Brief Summary

Rationale/Purpose: Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells. It is not yet known which combination chemotherapy regimen is more effective in treating young patients with acute lymphoblastic leukemia (ALL). This trial is studying several different combination chemotherapy regimens to compare how well they work in treating young patients with ALL. Study objectives Primary study questions:

Non high-risk (non-HR) precursor-B ALL (pB-ALL) patients with TEL/AML1-negative ALL or unknown TEL/AML1 status and flow cytometry minimal residual disease (MRD) in bone marrow on day 15 \<0.1% or with TEL/AML1-positive ALL (randomized study question R1): Can the daunorubicin dose in Protocol IA be safely reduced by 50 % with a non-inferior EFS and a reduction of toxicity (treatment-related mortality and AE/SAE in Protocol I)?
Patients with pB-ALL and risk group medium risk (MR) (randomized study question R2): Can the clinical outcome be improved by protracted asparagine depletion achieved through application of intensified PEG-L-asparaginase during reintensification and early maintenance?
High-risk (HR) patients (as identified by day 33 - randomized study question RHR): Can the clinical outcome be improved by protracted exposure to PEG-L-asparaginase during Protocol IB? Secondary study questions:
Standard risk (SR) patients identified by at least one sensitive marker: Is the clinical outcome comparable to that obtained in SR patients (identified with two sensitive markers) in AIEOP-BFM ALL 2000, or can the outcome even be improved with the use of PEG-L-asparaginase instead of native E. coli L-ASP?
T-ALL non-HR patients: Can the high level of outcome which was obtained for these patients in study AIEOP-BFM ALL 2000 be preserved or even improved with the use of PEG-L-ASP instead of native E. coli L-ASP?
HR patients with persisting high MRD levels despite the use of the HR blocks in the intensified consolidation phase "MRD Non-Responders": Is it possible to improve the outcome and to achieve a further reduction of leukemic cell burden by administration of an innovative treatment schedule (DNX-FLA)?
Patients participating in the randomized asparaginase studies (pB-ALL/MR, HR): Are asparaginase activity and asparaginase antibodies associated with development of allergic reactions, and do they have an effect on the outcome of the patients?
What is the relative value of different methods of MRD monitoring in the definition of alternative stratification systems within a BFM-oriented protocol?

Trial Health

On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment

6,136

participants targeted

Target at P75+ for phase_3 leukemia

Timeline

Completed

Started Jun 2010

Longer than P75 for phase_3 leukemia

Geographic Reach

6 countries

137 active sites

Status

completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

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Study Timeline

Key milestones and dates

11.6 years study duration

First Submitted

Initial submission to the registry

May 3, 2010

Completed

2 days until next milestone

First Posted

Study publicly available on registry

May 5, 2010

Completed

27 days until next milestone

Study Start

First participant enrolled

June 1, 2010

Completed

11.6 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

December 31, 2021

Completed

Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

December 31, 2021

Completed

Last Updated

May 24, 2022

Status Verified

May 1, 2022

Enrollment Period

11.6 years

First QC Date

May 3, 2010

Last Update Submit

May 17, 2022

Conditions

Leukemia

Outcome Measures

Primary Outcomes (3)

Event-free survival
* Randomization R1: Event-free survival from time of randomization * Historical comparison non-HR T-ALL: Event-free survival from diagnosis * Historical comparison "MRD Non-Responders": Event-free survival from start of DNX-FLA (morphological non-response after HR-3' is no event for this study question)
10 years from the start of recruitment
Disease-free survival
* Randomization R2: Disease-free survival from time of randomization * Historical comparison SR: Disease-free survival from start of Protocol M
10 years from the start of recruitment
minimal residual disease (MRD)
Randomization RHR: rate of MRD highly positive patients (MRD ≥ 10-3) at TP2 (week 12)
week 12 of treatment

Secondary Outcomes (5)

survival
10 years from the start of recruitment
treatment-related mortality
up to 25 months from the diagnosis
adverse events
up to 25 months from the diagnosis
event-free survival
10 years from the start of recruitment
minimal residual disease
after 24 weeks of treatment