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JOURNAL ONKOLOGIE – STUDIE

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

Rekrutierend

NCT-Nummer:
NCT04307576

Studienbeginn:
Juli 2020

Letztes Update:
19.03.2024

Wirkstoff:
Omitted Doxorubicin, Omitted Vincristine+Dexamethasone pulses, Inotuzumab Ozogamicin+Standard Maintenance Therapy, Imatinib, 6-tioguanine+Standard Maintenance Therapy, Blinatumomab

Indikation (Clinical Trials):
Leukemia, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Leukemia, Lymphoid

Geschlecht:
Alle

Altersgruppe:
Alle

Phase:
Phase 3

Sponsor:
Mats Heyman

Collaborator:
The Swedish Research Council, The Swedish Childhood Cancer Foundation, Pfizer, Servier, NordForsk, Aamu Pediatric Cancer Foundation, German Society for Pediatric Oncology and Hematology GPOH gGmbH, Clinical Trial Center North (CTC North GmbH & Co. KG), Belgium He

Studienleiter

Mats Heyman, MD, PhD
Study Chair
Karolinska University Hospital

Kontakt

Global Clinical Trial Manager ALLTogether1
Kontakt:
Phone: +46 8 524 800 00
E-Mail: karin.flood@ki.se» Kontaktdaten anzeigen

Studienlocations
(3 von 131)

