Primary objectives:- Overall: Improvement of event-free survival (EFS) probabilities in childhood relapsed ALL- Randomization 1: EFS of Arm A (ALL-REZ BFM 2002) versus B (ALLR3) in SR patients- Randomization 2: Influence of epratuzumab on EFS in…
ID
Source
Brief title
Condition
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary parameters:
- Overall: Improvement of event-free survival (EFS) probabilities in childhood
relapsed ALL
- Randomization 1: EFS of Arm A (ALL-REZ BFM 2002) versus B (ALLR3) in SR
patients
- Randomization 2: Influence of epratuzumab on EFS in consolidation of SR [The
2nd randomisation with/without Epratuzumab closed 01-02-2019]
Secondary outcome
Secondary parameters:
- OS of Arm A (ALL-REZ BFM 2002) versus B (ALLR3) in SR patients
- Influence of epratuzumab on OS in consolidation of SR patients
- Rate of second complete remission (CR2) of Arm A versus Arm B
- Rate of SCT performed in Arm A versus Arm B
- Toxicity of randomized SR arms A versus B
- Toxicity of consolidation with versus without epratuzumab
- Improvement of MRD reduction during consolidation with versus without
epratuzumab
- Rate of MRD negativity prior to SCT with Arm A vs. Arm B
- Rate of MRD negativity prior to SCT after consolidation with versus without
epratuzumab
- Pharmacokinetic of epratuzumab in context with arm A and arm B
Background summary
Though survival of children with acute lymphoblastic leukemia (ALL) has
considerably improved over the past few decades, relapsed ALL remains a leading
cause of mortality in children with cancer. Given the rarity of the disease,
prospective clinical trials need to be coordinated within an international
cooperative group such as the International BFM Study Group (I-BFM-SG).
Within the group, over the last few years two different treatment protocols,
ALL-REZ BFM 2002 and ALL R3 have been used by most study groups for treatment
of relapsed ALL. Both trials have produced comparable results. The trials risk
stratified patients based on duration of first
remission, immunophenotype, site of relapse and post induction minimal residual
disease (MRD) levels to identify patients who should be transplanted. For
non-HR or standard risk (SR) patients both ALL-REZ BFM 2002 and ALL R3 have
achieved better results than previous trials.
Both protocols have however been primarily used in patients relapsing off
different frontline protocols. Thus there is need for a prospective randomized
controlled comparison across the study groups (randomization 1), before a
uniform backbone for further trials can be developed.
[The 2nd randomisation with/without Epratuzumab closed 01-02-2019]
In SR patients, survival may be improved by modifying the consolidation therapy
using targeted non-myelotoxic drugs. As ideal candidate, epratuzumab (humanised
chimeric anti CD22 antibody) will be randomly tested in combination with
conventional chemotherapy (randomization 2). CD22 is well expressed in all
B-cell precursor ALL cells. Epratuzumab has been developed in combination phase
I and II trials in childhood relapsed ALL and has shown a favourable toxicity
profile and moderate antileukemic activity.
Study objective
Primary objectives:
- Overall: Improvement of event-free survival (EFS) probabilities in childhood
relapsed ALL
- Randomization 1: EFS of Arm A (ALL-REZ BFM 2002) versus B (ALLR3) in SR
patients
- Randomization 2: Influence of epratuzumab on EFS in consolidation of SR
patients [The 2nd randomisation with/without Epratuzumab closed 01-02-2019]
Secondary objectives:
- OS of Arm A (ALL-REZ BFM 2002) versus B (ALLR3) in SR patients
- Influence of epratuzumab on OS in consolidation of SR patients
- Rate of second complete remission (CR2) of Arm A versus Arm B
- Rate of SCT performed in Arm A versus Arm B
- Toxicity of randomized SR arms A versus B
- Toxicity of consolidation with versus without epratuzumab
- Improvement of MRD reduction during consolidation with versus without
epratuzumab
- Rate of MRD negativity prior to SCT with Arm A vs. Arm B
- Rate of MRD negativity prior to SCT after consolidation with versus without
epratuzumab
- Pharmacokinetic of epratuzumab in context with arm A and arm B
Study design
The IntReALL SR 2010 trial is an inter-group, international multi-centre,
treatment optimization trial. It contains the followings branches:
- SR induction/consolidation arm A (ALL-REZ BFM 2002, arm protocol II-IDA)
versus B (UKALL-R3, arm MITOX): prospective, randomized, open label, phase III
trial
[The 2nd randomisation with/without Epratuzumab closed 01-02-2019]
- SR consolidation +/- epratuzumab: prospective, randomized, open label, phase
III trial
Intervention
[The 2nd randomisation with/without Epratuzumab closed 01-02-2019]
- SR arm A (ALL-REZ BFM 2002 arm Prot II-IDA): Induction: SIA (F1, F2); Post
induction: SCA1 and SCA2 ± epratuzumab (8x360mg/m²/ 1 hrs IV weekly, week
5-12), 5 courses SCA3-7 (R1/2/1/2/1), 24 months maintenance (6MP, MTX) with 6 x
TIT / 4 weeks. Cranial irradiation 18Gy for CNS relapse.
- SR arm B (UK-R3, arm mitoxantrone): Induction: SIB (phase I); Post induction:
SCB1 and SCB2 (R3-consolidation and intensification) ± epratuzumab (8x360mg/m²/
1hrs IV weekly, week 6-13), 2 courses SCB3-4 (R3-interim maintenance 1 and 2),
88 weeks maintenance (6MP,
MTX, 4-weekly VCR/DEX/IT reinduction pulses). Cranial irradiation 18 Gy for CNS
disease.
- SCT indications: Any donor Arm A with MRD >10-3 after SIA, arm B with > 10-4
after SIB.
Matched donor any early combined, isolated extramedullary relapse or patients
without MRD results. SCT is scheduled at week 16
Study burden and risks
None, otherthan the usual risk of the intensive, standard-chemotherapy that is
needed in the treatment of children with relapsed ALL.
Augustenburger Platz 1
Berlin 13353
DE
Augustenburger Platz 1
Berlin 13353
DE
Listed location countries
Age
Inclusion criteria
• Morphologically confirmed diagnosis of 1st relapsed precursor B-cell or
T-cell ALL
• Children less than 18 years of age at inclusion
• Meeting SR criteria: late isolated or late/early combined BCP BM relapse, any
late/early isolated extramedullary relapse
• Patient enrolled in a participating centre
• Written informed consent
• Start of treatment falling into the study period
• No participation in other clinical trials 30 days prior to study enrolment
that interfere with this protocol, except trials for primary ALL
Inclusion criteria specific for the epratuzumab randomization: (Randomisation
closed 01-02-2019)
• Precursor B-cell immunophenotype. A specific CD22 expression level is not
required
• M1 or M2 status of the bone marrow after induction
Exclusion criteria
• BCR-ABL / t(9;22) positive ALL
• Pregnancy or positive pregnancy test (urine sample positive for β-HCG > 10
U/l)
• Sexually active adolescents not willing to use highly effective contraceptive
method (pearl index <1) until 2 years after end of antileukemic therapy
• Breast feeding
• Relapse post allogeneic stem-cell transplantation
• The whole protocol or essential parts are declined either by patient
himself/herself or the respective legal guardian
• No consent is given for saving and propagation of pseudonymized medical data
for study reasons
• Severe concomitant disease that does not allow treatment according to the
protocol at the investigator*s discretion (e.g. malformation syndromes, cardiac
malformations, metabolic
disorders)
•
• Subjects unwilling or unable to comply with the study procedures
• Subjects who are legally detained in an official institute
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2012-000793-30-NL |
| CCMO | NL42228.078.14 |
| OMON | NL-OMON27511 |