosed with T-lymphoblastic (T-cell) or B-lymphoblastic precursor (BCP) leukaemia (ALL) according to the WHO-classification of Tumours of Haematopoetic and Lymphoid Tissues (Revised 4th edition 2017) and with a diagnosis confirmed by an accredited laboratory at a participating paediatric oncology or adult haematology centre.

• Age 0 - < 46 years (one day before 46th birthday) at the time of diagnosis with the exception of infants with KMT2A-rearranged (KMT2A-r) BCP ALL.

• Patients with surface immunoglobulin negative (sIG-) BCP-ALL and an IG::MYC rearrangement, unless they have a concurrent BCL2/6 rearrangement. T-ALL patients with MYC translocations.

• Informed consent signed by the patient and/or parents/legal guardians according to country-specific age-related guidelines.

• The ALL diagnosis should be confirmed by an accredited laboratory at a participating paediatric oncology or adult haematology centre.

• The patient should be diagnosed and treated at a participating paediatric oncology or adult haematology centre in the participating countries.

• The patient should be a resident in one of the participating countries on a permanent basis or should intend to settle in a participating country, for instance by an application for asylum. Patients who are visiting the country as tourists should not be included. However, returning expatriots with primary diagnosis abroad may be included if no treatment has been administered and the diagnostic procedures are repeated at a participating centre.

• All women of childbearing potential (WOCBP) have to have a negative pregnancy test within 2 weeks prior to the start of treatment.

• For each intervention/randomisation an additional set of inclusion-criteria is provided.

Exclusion Criteria:

• Age < 365 days and KMT2A-rearranged (KMT2A-r) BCP-ALL (documented presence of a KMT2A-split by FISH and/or a KMT2A fusion transcript).

• Age >45 years at diagnosis.

• Patients with a previous malignant diagnosis (ALL as a second malignant neoplasm - SMN).

• Relapse of ALL.

• Patients with mature B-ALL (as defined by surface IG positivity) or any patients with IG::MYC and a concurrent BCL2/6 rearrangement.

• Patients with Ph-positive ALL (documented presence of t(9;22)(q34;q11) and/or of the BCR::ABL fusion transcript). These patients will be transferred to an appropriate trial for t(9;22) if available.

• Previously known ALL prone syndromes (e.g. Li-Fraumeni syndrome, germline ETV6 mutation), except for Down syndrome. Exploration for such ALL prone syndromes is not mandatory and patients in whom genetic work-up reveals a new germ-line mutation (index-cases) will remain in the study.

• Treatment with systemic corticosteroids (>10mg/m2/day) for more than one week and/or other chemotherapeutic agents in a 4-week interval prior to diagnosis (pre-treatment).

• Pre-existing contraindications to any treatment according to the ALLTogether protocol (constitutional or acquired disease prior to the diagnosis of ALL preventing adequate treatment).

• Any other disease or condition, as determined by the investigator, which could interfere with the participation in the study according to the study protocol, or with the ability of the patients to cooperate and comply with the study procedures.

• Women of childbearing potential who are pregnant at the time of diagnosis.

• Women of childbearing potential and fertile men who are sexually active and are unwilling to use adequate contraception during therapy. Efficient birth control is required.

• Female patients, who are breast-feeding.

• Essential data missing from the registration of characteristics at diagnosis (in consultation with the protocol chair).

• For each intervention/randomisation an additional set of exclusion-criteria is provided.