Evangelisches Klinikum Bethel
33617 Bielefeld
(Nordrhein-Westfalen)
GermanyRekrutierend» Google-Maps
Universitätsklinikum Bonn
53113 Bonn
(Nordrhein-Westfalen)
GermanyRekrutierend» Google-Maps
Klinikum Bremen Mitte
28177 Bremen
(Bremen)
GermanyRekrutierend» Google-Maps
Brustzentrum am Universitätsklinikum Hamburg-Eppendorf
Martinistraße 52
20251 Hamburg
DeutschlandRekrutierend» Google-Maps
Darmkrebszentrum am HELIOS Klinikum Krefeld
Lutherplatz 40
47805 Krefeld
DeutschlandRekrutierend» Google-Maps
Darmkrebszentrum der Universitätsmedizin Mainz
Langenbeckstraße 1
55131 Mainz
DeutschlandRekrutierend» Google-Maps
L'hôpital Universitaire des enfants Reine Fabiola (Huderf)
1020 Brussels
BelgiumRekrutierend» Google-Maps
Cliniques Universitaires Saint-Luc (UCL)
1200 Brussels
BelgiumRekrutierend» Google-Maps
University Hospital Leuven, Dept of Paediatrics
3000 Leuven
BelgiumRekrutierend» Google-Maps
CHC MontLégia, Boulevard Patience et Beaujonc 2
4000 Liège
BelgiumRekrutierend» Google-Maps
Aalborg University Hospital, Dept of Paediatrics
9000 Aalborg
DenmarkRekrutierend» Google-Maps
Aarhus University Hospital, Child and Adolescent Health
8200 Aarhus
DenmarkRekrutierend» Google-Maps
Rigshospitalet, Dept of Haematology
2100 Copenhagen
DenmarkRekrutierend» Google-Maps
Rigshospitalet, Dept of Paediatrics
2100 Copenhagen
DenmarkRekrutierend» Google-Maps
Odense University Hospital, Dept of Paediatrics
5000 Odense
DenmarkRekrutierend» Google-Maps
North Estonia Medical Centre, Dept of Haematology
13419 Tallinn
EstoniaRekrutierend» Google-Maps
Tallinn Children´s Hospital, Dept of Paediatrics
13419 Tallinn
EstoniaRekrutierend» Google-Maps
Helsinki University Hospital, Dept of Haematology
00029 Helsinki
FinlandRekrutierend» Google-Maps
Helsinki University Hospital, Dept of Paediatrics
00029 Helsinki
FinlandRekrutierend» Google-Maps
Kuopio University Hospital, Dept of Haematology
70029 Kuopio
FinlandRekrutierend» Google-Maps
Kuopio University Hospital, Dept of Paediatrics
70029 Kuopio
FinlandRekrutierend» Google-Maps
Oulu University Hospital, Dept of Haematology, Dept of Medicine
90029 Oulu
FinlandRekrutierend» Google-Maps
Oulu University Hospital, Dept of Paediatrics
90029 Oulu
FinlandRekrutierend» Google-Maps
Tampere University Hospital, Dept of Haematology
33521 Tampere
FinlandRekrutierend» Google-Maps
Tampere University Hospital, Dept of Paediatrics
33521 Tampere
FinlandRekrutierend» Google-Maps
Turku University Hospital, Clinical Haematology and Stem Cell Transplantation Unit
20520 Turku
FinlandRekrutierend» Google-Maps
Turku University Hospital, Dept of Paediatrics
20520 Turku
FinlandRekrutierend» Google-Maps
CHU Amiens Groupe Hospitalier Sud
80054 Amiens Cedex 1
FranceRekrutierend» Google-Maps
CHU Bordeaux - Groupe Hospitalier Pellegrin
33076 Bordeaux Cedex
FranceRekrutierend» Google-Maps
Centre Hospitalier Universitaire Caen
14033 Caen Cedex 9
FranceRekrutierend» Google-Maps
CHU Clermont-Ferrand
63000 Clermont-ferrand
FranceRekrutierend» Google-Maps
CHU Dijon Hôpital François Mitterrand
21000 Dijon
FranceRekrutierend» Google-Maps
CHU de Grenoble site Nord - Hôpital Albert Michallon
38043 Grenoble Cedex 9
FranceRekrutierend» Google-Maps
CHRU de Lille - Hôpital Jeanne de Flandre
59037 Lille Cedex
FranceRekrutierend» Google-Maps
Hôpital de la mère et de l'enfant
87042 Limoges
FranceRekrutierend» Google-Maps
CHU de Lyon HCL - GH Est-Institut d'hématologie et d'oncologie pédiatrique IHOP
69373 Lyon Cedex 08
FranceRekrutierend» Google-Maps
CHU de Marseille - Hôpital de la Timone
13385 Marseille Cedex 5
FranceRekrutierend» Google-Maps
CHU de Montpellier - Hôpital Arnaud de Villeneuve
34295 Montpellier Cedex 5
FranceRekrutierend» Google-Maps
CHU Nantes-Hôpital enfant-adolescent
44093 Nantes Cedex 01
FranceRekrutierend» Google-Maps
CHU Paris - Hôpital Robert Debré
75019 Paris
FranceRekrutierend» Google-Maps
CHU Rennes - Hôpital sud
35203 Rennes Cedex 2
FranceRekrutierend» Google-Maps
CHU De La Réunion - Site Nord (Hôpital Félix GUYON)
97400 Saint-Denis
FranceRekrutierend» Google-Maps
CHU Saint Etienne Hôpital Nord
42055 Saint-Étienne
FranceRekrutierend» Google-Maps
CHU Strasbourg -Hôpital de Hautepierre
67098 Strasbourg Cedex
FranceRekrutierend» Google-Maps
CHRU Tours- Hôpital Clocheville
37000 Tours
FranceRekrutierend» Google-Maps
CHU de Nancy - Hôpital de Brabois Enfant
54511 Vandoeuvre-les-nancy cedex
FranceRekrutierend» Google-Maps
Landspitali University Hospital, Children's Hospital
101 Reykjavík
IcelandRekrutierend» Google-Maps
Children's Hospital, Affiliate of Vilnius University Hospital Santaros Klinikos
08661 Vilnius
LithuaniaRekrutierend» Google-Maps
Vilnius University Hospital Santaros Klinikos
08661 Vilnius
LithuaniaNoch nicht rekrutierend» Google-Maps
University Medical Center Utrecht, Dept of Hematology
3584 CX Utrecht
NetherlandsRekrutierend» Google-Maps
Princess Máxima Center for Pediatric Oncology
3584 Utrecht
NetherlandsRekrutierend» Google-Maps
University Medical Center Utrecht
Utrecht
NetherlandsRekrutierend» Google-Maps
Haukeland University Hospital, Dept of Haematology
5021 Bergen
NorwayRekrutierend» Google-Maps
Haukeland University Hospital, Dept of Paediatrics
5021 Bergen
NorwayRekrutierend» Google-Maps
Oslo University Hospital, Dept of Haematology
0372 Oslo
NorwayRekrutierend» Google-Maps
Oslo University Hospital, Dept of paediatric haemato- and oncology
0424 Oslo
NorwayRekrutierend» Google-Maps
Stavanger University Hospital, Dept of Haematology
4011 Stavanger
NorwayRekrutierend» Google-Maps
University Hospital North Norway, Dept of Haematology
9019 Tromsø
NorwayRekrutierend» Google-Maps
University Hospital of North Norway, Dept of Paediatrics
