International Collaborative Treatment Protocol For Children And Adolescents With Acute Lymphoblastic Leukemia

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ClinicalTrials.gov Identifier: NCT01117441

Recruitment Status : Active, not recruiting

First Posted : May 5, 2010

Last Update Posted : June 4, 2019

Sponsor:

Collaborator:

Deutsche Krebshilfe e.V., Bonn (Germany)

Information provided by (Responsible Party):

Martin Schrappe, University of Schleswig-Holstein

Study Description

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?

Condition or disease	Intervention/treatment	Phase
Leukemia	Drug: PEG-L-asparaginase Drug: cyclophosphamide Drug: cytarabine Drug: daunorubicin hydrochloride Drug: dexamethasone Drug: doxorubicin hydrochloride Drug: etoposide Drug: ifosfamide Drug: mercaptopurine Drug: methotrexate Drug: prednisone Drug: thioguanine Drug: vincristine sulfate Drug: vindesine Drug: daunoxome Drug: fludarabine Radiation: Radiation Therapy	Phase 3

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Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	4750 participants
Allocation:	Randomized
Intervention Model:	Factorial Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	International Collaborative Treatment Protocol For Children And Adolescents With Acute Lymphoblastic Leukemia
Study Start Date :	June 2010
Estimated Primary Completion Date :	December 2021
Estimated Study Completion Date :	December 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Chronic Lymphocytic Leukemia Leukemia

Genetic and Rare Diseases Information Center resources: Acute Lymphoblastic Leukemia Lymphosarcoma

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: R1 control arm see detailed protocol description	Drug: PEG-L-asparaginase see detailed protocol description Other Name: Oncaspar medac Drug: cyclophosphamide see detailed protocol description Drug: cytarabine see detailed protocol description Drug: daunorubicin hydrochloride see detailed protocol description Drug: dexamethasone see detailed protocol description Drug: doxorubicin hydrochloride see detailed protocol description Drug: mercaptopurine see detailed protocol description Drug: methotrexate see detailed protocol description Drug: prednisone see detailed protocol description Drug: thioguanine see detailed protocol description Drug: vincristine sulfate see detailed protocol description Radiation: Radiation Therapy for eligibility for radiotherapy see detailed protocol description
Experimental: R1 experimental arm see detailed protocol description	Drug: PEG-L-asparaginase see detailed protocol description Other Name: Oncaspar medac Drug: cyclophosphamide see detailed protocol description Drug: cytarabine see detailed protocol description Drug: daunorubicin hydrochloride see detailed protocol description Drug: dexamethasone see detailed protocol description Drug: doxorubicin hydrochloride see detailed protocol description Drug: mercaptopurine see detailed protocol description Drug: methotrexate see detailed protocol description Drug: prednisone see detailed protocol description Drug: thioguanine see detailed protocol description Drug: vincristine sulfate see detailed protocol description Radiation: Radiation Therapy for eligibility for radiotherapy see detailed protocol description
Active Comparator: R2 control arm see detailed protocol description	Drug: PEG-L-asparaginase see detailed protocol description Other Name: Oncaspar medac Drug: cyclophosphamide see detailed protocol description Drug: cytarabine see detailed protocol description Drug: daunorubicin hydrochloride see detailed protocol description Drug: dexamethasone see detailed protocol description Drug: doxorubicin hydrochloride see detailed protocol description Drug: mercaptopurine see detailed protocol description Drug: methotrexate see detailed protocol description Drug: prednisone see detailed protocol description Drug: thioguanine see detailed protocol description Drug: vincristine sulfate see detailed protocol description Radiation: Radiation Therapy for eligibility for radiotherapy see detailed protocol description
Experimental: R2 experimental arm see detailed protocol description	Drug: PEG-L-asparaginase see detailed protocol description Other Name: Oncaspar medac Drug: cyclophosphamide see detailed protocol description Drug: cytarabine see detailed protocol description Drug: daunorubicin hydrochloride see detailed protocol description Drug: dexamethasone see detailed protocol description Drug: doxorubicin hydrochloride see detailed protocol description Drug: mercaptopurine see detailed protocol description Drug: methotrexate see detailed protocol description Drug: prednisone see detailed protocol description Drug: thioguanine see detailed protocol description Drug: vincristine sulfate see detailed protocol description Radiation: Radiation Therapy for eligibility for radiotherapy see detailed protocol description
Active Comparator: R-HR control arm see detailed protocol description	Drug: PEG-L-asparaginase see detailed protocol description Other Name: Oncaspar medac Drug: cyclophosphamide see detailed protocol description Drug: cytarabine see detailed protocol description Drug: daunorubicin hydrochloride see detailed protocol description Drug: dexamethasone see detailed protocol description Drug: doxorubicin hydrochloride see detailed protocol description Drug: etoposide see detailed protocol description Drug: ifosfamide see detailed protocol description Drug: mercaptopurine see detailed protocol description Drug: methotrexate see detailed protocol description Drug: prednisone see detailed protocol description Drug: thioguanine see detailed protocol description Drug: vincristine sulfate see detailed protocol description Drug: vindesine see detailed protocol description Drug: daunoxome see detailed protocol description; only given by patients with poor MRD-response during the high risk treatment Drug: fludarabine see detailed protocol description; only given by patients with poor MRD-response during the high risk treatment Radiation: Radiation Therapy for eligibility for radiotherapy see detailed protocol description
Experimental: R-HR experimental arm see detailed protocol description	Drug: PEG-L-asparaginase see detailed protocol description Other Name: Oncaspar medac Drug: cyclophosphamide see detailed protocol description Drug: cytarabine see detailed protocol description Drug: daunorubicin hydrochloride see detailed protocol description Drug: dexamethasone see detailed protocol description Drug: doxorubicin hydrochloride see detailed protocol description Drug: etoposide see detailed protocol description Drug: ifosfamide see detailed protocol description Drug: mercaptopurine see detailed protocol description Drug: methotrexate see detailed protocol description Drug: prednisone see detailed protocol description Drug: thioguanine see detailed protocol description Drug: vincristine sulfate see detailed protocol description Drug: vindesine see detailed protocol description Drug: daunoxome see detailed protocol description; only given by patients with poor MRD-response during the high risk treatment Drug: fludarabine see detailed protocol description; only given by patients with poor MRD-response during the high risk treatment Radiation: Radiation Therapy for eligibility for radiotherapy see detailed protocol description

