Trial document





This study has been imported from ClinicalTrials.gov without additional data checks.
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  DRKS00003772

Trial Description

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Title

International Collaborative Treatment Protocol For 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/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?

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Brief Summary in Scientific Language

Risk Stratification

- T/non-HR: T-ALL in absence of any HR criteria (see below)

- pB/non-HR: pB-ALL in absence of any HR criteria (see below).

- SR (polymerase chain reaction(PCR)-MRD-SR (MRD-negative on day 33 and 78) or, if
no PCR-MRD result available, FCM d15 < 0.1%)

- MR (no SR)

- HR: Prednisone poor-response (≥1000 blast cells/µl in peripheral blood on day 8), blast
cells ≥10% in bone marrow on day 15 as measured by FCM, non-remission on day 33,
positivity for MLL/AF4 or t(4;11), hypodiploidy (< 45 chromosomes), PCR-MRD-HR (MRD
≥10E-3 on day 78) or PCR-MRD-MR SER (only in pB-ALL, MRD ≥ 10-3 on day 33 and MRD
positive at a level of < 10E-3 on day 78)

Chemotherapy

According to the risk group, patients receive the following chemotherapy elements:

T/non-HR: Protocol I, Protocol M, Protocol II and Maintenance pB/non-HR: Protocol I,
Protocol M, Protocol II and Maintenance HR: Protocol I, HR-1', HR-2', HR-3', 3x Protocol
III, Maintenance Patients of the HR group with PCR-MRD ≥10E-3 after element HR-3' are
eligible for treatment with element DNX-FLA.

Protocol I Cytoreductive prephase: Prednisone (PDN) on days 1-7 and one dose of methotrexate
(MTX) intrathecal (IT) on day 1 Protocol IA: Prednisone (PDN) on days 8 to 28 (21 days);
vincristine (VCR) on days 8, 15, 22, 29 (4 doses); daunorubicin (DNR) on days 8, 15, 22 and
29 (4 doses); pegylated L-asparaginase (PEG-L-ASP) on days 12 and 26; MTX IT on days 12 and
33 and in case of blast cells in cerebrospinal fluid at diagnosis additional IT MTX is given
on days 19 and 26.

Protocol IA': Only two doses of DNR on days 8 and 15 given to patients eligible for
randomization R1 and randomized into the experimental arm Protocol IA-CPM: additional
cyclophosphamide (CPM) on day 10 only in T-ALL patients with prednisone poor-response
Protocol IA-Dexa (IAD): Dexamethasone (DXM) instead of PDN is given to all patients with
T-ALL without any high-risk criteria as identified by day 8.

Protocol IB: CPM on days 36 and 64; cytarabine (ARA-C) on days 38-41, 45-48, 52-55 and
59-62; 6-mercaptopurine (6-MP) on days 36 to 63 (28 days); MTX IT on day 45 and 59 Protocol
IB-ASP+: additional PEG-L-ASP on days 40, 47, 54, and 61 (4 doses) are given to the patients
eligible for randomization RHR and randomized into the experimental arm.

Protocol M 6-MP on days 1- 56, high-dose MTX (HD-MTX) on days 8, 22, 36, 50 and MTX IT on
days 8, 22, 36 and 50 Protocol II Protocol IIA: DXM on days 1 to 21 (21 days); VCR on days
8, 15, 22, 29 (4 doses); doxorubicine (DOX) on days 8, 15, 22 and 29 (4 doses); PEG-L-ASP on
day 8 (1 dose); MTX IT on days 1 and 18 only in patients with initial CNS involvement.

Protocol IIA-ASP+: additional PEG-L-ASP on day 22 for patients eligible for randomization R2
and randomized into the experimental arm.

Protocol IIB: CPM on day 36; ARA-C on days 38-41 and 45-48; thioguanine (TG) on days 36 to
49 (14 days) and MTX IT on days 38 and 45.

Protocol IIB-ASP+: additional PEG-L-ASP on days 36 and 50 for eligible for randomization R2
and randomized into the experimental arm.