9038 Tromsø
NorwayRekrutierend» Google-Maps
St. Olavs University Hospital, Dept of Paediatrics
7006 Trondheim
NorwayRekrutierend» Google-Maps
St. Olavs University Hospital, Dept of Haematology
7030 Trondheim
NorwayRekrutierend» Google-Maps
Centro Hospitalar e Universitário de Coimbra, EPE - Hospital Pediátrico de Coimbra
3000-602 Coimbra
PortugalNoch nicht rekrutierend» Google-Maps
Instituto Português de Oncologia de Lisboa Francisco Gentil, EPE
1099-023 Lisboa
PortugalRekrutierend» Google-Maps
Instituto Português de Oncologia do Porto Francisco Gentil, EPE
4200-072 Porto
PortugalNoch nicht rekrutierend» Google-Maps
Sahlgrenska University Hospital, Section for Haematology and coagulation
41345 Gothenburg
SwedenRekrutierend» Google-Maps
Sahlgrenska University Hospital, Dept of Paediatric Haematology and Oncology
41685 Gothenburg
SwedenRekrutierend» Google-Maps
Linköping University Hospital, Dept of Haematology
58185 Linköping
SwedenRekrutierend» Google-Maps
Linköping University Hospital, Dept of Paediatrics
58185 Linköping
SwedenRekrutierend» Google-Maps
Skåne University Hospital, Dept of Haematology
22185 Lund
SwedenRekrutierend» Google-Maps
Skåne University Hospital, Dept of Paediatrics
22185 Lund
SwedenRekrutierend» Google-Maps
Karolinska University Hospital, Dept of Paediatric Oncology and Haematology
17176 Stockholm
SwedenRekrutierend» Google-Maps
Karolinska University Hospital, Patient area Haematology
17176 Stockholm
SwedenRekrutierend» Google-Maps
Norrland University Hospital, Dept of Haematology
90185 Umeå
SwedenRekrutierend» Google-Maps
Norrland University Hospital, Dept of Paediatrics
90185 Umeå
SwedenRekrutierend» Google-Maps
Uppsala University Hospital, Dept of Haematology
75185 Uppsala
SwedenRekrutierend» Google-Maps
Uppsala University Hospital, Dept of Paediatric Haematology and Oncology
75185 Uppsala
SwedenRekrutierend» Google-Maps
Örebro University Hospital, Section for Haematology
70185 Örebro
SwedenRekrutierend» Google-Maps
Aberdeen Royal Infirmary, Aberdeen
AB25 2ZN Aberdeen
United KingdomRekrutierend» Google-Maps
Royal Aberdeen Children's Hospital, Aberdeen
Aberdeen
United KingdomRekrutierend» Google-Maps
Royal Belfast Hospital for Sick Children, Belfast
BT12 6BA Belfast
United KingdomNoch nicht rekrutierend» Google-Maps
Belfast City Hospital, Belfast
BT9 7AB Belfast
United KingdomNoch nicht rekrutierend» Google-Maps
The Queen Elizabeth Hospital, Birmingham
B15 2TH Birmingham
United KingdomRekrutierend» Google-Maps
Birmingham Children's Hospital, Birmingham
B4 6NH Birmingham
United KingdomRekrutierend» Google-Maps
Bristol Royal Hospital for Children / Bristol Haematology and Oncology Centre
BS2 8BJ Bristol
United KingdomRekrutierend» Google-Maps
Addenbrooke's Hospital, Cambridge
CB2 0QQ Cambridge
United KingdomRekrutierend» Google-Maps
Noah's Ark Children's Hospital for Wales, Cardiff
CF14 4XW Cardiff
United KingdomNoch nicht rekrutierend» Google-Maps
University Hospital of Wales, Cardiff
Cardiff
United KingdomNoch nicht rekrutierend» Google-Maps
Ninewells Hospital, Dundee
DD1 9SY Dundee
United KingdomNoch nicht rekrutierend» Google-Maps
Western General Hospital, Edinburgh
EH2 2XU Edinburgh
United KingdomNoch nicht rekrutierend» Google-Maps
Royal Hospital for Children and Young People, Edinburgh
EH9 1LF Edinburgh
United KingdomRekrutierend» Google-Maps
Beatson West of Scotland Cancer Centre, Glasgow
G12 0YN Glasgow
United KingdomNoch nicht rekrutierend» Google-Maps
Royal Hospital for Children, Glasgow
G51 4TF Glasgow
United KingdomRekrutierend» Google-Maps
Leeds General Infirmary, Leeds
LS1 3EX Leeds
United KingdomRekrutierend» Google-Maps
Leeds St James University Hospital
LS9 7TF Leeds
United KingdomRekrutierend» Google-Maps
Leicester Royal Infirmary, Leicester
LE1 5WW Leicester
United KingdomRekrutierend» Google-Maps
Alder Hey Children's Hospital, Liverpool
L12 2AP Liverpool
United KingdomRekrutierend» Google-Maps
The Clatterbridge Cancer Centre NHS Foundation Trust
Liverpool
United KingdomRekrutierend» Google-Maps
University College London Hospital, London
NW1 2BU London
United KingdomRekrutierend» Google-Maps
Great Ormond Street Hospital for Children, London
WC1N 3JH London
United KingdomRekrutierend» Google-Maps
King's College Hospital
London
United KingdomNoch nicht rekrutierend» Google-Maps
Royal Manchester Children's Hospital, Manchester
M13 9WL Manchester
United KingdomRekrutierend» Google-Maps
The Christie NHS Foundation Trust (PTC)
M20 4BX Manchester
United KingdomRekrutierend» Google-Maps
Royal Victoria Infirmary, Newcastle
NE1 4LP Newcastle upon Tyne
United KingdomRekrutierend» Google-Maps
Freeman Hospital, Newcastle
NE7 7DN Newcastle
United KingdomNoch nicht rekrutierend» Google-Maps
Nottingham City Hospital, Nottingham
NG5 1PB Nottingham
United KingdomNoch nicht rekrutierend» Google-Maps
Nottingham Queen's Medical Centre
NG7 2UH Nottingham
United KingdomRekrutierend» Google-Maps
Churchill Hospital, Oxford
OX3 7LE Oxford
United KingdomNoch nicht rekrutierend» Google-Maps
John Radcliffe Hospital, Oxford
OX3 9DU Oxford
United KingdomRekrutierend» Google-Maps
Royal Hallamshire Hospital, Sheffield
S10 2JF Sheffield
United KingdomNoch nicht rekrutierend» Google-Maps
Sheffield Children's Hospital, Sheffield
S10 2TH Sheffield
United KingdomRekrutierend» Google-Maps
Southampton General Hospital, Southampton
SO16 6YD Southampton
United KingdomRekrutierend» Google-Maps
Royal Stoke University Hospital, Stoke
ST4 6QG Stoke
United KingdomNoch nicht rekrutierend» Google-Maps
Royal Marsden Hospital, Sutton
SM2 5PT Sutton
United KingdomRekrutierend» Google-Maps
Alle anzeigen