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Acute Lymphoblastic
• Leukemia, Lymphoid
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

Drug:
• Omitted Doxorubicin
Omission of IV Doxorubicin
• Omitted Vincristine+Dexamethasone pulses
Omission of Vincristine+Dexamethasone pulses
• Inotuzumab Ozogamicin+Standard Maintenance Therapy
Addition of IV Inotuzumab ozogamicin before Maintenance Therapy
• Imatinib
p.o. Imatinib
• 6-tioguanine+Standard Maintenance Therapy
Addition of p.o. 6-tioguanine to Standard Maintenance Therapy
• Blinatumomab
IV Blinatumomab

Locations

Country	Name	City	State
Belgium	Cliniques Universitaires Saint-Luc (UCL)	Brussels
Belgium	L'hôpital Universitaire des enfants Reine Fabiola (Huderf)	Brussels
Belgium	University Hospital Antwerp	Edegem
Belgium	University Hospital Ghent	Ghent
Belgium	University Hospital Leuven, Dept of Paediatrics	Leuven
Belgium	CHC MontLégia, Boulevard Patience et Beaujonc 2	Liège
Belgium	CHR de la Citadelle	Liège
Denmark	Aalborg University Hospital, Dept of Paediatrics	Aalborg
Denmark	Aarhus University Hospital	Aarhus
Denmark	Aarhus University Hospital, Child and Adolescent Health	Aarhus
Denmark	Rigshospitalet, Dept of Haematology	Copenhagen
Denmark	Rigshospitalet, Dept of Paediatrics	Copenhagen
Denmark	Odense University Hospital, Dept of Paediatrics	Odense
Estonia	North Estonia Medical Centre, Dept of Haematology	Tallinn
Estonia	Tallinn Children´s Hospital, Dept of Paediatrics	Tallinn
Estonia	Tartu University Hospital	Tartu
Finland	Helsinki University Hospital, Dept of Haematology	Helsinki
Finland	Helsinki University Hospital, Dept of Paediatrics	Helsinki
Finland	Kuopio University Hospital, Dept of Haematology	Kuopio
Finland	Kuopio University Hospital, Dept of Paediatrics	Kuopio
Finland	Oulu University Hospital, Dept of Haematology, Dept of Medicine	Oulu
Finland	Oulu University Hospital, Dept of Paediatrics	Oulu
Finland	Tampere University Hospital, Dept of Haematology	Tampere
Finland	Tampere University Hospital, Dept of Paediatrics	Tampere
Finland	Turku University Hospital, Clinical Haematology and Stem Cell Transplantation Unit	Turku
Finland	Turku University Hospital, Dept of Paediatrics	Turku
France	CHU Amiens Groupe Hospitalier Sud	Amiens Cedex 1
France	CHU Angers	Angers Cedex 9
France	CHRU Besançon	Besancon Cedex 03
France	CHU Bordeaux - Groupe Hospitalier Pellegrin	Bordeaux Cedex
France	CHRU Brest - Morvan	Brest Cedex
France	Centre Hospitalier Universitaire Caen	Caen Cedex 9
France	CHU Clermont-Ferrand	Clermont-ferrand
France	CHU Dijon Hôpital François Mitterrand	Dijon
France	CHU de Grenoble site Nord - Hôpital Albert Michallon	Grenoble Cedex 9
France	CHRU de Lille - Hôpital Jeanne de Flandre	Lille Cedex
France	Hôpital de la mère et de l'enfant	Limoges
France	CHU de Lyon HCL - GH Est-Institut d'hématologie et d'oncologie pédiatrique IHOP	Lyon Cedex 08
