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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 : May 23, 2018
Sponsor:
Collaborator:
Deutsche Krebshilfe e.V., Bonn (Germany)
Information provided by (Responsible Party):
Martin Schrappe, University of Schleswig-Holstein

Brief Summary:

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

  Hide Detailed Description

Detailed Description:

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).


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




Primary Outcome Measures :
  1. 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)

  2. 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

  3. 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)


Secondary Outcome Measures :
  1. survival [ Time Frame: 10 years from the start of recruitment ]
    All randomized and historical comparisons: Survival

  2. 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)

  3. 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

  4. event-free survival [ Time Frame: 10 years from the start of recruitment ]
    Randomization R-HR: Event-free survival from time of randomization

  5. minimal residual disease [ Time Frame: after 24 weeks of treatment ]
    "MRD Non-Responders": MRD levels after DNX-FLA



Information from the National Library of Medicine

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, Learn About Clinical Studies.


Ages Eligible for Study:   1 Year to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
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

Information from the National Library of Medicine

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


  Show 139 Study Locations
Sponsors and Collaborators
University of Schleswig-Holstein
Deutsche Krebshilfe e.V., Bonn (Germany)
Investigators
Principal Investigator: Martin Schrappe, MD PhD Department of Pediatrics, University Hospital of Schleswig-Holstein, Campus Kiel

Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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
First Posted: May 5, 2010    Key Record Dates
Last Update Posted: May 23, 2018
Last Verified: May 2018

Additional relevant MeSH terms:
Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Dexamethasone
Prednisone
Fludarabine
Liposomal doxorubicin
Pegaspargase
Cyclophosphamide
Doxorubicin
Methotrexate
Etoposide
Cytarabine
Vincristine
Ifosfamide
Daunorubicin
Asparaginase
6-Mercaptopurine
Thioguanine
Vindesine
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents