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Trial record 15 of 48 for:    "Acute Lymphoblastic Leukemia, Childhood" | "Pegaspargase"

Treatment Protocol for Children and Adolescents With Acute Lymphoblastic Leukemia - AIEOP-BFM ALL 2017

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ClinicalTrials.gov Identifier: NCT03643276
Recruitment Status : Recruiting
First Posted : August 22, 2018
Last Update Posted : June 4, 2019
Sponsor:
Collaborator:
Deutsche Krebshilfe e.V., Bonn (Germany)
Information provided by (Responsible Party):
Martin Schrappe, University of Schleswig-Holstein

Tracking Information
First Submitted Date  ICMJE July 12, 2018
First Posted Date  ICMJE August 22, 2018
Last Update Posted Date June 4, 2019
Actual Study Start Date  ICMJE July 15, 2018
Estimated Primary Completion Date July 14, 2028   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 20, 2018)
  • Event-free survival [ Time Frame: Assessed up to 120 months from start of study ]
    Randomization R-eHR, R-HR and R-T: Time from randomization until the first event defined as follow: cytomorphological or molecular non-response (resistance to protocol treatment, considered as event at day zero), relapse, second malignancy or death from any cause. This will be called EFS time.
  • Disease-free survival [ Time Frame: Assessed up to 120 months from start of study ]
    Randomization R-MR: Time from randomization until the first event defined as follow: Relapse, second malignancy or death from any cause. This will be called DFS time.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03643276 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 20, 2018)
  • Survival [ Time Frame: Assessed up to 120 months from start of study ]
    All patients/randomizations: Time until death from any cause, starting at the same time point as the EFS/DFS.
  • Treatment-related mortality [ Time Frame: Assessed up to 120 months from start of study ]
    Frequency and incidence of treatment-related mortality in induction or continuous complete remission
  • Adverse Events of interest/Serious Adverse Events [ Time Frame: Assessed up to 120 months from start of study ]
    Frequency and incidence of adverse events of interest and serious adverse events in specific protocol phases, randomized arms and overall during follow-up
  • MRD response [ Time Frame: Measurements of MRD response at end of randomized treatments (intended time frame 13 weeks in R-eHR/R-T, 26 weeks in R-HR, 34 weeks in R-MR). ]
    MRD load after the randomized treatment phases (R-eHR, R-HR, R-MR and R-T) as well as after the first/second cycle of Blinatumomab or after the HR 2'/HR 3' block (R-HR)
  • Proportion of patients with Blina Poor-Response [ Time Frame: Measurements of MRD response intended after 30 weeks from individual start of treatment, assessment of proportion at 120 months from start of study ]
    Proportion of patients with poor MRD response to the first Blinatumomab cycle ("Blinatumomab Poor-Response") (R-HR)
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Treatment Protocol for Children and Adolescents With Acute Lymphoblastic Leukemia - AIEOP-BFM ALL 2017
Official Title  ICMJE International Collaborative Treatment Protocol for Children and Adolescents With Acute Lymphoblastic Leukemia - AIEOP-BFM ALL 2017
Brief Summary

The understanding of acute lymphoblastic leukemia (ALL) in childhood and adolescence has largely changed due to extensive genetic research in recent years: ALL is now considered to be a very heterogeneous disease group. The leukemia cells present themselves with quite differently activated regulatory mechanisms of the malignant phenotype. The introduction of more accurate methods of assessing therapy response ("minimal residual disease [MRD] tests") has provided new insights into very different mechanisms of action, including factors influenced by host factors; this has had practical clinical consequences for the use of more individualized therapy. Multimodal therapies have enabled a cure level of over 80% for ALL in this age group. However, the own and international study data show that the therapy toxicity of the contemporary chemotherapy concepts has become unacceptably high, in particular with respect to those intensified therapies used for the treatment of patients at high risk of ALL relapse.