France	CHU de Marseille - Hôpital de la Timone	Marseille Cedex 5
France	CHU de Montpellier - Hôpital Arnaud de Villeneuve	Montpellier Cedex 5
France	CHU Nantes-Hôpital enfant-adolescent	Nantes Cedex 01
France	CHU Nice - Hôpital l'Archet 2	Nice
France	CHU Paris - Hôpital Robert Debré	Paris
France	CHU Paris Armand Trousseau	Paris
France	CHU Paris Saint Louis	Paris
France	CHU Poitiers	Poitiers Cedex 6
France	CHU Reims-American Hospital	Reims
France	CHU Rennes - Hôpital sud	Rennes Cedex 2
France	CHU Rouen	Rouen Cedex
France	CHU De La Réunion - Site Nord (Hôpital Félix GUYON)	Saint-Denis
France	CHU Saint Etienne Hôpital Nord	Saint-Étienne
France	CHU Strasbourg -Hôpital de Hautepierre	Strasbourg Cedex
France	CHU Toulouse	TOULOUSE Cedex 9
France	CHRU Tours- Hôpital Clocheville	Tours
France	CHU de Nancy - Hôpital de Brabois Enfant	Vandoeuvre-les-nancy cedex
Germany	Evangelisches Klinikum Bethel	Bielefeld
Germany	Universitätsklinikum Bonn	Bonn
Germany	Klinikum Bremen Mitte	Bremen
Germany	Universitätsklinikum Hamburg-Eppendorf	Hamburg
Germany	HELIOS Klinikum Krefeld	Krefeld
Germany	Universitätsmedizin Mainz	Mainz
Iceland	Landspitali University Hospital, Children's Hospital	Reykjavík
Ireland	Our Lady's Children's Hospital	Dublin
Lithuania	Children's Hospital, Affiliate of Vilnius University Hospital Santaros Klinikos	Vilnius
Lithuania	Vilnius University Hospital Santaros Klinikos	Vilnius
Netherlands	Princess Máxima Center for Pediatric Oncology	Utrecht
Netherlands	University Medical Center Utrecht	Utrecht
Netherlands	University Medical Center Utrecht, Dept of Hematology	Utrecht
Norway	Haukeland University Hospital, Dept of Haematology	Bergen
Norway	Haukeland University Hospital, Dept of Paediatrics	Bergen
Norway	Oslo University Hospital, Dept of Haematology	Oslo
Norway	Oslo University Hospital, Dept of paediatric haemato- and oncology	Oslo
Norway	Stavanger University Hospital, Dept of Haematology	Stavanger
Norway	University Hospital North Norway, Dept of Haematology	Tromsø
Norway	University Hospital of North Norway, Dept of Paediatrics	Tromsø
Norway	St. Olavs University Hospital, Dept of Haematology	Trondheim
Norway	St. Olavs University Hospital, Dept of Paediatrics	Trondheim
Portugal	Centro Hospitalar e Universitário de Coimbra, EPE - Hospital Pediátrico de Coimbra	Coimbra
Portugal	Instituto Português de Oncologia de Lisboa Francisco Gentil, EPE	Lisboa
Portugal	Instituto Português de Oncologia do Porto Francisco Gentil, EPE	Porto
Sweden	Sahlgrenska University Hospital, Dept of Paediatric Haematology and Oncology	Gothenburg
Sweden	Sahlgrenska University Hospital, Section for Haematology and coagulation	Gothenburg
Sweden	Linköping University Hospital, Dept of Haematology	Linköping
Sweden	Linköping University Hospital, Dept of Paediatrics	Linköping
Sweden	Skåne University Hospital, Dept of Haematology	Lund
Sweden	Skåne University Hospital, Dept of Paediatrics	Lund
Sweden	Örebro University Hospital, Section for Haematology	Örebro
Sweden	Karolinska University Hospital, Dept of Paediatric Oncology and Haematology	Stockholm
Sweden	Karolinska University Hospital, Patient area Haematology	Stockholm
Sweden	Norrland University Hospital, Dept of Haematology	Umeå
Sweden	Norrland University Hospital, Dept of Paediatrics	Umeå
Sweden	Uppsala University Hospital, Dept of Haematology	Uppsala
Sweden	Uppsala University Hospital, Dept of Paediatric Haematology and Oncology	Uppsala
United Kingdom	Aberdeen Royal Infirmary, Aberdeen	Aberdeen
United Kingdom	Royal Aberdeen Children's Hospital, Aberdeen	Aberdeen
United Kingdom	Belfast City Hospital, Belfast	Belfast
United Kingdom	Royal Belfast Hospital for Sick Children, Belfast	Belfast
United Kingdom	Birmingham Children's Hospital, Birmingham	Birmingham
United Kingdom	The Queen Elizabeth Hospital, Birmingham	Birmingham
United Kingdom	Bristol Royal Hospital for Children / Bristol Haematology and Oncology Centre	Bristol
United Kingdom	Addenbrooke's Hospital, Cambridge	Cambridge
United Kingdom	Noah's Ark Children's Hospital for Wales, Cardiff	Cardiff
United Kingdom	University Hospital of Wales, Cardiff	Cardiff
United Kingdom	Ninewells Hospital, Dundee	Dundee
United Kingdom	Royal Hospital for Children and Young People, Edinburgh	Edinburgh
United Kingdom	Western General Hospital, Edinburgh	Edinburgh
United Kingdom	Beatson West of Scotland Cancer Centre, Glasgow	Glasgow
United Kingdom	Royal Hospital for Children, Glasgow	Glasgow
United Kingdom	Leeds General Infirmary, Leeds	Leeds
United Kingdom	Leeds St James University Hospital	Leeds
United Kingdom	Leicester Royal Infirmary, Leicester	Leicester
United Kingdom	Alder Hey Children's Hospital, Liverpool	Liverpool
United Kingdom	The Clatterbridge Cancer Centre NHS Foundation Trust	Liverpool
United Kingdom	Great Ormond Street Hospital for Children, London	London
United Kingdom	King's College Hospital	London
United Kingdom	St. Bartholomews Hospital	London
United Kingdom	University College London Hospital, London	London
United Kingdom	Royal Manchester Children's Hospital, Manchester	Manchester
United Kingdom	The Christie NHS Foundation Trust (PTC)	Manchester
United Kingdom	Freeman Hospital, Newcastle	Newcastle
United Kingdom	Royal Victoria Infirmary, Newcastle	Newcastle upon Tyne
United Kingdom	Nottingham City Hospital, Nottingham	Nottingham
United Kingdom	Nottingham Queen's Medical Centre	Nottingham
United Kingdom	Churchill Hospital, Oxford	Oxford
United Kingdom	John Radcliffe Hospital, Oxford	Oxford
United Kingdom	Derriford Hospital	Plymouth
United Kingdom	Royal Hallamshire Hospital, Sheffield	Sheffield
United Kingdom	Sheffield Children's Hospital, Sheffield	Sheffield
United Kingdom	Southampton General Hospital, Southampton	Southampton
United Kingdom	Royal Stoke University Hospital, Stoke	Stoke
United Kingdom	Royal Marsden Hospital, Sutton	Sutton

Sponsors (22)

Lead Sponsor

Collaborator

Mats Heyman

Aamu Pediatric Cancer Foundation, Acreditar - Associação de Pais e Amigos das Crianças com Cancro, Amgen, Assistance Publique - Hôpitaux de Paris, Belgium Health Care Knowledge Centre, Cancer Research UK, Clinical Trial Center North (CTC North GmbH & Co. KG), Danish Cancer Society, Danish Child Cancer Foundation, Direction Générale de l'Offre de Soins, Fundação Rui Osório de Castro, German Society for Pediatric Oncology and Hematology GPOH gGmbH, Grupo Português De Leucemias Pediátricas, Karolinska Institutet, NordForsk, Nova Laboratories Limited, Pfizer, Servier, The Novo Nordic Foundation, The Swedish Childhood Cancer Foundation, The Swedish Research Council

Countries where clinical trial is conducted

Belgium,  Denmark,  Estonia,  Finland,  France,  Germany,  Iceland,  Ireland,  Lithuania,  Netherlands,  Norway,  Portugal,  Sweden,  United Kingdom, 

References & Publications (5)

Mondelaers V, Suciu S, De Moerloose B, Ferster A, Mazingue F, Plat G, Yakouben K, Uyttebroeck A, Lutz P, Costa V, Sirvent N, Plouvier E, Munzer M, Poiree M, Minckes O, Millot F, Plantaz D, Maes P, Hoyoux C, Cave H, Rohrlich P, Bertrand Y, Benoit Y; Children-s Leukemia Group (CLG) of the European Organization for Research and Treatment of Cancer (EORTC). Prolonged versus standard native E. coli asparaginase therapy in childhood acute lymphoblastic leukemia and non-Hodgkin lymphoma: final results of the EORTC-CLG randomized phase III trial 58951. Haematologica. 2017 Oct;102(10):1727-1738. doi: 10.3324/haematol.2017.165845. Epub 2017 Jul 27. — View Citation

Pieters R, de Groot-Kruseman H, Van der Velden V, Fiocco M, van den Berg H, de Bont E, Egeler RM, Hoogerbrugge P, Kaspers G, Van der Schoot E, De Haas V, Van Dongen J. Successful Therapy Reduction and Intensification for Childhood Acute Lymphoblastic Leukemia Based on Minimal Residual Disease Monitoring: Study ALL10 From the Dutch Childhood Oncology Group. J Clin Oncol. 2016 Aug 1;34(22):2591-601. doi: 10.1200/JCO.2015.64.6364. Epub 2016 Jun 6. — View Citation

Schramm F, Zimmermann M, Jorch N, Pekrun A, Borkhardt A, Imschweiler T, Christiansen H, Faber J, Feuchtinger T, Schmid I, Beron G, Horstmann MA, Escherich G. Daunorubicin during delayed intensification decreases the incidence of infectious complications - a randomized comparison in trial CoALL 08-09. Leuk Lymphoma. 2019 Jan;60(1):60-68. doi: 10.1080/10428194.2018.1473575. Epub 2018 Jul 3. — View Citation

Toft N, Birgens H, Abrahamsson J, Griskevicius L, Hallbook H, Heyman M, Klausen TW, Jonsson OG, Palk K, Pruunsild K, Quist-Paulsen P, Vaitkeviciene G, Vettenranta K, Asberg A, Frandsen TL, Marquart HV, Madsen HO, Noren-Nystrom U, Schmiegelow K. Results of NOPHO ALL2008 treatment for patients aged 1-45 years with acute lymphoblastic leukemia. Leukemia. 2018 Mar;32(3):606-615. doi: 10.1038/leu.2017.265. Epub 2017 Aug 18. — View Citation

Vora A, Goulden N, Wade R, Mitchell C, Hancock J, Hough R, Rowntree C, Richards S. Treatment reduction for children and young adults with low-risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial. Lancet Oncol. 2013 Mar;14(3):199-209. doi: 10.1016/S1470-2045(12)70600-9. Epub 2013 Feb 7. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	6-mercaptopurine and Methotrexate metabolite pharmacokinetics (i.e. Ery-TGN/MeMP/MTXpg) for R3-TEAM	Measurements of metabolites Ery-TGN/MeMP/MTXpg during Maintenance therapy.	From start of Maintenance therapy until the end of Maintenance therapy (protocol week 38 until protocol week 108)
Other	Abnormal liver function parameters (including hypoglycemia) for R3-TEAM	Liver function parameters including hypoglycemia during Maintenance therapy	From start of Maintenance therapy until the end of Maintenance therapy (protocol week 38 until protocol week 108)
Primary	Event-free survival (EFS) for the whole protocol	The primary endpoint for the whole protocol (compared with the legacy protocols of the participating study-groups forming the consortium) is event-free survival (EFS) - as defined in the protocol.	5 year estimates from the time of diagnosis will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.
Primary	Event-free survival (EFS) for the TKI intervention	The primary endpoint for the TKI intervention is event-free survival (EFS) - as defined in the protocol, from the start of TKI until event or end of follow-up	From the start of TKI (day 15 or day 30), 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up for all interventions except Inotuzumab-randomisation (minimum 2-year follow-up).
Primary	Disease-free survival (DFS) R1 + R2	The primary endpoint for Randomisation 1 and 2 is disease-free survival (DFS) - as defined in the protocol counting from the time of randomisation	5 and 8 year estimates from the time of randomisation will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.
Primary	Disease-free survival (DFS) R3	The primary endpoint for Randomisation 3 and the ABL-class fusion intervention is disease-free survival (DFS) - as defined in the protocol counting from the time of randomisation (R3) and the start of TKI-therapy (ABL-class fusion intervention).	5 year estimates from the time of randomisation will be measured but adequate follow-up for these estimates will be ensured: at least 2-year follow-up
Primary	MRD response after 1 cycle of Blinatumomab	Fraction of patients with undetectable MRD ("Complete MRD response") at the end of one cycle of Blinatumomab (+/- 1 week)	End of first Blinatumomab infusion +/- 1 week
Secondary	Overall survival (OS) for the whole protocol	Overall survival defined as time from diagnosis to death or end of follow-up for surviving patients.	5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.
Secondary	Overall survival (OS) for R1 + R2	Overall survival defined as time from randomisation to death or end of follow-up for surviving patients.	5 and 8 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.
Secondary	Overall survival (OS) for R3	Overall survival defined as time from randomisation to death or end of follow-up for surviving patients.	5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up
Secondary	Overall survival (OS) for R3-TEAM associated with DNA-TG	Overall survival as defined above in relation to DNA-TG.	5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up
Secondary	Overall survival (OS) for TKI	Overall survival defined as time from start of TKI to death or end of follow-up for surviving patients	5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up (TKI).
Secondary	Overall survival (OS) for ALLTogether1 DS	Overall survival defined as time from start of Blinatumomab to death or end of follow-up for surviving patients	5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.
Secondary	Induction death	Fraction of patients who die as well as cumulative incidence of death before achieved complete remission (CR) within the time-frame described in the protocol	From diagnosis until death before remission (at the earliest, day 29) or in case of no CR day 29, completion of induction and consolidation 1 (protocol day 99 - Down) and in addition 3 high-risk blocks (protocol day 134 - all other patients)
Secondary	Resistant disease	Fraction of patients as well as cumulative incidence of resistant disease as described in the protocol. Induction death as competing risk.	From diagnosis until achieved complete remission (at the earliest, day 29) or in case of no CR day 29, assessment after induction and consolidation 1 (protocol day 99-Down patients) and in addition 3 high-risk blocks (protocol day 134-all other patients)
Secondary	Cumulative incidence of relapse for the whole protocol	Time from achieved complete remission until relapse as defined in the protocol or end of follow-up. Second malignancy, death in complete remission as competing events.	5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.
Secondary	Cumulative incidence of relapse for R1 + R2	Time from randomisation until relapse as defined in the protocol or end of follow-up. Second malignancy, death in complete remission as competing events.	5 and 8 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.