Studien-Informationen

Detailed 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.

Ein-/Ausschlusskriterien

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.

Studien-Rationale

Primary outcome:

1. Event-free survival (EFS) for the whole protocol (Time Frame - 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.):
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.

2. Event-free survival (EFS) for the TKI intervention (Time Frame - 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).):
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

3. Disease-free survival (DFS) R1 + R2 (Time Frame - 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.):
The primary endpoint for Randomisation 1 and 2 is disease-free survival (DFS) - as defined in the protocol counting from the time of randomisation

4. Disease-free survival (DFS) R3 (Time Frame - 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):
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. MRD response after 1 cycle of Blinatumomab (Time Frame - End of first Blinatumomab infusion +/- 1 week):
Fraction of patients with undetectable MRD ("Complete MRD response") at the end of one cycle of Blinatumomab (+/- 1 week)

Secondary outcome:

1. Overall survival (OS) for the whole protocol (Time Frame - 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.):
Overall survival defined as time from diagnosis to death or end of follow-up for surviving patients.

2. Overall survival (OS) for R1 + R2 (Time Frame - 5 and 8 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.):
Overall survival defined as time from randomisation to death or end of follow-up for surviving patients.

3. Overall survival (OS) for R3 (Time Frame - 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up):
Overall survival defined as time from randomisation to death or end of follow-up for surviving patients.

4. Overall survival (OS) for R3-TEAM associated with DNA-TG (Time Frame - 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up):
Overall survival as defined above in relation to DNA-TG.

5. Overall survival (OS) for TKI (Time Frame - 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up (TKI).):
Overall survival defined as time from start of TKI to death or end of follow-up for surviving patients

6. Overall survival (OS) for ALLTogether1 DS (Time Frame - 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.):
Overall survival defined as time from start of Blinatumomab to death or end of follow-up for surviving patients

7. Induction death (Time Frame - 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)):
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

8. Resistant disease (Time Frame - 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)):
Fraction of patients as well as cumulative incidence of resistant disease as described in the protocol. Induction death as competing risk.