The AIEOP-BFM ALL 2017 study therefore aims for an innovative integrated approach that will not only adapt the risk stratification to new prognostic markers using more comprehensive diagnostics, but above all, qualitatively reorient the therapy. The most important consequence will be that this study is testing immunotherapy with the bispecific antibody blinatumomab as an alternative to particularly intensive and toxic chemotherapy elements in precursor B-cell ALL (pB-ALL) patients with detectable chemotherapy resistance and at high risk of relapse. With the aim to complement the effects of the conventional chemotherapy, Blinatumomab is in addition tested in the large group of pB-ALL patients at intermediate relapse risk with seemingly unremarkable leukemia, but who account for a large proportion of all relapses. Targeted therapy is also used in the form of the proteasome inhibitor bortezomib for patients with pB-ALL and slow response to the drugs of the induction chemotherapy with the aim to overcome intrinsic chemotherapy resistance of the ALL cells. In patients with T-lineage ALL, who have particularly poor chances for cure after relapse, the established consolidation chemotherapy has proved to be particularly effective. This chemotherapy phase is therefore tested in a longer and more intensive form in such T-ALL patients with intermediate or slow early treatment response with the aim to reduce the relapses rate in this subgroup.

Detailed Description

Patients are stratified into 4 early risk groups for therapy during the consolidation phase (T/early SR, T/early non-SR, pB/early non-HR, pB/early HR) and 5 risk groups for post-consolidation therapy (T/non-HR, T/HR, pB/SR, pB/MR, pB/HR). Risk stratification is based on immunophenotypic lineage, genetics of leukemic cells and treatment response on the basis of cytomorphology and methods for detection minimal residual disease.

The trial includes four randomized study questions testing experimental treatments on top of the risk-stratified standard chemotherapy backbone:

Primary study questions:

Randomization R-eHR: Early High-risk (early HR) pB-ALL defined by genetics and/or inadequate treatment response over the course of induction: Can the probability of event-free survival (pEFS) from time of randomization be improved by additional therapy with the proteasome inhibitor bortezomib during an extended consolidation treatment phase compared with standard extended consolidation?

Randomization R-HR: High-risk (HR) pB-ALL defined by genetics and/or inadequate treatment response by the end of consolidation: Can the pEFS from time of randomization be improved by a treatment concept including two cycles of post-consolidation immunotherapy with blinatumomab (15 µg/m²/d for 28 days per cycle) plus 4 doses intrathecal Methotrexate replacing two conventional highly intensive chemotherapy courses?

Randomization R-MR: Intermediate risk (MR) pB-ALL defined by genetics and intermediate MRD response: Can the probability of disease-free survival (pDFS) from time of randomization be improved by additional therapy with one cycle of post-reintensification immunotherapy with blinatumomab (15 µg/m²/d for 28 days)?

Randomization R-T: Early non-standard risk (early non-SR) T-ALL patients defined by treatment response over the course of induction: Can the pEFS from time of randomization be improved by the extension of the standard of care consolidation phase by 14 days with an increase of the consolidation cumulative doses of Cyclophosphamide, Cytarabine and 6-Mercaptopurine by 50%?

Secondary study questions:

All randomizations: Can the overall survival be improved by the treatment in the experimental arm?

All randomizations: What is the incidence of treatment-related toxicities and mortality in the experimental arm compared to the standard arm?

Randomization R-eHR: Can the MRD load after consolidation treatment be reduced by the additional treatment with bortezomib?

Randomization R-HR: Can treatment-related life-threatening complications and mortality during the intensified consolidation phase of high-risk treatment be reduced when replacing two intensive chemotherapy courses by two cycles of immunotherapy with blinatumomab?

Randomization R-HR: What is the proportion of patients with insufficient MRD response to blinatumomab as defined in the protocol as compared to the MRD response after the HR-2' block in the control arm?

Randomization R-HR: Can the MRD load after the first treatment cycle (HR 2'/blinatumomab) and the second cycle (HR-3'/blinatumomab) be reduced in the experimental arm when compared with conventional intensive chemotherapy? Randomization R-MR: What is the proportion of patients with positive MRD after reintensification Protocol II who become MRD-negative over the blinatumomab cycle compared to 4 weeks of standard maintenance therapy?