Secondary	Cumulative incidence relapse for R3	Time from randomisation until relapse as defined in the protocol or end of follow-up. Second malignancy, death in complete remission as competing events.	5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up
Secondary	Cumulative incidence relapse for R3-TEAM in association with DNA-TG	Cumulative incidence of relapse as defined for R3 in association with DNA-TG for R3-TEAM. Second malignancy, death in complete remission as competing events.	5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up
Secondary	Cumulative incidence CD22 negative relapse for R3	Time from randomisation until relapse without expression of CD22 as defined in the protocol or end of follow-up. Second malignancy, death in complete remission and relapse with CD22 expression as competing events.	5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up
Secondary	Cumulative incidence relapse for TKI	Time from start of TKI until relapse as defined in the protocol or end of follow-up. Second malignancy, death in complete remission as competing events.	5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up
Secondary	Cumulative incidence relapse for ALLTogether1 DS	Time from start of Blinatumomab until relapse as defined in the protocol or end of follow-up. Second malignancy, death in complete remission as competing events.	5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up
Secondary	Cumulative incidence of CD19 negative relapse for ALLTogether1 DS	Time from start of Blinatumomab until CD19 negative relapse as defined in the protocol or end of follow-up. Second malignancy, death in complete remission and CD19 positive relapse as competing events.	5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up
Secondary	Cumulative incidence of second malignant neoplasm (SMN) for the whole protocol	Time from achieved complete remission until diagnosis of second malignant neoplasm as defined in the protocol or end of follow-up. Relapse and death in complete remission as competing events.	5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.
Secondary	Cumulative incidence of second malignancy for R1+R2	Time from randomisation until diagnosis of second malignant neoplasm as defined in the protocol or end of follow-up. Relapse and death in complete remission as competing events.	5 and 8 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.
Secondary	Cumulative incidence of second malignancy for R3	Time from randomisation until diagnosis of second malignant neoplasm as defined in the protocol or end of follow-up. Relapse and death in complete remission as competing events.	5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up.
Secondary	Cumulative incidence of second malignancy for R3-TEAM in association with DNA-TG	Cumulative incidence of second malignancy as defined above for R3 in association with DNA-TG for R3-TEAM. Relapse and death in complete remission as competing events.	5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up.
Secondary	Cumulative incidence of second malignancy for TKI	Time from start of TKI until diagnosis of second malignant neoplasm as defined in the protocol or end of follow-up. Relapse and death in complete remission as competing events.	5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.
Secondary	Cumulative incidence of second malignancy for ALLTogether1 DS	Time from start of Blinatumomab until diagnosis of second malignant neoplasm as defined in the protocol or end of follow-up. Relapse and death in complete remission as competing events.	5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.
Secondary	Cumulative incidence of death in complete remission for the whole protocol	Time from achieved complete remission until death in complete remission as defined in the protocol or end of follow-up. Relapse and second malignant neoplasm as competing events.	5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.
Secondary	Cumulative incidence of death in complete remission for R1+R2	Time from randomisation until death in complete remission as defined in the protocol or end of follow-up. Relapse and second malignant neoplasm as competing events.	5 and 8 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up.
Secondary	Cumulative incidence of death in complete remission for R3	Time from randomisation until death in complete remission as defined in the protocol or end of follow-up. Relapse and second malignant neoplasm as competing events.	5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up
Secondary	Cumulative incidence of death in complete remission for TKI	Time from start of TKI until death in complete remission as defined in the protocol or end of follow-up. Relapse and second malignant neoplasm as competing events.	5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up
Secondary	Cumulative incidence of death in complete remission for ALLTogether1 DS	Time from start of Blinatumomab until death in complete remission as defined in the protocol or end of follow-up. Relapse and second malignant neoplasm as competing events.	5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up
Secondary	Cumulative incidence of treatment-related mortality for the whole protocol	Time from diagnosis until death during induction, death in complete remission or death from second malignant neoplasm (if not related to SMN-treatment).	5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.