9. Cumulative incidence of relapse for the whole protocol (Time Frame - 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.):
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.

10. Cumulative incidence of relapse for R1 + R2 (Time Frame - 5 and 8 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.):
Time from randomisation until relapse as defined in the protocol or end of follow-up. Second malignancy, death in complete remission as competing events.

11. Cumulative incidence relapse for R3 (Time Frame - 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up):
Time from randomisation until relapse as defined in the protocol or end of follow-up. Second malignancy, death in complete remission as competing events.

12. Cumulative incidence relapse for R3-TEAM in association with DNA-TG (Time Frame - 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up):
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.

13. Cumulative incidence CD22 negative relapse for R3 (Time Frame - 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up):
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.

14. Cumulative incidence relapse for TKI (Time Frame - 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up):
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.

15. Cumulative incidence relapse for ALLTogether1 DS (Time Frame - 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up):
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.

16. Cumulative incidence of CD19 negative relapse for ALLTogether1 DS (Time Frame - 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up):
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.

17. Cumulative incidence of second malignant neoplasm (SMN) for the whole protocol (Time Frame - 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.):
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.

18. Cumulative incidence of second malignancy for R1+R2 (Time Frame - 5 and 8 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.):
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.

19. Cumulative incidence of second malignancy for R3 (Time Frame - 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up.):
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.

20. Cumulative incidence of second malignancy for R3-TEAM in association with DNA-TG (Time Frame - 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up.):
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.

21. Cumulative incidence of second malignancy for TKI (Time Frame - 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.):
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.

22. Cumulative incidence of second malignancy for ALLTogether1 DS (Time Frame - 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.):
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.

23. Cumulative incidence of death in complete remission for the whole protocol (Time Frame - 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.):
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.

24. Cumulative incidence of death in complete remission for R1+R2 (Time Frame - 5 and 8 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up.):
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.

25. Cumulative incidence of death in complete remission for R3 (Time Frame - 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up):
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.

26. Cumulative incidence of death in complete remission for TKI (Time Frame - 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up):
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.

27. Cumulative incidence of death in complete remission for ALLTogether1 DS (Time Frame - 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up):
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.

28. Cumulative incidence of treatment-related mortality for the whole protocol (Time Frame - 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.):
Time from diagnosis until death during induction, death in complete remission or death from second malignant neoplasm (if not related to SMN-treatment).

29. Cumulative incidence of treatment-related mortality R1+R2 (Time Frame - 5 and 8 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up.):
Time from randomisation until death in complete remission or death from second malignant neoplasm (if not related to SMN-treatment).

30. Cumulative incidence of treatment-related mortality R3 (Time Frame - 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up):
Time from randomisation until death in complete remission or death from second malignant neoplasm (if not related to SMN-treatment).

31. Cumulative incidence of treatment-related mortality TKI (Time Frame - 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up):
Time from start of TKI until death in complete remission or death from second malignant neoplasm (if not related to SMN-treatment).

32. Leukaemia specific mortality for the whole protocol (Time Frame - 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.):
Time from diagnosis until death after resistant disease or relapse - as defined in the protocol.

33. Leukaemia specific mortality for R1+R2 (Time Frame - 5 and 8 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up.):
Time from randomisation until death after relapse - as defined in the protocol.

34. Leukaemia specific mortality for R3 (Time Frame - 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 2 years follow-up):
Time from randomisation until death after relapse - as defined in the protocol.

35. Leukaemia specific mortality for TKI (Time Frame - 5 year estimates will be measured but adequate follow-up for these estimates will be ensured: at least 5 years follow-up):
Time from start of TKI until death after relapse - as defined in the protocol.

36. Incidence of Adverse Events of Special Interest (AESIs) per treatment-phase in the whole protocol and TKI intervention (Time Frame - From time of diagnosis after each treatment-phase (one extra in the middle of maintenance) and annually until 5 years from discontinuation of therapy.):
Cumulative incidence of 19 AESIs as defined in the protocol

37. Incidence of Adverse Events of Special Interest (AESIs) extra assessment (R1+R2) (Time Frame - Cumulative incidence of AESIs estimated 3 months after start of maintenance (R1+R2) and at the end of maintenance (R2)):
Cumulative incidence of 4 additional AESIs as defined in the protocol

38. Incidence of Adverse Events of Special Interest (AESIs) extra assessment (R3) (Time Frame - Cumulative incidence of AESIs estimated at the end of maintenance.):
Cumulative incidence of 3 additional AESIs as defined in the protocol

