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

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2013 by University of Schleswig-Holstein
Sponsor:
Collaborators:
Deutsche Krebshilfe e.V., Bonn (Germany)
SIGMA TAU RARE DISEASES, S.A.
medac GmbH
Information provided by (Responsible Party):
Martin Schrappe, University of Schleswig-Holstein
ClinicalTrials.gov Identifier:
NCT01117441
First received: May 3, 2010
Last updated: August 15, 2013
Last verified: August 2013
  Purpose

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 Intervention 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
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Factorial Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: International Collaborative Treatment Protocol For Children And Adolescents With Acute Lymphoblastic Leukemia

Resource links provided by NLM:


Further study details as provided by University of Schleswig-Holstein:

Primary Outcome Measures:
  • Event-free survival [ Time Frame: 10 years from the start of recruitment ] [ Designated as safety issue: No ]
    • 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 ] [ Designated as safety issue: No ]
    • 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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    All randomized and historical comparisons: Survival

  • treatment-related mortality [ Time Frame: up to 25 months from the diagnosis ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    Randomization R-HR: Event-free survival from time of randomization

  • minimal residual disease [ Time Frame: after 24 weeks of treatment ] [ Designated as safety issue: No ]
    "MRD Non-Responders": MRD levels after DNX-FLA


Estimated Enrollment: 4750
Study Start Date: June 2010
Estimated Study Completion Date: May 2020
Estimated Primary Completion Date: May 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   1 Year to 18 Years
Genders Eligible for Study:   Both
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01117441

  Show 141 Study Locations
Sponsors and Collaborators
University of Schleswig-Holstein
Deutsche Krebshilfe e.V., Bonn (Germany)
SIGMA TAU RARE DISEASES, S.A.
medac GmbH
Investigators
Principal Investigator: Martin Schrappe, MD PhD Department of Pediatrics, University Hospital of Schleswig-Holstein, Campus Kiel
  More Information

Publications:

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
Study First Received: May 3, 2010
Last Updated: August 15, 2013
Health Authority: Germany: Federal Institute for Drugs and Medical Devices
Austria: Federal Office for Safety in Health Care
Czech Republic: State Institute for Drug Control
Italy: The Italian Medicines Agency
Switzerland: Swissmedic
Australia: Department of Health and Ageing Therapeutic Goods Administration
Israel: Ministry of Health

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphoid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
6-Mercaptopurine
Cytarabine
Methotrexate
Thioguanine
Fludarabine phosphate
Cyclophosphamide
Liposomal doxorubicin
Isophosphamide mustard
Fludarabine
Pegaspargase
Asparaginase
Daunorubicin
Dexamethasone
Doxorubicin
Etoposide
Ifosfamide
Prednisone
Vincristine
Vindesine
BB 1101
Dexamethasone acetate

ClinicalTrials.gov processed this record on August 28, 2014