Randomization R-T: Can the MRD load after consolidation treatment be reduced by extension of the consolidation phase?

Standard-risk patients: Is the clinical outcome comparable to that obtained for standard-risk patients in study AIEOP-BFM ALL 2009?

A small subgroup of patients at very high relapse risk is eligible for allogeneic hematopoietic stem cell transplantation after the intensified consolidation therapy phase.

Patients with T-ALL and hyperleukocytosis (>=100,000/µL) and patients with CNS involvement at diagnosis (CNS3 status) are eligible for cranial irradiation with 12 Gy if age at time of irradiation is at least 4 years.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Factorial Assignment
Intervention Model Description:

pB-ALL/MR: 2 parallel groups (R-MR) or 2x2 factorial design (R-eHR, R-MR) depending on early risk group assignment.

pB-ALL/HR: 2 parallel groups (R-HR) or 2x2 factorial design (R-eHR, R-HR) depending on early risk group assignment.

T-ALL/early non-SR: 2 parallel groups (R-T).

pB-ALL/SR: Single group.

T-ALL/early SR: Single group.

Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Acute Lymphoblastic Leukemia, Pediatric
Intervention  ICMJE
  • Drug: Blinatumomab
    Experimental therapy in randomizations R-HR and R-MR
  • Drug: Bortezomib
    Experimental therapy in randomization R-eHR
  • Drug: Cyclophosphamide
    Part of standard chemotherapy and included in experimental treatment phase Protocol IB long in randomization R-T
  • Drug: Cytarabine
    Part of standard chemotherapy and included in experimental treatment phase Protocol IB long in randomization R-T and in the intensification block DNX-FLA for patients with very high relapse risk
  • Drug: Daunorubicin
    Part of standard chemotherapy
  • Drug: DAUNOrubicin Liposomal Injection [DaunoXome]
    Part of intensification block DNX-FLA for patients with very high relapse risk
    Other Name: Liposomal Daunorubicin
  • Drug: Dexamethasone
    Part of standard chemotherapy
  • Drug: Doxorubicin
    Part of standard chemotherapy
  • Drug: Etoposide
    Part of standard chemotherapy
  • Drug: Fludarabine Phosphate
    Part of intensification block DNX-FLA for patients with very high relapse risk
  • Drug: Ifosfamide
    Part of standard chemotherapy
  • Drug: 6-Mercaptopurine
    Part of standard chemotherapy and included in experimental treatment phase Protocol IB long in randomization R-T
  • Drug: Methotrexate
    Part of standard chemotherapy
  • Drug: Pegaspargase
    Part of standard chemotherapy
  • Drug: Prednisolone
    Part of standard chemotherapy
    Other Name: Prednisone
  • Drug: Tioguanin
    Part of standard chemotherapy
  • Drug: Vincristine
    Part of standard chemotherapy
  • Drug: Vindesine
    Part of standard chemotherapy
  • Drug: Erwinase
    Part of standard chemotherapy as substitute for PEG-L-Asparaginase in case of allergic reaction
Study Arms  ICMJE
  • Active Comparator: pB: early (non-)HR-standard/MR-standard

    Induction (5 wks): "Protocol IA" with prednisolone, vincristine, daunorubicin, pegaspargase, IT methotrexate (MTX)

    Consolidation (6 w/4 w): "Consolidation extended" (control arm of randomization R-eHR) with cyclophosphamide, cytarabine, 6-mercaptopurine (6-MP), IT MTX, dexamethasone, vincristine, pegaspargase or "Consolidation short" (standard arm of early non-HR group) with cyclophosphamide, cytarabine, 6-mercaptopurine, IT MTX

    Extra-compartment phase (8 wks): "Protocol M" with 6-MP, HD-MTX, IT MTX

    Reinduction (6 wks): "Protocol II" with dexamethasone, vincristine, doxorubicin, pegaspargase, IT MTX, cyclophosphamide, tioguanine, cytarabine

    Maintenance (until 2 years after initial diagnosis): 6-MP, MTX [without preceding blinatumomab (control arm of randomization R-MR)]

    Erwinase is given in case of allergy to pegaspargase.

    Interventions:
    • Drug: Cyclophosphamide
    • Drug: Cytarabine
    • Drug: Daunorubicin
    • Drug: Dexamethasone
    • Drug: Doxorubicin
    • Drug: 6-Mercaptopurine
    • Drug: Methotrexate
    • Drug: Pegaspargase
    • Drug: Prednisolone
    • Drug: Tioguanin
    • Drug: Vincristine
    • Drug: Erwinase
  • Experimental: pB: early HR-exp./MR-standard

    Induction (5 w): "Protocol IA" with prednisolone, vincristine, daunorubicin, pegaspargase, IT MTX

    Consolidation (6 w): "Consolidation extended+BZM" (experimental arm of randomization R-eHR) with cyclophosphamide, cytarabine, 6-MP, IT MTX, dexamethasone, vincristine, pegaspargase, bortezomib (given at 1.3 mg/m²/dose on days 50, 53, 56 and 59)

    Extra-compartment phase (8 wks): "Protocol M" with 6-MP, HD-MTX, IT MTX

    Reinduction (6 wks): "Protocol II" with dexamethasone, vincristine, doxorubicin, pegaspargase, IT MTX, cyclophosphamide, tioguanine, cytarabine

    Maintenance (until 2 yrs after initial diagnosis): 6-MP, MTX [without preceding blinatumomab (control arm of randomization R-MR)]

    Erwinase is given in case of allergy to pegaspargase.

    Interventions:
    • Drug: Bortezomib
    • Drug: Cyclophosphamide
    • Drug: Cytarabine
    • Drug: Daunorubicin
    • Drug: Dexamethasone
    • Drug: Doxorubicin
    • Drug: 6-Mercaptopurine
    • Drug: Methotrexate
    • Drug: Pegaspargase
    • Drug: Prednisolone
    • Drug: Tioguanin
    • Drug: Vincristine
    • Drug: Erwinase
  • Experimental: pB: early (non)HR-standard/MR-exp.

    Induction (5 w): "Protocol IA" with prednisolone, vincristine, daunorubicin, pegaspargase, IT MTX

    Consolidation (6 w/4 w): "Consolidation extended" (control arm in randomization R-eHR) with cyclophosphamide, cytarabine, 6-MP, IT MTX, dexamethasone, vincristine, pegaspargase or "Consolidation short" (standard arm of early non-HR group) with cyclophosphamide, cytarabine, 6-mercaptopurine, IT MTX

    Extra-compartment phase (8 w): "Protocol M" with 6-MP, HD-MTX, IT MTX

    Reinduction (6 w): "Protocol II" with dexamethasone, vincristine, doxorubicin, pegaspargase, IT MTX, cyclophosphamide, tioguanine, cytarabine

    Blinatumomab (4 w): 1 cycle blinatumomab given at 15 µg/m²/day for 28 days (experimental arm of randomization R-MR)

    Maintenance (until 2 yrs after initial diagnosis): 6-MP, MTX

    Erwinase is given in case of allergy to pegaspargase.

    Interventions:
    • Drug: Blinatumomab
    • Drug: Cyclophosphamide
    • Drug: Cytarabine
    • Drug: Daunorubicin
    • Drug: Dexamethasone
    • Drug: Doxorubicin
    • Drug: 6-Mercaptopurine
    • Drug: Methotrexate
    • Drug: Pegaspargase
    • Drug: Prednisolone
    • Drug: Tioguanin
    • Drug: Vincristine
    • Drug: Erwinase
  • Experimental: pB: early HR-exp./MR-exp.

    Induction (5 w): "Protocol IA" with prednisolone, vincristine, daunorubicin, pegaspargase, IT MTX

    Consolidation (6 w): "Consolidation extended+BZM" (experimental arm of randomization R-eHR) with cyclophosphamide, cytarabine, 6-MP, IT MTX, dexamethasone, vincristine, pegaspargase, bortezomib (given at 1.3 mg/m²/dose on days 50, 53, 56 and 59)

    Extra-compartment phase (8 w): "Protocol M" with 6-MP, HD-MTX,IT MTX

    Reinduction (6 weeks): "Protocol II" with dexamethasone, vincristine, doxorubicin, PEG-L-asparaginase, IT MTX, cyclophosphamide, tioguanine, cytarabine

    Blinatumomab (4 w): 1 cycle blinatumomab given at 15 µg/m²/day for 28 days (experimental arm of randomization R-MR)

    Maintenance phase (until 2 yrs after initial diagnosis): 6-MP, MTX

    Erwinase is given in case of allergy to pegaspargase.

    Interventions:
    • Drug: Blinatumomab
    • Drug: Bortezomib
    • Drug: Cyclophosphamide
    • Drug: Cytarabine
    • Drug: Daunorubicin
    • Drug: Dexamethasone
    • Drug: Doxorubicin
    • Drug: 6-Mercaptopurine
    • Drug: Methotrexate
    • Drug: Pegaspargase
    • Drug: Prednisolone
    • Drug: Tioguanin
    • Drug: Vincristine
    • Drug: Erwinase
  • Active Comparator: pB: early (non-)HR-standard/HR-standard

    Induction (5 w): as in other pB arms

    Consolidation (6 w/4 w): "Consolidation extended" (control arm in randomization R-eHR) with cyclophosphamide, cytarabine, 6-MP, IT methotrexate, dexamethasone, vincristine, pegaspargase or "Consolidation short" (standard arm of early non-HR group) with cyclophosphamide, cytarabine, 6-MP, IT MTX

    Intensified consolidation (3x5 d): Block HR-1' followed by HR-2' and HR-3' (control arm in randomization R-HR) with dexamethasone, vincristine, vindesine, daunorubicin, HD-MTX, IT MTX, HD-cytarabine, cyclophosphamide, ifosfamide, pegaspargase, etoposide

    Reinduction (3x4 w): "Protocol III" given 3 times with dexamethasone, vincristine, doxorubicin, pegaspargase, IT MTX, cyclophosphamide, tioguanine, cytarabine

    Maintenance (until 2 yrs after init. diagnosis): 6-MP, MTX

    Erwinase is given in case pegaspargase allergy. Pts with poor response to intensified consolidation receive DNX-FLA (liposomal daunorubicin, fludarabine, HD-cytarabine, IT-MTX).

    Interventions:
    • Drug: Cyclophosphamide
    • Drug: Cytarabine
    • Drug: Daunorubicin
    • Drug: DAUNOrubicin Liposomal Injection [DaunoXome]
    • Drug: Dexamethasone
    • Drug: Doxorubicin
    • Drug: Etoposide
    • Drug: Fludarabine Phosphate
    • Drug: Ifosfamide
    • Drug: 6-Mercaptopurine
    • Drug: Methotrexate
    • Drug: Pegaspargase
    • Drug: Prednisolone
    • Drug: Tioguanin
    • Drug: Vincristine
    • Drug: Vindesine
    • Drug: Erwinase
  • Experimental: pB: early HR-exp./HR-standard

    Induction (5 w): as in other pB arms

    Consolidation (6 w): "Consolidation extended+BZM" (experimental arm of randomization R-eHR) with cyclophosphamide, cytarabine, 6-MP, IT MTX, dexamethasone, vincristine, pegaspargase, bortezomib (1.3 mg/m²/dose on days 50, 53, 56 and 59)

    Intensified consolidation (3x5 d): Block HR-1' followed by HR-2' and HR-3' (control arm in randomization R-HR) with dexamethasone, vincristine, vindesine, daunorubicin, HD-MTX, IT MTX, HD-cytarabine, cyclophosphamide, ifosfamide, pegaspargase, etoposide

    Reinduction (3x4 w): as in arm "pB: early (non-)HR-standard/HR-standard"

    Maintenance (until 2 yrs after initial diagnosis): 6-MP, MTX

    Erwinase is given in case of allergy to pegaspargase. Pts with poor response to intensified consolidation receive DNX-FLA (liposomal daunorubicin, fludarabine, HD-cytarabine, IT-MTX)

    Interventions:
    • Drug: Cyclophosphamide
    • Drug: Cytarabine
    • Drug: Daunorubicin
    • Drug: DAUNOrubicin Liposomal Injection [DaunoXome]
    • Drug: Dexamethasone
    • Drug: Doxorubicin
    • Drug: Etoposide
    • Drug: Fludarabine Phosphate
    • Drug: Ifosfamide
    • Drug: 6-Mercaptopurine
    • Drug: Methotrexate
    • Drug: Pegaspargase
    • Drug: Prednisolone
    • Drug: Tioguanin
    • Drug: Vincristine
    • Drug: Vindesine
    • Drug: Erwinase
  • Experimental: pB: early (non-)HR-standard/HR-exp.

    Induction (5 w): as in other pB arms

    Consolidation (6 w/4 w): "Consolidation extended" (control arm in randomization R-eHR) with cyclophosphamide, cytarabine, 6-MP, IT MTX, dexamethasone, vincristine, pegaspargase or "Consolidation short" (standard arm of early non-HR group) with cyclophosphamide, cytarabine, 6-MP, IT MTX

    Intensified consolidation (1x5 d + 2x28 d): Block HR-1' with dexamethasone, vincristine, HD-MTX, IT MTX, HD-cytarabine, cyclophosphamide, pegaspargase followed by 2 cycles blinatumomab at 15 µg/m²/day for 28 days per cycle plus 2x2 doses IT MTX (experimental arm of randomization R-HR)

    Reinduction (3x4 weeks): as in arm "pB: early (non-)HR-standard/HR-standard"

    Maintenance (until 2 yrs after init. diagnosis): 6-MP, MTX

    Erwinase is given in case of pegaspargase allergy. Pts with poor response to intensified consolidation receive DNX-FLA (liposomal daunorubicin, fludarabine, HD-cytarabine, IT-MTX)

    Interventions:
    • Drug: Blinatumomab
    • Drug: Cyclophosphamide
    • Drug: Cytarabine
    • Drug: Daunorubicin
    • Drug: DAUNOrubicin Liposomal Injection [DaunoXome]
    • Drug: Dexamethasone
    • Drug: Doxorubicin
    • Drug: 6-Mercaptopurine
    • Drug: Methotrexate
    • Drug: Pegaspargase
    • Drug: Prednisolone
    • Drug: Tioguanin
    • Drug: Vincristine
    • Drug: Erwinase
  • Experimental: pB: early HR-exp./HR-exp.

    Induction (5 w): as in other pB arms

    Consolidation (6 w): "Consolidation extended+BZM" (experimental arm of randomization R-eHR) with cyclophosphamide, cytarabine, 6-MP, IT MTX, dexamethasone, vincristine, pegaspargase, bortezomib (1.3 mg/m²/dose on days 50, 53, 56 and 59)

    Intensified consolidation (1x5 d + 2x28 d): Block HR-1' with dexamethasone, vincristine, HD-MTX, IT MTX, HD-cytarabine, cyclophosphamide, pegaspargase followed by 2 cycles blinatumomab at 15 µg/m²/day for 28 days per cycle plus 2x2 doses IT MTX (experimental arm of randomization R-HR)

    Reinduction (3x4 weeks): as in arm "pB: early (non-)HR-standard/HR-standard" Maintenance (until 2 yrs after initial diagnosis): 6-MP, MTX

    Erwinase is given in case of allergy to pegaspargase. Pts with poor response to intensified consolidation receive DNX-FLA (liposomal daunorubicin, fludarabine, HD-cytarabine, IT-MTX)

    Interventions:
    • Drug: Blinatumomab
    • Drug: Cyclophosphamide
    • Drug: Cytarabine
    • Drug: Daunorubicin
    • Drug: DAUNOrubicin Liposomal Injection [DaunoXome]
    • Drug: Dexamethasone
    • Drug: Doxorubicin
    • Drug: 6-Mercaptopurine
    • Drug: Methotrexate
    • Drug: Pegaspargase
    • Drug: Prednisolone
    • Drug: Tioguanin
    • Drug: Vincristine
    • Drug: Erwinase
  • pB: early non-HR/SR

    Induction (5 w): "Protocol IA" with prednisolone, vincristine, daunorubicin, pegaspargase, IT MTX

    Consolidation (4 w): "Consolidation short" with cyclophosphamide, cytarabine, 6-mercaptopurine, IT MTX

    Extra-compartment phase (8 w): "Protocol M" with 6-MP, HD-MTX, IT MTX

    Reinduction (6 w): "Protocol II" with dexamethasone, vincristine, doxorubicin, pegaspargase, IT MTX, cyclophosphamide, tioguanine, cytarabine

    Maintenance (until 2 yrs after initial diagnosis): 6-MP, MTX

    Erwinase is given in case of allergy to pegaspargase.

    Interventions:
    • Drug: Cyclophosphamide
    • Drug: Cytarabine
    • Drug: Daunorubicin
    • Drug: Dexamethasone
    • Drug: Doxorubicin
    • Drug: 6-Mercaptopurine
    • Drug: Methotrexate
    • Drug: Pegaspargase
    • Drug: Prednisolone
    • Drug: Tioguanin
    • Drug: Vincristine
    • Drug: Erwinase
  • Active Comparator: T: early non-SR-standard/(non-)HR

    Induction (5 w): "Protocol IA-Dexa" with prednisolone/dexamethasone, vincristine, daunorubicin, pegaspargase, IT MTX or "Protocol IA-CPM" with prednisolone instead of dexamethasone and additional CPM

    Consolidation (4 w): "Protocol IB regular" (control arm in randomization. R-T) with cyclophosphamide, cytarabine, 6-mercaptopurine, IT MTX

    non-HR extra-compartment phase and reinduction: as in arm "pB: early non-HR/SR"

    HR intensified consolidation and reinduction: as in arm "pB: early (non-)HR-standard/HR-standard"

    Maintenance (until 2 yrs after initial diagnosis): 6-MP, MTX

    Erwinase is given in case of allergy to pegaspargase. Pts with poor response to intensified consolidation receive DNX-FLA (liposomal daunorubicin, fludarabine, HD-cytarabine, IT-MTX)

    Interventions:
    • Drug: Cyclophosphamide
    • Drug: Cytarabine
    • Drug: Daunorubicin
    • Drug: DAUNOrubicin Liposomal Injection [DaunoXome]
    • Drug: Dexamethasone
    • Drug: Doxorubicin
    • Drug: Etoposide
    • Drug: Fludarabine Phosphate
    • Drug: Ifosfamide
    • Drug: 6-Mercaptopurine
    • Drug: Methotrexate
    • Drug: Pegaspargase
    • Drug: Prednisolone
    • Drug: Tioguanin
    • Drug: Vincristine
    • Drug: Vindesine
    • Drug: Erwinase
  • Experimental: T: early non-SR-exp/(non-)HR

    Induction (5 w): "Protocol IA-Dexa" with prednisolone/dexamethasone, vincristine, daunorubicin, pegaspargase, IT MTX or "Protocol IA-CPM" with prednisolone instead of dexamethasone and additional CPM

    Consolidation (6 w): "Protocol IB long" (experimental arm in randomization R-T) with cyclophosphamide, cytarabine, 6-mercaptopurine, IT MTX

    non-HR extra-compartment phase and reinduction: as in arm "pB: early non-HR/SR"

    HR intensified consolidation and reinduction: as in arm "pB: early (non-)HR-standard/HR-standard"

    Maintenance (until 2 yrs after initial diagnosis): 6-MP, MTX

    Erwinase is given in case of allergy to pegaspargase. Pts with poor response to intensified consolidation receive DNX-FLA (liposomal daunorubicin, fludarabine, HD-cytarabine, IT-MTX)