Protocol III DXM on days 1-15; VCR on days 1 and 8; DOX on days 1 and 8; PEG-L-ASP on day 1;
CPM on day 15; ARA-C on days 17-20 and 24-27; TG on days 15 - 28 and MTX IT on days 17 and
24, also on day 1 in patients with initial CNS involvement HR-1' DXM on days 1-5; VCR on
days 1 and 6; HD-MTX on day 1; CPM every 12 hours on days 2-4 (5 doses); HD-ARA-C every 12
hours on day 5 (2 doses); PEG-L-ASP on day 6, MTX IT on day 1 HR-2' DXM on days 1 to 5; VDS
on days 1 and 6; HD-MTX on day 1; IFO every 12 hours on days 2-4 (5 doses); DNR on day 5;
PEG-L-ASP on day 6; MTX IT on day 1 and 1 in patients with initial CNS involvement also day
5 HR-3' DXM on days 1-5; ARA-C 4 x on days 1-2 in 12 h intervals; etoposide (VP-16) every
12 hours on days 3-5 (5 doses); PEG-L-ASP on day 6; MTX IT on day 1 DNX-FLA Flucytosine
(FLU) on days 1-5 (5 doses); HD-ARA-C on days 1 to 5 (5 doses); liposomal daunorubicin (DNX)
on days 1, 3 and 5 (3 doses); MTX IT on day 1

Interim/Maintenance (until week 104):

6-MP p.o. daily; MTX p.o. once a week, doses adjusted to white blood cell count; PEG-L-ASP:
every second week (6 doses), only for patients eligible for randomization R2 and randomized
into the experimental arm; MTX IT every 6 weeks up to a total of 6 doses for the following
subgroups (all CNS-negative):

- T-ALL (HR or non-HR) with < 2 years of age at start of maintenance,

- T-ALL, non-HR and initial WBC < 100 000/μl

- pB-ALL with PPR and/or FCM-MRD day 15 ≥ 10 % and/or PCR-MRDMR SER as only HR criteria

Radiotherapy Patients without CNS involvement and

- T-ALL/non-HR, WBC ≥ 100 000/μl, and age ≥ 2 years at start of pCRT or

- with risk group HR and age ≥ 2 years at start of pCRT except pB-ALL with PPR and/or
FCM-MRD day 15 ≥ 10 % and/or PCR-MRD-MR SER as only HR criteria receive preventive
cranial radiotherapy with 12 Gy

Patients with CNS involvement receive therapeutic cranial radiotherapy with 18 Gy (age 1 to
<2 years 12 Gy).

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Organizational Data

  •   DRKS00003772
  •   2012/04/24
  •   2010/05/03
  •   yes
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Secondary IDs

  •   NCT01117441  (ClinicalTrials.gov)
  •   AIEOP-BFM ALL 2009  (University of Schleswig-Holstein)
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Health Condition or Problem studied

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

  •   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
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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

- 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)

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Secondary Outcome

- 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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Countries of Recruitment

  •   Australia
  •   Austria
  •   Czech Republic
  •   Germany
  •   Israel
  •   Italy
  •   Switzerland
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Locations of Recruitment

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Recruitment

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  •   2010/06/30
  •   4750
  •   Multicenter trial
  •   International
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Inclusion Criteria

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

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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

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Addresses

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    • University of Schleswig-Holstein
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    • Deutsche Krebshilfe e.V., Bonn (Germany)
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    • SIGMA TAU RARE DISEASES, S.A.
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    • medac GmbH
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    • Department of Pediatrics, University Hospital of Schleswig-Holstein, Campus Kiel
    • Martin Schrappe, MD PhD 
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    • Department of Pediatrics, University Hospital of Schleswig-Holstein, Campus Kiel
    • Martin Schrappe, MD PhD 
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Sources of Monetary or Material Support

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    • Bitte wenden Sie sich an den Sponsor / Please refer to primary sponsor
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Status

  •   Recruiting ongoing
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Trial Publications, Results and other Documents

  •   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
  •   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
  •   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. Epub 2009 Dec 10.; 20010625
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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 .
  •   366
  •   2013/10/30
* This entry means the parameter is not applicable or has not been set.