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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT01117441




Registration number
NCT01117441
Ethics application status
Date submitted
3/05/2010
Date registered
5/05/2010
Date last updated
24/05/2022

Titles & IDs
Public title
International Collaborative Treatment Protocol For Children And Adolescents With Acute Lymphoblastic Leukemia
Scientific title
International Collaborative Treatment Protocol For Children And Adolescents With Acute Lymphoblastic Leukemia
Secondary ID [1] 0 0
AIEOP-BFM ALL 2009
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Leukemia 0 0
Condition category
Condition code
Cancer 0 0 0 0
Leukaemia - Acute leukaemia
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia
Cancer 0 0 0 0
Children's - Leukaemia & Lymphoma
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - PEG-L-asparaginase
Treatment: Drugs - cyclophosphamide
Treatment: Drugs - cytarabine
Treatment: Drugs - daunorubicin hydrochloride
Treatment: Drugs - dexamethasone
Treatment: Drugs - doxorubicin hydrochloride
Treatment: Drugs - etoposide
Treatment: Drugs - ifosfamide
Treatment: Drugs - mercaptopurine
Treatment: Drugs - methotrexate
Treatment: Drugs - prednisone
Treatment: Drugs - thioguanine
Treatment: Drugs - vincristine sulfate
Treatment: Drugs - vindesine
Treatment: Drugs - daunoxome
Treatment: Drugs - fludarabine
Treatment: Other - Radiation Therapy

Active comparator: R1 control arm - see detailed protocol description

Experimental: R1 experimental arm - see detailed protocol description

Active comparator: R2 control arm - see detailed protocol description

Experimental: R2 experimental arm - see detailed protocol description

Active comparator: R-HR control arm - see detailed protocol description

Experimental: R-HR experimental arm - see detailed protocol description


Treatment: Drugs: PEG-L-asparaginase
see detailed protocol description

Treatment: Drugs: cyclophosphamide
see detailed protocol description

Treatment: Drugs: cytarabine
see detailed protocol description

Treatment: Drugs: daunorubicin hydrochloride
see detailed protocol description

Treatment: Drugs: dexamethasone
see detailed protocol description

Treatment: Drugs: doxorubicin hydrochloride
see detailed protocol description

Treatment: Drugs: etoposide
see detailed protocol description

Treatment: Drugs: ifosfamide
see detailed protocol description

Treatment: Drugs: mercaptopurine
see detailed protocol description

Treatment: Drugs: methotrexate
see detailed protocol description

Treatment: Drugs: prednisone
see detailed protocol description

Treatment: Drugs: thioguanine
see detailed protocol description

Treatment: Drugs: vincristine sulfate
see detailed protocol description

Treatment: Drugs: vindesine
see detailed protocol description

Treatment: Drugs: daunoxome
see detailed protocol description; only given by patients with poor MRD-response during the high risk treatment

Treatment: Drugs: fludarabine
see detailed protocol description; only given by patients with poor MRD-response during the high risk treatment

Treatment: Other: Radiation Therapy
for eligibility for radiotherapy see detailed protocol description
Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Treatment: Other
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Event-free survival
Timepoint [1] 0 0
10 years from the start of recruitment
Primary outcome [2] 0 0
Disease-free survival
Timepoint [2] 0 0
10 years from the start of recruitment
Primary outcome [3] 0 0
minimal residual disease (MRD)
Timepoint [3] 0 0
week 12 of treatment
Secondary outcome [1] 0 0
survival
Timepoint [1] 0 0
10 years from the start of recruitment
Secondary outcome [2] 0 0
treatment-related mortality
Timepoint [2] 0 0
up to 25 months from the diagnosis
Secondary outcome [3] 0 0
adverse events
Timepoint [3] 0 0
up to 25 months from the diagnosis
Secondary outcome [4] 0 0
event-free survival
Timepoint [4] 0 0
10 years from the start of recruitment
Secondary outcome [5] 0 0
minimal residual disease
Timepoint [5] 0 0
after 24 weeks of treatment

Eligibility
Key inclusion criteria
* newly diagnosed acute lymphoblastic leukemia
* age = 1 year (> 365 days) and < 18 years old (up to 17 years old and 365 days)
* no Ph+ (BCR/ABL or t(9;22)-positive) ALL
* no evidence of pregnancy or lactation period
* no participation in another clinical study
* patient enrolled in a participating center
* written informed consent
Minimum age
1 Year
Maximum age
18 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
* pre-treatment with cytostatic drugs
* pre-treatment with cytostatic drugs
* steroid pre-treatment with = 1 mg/kg/d for more than two weeks during the last month before diagnosis
* treatment started according to another protocol
* underlying diseases that prohibit treatment according to the protocol
* ALL diagnosed as second malignancy steroid pre-treatment with = 1 mg/kg/d for more than two weeks during the last month before diagnosis

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Factorial
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
1/06/2010
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
31/12/2021
Sample size
Target
Accrual to date
Final
6136
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
The Sydney Children's Hospital, Centre for Children's Cancer and Blood Disorders - Randwick
Recruitment hospital [2] 0 0
The Children's Hospital at Westmead, Department of Oncology - Westmead
Recruitment postcode(s) [1] 0 0
NSW 2031 - Randwick
Recruitment postcode(s) [2] 0 0
NSW 2145 - Westmead
Recruitment outside Australia
Country [1] 0 0
Austria
State/province [1] 0 0
Dornbirn
Country [2] 0 0
Austria
State/province [2] 0 0
Graz
Country [3] 0 0
Austria
State/province [3] 0 0
Innsbruck
Country [4] 0 0
Austria
State/province [4] 0 0
Klagenfurt
Country [5] 0 0
Austria
State/province [5] 0 0
Leoben
Country [6] 0 0
Austria
State/province [6] 0 0
Linz
Country [7] 0 0
Austria
State/province [7] 0 0
Salzburg
Country [8] 0 0
Austria
State/province [8] 0 0
Wien
Country [9] 0 0
Czechia
State/province [9] 0 0
Brno
Country [10] 0 0
Czechia
State/province [10] 0 0
Hradec Králové
Country [11] 0 0
Czechia
State/province [11] 0 0
Olomouc
Country [12] 0 0
Czechia
State/province [12] 0 0
Ostrava-Poruba
Country [13] 0 0
Czechia
State/province [13] 0 0
Plzen
Country [14] 0 0
Czechia
State/province [14] 0 0
Praha 5
Country [15] 0 0
Czechia
State/province [15] 0 0
Ústí nad Labem
Country [16] 0 0
Czechia
State/province [16] 0 0
Ceské Budejovice
Country [17] 0 0
Germany
State/province [17] 0 0
Aachen
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Germany
State/province [18] 0 0
Augsburg
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Germany
State/province [19] 0 0
Bayreuth
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Germany
State/province [20] 0 0
Berlin
Country [21] 0 0
Germany
State/province [21] 0 0
Braunschweig
Country [22] 0 0
Germany
State/province [22] 0 0
Chemnitz
Country [23] 0 0
Germany
State/province [23] 0 0
Cottbus
Country [24] 0 0
Germany
State/province [24] 0 0
Datteln
Country [25] 0 0
Germany
State/province [25] 0 0
Detmold
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Germany
State/province [26] 0 0
Dortmund
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Germany
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Dresden
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Germany
State/province [28] 0 0
Düsseldorf
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Germany
State/province [29] 0 0
Erfurt
Country [30] 0 0
Germany
State/province [30] 0 0
Erlangen
Country [31] 0 0
Germany
State/province [31] 0 0
Essen
Country [32] 0 0
Germany
State/province [32] 0 0
Frankfurt
Country [33] 0 0
Germany
State/province [33] 0 0
Freiburg
Country [34] 0 0
Germany
State/province [34] 0 0
Gießen
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Germany
State/province [35] 0 0
Greifswald
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Germany
State/province [36] 0 0
Göttingen
Country [37] 0 0
Germany
State/province [37] 0 0
Halle
Country [38] 0 0
Germany
State/province [38] 0 0
Hannover
Country [39] 0 0
Germany
State/province [39] 0 0
Heidelberg
Country [40] 0 0
Germany
State/province [40] 0 0
Heilbronn
Country [41] 0 0
Germany
State/province [41] 0 0
Herdecke
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Germany
State/province [42] 0 0
Homburg / Saar
Country [43] 0 0
Germany
State/province [43] 0 0
Jena
Country [44] 0 0
Germany
State/province [44] 0 0
Karlsruhe
Country [45] 0 0
Germany
State/province [45] 0 0
Kassel
Country [46] 0 0
Germany
State/province [46] 0 0
Kiel
Country [47] 0 0
Germany
State/province [47] 0 0
Koblenz
Country [48] 0 0
Germany
State/province [48] 0 0
Köln
Country [49] 0 0
Germany
State/province [49] 0 0
Leipzig
Country [50] 0 0
Germany
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Lübeck
Country [51] 0 0
Germany
State/province [51] 0 0
Magdeburg
Country [52] 0 0
Germany
State/province [52] 0 0
Mannheim
Country [53] 0 0
Germany
State/province [53] 0 0
Minden
Country [54] 0 0
Germany
State/province [54] 0 0
München
Country [55] 0 0
Germany
State/province [55] 0 0
Münster
Country [56] 0 0
Germany
State/province [56] 0 0
Nürnberg
Country [57] 0 0
Germany
State/province [57] 0 0
Oldenburg
Country [58] 0 0
Germany
State/province [58] 0 0
Rostock
Country [59] 0 0
Germany
State/province [59] 0 0
Sankt Augustin
Country [60] 0 0
Germany
State/province [60] 0 0
Schwerin
Country [61] 0 0
Germany
State/province [61] 0 0
Stuttgart
Country [62] 0 0
Germany
State/province [62] 0 0
Trier
Country [63] 0 0
Germany
State/province [63] 0 0
Tübingen
Country [64] 0 0
Germany
State/province [64] 0 0
Ulm
Country [65] 0 0
Germany
State/province [65] 0 0
Wolfsburg
Country [66] 0 0
Germany
State/province [66] 0 0
Würzburg
Country [67] 0 0
Israel
State/province [67] 0 0
Afula
Country [68] 0 0
Israel
State/province [68] 0 0
Beer-Sheva
Country [69] 0 0
Israel
State/province [69] 0 0
Haifa
Country [70] 0 0
Israel
State/province [70] 0 0
Jerusalem
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Israel
State/province [71] 0 0
Petach Tikva
Country [72] 0 0
Israel
State/province [72] 0 0
Tel-Aviv
Country [73] 0 0
Israel
State/province [73] 0 0
Tel-Hashomer
Country [74] 0 0
Italy
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Ancona
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Italy
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Bari
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Italy
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Belluno
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Bergamo
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Italy
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Bologna
Country [79] 0 0
Italy
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Bolzano
Country [80] 0 0
Italy
State/province [80] 0 0
Brescia
Country [81] 0 0
Italy
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Cagliari
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Italy
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Catania
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Italy
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Catanzaro
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Cosenza
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Ferrara
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Firenze
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Genova
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Lecce
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Italy
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Milano
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Italy
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Modena
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Monza
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Napoli
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Nocera Inferiore
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Novara
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Padova
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Palermo
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Parma
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Pavia
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Perugia
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Pesaro
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Pescara
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Pisa
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Italy
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Pordenone
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Reggio Calabria
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Italy
State/province [105] 0 0
Rimini
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Italy
State/province [106] 0 0
Roma
Country [107] 0 0
Italy
State/province [107] 0 0
San Giovanni Rotondo
Country [108] 0 0
Italy
State/province [108] 0 0
Sassari
Country [109] 0 0
Italy
State/province [109] 0 0
Siena
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Italy
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Torino
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Italy
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Tricase
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Trieste
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Udine
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State/province [114] 0 0
Varese
Country [115] 0 0
Italy
State/province [115] 0 0
Verona
Country [116] 0 0
Italy
State/province [116] 0 0
Vicenza
Country [117] 0 0
Switzerland
State/province [117] 0 0
Aarau
Country [118] 0 0
Switzerland
State/province [118] 0 0
Basel
Country [119] 0 0
Switzerland
State/province [119] 0 0
Bellinzona
Country [120] 0 0
Switzerland
State/province [120] 0 0
Luzern
Country [121] 0 0
Switzerland
State/province [121] 0 0
St. Gallen
Country [122] 0 0
Switzerland
State/province [122] 0 0
Zürich

Funding & Sponsors
Primary sponsor type
Other
Name
University Hospital Schleswig-Holstein
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
Deutsche Krebshilfe e.V., Bonn (Germany)
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
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 website
https://clinicaltrials.gov/study/NCT01117441
Trial related presentations / publications
Conter V, Bartram CR, Valsecchi MG, Schrauder A, Panzer-Grumayer R, Moricke A, Arico M, Zimmermann M, Mann G, De Rossi G, Stanulla M, Locatelli F, Basso G, Niggli F, Barisone E, Henze G, Ludwig WD, Haas OA, Cazzaniga G, Koehler R, Silvestri D, Bradtke J, Parasole R, Beier R, van Dongen JJ, Biondi A, Schrappe M. Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study. Blood. 2010 Apr 22;115(16):3206-14. doi: 10.1182/blood-2009-10-248146. Epub 2010 Feb 12.
Flohr T, Schrauder A, Cazzaniga G, Panzer-Grumayer R, van der Velden V, Fischer S, Stanulla M, Basso G, Niggli FK, Schafer BW, Sutton R, Koehler R, Zimmermann M, Valsecchi MG, Gadner H, Masera G, Schrappe M, van Dongen JJ, Biondi A, Bartram CR; International BFM Study Group (I-BFM-SG). Minimal residual disease-directed risk stratification using real-time quantitative PCR analysis of immunoglobulin and T-cell receptor gene rearrangements in the international multicenter trial AIEOP-BFM ALL 2000 for childhood acute lymphoblastic leukemia. Leukemia. 2008 Apr;22(4):771-82. doi: 10.1038/leu.2008.5. Epub 2008 Jan 31.
Moricke A, Zimmermann M, Reiter A, Henze G, Schrauder A, Gadner H, Ludwig WD, Ritter J, Harbott J, Mann G, Klingebiel T, Zintl F, Niemeyer C, Kremens B, Niggli F, Niethammer D, Welte K, Stanulla M, Odenwald E, Riehm H, Schrappe M. Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALL-BFM study group from 1981 to 2000. Leukemia. 2010 Feb;24(2):265-84. doi: 10.1038/leu.2009.257. Epub 2009 Dec 10.
Wurthwein G, Lanvers-Kaminsky C, Siebel C, Gerss J, Moricke A, Zimmermann M, Stary J, Smisek P, Schrappe M, Rizzari C, Zucchetti M, Hempel G, Wicha SG, Boos J; AIEOP-BFM ALL 2009 Asparaginase Working Party. Population Pharmacokinetics of PEGylated Asparaginase in Children with Acute Lymphoblastic Leukemia: Treatment Phase Dependency and Predictivity in Case of Missing Data. Eur J Drug Metab Pharmacokinet. 2021 Mar;46(2):289-300. doi: 10.1007/s13318-021-00670-8. Epub 2021 Feb 17.
Tasian SK, Peters C. Targeted therapy or transplantation for paediatric ABL-class Ph-like acute lymphocytic leukaemia? Lancet Haematol. 2020 Dec;7(12):e858-e859. doi: 10.1016/S2352-3026(20)30369-0. No abstract available.
Cario G, Leoni V, Conter V, Attarbaschi A, Zaliova M, Sramkova L, Cazzaniga G, Fazio G, Sutton R, Elitzur S, Izraeli S, Lauten M, Locatelli F, Basso G, Buldini B, Bergmann AK, Lentes J, Steinemann D, Gohring G, Schlegelberger B, Haas OA, Schewe D, Buchmann S, Moericke A, White D, Revesz T, Stanulla M, Mann G, Bodmer N, Arad-Cohen N, Zuna J, Valsecchi MG, Zimmermann M, Schrappe M, Biondi A. Relapses and treatment-related events contributed equally to poor prognosis in children with ABL-class fusion positive B-cell acute lymphoblastic leukemia treated according to AIEOP-BFM protocols. Haematologica. 2020 Jul;105(7):1887-1894. doi: 10.3324/haematol.2019.231720. Epub 2019 Oct 10.
Kroll M, Kaupat-Bleckmann K, Morickel A, Altenl J, Schewel DM, Stanullal M, Zimmermann M, Schrappe M, Cario G. Methotrexate-associated toxicity in children with Down syndrome and acute lymphoblastic leukemia during consolidation therapy with high dose methotrexate according to ALL-BFM treatment regimen. Haematologica. 2020 Apr;105(4):1013-1020. doi: 10.3324/haematol.2019.224774. Epub 2019 Aug 1.
Wurthwein G, Lanvers-Kaminsky C, Hempel G, Gastine S, Moricke A, Schrappe M, Karlsson MO, Boos J. Population Pharmacokinetics to Model the Time-Varying Clearance of the PEGylated Asparaginase Oncaspar(R) in Children with Acute Lymphoblastic Leukemia. Eur J Drug Metab Pharmacokinet. 2017 Dec;42(6):955-963. doi: 10.1007/s13318-017-0410-5.
Public notes

Contacts
Principal investigator
Name 0 0
Martin Schrappe, MD PhD
Address 0 0
Department of Pediatrics, University Hospital of Schleswig-Holstein, Campus Kiel
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT01117441