    Interventions:
    • Drug: Cyclophosphamide
    • Drug: Cytarabine
    • Drug: Daunorubicin
    • Drug: DAUNOrubicin Liposomal Injection [DaunoXome]
    • Drug: Dexamethasone
    • Drug: Doxorubicin
    • Drug: Etoposide
    • Drug: Fludarabine Phosphate
    • Drug: Ifosfamide
    • Drug: 6-Mercaptopurine
    • Drug: Methotrexate
    • Drug: Pegaspargase
    • Drug: Prednisolone
    • Drug: Tioguanin
    • Drug: Vincristine
    • Drug: Vindesine
    • Drug: Erwinase
  • T: early SR/non-HR

    Induction (5 w): "Protocol IA-Dexa" with prednisolone/dexamethasone, vincristine, daunorubicin, pegaspargase, IT MTX

    Consolidation (4 w): "Protocol IB regular" with cyclophosphamide, cytarabine, 6-mercaptopurine, IT MTX

    Extra-compartment phase (8 w): "Protocol M" with 6-MP, HD-MTX, IT MTX

    Reinduction (6 w): "Protocol II" with dexamethasone, vincristine, doxorubicin, pegaspargase, IT MTX, cyclophosphamide, tioguanine, cytarabine

    Maintenance (until 2 yrs after initial diagnosis): 6-MP, MTX

    Erwinase is given in case of allergy to pegaspargase.

    Interventions:
    • Drug: Cyclophosphamide
    • Drug: Cytarabine
    • Drug: Daunorubicin
    • Drug: Dexamethasone
    • Drug: Doxorubicin
    • Drug: 6-Mercaptopurine
    • Drug: Methotrexate
    • Drug: Pegaspargase
    • Drug: Prednisolone
    • Drug: Tioguanin
    • Drug: Vincristine
    • Drug: Erwinase
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 20, 2018)
5000
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 14, 2028
Estimated Primary Completion Date July 14, 2028   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • newly diagnosed acute lymphoblastic leukemia or
  • newly diagnosed mixed phenotype acute leukemia (MPAL) meeting one of the following criteria:
  • biphenotypic with a dominant T or B lineage assignment
  • bilineal either with a dominant lymphoblastic population or if another reasonable rationale exists to treat the patient with an ALL-based therapy regimen
  • newly diagnosed acute undifferentiated leukemia
  • age < 18 years (up to 17 years and 365 days) at the day of diagnosis
  • patient enrolled in a participating center
  • written informed consent to trial participation and transfer and processing of data A subsequent removal from the study is only allowed if the inclusion criteria turn out not to be fulfilled or in the case of pregnancy of the patient.

Exclusion Criteria:

  • Ph+ (BCR-ABL1 or t(9;22)-positive) ALL
  • bilineal leukemia with a lymphoblastic and a separate non-lymphoblastic (≥ 10% of total cells) blast subset
  • pre-treatment with cytostatic drugs
  • glucocorticoid 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 disease that does not allow treatment according to the protocol (e.g. severe congenital heart disease, Charcot-Marie Syndrome, Ataxia-teleangiectasia…)
  • ALL diagnosed as second malignancy and preceding chemotherapy and/or radiotherapy
  • evidence of pregnancy or lactation period
  • Sexually active adolescents not willing to use highly effective contraceptive method (pearl index <1) until 12 months after end of anti-leukemic therapy
  • participation in another clinical trial except for add-on trials within the scope of supportive care approved by the sponsor
  • live vaccine immunization within 2 weeks before start of protocol treatment
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 17 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Anja Möricke, MD +4943150020150 a.moericke@pediatrics.uni-kiel.de
Contact: Lile Bauer +4943150020152 lile.bauer@uksh.de
Listed Location Countries  ICMJE Austria,   Czechia,   Germany,   Israel,   Italy,   Slovakia,   Switzerland
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03643276
Other Study ID Numbers  ICMJE AIEOP-BFM ALL 2017
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Martin Schrappe, University of Schleswig-Holstein
Study Sponsor  ICMJE Martin Schrappe
Collaborators  ICMJE Deutsche Krebshilfe e.V., Bonn (Germany)
Investigators  ICMJE
Principal Investigator: Martin Schrappe, MD Department of Pediatrics, University Hospital of Schleswig-Holstein, Campus Kiel
PRS Account University of Schleswig-Holstein
Verification Date June 2019

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