Trial document





This study has been imported from ClinicalTrials.gov without additional data checks.
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  DRKS00003792

Trial Description

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Title

ALL-BFM 2000 Multi-Center Study for the Treatment of Children and Adolescents With Acute Lymphoblastic Leukemia

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Trial Acronym

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URL of the Trial

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Brief Summary in Lay Language

RATIONALE: 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.

PURPOSE: Thisphase III trial is studying several different combination chemotherapy regimens
to compare how well they work in treating young patients with acute lymphoblastic leukemia.

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Brief Summary in Scientific Language

OBJECTIVES:

- Compare the relative efficacy of induction therapy comprising dexamethasone or
prednisone, in terms of a higher rate of event-free survival (EFS) and overall survival
and a reduced rate of relapse, in pediatric patients with intermediate-risk or
high-risk acute lymphoblastic leukemia (ALL).

- Compare the relative safety of a reduced-intensity reintensification regimen comprising
dexamethasone, vincristine, cyclophosphamide, and anthracyclines vs a standard
treatment regimen in pediatric patients with standard-risk ALL identified by fast
clearance of leukemic cells.

- Compare the efficacy of a second delayed reintensification regimen vs standard
reintensification therapy, in terms of improved EFS, in pediatric patients with
intermediate-risk ALL.

- Compare the efficacy of extended reintensification therapy (triple reinduction) vs
standard reintensification therapy (intensive pulses and one reintensification) in
pediatric patients with high-risk ALL.

OUTLINE: This is a randomized, multicenter study.

- Prednisone prephase therapy: Patients receive oral prednisone on days 1-7 and one dose
of methotrexate (MTX) intrathecally (IT) on day 1.

- Induction/consolidation therapy, protocol I: Patients are randomized to 1 of 2
treatment arms.

- Arm I (closed to accrual as of 6/30/2006): Patients receive prednisone (PRED) on
days 8-28.

- Arm II (closed to accrual as of 6/30/2006): Patients receive dexamethasone (DEXA)
on days 8-28.

Patients in both arms also receive vincristine (VCR) and daunorubicin hydrochloride (DNR)
once weekly in weeks 2-5; asparaginase (ASP) on days 12-33; cyclophosphamide (CPM) on days
36 and 64; cytarabine (ARA-C) in weeks 6-9; mercaptopurine (MP) on days 36-63; and MTX IT on
days 1, 12, 33, 45, and 59.*

NOTE: *Patients with CNS disease also receive MTX IT on days 18 and 27.

After completion of induction/consolidation therapy, patients are stratified according to
risk group based on disease response (standard-risk [SR] group [negative minimal residual
disease (MRD) on day 33 and before protocol M, day 78] vs high-risk [HR] group [MRD ≥ 10^-³
on day 78] vs intermediate-risk [IR] group [all nonSR/nonHR]).* Patients with SR and IR
disease proceed to extracompartment therapy. Patients with HR disease proceed to
reintensification therapy.

NOTE: *Patients meeting any of the following criteria are placed in the HR group regardless
of MRD response: Philadelphia chromosome-positive disease (BCR/ABL or t[9;22];
translocations [t4;11][q11;q23] or MLL/AF4); "prednisone-poor-response" (≥ 1,000 blasts/mm³
in the peripheral blood on day 8 after prednisone prephase therapy); or no response to study
induction therapy (M2/3 at day 33).

- Extracompartment therapy, protocol M: Patients receive MP on days 1-56 and MTX on days
8, 22, 36, and 50.

After completion of extracompartment therapy, SR and IR patients proceed to
reintensification therapy. SR patients are randomized to arms I or II. IR patients are
randomized to arms I or III. HR patients who have completed induction/consolidation therapy
are randomized to arms IV or V.

- Reintensification therapy:

- Arm I (standard reinduction therapy, protocol II [closed to accrual as of
6/30/2006]): SR and IR patients receive DEXA on days 1-22; VCR and doxorubicin
hydrochloride (DOX) in weeks 2-5; ASP on days 8, 11, 15, and 18; CPM on day 36;
ARA-C and thioguanine (TG) on days 36-49; and MTX IT on days 38 and 45.* Patients
then proceed to maintenance therapy.

NOTE: *Patients with CNS disease also receive MTX IT on days 1 and 18.