39. Incidence of Serious Adverse Events (SAEs) and Adverse Events (AEs) related to R3 (Time Frame - From time of randomisation until the end of maintenance therapy (approximately 77 weeks from randomisation)):
Cumulative incidence of SAEs and AEs (with limitations) as defined in the protocol

40. Quantitative measures of toxicity R1+R2 (Time Frame - From time of randomisation, assessment after delayed intensification and 6 weeks after start of maintenance):
Days: in hospital, with iv antibiotics, with iv analgesics, with iv nutritional support

41. Metabolic consequences of steroid exposure (R2) (Time Frame - At the end of therapy (approximately 94 weeks from randomisation) and 5 years after discontinuation of treatment):
Measurements of BMI

42. Association of Disease-free survival (DFS) with DNA-TG for R3-TEAM (Time Frame - 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):
Disease-free survival (DFS) - as defined above associated with DNA-TG.

43. Cumulative incidence of Sinusoidal Obstruction Syndrome (SOS) and Nodular Regenerative Hyperplasia (NRH) for R3-TEAM (Time Frame - Cumulative incidence of SOS/NRH estimated at the end of follow-up.):
Time from randomisation until diagnosis of SOS or NRH as defined in the protocol or end of follow-up.

44. Cumulative incidence of Osteonecrosis for R3-TEAM (Time Frame - Cumulative incidence of osteonecrosis estimated at the end of follow-up.):
Time from randomisation until diagnosis of osteonecrosis as defined in the protocol or end of follow-up.

45. Event-free survival (EFS) for ALLTogether1 DS (Time Frame - 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.):
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.

46. Incidence of Blinatumomab refractory disease for ALLTogether1 DS (Time Frame - 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)):
Incidence of progressive disease under Blinatumomab treatment or MRD ≥1% at the end of the 2nd cycle of Blinatumomab.

47. Incidence of Protocol Therapy Failure for ALLTogether1 DS (Time Frame - 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)):
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.

Studien-Arme

  • No Intervention: R1 - SR standard arm
    Standard risk arm receiving standard treatment (Delayed Intensification including Doxorubicin).
  • Experimental: R1 - SR experimental arm
    Standard risk arm, receiving Delayed Intensification without Doxorubicin IV 3 x 30 mg/m2/dose.
  • No Intervention: R2 - IR-low standard arm
    Standard treatment with Delayed Intensification including Doxorubicin and Maintenance including Vincristine+Dexamethasone pulses.
  • Experimental: R2 - IR-low experimental arm A
    Standard treatment with omission of Doxorubicin IV 3 x 30 mg/m2/dose in the Delayed Intensification phase.
  • No Intervention: R3 - IR-high standard arm
    Intermediate risk high arm receiving Standard Maintenance Therapy.
  • Experimental: R3-InO - IR-high experimental arm
    Inotuzumab IV 0,5 mg/m2, given on days 253, 260, 267 and on days 274, 281, 288 before start of Standard Maintenance Therapy.
  • Experimental: ABL-class fusions intervention
    Imatinib p.o. 340 mg/m2 given daily from day 15 or 30 (depending on age) to the end of therapy (week 106) in addition to Standard IR-high chemotherapy.
  • Experimental: R3-TEAM - IR-high experimental arm
    6-tioguanine p.o, 2,5-12,5 mg/m2, given daily in addition to Standard Maintenance Therapy.
  • Experimental: ALLTogether1 DS Blinatumomab intervention
    Blinatumomab IV, 5 mcg/m2/day up to 28 mcg/day (detailed dosing in protocol) continous infusion. Two 28 day courses with a two week treatment free interval in between. Blinatumomab courses replace Consolidation 1 and Consolidation 2 in the standard protocol adapted for Down syndrome patients.
  • Experimental: R2 - IR-low experimental arm B
    Standard treatment with omission of monthly pulses of Vincristine IV 1,5 mg/m2/dose and 5 days of Dexamethasone p.o. 6 mg/m2/day in the Maintenance Phase.

Geprüfte Regime

  • Omitted Doxorubicin:
    Omission of IV Doxorubicin
  • Omitted Vincristine+Dexamethasone pulses:
    Omission of Vincristine+Dexamethasone pulses
  • Inotuzumab Ozogamicin+Standard Maintenance Therapy (Besponsa+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 (Blincyto):
    IV Blinatumomab

Quelle: ClinicalTrials.gov


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