Secondary	Cumulative incidence of treatment-related mortality R1+R2	Time from randomisation until death in complete remission or death from second malignant neoplasm (if not related to SMN-treatment).	5 and 8 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up.
Secondary	Cumulative incidence of treatment-related mortality R3	Time from randomisation until death in complete remission or death from second malignant neoplasm (if not related to SMN-treatment).	5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up
Secondary	Cumulative incidence of treatment-related mortality TKI	Time from start of TKI until death in complete remission or death from second malignant neoplasm (if not related to SMN-treatment).	5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up
Secondary	Leukaemia specific mortality for the whole protocol	Time from diagnosis until death after resistant disease or relapse - as defined in the protocol.	5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.
Secondary	Leukaemia specific mortality for R1+R2	Time from randomisation until death after relapse - as defined in the protocol.	5 and 8 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.
Secondary	Leukaemia specific mortality for R3	Time from randomisation until death after relapse - as defined in the protocol.	5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up
Secondary	Leukaemia specific mortality for TKI	Time from start of TKI until death after relapse - as defined in the protocol.	5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up
Secondary	Incidence of Adverse Events of Special Interest (AESIs) per treatment-phase in the whole protocol and TKI intervention	Cumulative incidence of 19 AESIs as defined in the protocol	From time of diagnosis after each treatment-phase (one extra in the middle of maintenance) and annually until 5 years from discontinuation of therapy.
Secondary	Incidence of Adverse Events of Special Interest (AESIs) extra assessment (R1+R2)	Cumulative incidence of 4 additional AESIs as defined in the protocol	Cumulative incidence of AESIs estimated 3 months after start of maintenance (R1+R2) and at the end of maintenance (R2)
Secondary	Incidence of Adverse Events of Special Interest (AESIs) extra assessment (R3)	Cumulative incidence of 3 additional AESIs as defined in the protocol	Cumulative incidence of AESIs estimated at the end of maintenance.
Secondary	Incidence of Serious Adverse Events (SAEs) and Adverse Events (AEs) related to R3	Cumulative incidence of SAEs and AEs (with limitations) as defined in the protocol	From time of randomisation until the end of maintenance therapy (approximately 77 weeks from randomisation)
Secondary	Quantitative measures of toxicity R1+R2	Days: in hospital, with iv antibiotics, with iv analgesics, with iv nutritional support	From time of randomisation, assessment after delayed intensification and 6 weeks after start of maintenance
Secondary	Metabolic consequences of steroid exposure (R2)	Measurements of BMI	At the end of therapy (approximately 94 weeks from randomisation) and 5 years after discontinuation of treatment
Secondary	Association of Disease-free survival (DFS) with DNA-TG for R3-TEAM	Disease-free survival (DFS) - as defined above associated with DNA-TG.	5 year estimates from the time of randomisation will be measured but adequate follow-up for these estimates will be ensured: at least 2-year follow-up
Secondary	Cumulative incidence of Sinusoidal Obstruction Syndrome (SOS) and Nodular Regenerative Hyperplasia (NRH) for R3-TEAM	Time from randomisation until diagnosis of SOS or NRH as defined in the protocol or end of follow-up.	Cumulative incidence of SOS/NRH estimated at the end of follow-up.
Secondary	Cumulative incidence of Osteonecrosis for R3-TEAM	Time from randomisation until diagnosis of osteonecrosis as defined in the protocol or end of follow-up.	Cumulative incidence of osteonecrosis estimated at the end of follow-up.
Secondary	Event-free survival (EFS) for ALLTogether1 DS	Event-free survival as defined in the protocol, from the start of Blinatumomab until death from any cause, relapse, second malignancy, protocol therapy failure (MRD>1% after 2 cycles blinatumomab and Augmented BFM consolidation) or end of follow-up.	From the start of Blinatumomab, 5 year estimate will be measured but adequate follow-up for this estimate will be ensured: at least 5 years follow-up.
Secondary	Incidence of Blinatumomab refractory disease for ALLTogether1 DS	Incidence of progressive disease under Blinatumomab treatment or MRD =1% at the end of the 2nd cycle of Blinatumomab.	From the start of Blinatumomab until end of 2nd cycle of Blinatumomab (each cycle is 4 weeks followed by a 2-week treatment free period)
Secondary	Incidence of Protocol Therapy Failure for ALLTogether1 DS	Incidence of patients who have MRD =1 % post 2 cycles of Blinatumomab followed by Augmented BFM consolidation, corresponding to original protocol day 99, or unchanged/increasing MRD during Augmented BFM consolidation corresponding to original protocol day 57.	From the start of Blinatumomab until the end of Consolidation 1 (85-140 days: 15-70 days of Blinatumomab therapy + 70 days of Consolidation 1)