- Arm II (reduced-intensity reinduction therapy, protocol III [closed to accrual as of
6/30/2006]): SR patients receive DEXA on days 1-15; VCR and DOX on days 1 and 8; ASP on
days 1, 4, 8, and 11; CPM on day 15; ARA-C and TG on days 15-28; and MTX IT on days 17
and 24.* Patients then proceed to maintenance therapy.

NOTE: *Patients with CNS disease also receive MTX on day 1.

- Arm III (reduced-intensity reinduction/second delayed reinduction therapy [double
reintensification therapy] [closed to accrual as of 6/30/2006]): IR patients receive
reduced-intensity reintensification therapy as in arm II. After a 10-week interim
maintenance phase, treatment repeats once for a second delayed course of
reintensification therapy. Patients then proceed to maintenance therapy.

- Arm IV (standard reintensification therapy [closed to accrual as of 6/30/2006]): HR
patients receive two sequences of the following HR therapy elements (i.e., in this
order: 1, 2, 3, 1, 2, 3) following reintensification therapy as in arm I. Patients then
proceed to maintenance therapy.

- Element HR-1: Patients receive DEXA on days 1-5; VCR on days 1 and 6; ARA-C twice
on day 5; MTX and CPM every 12 hours on days 2-4 (5 doses); ASP on days 6 and 11;
and MTX/ARA-C/PRED IT on day 1.

- Element HR-2: Patients receive DEXA on days 1-5; vindesine on days 1 and 6; DNR on
day 5; MTX and ifosfamide every 12 hours on days 2-4 (5 doses); ASP on days 6 and
11; and MTX/ARA-C/PRED IT on day 1.* NOTE: *HR patients with CNS disease also
receive IT therapy on day 5.

- Element HR-3: Patients receive DEXA on days 1-5; ARA-C every 12 hours on days 1-2
(4 doses); etoposide five times daily on days 3-5; ASP on days 6 and 11; and
MTX/ARA-C/PRED IT on day 1.

- Arm V (extended reintensification therapy [triple protocol III] [closed to accrual as
of 6/30/2006]): HR patients receive HR therapy elements 3, 2, and 1 as in arm IV
following reintensification therapy as in arm II repeated the therapy element twice
with 4-week interim maintenance phases in between. Patients then proceed to maintenance
therapy.

- Interim maintenance/maintenance therapy: Patients receive MTX once weekly and MP
daily until week 104.

- Radiotherapy: HR patients or patients with T-cell acute lymphoblastic leukemia or
CNS disease undergo CNS radiotherapy.

PROJECTED ACCRUAL: A total of 2,000 patients will be accrued for this study.

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Organizational Data

  •   DRKS00003792
  •   2012/05/04
  •   2007/01/30
  •   yes
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Secondary IDs

  •   NCT00430118  (ClinicalTrials.gov)
  •   CDR0000528029  (University of Schleswig-Holstein)
  •   ALL-BFM-2000 
  •   EU-20682 
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Health Condition or Problem studied

  •   Leukemia
  •   C91.0 -  Acute lymphoblastic leukaemia
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Interventions/Observational Groups

  •   Drug: 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
  •   Radiation: radiation therapy
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Characteristics

  •   Interventional
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  •   Randomized controlled trial
  •   Open (masking not used)
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  •   Active control (effective treament of control group)
  •   Treatment
  •   Factorial
  •   III
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Primary Outcome

- Efficacy of dexamethasone vs prednisone during the induction phase; time frame: End of Trial
- Event-free survival (EFS) and overall survival after initial remission in intermediate-risk and high-risk patients; time frame: End of Trial
- Safety and efficacy of treatment reduction during reintensification in standard-risk patients; time frame: End of Trial
- EFS after second delayed reintensification in intermediate-risk patients; time frame: End of Trial
- Outcome after extended reintensification therapy in high-risk patients; time frame: End of Trial

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Secondary Outcome

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Countries of Recruitment

  •   Austria
  •   Germany
  •   Switzerland
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Locations of Recruitment

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Recruitment

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  •   2000/07/31
  •   2000
  •   Multicenter trial
  •   International
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Inclusion Criteria

  •   Both, male and female
  •   1   Years
  •   18   Years
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Additional Inclusion Criteria

DISEASE CHARACTERISTICS:

- Histologically confirmed acute lymphoblastic leukemia (ALL)

- No secondary ALL

PATIENT CHARACTERISTICS:

- No prior disease that would preclude treatment with chemotherapy

PRIOR CONCURRENT THERAPY:

- More than 4 weeks since prior chemotherapy

- More than 4 weeks since prior steroids

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Exclusion Criteria

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Addresses

  • start of 1:1-Block address primary-sponsor
    • University of Schleswig-Holstein
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    • University of Schleswig-Holstein
    • Martin Schrappe, MD, PhD 
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    • University of Schleswig-Holstein
    • Martin Schrappe, MD, PhD 
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Sources of Monetary or Material Support

  • start of 1:1-Block address materialSupport
    • Bitte wenden Sie sich an den Sponsor / Please refer to primary sponsor
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Status

  •   Recruiting complete, follow-up complete
  •   2012/01/01
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Trial Publications, Results and other Documents

  •   Clinical trial summary from the National Cancer Institute's PDQ® database
  •   Attarbaschi A, Mann G, Panzer-Grümayer R, Röttgers S, Steiner M, König M, Csinady E, Dworzak MN, Seidel M, Janousek D, Möricke A, Reichelt C, Harbott J, Schrappe M, Gadner H, Haas OA. Minimal residual disease values discriminate between low and high relapse risk in children with B-cell precursor acute lymphoblastic leukemia and an intrachromosomal amplification of chromosome 21: the Austrian and German acute lymphoblastic leukemia Berlin-Frankfurt-Munster (ALL-BFM) trials. J Clin Oncol. 2008 Jun 20;26(18):3046-50.; 18565891
  •   Schrappe M, Valsecchi MG, Bartram CR, Schrauder A, Panzer-Grümayer R, Möricke A, Parasole R, Zimmermann M, Dworzak M, Buldini B, Reiter A, Basso G, Klingebiel T, Messina C, Ratei R, Cazzaniga G, Koehler R, Locatelli F, Schäfer BW, Aricò M, Welte K, van Dongen JJ, Gadner H, Biondi A, Conter V. Late MRD response determines relapse risk overall and in subsets of childhood T-cell ALL: results of the AIEOP-BFM-ALL 2000 study. Blood. 2011 Aug 25;118(8):2077-84. Epub 2011 Jun 30.; 21719599
  •   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. Epub 2010 Feb 12.; 20154213
  •   Kox C, Zimmermann M, Stanulla M, Leible S, Schrappe M, Ludwig WD, Koehler R, Tolle G, Bandapalli OR, Breit S, Muckenthaler MU, Kulozik AE. The favorable effect of activating NOTCH1 receptor mutations on long-term outcome in T-ALL patients treated on the ALL-BFM 2000 protocol can be separated from FBXW7 loss of function. Leukemia. 2010 Dec;24(12):2005-13. Epub 2010 Oct 14.; 20944675
  •   Schrey D, Borghorst S, Lanvers-Kaminsky C, Hempel G, Gerss J, Möricke A, Schrappe M, Boos J. Therapeutic drug monitoring of asparaginase in the ALL-BFM 2000 protocol between 2000 and 2007. Pediatr Blood Cancer. 2010 Jul 1;54(7):952-8.; 20108339
  •   Kox C, Zimmermann M, Stanulla M, et al.: The favorable effect of activating NOTCH1 receptor mutations on long term outcome in T-ALL is treatment related and can be separated from NOTCH pathway activation by FBXW7 loss of function. [Abstract] Blood 114 (22): A-908, 2009.
  •   Dworzak MN, Schumich A, Printz D, Pötschger U, Husak Z, Attarbaschi A, Basso G, Gaipa G, Ratei R, Mann G, Gadner H. CD20 up-regulation in pediatric B-cell precursor acute lymphoblastic leukemia during induction treatment: setting the stage for anti-CD20 directed immunotherapy. Blood. 2008 Nov 15;112(10):3982-8. Epub 2008 Sep 9.; 18780832
  •   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. Epub 2008 Jan 31.; 18239620
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The parameters in ClinicalTrials.gov and DRKS are not identical. Therefore the data import from ClinicalTrials.gov required adjustments. For full details please see the DRKS FAQs .
  •   10
  •   2013/10/30
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