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 : October 20, 2020
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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 |

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 |

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 |
- 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)
- 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

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

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

Principal Investigator: | Martin Schrappe, MD PhD | Department of Pediatrics, University Hospital of Schleswig-Holstein, Campus Kiel |
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: | Martin Schrappe, Prof. Dr. med., University Hospital Schleswig-Holstein |
ClinicalTrials.gov Identifier: | NCT01117441 |
Other Study ID Numbers: |
AIEOP-BFM ALL 2009 |
First Posted: | May 5, 2010 Key Record Dates |
Last Update Posted: | October 20, 2020 |
Last Verified: | October 2020 |
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 Ifosfamide Doxorubicin |
Liposomal doxorubicin Methotrexate Fludarabine Etoposide Vincristine Daunorubicin Asparaginase Mercaptopurine Thioguanine Pegaspargase Vindesine Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Antirheumatic Agents |