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Treatment Protocol for Children and Adolescents With Acute Lymphoblastic Leukemia - AIEOP-BFM ALL 2017

ConditionAcute Lymphoblastic Leukemia, Pediatric
Trial statusRecruiting
Trial phasePhase 3
Trial typeInterventional
Biological sexAll
AgeUp to 17
SponsorMartin Schrappe

About this trial

The understanding of acute lymphoblastic leukemia (ALL) in childhood and adolescence has largely changed due to extensive genetic research in recent years: ALL is now considered to be a very heterogeneous disease group. The leukemia cells present themselves with quite differently activated regulatory mechanisms of the malignant phenotype. The introduction of more accurate methods of assessing therapy response ("minimal residual disease \[MRD\] tests") has provided new insights into very different mechanisms of action, including factors influenced by host factors; this has had practical clinical consequences for the use of more individualized therapy. Multimodal therapies have enabled a cure level of over 80% for ALL in this age group. However, the own and international study data show that the therapy toxicity of the contemporary chemotherapy concepts has become unacceptably high, in particular with respect to those intensified therapies used for the treatment of patients at high risk of ALL relapse.

The AIEOP-BFM ALL 2017 study therefore aims for an innovative integrated approach that will not only adapt the risk stratification to new prognostic markers using more comprehensive diagnostics, but above all, qualitatively reorient the therapy. The most important consequence will be that this study is testing immunotherapy with the bispecific antibody blinatumomab as an alternative to particularly intensive and toxic chemotherapy elements in precursor B-cell ALL (pB-ALL) patients with detectable chemotherapy resistance and at high risk of relapse. With the aim to complement the effects of the conventional chemotherapy, Blinatumomab is in addition tested in the large group of pB-ALL patients at intermediate relapse risk with seemingly unremarkable leukemia, but who account for a large proportion of all relapses. Targeted therapy is also used in the form of the proteasome inhibitor bortezomib for patients with pB-ALL and slow response to the drugs of the induction chemotherapy with the aim to overcome intrinsic chemotherapy resistance of the ALL cells. In patients with T-lineage ALL, who have particularly poor chances for cure after relapse, the established consolidation chemotherapy has proved to be particularly effective. This chemotherapy phase is therefore tested in a longer and more intensive form in such T-ALL patients with intermediate or slow early treatment response with the aim to reduce the relapses rate in this subgroup.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

newly diagnosed acute lymphoblastic leukemia or

biphenotypic with a dominant T or B lineage assignment

bilineal either with a dominant lymphoblastic population or if another reasonable rationale exists to treat the patient with an ALL-based therapy regimen

newly diagnosed acute undifferentiated leukemia

Disqualifiers

Ph+ (BCR-ABL1 or t(9;22)-positive) ALL

bilineal leukemia with a lymphoblastic and a separate non-lymphoblastic (≥ 10% of total cells) blast subset

pre-treatment with cytostatic drugs

glucocorticoid pre-treatment with ≥ 1 mg/kg/d for more than two weeks during the last month before diagnosis

Trial design

Design model

Factorial

Treatments tested in this trial

  • Blinatumomab

    Drug

    Experimental therapy in randomizations R-HR and R-MR

  • Bortezomib

    Drug

    Experimental therapy in randomization R-eHR

  • Cyclophosphamide

    Drug

    Part of standard chemotherapy and included in experimental treatment phase Protocol IB long in randomization R-T

  • Cytarabine

    Drug

    Part of standard chemotherapy and included in experimental treatment phase Protocol IB long in randomization R-T and in the intensification block Myocet-FLA for patients with very high relapse risk

  • Daunorubicin

    Drug

    Part of standard chemotherapy

  • Myocet

    Drug

    Part of intensification block Myocet-FLA for patients with very high relapse risk

  • Dexamethasone

    Drug

    Part of standard chemotherapy

  • Doxorubicin

    Drug

    Part of standard chemotherapy

  • Etoposide

    Drug

    Part of standard chemotherapy

  • Fludarabine Phosphate

    Drug

    Part of intensification block Myocet-FLA for patients with very high relapse risk

  • Ifosfamide

    Drug

    Part of standard chemotherapy

  • 6-Mercaptopurine

    Drug

    Part of standard chemotherapy and included in experimental treatment phase Protocol IB long in randomization R-T

  • Methotrexate

    Drug

    Part of standard chemotherapy

  • Pegaspargase

    Drug

    Part of standard chemotherapy

  • Prednisolone

    Drug

    Part of standard chemotherapy

  • Tioguanin

    Drug

    Part of standard chemotherapy

  • Vincristine

    Drug

    Part of standard chemotherapy

  • Vindesine

    Drug

    Part of standard chemotherapy

  • Erwinase

    Drug

    Part of standard chemotherapy as substitute for PEG-L-Asparaginase in case of allergic reaction

Treatment groups

5,000 Participants
are divided into 12 treatment groups

12

Treatment groups

See each treatment group below.

Group A: pB: early (non-)HR-standard/MR-standardActive comparator 12 interventions
Group B: pB: early HR-exp./MR-standardExperimental treatment 13 interventions
Group C: pB: early (non)HR-standard/MR-exp.Experimental treatment 13 interventions
Group D: pB: early HR-exp./MR-exp.Experimental treatment 14 interventions
Group E: pB: early (non-)HR-standard/HR-standardActive comparator 17 interventions
Group F: pB: early HR-exp./HR-standardExperimental treatment 17 interventions
Group G: pB: early (non-)HR-standard/HR-exp.Experimental treatment 14 interventions
Group H: pB: early HR-exp./HR-exp.Experimental treatment 14 interventions
Group I: pB: early non-HR/SROther 12 interventions
Group J: T: early non-SR-standard/(non-)HRActive comparator 17 interventions
Group K: T: early non-SR-exp/(non-)HRExperimental treatment 17 interventions
Group L: T: early SR/non-HROther 12 interventions

Trial outcomes

Primary outcomes

1

Event-free survival

Randomization R-eHR, R-HR and R-T: Time from randomization until the first event defined as follow: cytomorphological or molecular non-response (resistance to protocol treatment, considered as event at day zero), relapse, second malignancy or death from any cause. This will be called EFS time.

Time frame
Assessed up to 120 months from start of study
2

Disease-free survival

Randomization R-MR: Time from randomization until the first event defined as follow: Relapse, second malignancy or death from any cause. This will be called DFS time.

Time frame
Assessed up to 120 months from start of study

Secondary outcomes

1

Survival

All patients/randomizations: Time until death from any cause, starting at the same time point as the EFS/DFS.

Time frame
Assessed up to 120 months from start of study
2

Treatment-related mortality

Frequency and incidence of treatment-related mortality in induction or continuous complete remission

Time frame
Assessed up to 120 months from start of study
3

Adverse Events of interest/Serious Adverse Events

Frequency and incidence of adverse events of interest and serious adverse events in specific protocol phases, randomized arms and overall during follow-up

Time frame
Assessed up to 120 months from start of study
4

MRD response

MRD load after the randomized treatment phases (R-eHR, R-HR, R-MR and R-T) as well as after the first/second cycle of Blinatumomab or after the HR 2'/HR 3' block (R-HR)

Time frame
Measurements of MRD response at end of randomized treatments (intended time frame 13 weeks in R-eHR/R-T, 26 weeks in R-HR, 34 weeks in R-MR).

Other outcomes

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

Martin Schrappe

Lead sponsor

University Hospital Schleswig-Holstein

Sponsor institution

Deutsche Krebshilfe e.V., Bonn (Germany)

Collaborator

Source ClinicalTrials.gov
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