Outcome Measures

Primary Outcome Measures :

Event-free survival [ Time Frame: 10 years from the start of recruitment ]
- 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)
Disease-free survival [ Time Frame: 10 years from the start of recruitment ]
- Randomization R2: Disease-free survival from time of randomization
- Historical comparison SR: Disease-free survival from start of Protocol M
minimal residual disease (MRD) [ Time Frame: week 12 of treatment ]
Randomization RHR: rate of MRD highly positive patients (MRD ≥ 10-3) at TP2 (week 12)

Secondary Outcome Measures :

survival [ Time Frame: 10 years from the start of recruitment ]
All randomized and historical comparisons: Survival
treatment-related mortality [ Time Frame: up to 25 months from the diagnosis ]
All randomized and historical comparisons: treatment-related mortality in induction or CCR (overall and by chemotherapy/SCT)
adverse events [ Time Frame: up to 25 months from the diagnosis ]
All randomized and historical comparisons: incidence and frequency of adverse events of interest and serious adverse events
event-free survival [ Time Frame: 10 years from the start of recruitment ]
Randomization R-HR: Event-free survival from time of randomization
minimal residual disease [ Time Frame: after 24 weeks of treatment ]
"MRD Non-Responders": MRD levels after DNX-FLA

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:	1 Year to 18 Years (Child, Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

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

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01117441

Show 139 Study Locations

Sponsors and Collaborators

University of Schleswig-Holstein

Deutsche Krebshilfe e.V., Bonn (Germany)

Investigators

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Principal Investigator:	Martin Schrappe, MD PhD	Department of Pediatrics, University Hospital of Schleswig-Holstein, Campus Kiel

More Information

Publications:

Conter V, Bartram CR, Valsecchi MG, Schrauder A, Panzer-Grümayer R, Möricke A, Aricò 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-Grümayer R, van der Velden V, Fischer S, Stanulla M, Basso G, Niggli FK, Schäfer 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.

Möricke 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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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, Göhring 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. 2019 Oct 10. pii: haematol.2019.231720. doi: 10.3324/haematol.2019.231720. [Epub ahead of print]

Würthwein G, Lanvers-Kaminsky C, Hempel G, Gastine S, Möricke A, Schrappe M, Karlsson MO, Boos J. Population Pharmacokinetics to Model the Time-Varying Clearance of the PEGylated Asparaginase Oncaspar(®) in Children with Acute Lymphoblastic Leukemia. Eur J Drug Metab Pharmacokinet. 2017 Dec;42(6):955-963. doi: 10.1007/s13318-017-0410-5.

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Responsible Party:	Martin Schrappe, Prof. Dr. med., University of Schleswig-Holstein
ClinicalTrials.gov Identifier:	NCT01117441 History of Changes
Other Study ID Numbers:	AIEOP-BFM ALL 2009
First Posted:	May 5, 2010 Key Record Dates
Last Update Posted:	June 4, 2019
Last Verified:	June 2019

Additional relevant MeSH terms:

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Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid Neoplasms by Histologic Type Neoplasms Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Cytarabine Dexamethasone Prednisone Cyclophosphamide Doxorubicin Methotrexate	Fludarabine Etoposide Vincristine Ifosfamide Daunorubicin Asparaginase Mercaptopurine Thioguanine Vindesine Pegaspargase Anti-Inflammatory Agents Antiemetics Autonomic Agents Peripheral Nervous System Agents Physiological Effects of Drugs

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