ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01117441
Recruitment Status : Active, not recruiting
First Posted : May 5, 2010
Last Update Posted : May 23, 2018
Sponsor:
Collaborator:
Deutsche Krebshilfe e.V., Bonn (Germany)
Information provided by (Responsible Party):
Martin Schrappe, University of Schleswig-Holstein

May 3, 2010
May 5, 2010
May 23, 2018
June 2010
December 2021   (Final data collection date for primary outcome measure)
  • 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)
Same as current
Complete list of historical versions of study NCT01117441 on ClinicalTrials.gov Archive Site
  • 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
Same as current
Not Provided
Not Provided
 
International Collaborative Treatment Protocol For Children And Adolescents With Acute Lymphoblastic Leukemia
International Collaborative Treatment Protocol For Children And Adolescents With Acute Lymphoblastic Leukemia

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?

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).

Interventional
Phase 3
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Leukemia
  • 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
  • Active Comparator: R1 control arm
    see detailed protocol description
    Interventions:
    • Drug: PEG-L-asparaginase
    • Drug: cyclophosphamide
    • Drug: cytarabine
    • Drug: daunorubicin hydrochloride
    • Drug: dexamethasone
    • Drug: doxorubicin hydrochloride
    • Drug: mercaptopurine
    • Drug: methotrexate
    • Drug: prednisone
    • Drug: thioguanine
    • Drug: vincristine sulfate
    • Radiation: Radiation Therapy
  • Experimental: R1 experimental arm
    see detailed protocol description
    Interventions:
    • Drug: PEG-L-asparaginase
    • Drug: cyclophosphamide
    • Drug: cytarabine
    • Drug: daunorubicin hydrochloride
    • Drug: dexamethasone
    • Drug: doxorubicin hydrochloride
    • Drug: mercaptopurine
    • Drug: methotrexate
    • Drug: prednisone
    • Drug: thioguanine
    • Drug: vincristine sulfate
    • Radiation: Radiation Therapy
  • Active Comparator: R2 control arm
    see detailed protocol description
    Interventions:
    • Drug: PEG-L-asparaginase
    • Drug: cyclophosphamide
    • Drug: cytarabine
    • Drug: daunorubicin hydrochloride
    • Drug: dexamethasone
    • Drug: doxorubicin hydrochloride
    • Drug: mercaptopurine
    • Drug: methotrexate
    • Drug: prednisone
    • Drug: thioguanine
    • Drug: vincristine sulfate
    • Radiation: Radiation Therapy
  • Experimental: R2 experimental arm
    see detailed protocol description
    Interventions:
    • Drug: PEG-L-asparaginase
    • Drug: cyclophosphamide
    • Drug: cytarabine
    • Drug: daunorubicin hydrochloride
    • Drug: dexamethasone
    • Drug: doxorubicin hydrochloride
    • Drug: mercaptopurine
    • Drug: methotrexate
    • Drug: prednisone
    • Drug: thioguanine
    • Drug: vincristine sulfate
    • Radiation: Radiation Therapy
  • Active Comparator: R-HR control arm
    see detailed protocol description
    Interventions:
    • 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
  • Experimental: R-HR experimental arm
    see detailed protocol description
    Interventions:
    • 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

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
4750
Same as current
December 2021
December 2021   (Final data collection date for primary outcome measure)

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
Sexes Eligible for Study: All
1 Year to 18 Years   (Child, Adult)
No
Contact information is only displayed when the study is recruiting subjects
Australia,   Austria,   Czechia,   Germany,   Israel,   Italy,   Switzerland
Czech Republic
 
NCT01117441
AIEOP-BFM ALL 2009
Yes
Not Provided
Not Provided
Martin Schrappe, University of Schleswig-Holstein
University of Schleswig-Holstein
Deutsche Krebshilfe e.V., Bonn (Germany)
Principal Investigator: Martin Schrappe, MD PhD Department of Pediatrics, University Hospital of Schleswig-Holstein, Campus Kiel
University of Schleswig-Holstein
May 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP