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

NCT03643276 | Recruiting Phase 3 DMC

• 1 other identifier: AIEOP-BFM ALL 2017
• Study Type: interventional
• Target: 5,000
• Locations: 7 countries
• Sites: 110

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.

Conditions

Acute Lymphoblastic Leukemia, Pediatric

Keywords

Acute Lymphoblastic Leukemia; Childhood; Pediatric; Immunotherapy; Blinatumomab; Proteasome Inhibitor; Bispecific antibody; Bortezomib; Chemotherapy; Randomized trial

Outcome Measures

Primary Outcomes (2)

• Event-free survival

  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.

  Assessed up to 120 months from start of study

• Disease-free survival

  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.

  Assessed up to 120 months from start of study

Secondary Outcomes (5)

• Survival

  Assessed up to 120 months from start of study

• Treatment-related mortality

  Assessed up to 120 months from start of study

• Adverse Events of interest/Serious Adverse Events

  Assessed up to 120 months from start of study

• MRD response

  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).

• Proportion of patients with Blina Poor-Response

  Measurements of MRD response intended after 30 weeks from individual start of treatment, assessment of proportion at 120 months from start of study

Study Arms (12)

pB: early (non-)HR-standard/MR-standard

ACTIVE COMPARATOR

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.

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

pB: early HR-exp./MR-standard

EXPERIMENTAL

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.

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

pB: early (non)HR-standard/MR-exp.

EXPERIMENTAL

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.

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

pB: early HR-exp./MR-exp.

EXPERIMENTAL

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.

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

pB: early (non-)HR-standard/HR-standard

ACTIVE COMPARATOR

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 Myocet-FLA (Myocet, fludarabine, HD-cytarabine, IT-MTX).

Drug: Cyclophosphamide; Drug: Cytarabine; Drug: Daunorubicin; Drug: Myocet; 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

pB: early HR-exp./HR-standard

EXPERIMENTAL

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 Myocet-FLA (Myocet, fludarabine, HD-cytarabine, IT-MTX)

Drug: Cyclophosphamide; Drug: Cytarabine; Drug: Daunorubicin; Drug: Myocet; 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

pB: early (non-)HR-standard/HR-exp.

EXPERIMENTAL

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 Myocet-FLA (Myocet, fludarabine, HD-cytarabine, IT-MTX)

Drug: Blinatumomab; Drug: Cyclophosphamide; Drug: Cytarabine; Drug: Daunorubicin; Drug: Myocet; Drug: Dexamethasone; Drug: Doxorubicin; Drug: 6-Mercaptopurine; Drug: Methotrexate; Drug: Pegaspargase; Drug: Prednisolone; Drug: Tioguanin; Drug: Vincristine; Drug: Erwinase

pB: early HR-exp./HR-exp.

EXPERIMENTAL

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 Myocet-FLA (Myocet, fludarabine, HD-cytarabine, IT-MTX)

Drug: Blinatumomab; Drug: Cyclophosphamide; Drug: Cytarabine; Drug: Daunorubicin; Drug: Myocet; Drug: Dexamethasone; Drug: Doxorubicin; Drug: 6-Mercaptopurine; Drug: Methotrexate; Drug: Pegaspargase; Drug: Prednisolone; Drug: Tioguanin; Drug: Vincristine; Drug: Erwinase

pB: early non-HR/SR

OTHER

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.

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

T: early non-SR-standard/(non-)HR

ACTIVE COMPARATOR

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 Myocet-FLA (Myocet, fludarabine, HD-cytarabine, IT-MTX)

Drug: Cyclophosphamide; Drug: Cytarabine; Drug: Daunorubicin; Drug: Myocet; 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 non-SR-exp/(non-)HR

EXPERIMENTAL

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 Myocet-FLA (Myocet, fludarabine, HD-cytarabine, IT-MTX)

Drug: Cyclophosphamide; Drug: Cytarabine; Drug: Daunorubicin; Drug: Myocet; 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

OTHER

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.

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

Interventions

Blinatumomab DRUG

Experimental therapy in randomizations R-HR and R-MR

pB: early (non)HR-standard/MR-exp.; pB: early (non-)HR-standard/HR-exp.; pB: early HR-exp./HR-exp.; pB: early HR-exp./MR-exp.

Bortezomib DRUG

Experimental therapy in randomization R-eHR

pB: early HR-exp./MR-exp.; pB: early HR-exp./MR-standard

Cyclophosphamide DRUG

Part of standard chemotherapy and included in experimental treatment phase Protocol IB long in randomization R-T

T: early SR/non-HR; T: early non-SR-exp/(non-)HR; T: early non-SR-standard/(non-)HR; pB: early (non)HR-standard/MR-exp.; pB: early (non-)HR-standard/HR-exp.; pB: early (non-)HR-standard/HR-standard; pB: early (non-)HR-standard/MR-standard; pB: early HR-exp./HR-exp.; pB: early HR-exp./HR-standard; pB: early HR-exp./MR-exp.; pB: early HR-exp./MR-standard; pB: early non-HR/SR

Cytarabine DRUG

Part of standard chemotherapy and included in experimental treatment phase Protocol IB long in randomization R-T and in the intensification block Myocet-FLA for patients with very high relapse risk

T: early SR/non-HR; T: early non-SR-exp/(non-)HR; T: early non-SR-standard/(non-)HR; pB: early (non)HR-standard/MR-exp.; pB: early (non-)HR-standard/HR-exp.; pB: early (non-)HR-standard/HR-standard; pB: early (non-)HR-standard/MR-standard; pB: early HR-exp./HR-exp.; pB: early HR-exp./HR-standard; pB: early HR-exp./MR-exp.; pB: early HR-exp./MR-standard; pB: early non-HR/SR

Daunorubicin DRUG

Part of standard chemotherapy

T: early SR/non-HR; T: early non-SR-exp/(non-)HR; T: early non-SR-standard/(non-)HR; pB: early (non)HR-standard/MR-exp.; pB: early (non-)HR-standard/HR-exp.; pB: early (non-)HR-standard/HR-standard; pB: early (non-)HR-standard/MR-standard; pB: early HR-exp./HR-exp.; pB: early HR-exp./HR-standard; pB: early HR-exp./MR-exp.; pB: early HR-exp./MR-standard; pB: early non-HR/SR

Myocet DRUG

Part of intensification block Myocet-FLA for patients with very high relapse risk

T: early non-SR-exp/(non-)HR; T: early non-SR-standard/(non-)HR; pB: early (non-)HR-standard/HR-exp.; pB: early (non-)HR-standard/HR-standard; pB: early HR-exp./HR-exp.; pB: early HR-exp./HR-standard

Dexamethasone DRUG

Part of standard chemotherapy

T: early SR/non-HR; T: early non-SR-exp/(non-)HR; T: early non-SR-standard/(non-)HR; pB: early (non)HR-standard/MR-exp.; pB: early (non-)HR-standard/HR-exp.; pB: early (non-)HR-standard/HR-standard; pB: early (non-)HR-standard/MR-standard; pB: early HR-exp./HR-exp.; pB: early HR-exp./HR-standard; pB: early HR-exp./MR-exp.; pB: early HR-exp./MR-standard; pB: early non-HR/SR

Doxorubicin DRUG

Part of standard chemotherapy

T: early SR/non-HR; T: early non-SR-exp/(non-)HR; T: early non-SR-standard/(non-)HR; pB: early (non)HR-standard/MR-exp.; pB: early (non-)HR-standard/HR-exp.; pB: early (non-)HR-standard/HR-standard; pB: early (non-)HR-standard/MR-standard; pB: early HR-exp./HR-exp.; pB: early HR-exp./HR-standard; pB: early HR-exp./MR-exp.; pB: early HR-exp./MR-standard; pB: early non-HR/SR

Etoposide DRUG

Part of standard chemotherapy

T: early non-SR-exp/(non-)HR; T: early non-SR-standard/(non-)HR; pB: early (non-)HR-standard/HR-standard; pB: early HR-exp./HR-standard

Fludarabine Phosphate DRUG

Part of intensification block Myocet-FLA for patients with very high relapse risk

T: early non-SR-exp/(non-)HR; T: early non-SR-standard/(non-)HR; pB: early (non-)HR-standard/HR-standard; pB: early HR-exp./HR-standard

Ifosfamide DRUG

Part of standard chemotherapy

T: early non-SR-exp/(non-)HR; T: early non-SR-standard/(non-)HR; pB: early (non-)HR-standard/HR-standard; pB: early HR-exp./HR-standard

6-Mercaptopurine DRUG

Part of standard chemotherapy and included in experimental treatment phase Protocol IB long in randomization R-T

T: early SR/non-HR; T: early non-SR-exp/(non-)HR; T: early non-SR-standard/(non-)HR; pB: early (non)HR-standard/MR-exp.; pB: early (non-)HR-standard/HR-exp.; pB: early (non-)HR-standard/HR-standard; pB: early (non-)HR-standard/MR-standard; pB: early HR-exp./HR-exp.; pB: early HR-exp./HR-standard; pB: early HR-exp./MR-exp.; pB: early HR-exp./MR-standard; pB: early non-HR/SR

Methotrexate DRUG

Part of standard chemotherapy

T: early SR/non-HR; T: early non-SR-exp/(non-)HR; T: early non-SR-standard/(non-)HR; pB: early (non)HR-standard/MR-exp.; pB: early (non-)HR-standard/HR-exp.; pB: early (non-)HR-standard/HR-standard; pB: early (non-)HR-standard/MR-standard; pB: early HR-exp./HR-exp.; pB: early HR-exp./HR-standard; pB: early HR-exp./MR-exp.; pB: early HR-exp./MR-standard; pB: early non-HR/SR

Pegaspargase DRUG

Part of standard chemotherapy

T: early SR/non-HR; T: early non-SR-exp/(non-)HR; T: early non-SR-standard/(non-)HR; pB: early (non)HR-standard/MR-exp.; pB: early (non-)HR-standard/HR-exp.; pB: early (non-)HR-standard/HR-standard; pB: early (non-)HR-standard/MR-standard; pB: early HR-exp./HR-exp.; pB: early HR-exp./HR-standard; pB: early HR-exp./MR-exp.; pB: early HR-exp./MR-standard; pB: early non-HR/SR

Prednisolone DRUG

Part of standard chemotherapy

Also known as: Prednisone

T: early SR/non-HR; T: early non-SR-exp/(non-)HR; T: early non-SR-standard/(non-)HR; pB: early (non)HR-standard/MR-exp.; pB: early (non-)HR-standard/HR-exp.; pB: early (non-)HR-standard/HR-standard; pB: early (non-)HR-standard/MR-standard; pB: early HR-exp./HR-exp.; pB: early HR-exp./HR-standard; pB: early HR-exp./MR-exp.; pB: early HR-exp./MR-standard; pB: early non-HR/SR

Tioguanin DRUG

Part of standard chemotherapy

T: early SR/non-HR; T: early non-SR-exp/(non-)HR; T: early non-SR-standard/(non-)HR; pB: early (non)HR-standard/MR-exp.; pB: early (non-)HR-standard/HR-exp.; pB: early (non-)HR-standard/HR-standard; pB: early (non-)HR-standard/MR-standard; pB: early HR-exp./HR-exp.; pB: early HR-exp./HR-standard; pB: early HR-exp./MR-exp.; pB: early HR-exp./MR-standard; pB: early non-HR/SR

Vincristine DRUG

Part of standard chemotherapy

T: early SR/non-HR; T: early non-SR-exp/(non-)HR; T: early non-SR-standard/(non-)HR; pB: early (non)HR-standard/MR-exp.; pB: early (non-)HR-standard/HR-exp.; pB: early (non-)HR-standard/HR-standard; pB: early (non-)HR-standard/MR-standard; pB: early HR-exp./HR-exp.; pB: early HR-exp./HR-standard; pB: early HR-exp./MR-exp.; pB: early HR-exp./MR-standard; pB: early non-HR/SR

Vindesine DRUG

Part of standard chemotherapy

T: early non-SR-exp/(non-)HR; T: early non-SR-standard/(non-)HR; pB: early (non-)HR-standard/HR-standard; pB: early HR-exp./HR-standard

Erwinase DRUG

Part of standard chemotherapy as substitute for PEG-L-Asparaginase in case of allergic reaction

T: early SR/non-HR; T: early non-SR-exp/(non-)HR; T: early non-SR-standard/(non-)HR; pB: early (non)HR-standard/MR-exp.; pB: early (non-)HR-standard/HR-exp.; pB: early (non-)HR-standard/HR-standard; pB: early (non-)HR-standard/MR-standard; pB: early HR-exp./HR-exp.; pB: early HR-exp./HR-standard; pB: early HR-exp./MR-exp.; pB: early HR-exp./MR-standard; pB: early non-HR/SR

Eligibility Criteria

• Age: Up to 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Martin Schrappe: lead
• Deutsche Krebshilfe e.V., Bonn (Germany): collaborator

Study Sites (115)

Sydney Children's Hospital

Sydney, Australia

RECRUITING

The Children's Hospital at Westmead

Westmead, Australia

RECRUITING

Univ.Klinik für Kinder- und Jugendheilkunde Graz

Graz, Austria

RECRUITING

Univ.Klinik für Kinder- und Jugendheilkunde Innsbruck

Innsbruck, Austria

RECRUITING

Kepler Universitätsklinikum

Linz, Austria

RECRUITING

LKH Salzburg

Salzburg, Austria

RECRUITING

St. Anna Kinderspital

Vienna, Austria

RECRUITING

University Hospital Brno

Brno, Czechia

RECRUITING

Regional Hospital České Budějovice

České Budějovice, Czechia

RECRUITING

University Hospital Hradec Králové

Hradec Králové, Czechia

RECRUITING

University Hospital Olomouc

Olomouc, Czechia

RECRUITING

University Hospital Ostrava-Poruba

Ostrava-Poruba, Czechia

RECRUITING

University Hospital Plzeň

Pilsen, Czechia

RECRUITING

University Hospital Motol

Prague, Czechia

RECRUITING

Masaryk´s Hospital Ústí nad Labem

Ústí nad Labem, Czechia

RECRUITING

Kinderklinik der med. Fakultät der RWTH, Bereich Hämatologie/Onkologie

Aachen, 52074, Germany

RECRUITING

I. Klinik für Kinder u. Jugendliche, Klinikum Augsburg, Hämatologie/ Onkologie

Augsburg, 86156, Germany

RECRUITING

Klinikum Berlin-Buch II. Kinderklinik, Bereich Onkologie/Allg. Pädiatrie

Berlin, 13125, Germany

RECRUITING

Kinderklinik der Charité, Campus Virchow Klinikum (CVK), Abt.: Kinderhämatologie

Berlin, 13353, Germany

RECRUITING

Städtisches Krankenhaus, Kinderklinik

Braunschweig, 38118, Germany

RECRUITING

Klinikum Chemnitz gGmbH, Klinik für Kinder- und Jugendmedizin, Hämatologie / Onkologie

Chemnitz, 09009, Germany

RECRUITING

Kliniken der Stadt Köln GmbH, Kinderkrankenhaus Riehl

Cologne, 50735, Germany

RECRUITING

Med. Einrichtungen der Universität zu Köln, Klinik für Allg. Kinderheilkunde, Onkologisch-hämatologische Station

Cologne, 50937, Germany

RECRUITING

Carl-Thiem-Klinikum, Kinderklinik, Abt. Hämatologie/Onkologie

Cottbus, 03048, Germany

RECRUITING

Vestische Kinder- u. Jugendklinik, Universitätsklinik Witten/Herdecke

Datteln, 45711, Germany

RECRUITING

Klinikum Dortmund, Klinik f. Kinder- und Jugendmedizin

Dortmund, 44137, Germany

RECRUITING

Universitatsklinikum Carl Gustav Carus

Dresden, D-01307, Germany

RECRUITING

Universitätsklinik

Düsseldorf, Germany

RECRUITING

Helios Klinikum Erfurt GmbH, Klinik für Kinderheilkunde

Erfurt, 99089, Germany

RECRUITING

Universitaets - Kinderklinik

Erlangen, 91054, Germany

RECRUITING

Universitaetsklinikum Essen

Essen, D-45147, Germany

RECRUITING

Klinikum der J.W. Goethe Universitaet

Frankfurt, D-60590, Germany

RECRUITING

Universitaetskinderklinik - Universitaetsklinikum Freiburg

Freiburg im Breisgau, D-79106, Germany

RECRUITING

Klinikum der Justus-Liebig-Universität, Zentrum für Kinderheilkunde, Abt. Hämatologie/Onkologie

Giessen, 35385, Germany

RECRUITING

Universitäts-Kinderklinik Päd. I, Hämatologie/Onkologie

Göttingen, 37099, Germany

RECRUITING

Klinik und Poliklinik für Kinder und Jugendmedizin, Allgemeine Pädiatrie mit Poliklinik/Pädiatrische Onkologie und Hämatologie

Greifswald, 17475, Germany

RECRUITING

Medizinische Hochschule Hannover, Zentrum Kinderheilkunde u. Jugendmedizin

Hanover, 30625, Germany

RECRUITING

Universitäts-Kinderklinik, Päd. Onkologie, Hämatologie, und Immunologie

Heidelberg, 69120, Germany

RECRUITING

Klinikum Heilbronn GmbH, Klinik für Kinderheilkunde und Jugendmedizin/Perinatalzentrum

Heilbronn, 74078, Germany

RECRUITING

Gemeinschaftskrankenhaus Herdecke, Kinderabteilung

Herdecke, 58313, Germany

RECRUITING

Universitaetsklinikum des Saarlandes

Homburg, 66421, Germany

RECRUITING

Klinikum, der Friedrich-Schiller-Universität, Klinik für Kinder- und Jugendmedizin

Jena, 7740, Germany

RECRUITING

Staedtisches Klinikum Karlsruhe gGmbH

Karlsruhe, 76133, Germany

RECRUITING

Klinikum Kassel

Kassel, D-34125, Germany

RECRUITING

Klinik für Allgemeine Paediatrie, Univ.-Klinikum Schleswig-Holstein, Campus Kiel

Kiel, 24105, Germany

RECRUITING

Department für Frauen- und Kindermedizin, Abteilung für Pädiatrische Onkologie, Hämatologie und Hämostaseologie

Leipzig, 04103, Germany

RECRUITING

Universität zu Lübeck, Klinik für Kinder- u. Jugendmedizin, Abt. Hämatologie/ Onkologie/Immunologie

Lübeck, 23538, Germany

RECRUITING

Universitätsklinikum Magdeburg, Klinik für Päd. Hämatologie/Onkologie

Magdeburg, 39120, Germany

RECRUITING

Klinikum Mannheim gGmbH, Kinderklinik, Abt. Hämatologie/Onkologie

Mannheim, 68167, Germany

RECRUITING

Universitätsklinikum

Mannheim, Germany

RECRUITING

Johannes Wesling Klinikum Minden

Minden, 32429, Germany

RECRUITING

Städt. Krankenhaus München GmbH, Krankenhaus München-Schwabingen, Kinderklinik d. TU

München, 80804, Germany

RECRUITING

Ludwig-Maximilian-Universität, Dr. von Haunersches Kinderspital

München, Germany

RECRUITING

Universitäts-Kinderklinik, Päd. Hämatologie und Onkologie

Münster, 48149, Germany

RECRUITING

Cnopf'sche Kinderklinik, Onkologie

Nuremberg, 90419, Germany

RECRUITING

Klinikum Oldenburg gGmbH, Zentrum für Kinder- u. Jugendmedizin, (Elisabeth Kinderkrankenhaus)

Oldenburg, 26133, Germany

RECRUITING

Universitätsklinikum

Regensburg, Germany

RECRUITING

Universitäts-Kinderklinik

Rostock, 18055, Germany

RECRUITING

Asklepios-Klinik, Sankt Augustin GmbH

Sankt Augustin, 53757, Germany

RECRUITING

HELIOS Kliniken Schwerin, Klinik f. Kinder-u. Jugendmedizin

Schwerin, 19049, Germany

RECRUITING

Olga-Hospital, Kinderklinik, Pädiatrisches Zentrum, Abt. Hämatologie/Onkologie

Stuttgart, 70176, Germany

RECRUITING

Krankenanstalt Trier, Mutterhaus der Borromaeerinnen, Pädiatrische Abteilung

Trier, 54290, Germany

RECRUITING

Universitaetsklinikum Tuebingen

Tübingen, D-72076, Germany

RECRUITING

Comprehensive Cancer Center Ulm at Universitaetsklinikum Ulm

Ulm, D-89075, Germany

RECRUITING

Stadtkrankenhaus, Kinderklinik

Wolfsburg, 38440, Germany

RECRUITING

Universitaets - Kinderklinik Wuerzburg

Würzburg, D-97080, Germany

RECRUITING

Soroka University Medical Center

Beersheba, Israel

RECRUITING

Rambam Health Care Campus

Haifa, Israel

RECRUITING

Hadassah Medical center

Jerusalem, Israel

RECRUITING

Schneider Children Medical Center of Israel

Petah Tikva, Israel

RECRUITING

Sheba Medical Center Tel-Hashomer

Ramat Gan, Israel

RECRUITING

Dana children hospital

Tel Aviv, Israel

RECRUITING

Azienda ospedali riuniti

Ancona, Italy

RECRUITING

AOUC Policlinico Bari

Bari, Italy

RECRUITING

A.O. Papa Giovanni XXIII

Bergamo, Italy

RECRUITING

Università di Bologna

Bologna, Italy

RECRUITING

ASST Spedali Civili di Brescia

Brescia, Italy

RECRUITING

Ospedale Businco

Cagliari, Italy

RECRUITING

Azienda ospedaliero universitaria

Catania, Italy

RECRUITING

AO Pugliese Ciaccio

Catanzaro, Italy

RECRUITING

S.O. Annunziata - A. O. Cosenza

Cosenza, Italy

RECRUITING

Ospedale Meyer

Florence, Italy

RECRUITING

Istituto Giannina Gaslini

Genova, Italy

RECRUITING

Policlinico di Modena Azienda Ospedaliero-Universitaria

Modena, Italy

RECRUITING

Clinica pediatrica Fondazione MBBM

Monza, Italy

RECRUITING

A.O.U. Vanvitelli

Napoli, Italy

RECRUITING

AORN Santobono Pausilipon

Napoli, Italy

RECRUITING

Azienda ospedaliera di Padova

Padua, Italy

RECRUITING

Ospedale Civico ARNAS Civico e Di Cristina

Palermo, Italy

RECRUITING

Azienda ospedaliero-universitaria di Parma

Parma, Italy

RECRUITING

Fondazione IRCCS Policlinico San Matteo

Pavia, Italy

RECRUITING

Ospedale S. Maria della misericordia

Perugia, Italy

RECRUITING

Ospedale Civile di Pescara

Pescara, Italy

RECRUITING

Ospedale Santa Chiara Pisa

Pisa, Italy

RECRUITING

Grande ospedale metropolitano B-M-M

Reggio Calabria, Italy

RECRUITING

Ospedale infermi

Rimini, Italy

RECRUITING

Fondazione Policlinico Gemelli

Roma, Italy

RECRUITING

Ospedale Bambino Gesù

Roma, Italy

RECRUITING

Policlinico Umberto I Università Sapienza di Roma

Roma, Italy

RECRUITING

Ospedale "Casa sollievo della sofferenza"

San Giovanni Rotondo, Italy

RECRUITING

A.O.U. Città della salute e della scienza di Torino

Torino, Italy

RECRUITING

IRCCS Burlo Garofolo

Trieste, Italy

RECRUITING

AOU Verona

Verona, Italy

RECRUITING

Klinika pediatrickej hematológie a onkológie SZU a DFNsP

Banská Bystrica, Slovakia

RECRUITING

Comenius University Children's Hospital

Bratislava, Slovakia

RECRUITING

Detská fakultná nemocnica Košice

Košice, Slovakia

RECRUITING

Kantonsspital Aarau

Aarau, Switzerland

RECRUITING

Universitäts-Kinderspital beider Basel

Basel, Switzerland

RECRUITING

Ospedale San Giovanni Bellinzona

Bellinzona, Switzerland

RECRUITING

Inselspital Bern

Bern, Switzerland

RECRUITING

HUG Hôpitaux Universitaires de Gèneve

Geneva, Switzerland

RECRUITING

CHUV Centre Hospitalier Universitaire Vaudois

Lausanne, Switzerland

RECRUITING

Luzerner Kantonsspital-Kinderspital Luzern

Lucerne, Switzerland

RECRUITING

Ostschweizer Kinderspital

Sankt Gallen, Switzerland

RECRUITING

Universitäts-Kinderspital Zürich

Zurich, Switzerland

RECRUITING

Related Publications (1)

• Tufekci O, Evim MS, Gunes AM, Celkan T, Karapinar DY, Kaya Z, Baysal B, Baytan B, Kocak U, Yilmaz S, Cinar S, Oren H. Assessment of Minimal Residual Disease in Childhood Acute Lymphoblastic Leukemia: A Multicenter Study From Turkey. J Pediatr Hematol Oncol. 2022 Mar 1;44(2):e396-e402. doi: 10.1097/MPH.0000000000002419.

  PMID: 35129146 DERIVED

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Interventions

blinatumomab; Bortezomib; Cyclophosphamide; Cytarabine; Daunorubicin; Doxorubicin; Dexamethasone; Etoposide; fludarabine phosphate; Ifosfamide; Mercaptopurine; Methotrexate; pegaspargase; Prednisolone; Prednisone; Thioguanine; Vincristine; Vindesine; Asparaginase

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Organic Chemicals; Pyrazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Phosphoramides; Organophosphorus Compounds; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Steroids, Fluorinated; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Glucosides; Oxazines; Sulfhydryl Compounds; Sulfur Compounds; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Aminopterin; Pterins; Pteridines; Pregnadienediols; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Indoles; Indolizidines; Indolizines; Amidohydrolases; Hydrolases; Enzymes; Enzymes and Coenzymes

Study Officials

• Martin Schrappe, MD

  Department of Pediatrics, University Hospital of Schleswig-Holstein, Campus Kiel

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Anja Möricke, MD

CONTACT

+4943150020150; a.moericke@pediatrics.uni-kiel.de

Lile Bauer

CONTACT

+4943150020152; lile.bauer@uksh.de

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor MD, FRCP (Glasg), Chair of Pediatrics I

Model Details: 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.

Study Record Dates

• First Submitted: July 12, 2018
• First Posted: August 22, 2018
• Study Start: July 15, 2018
• Primary Completion (Estimated): July 14, 2028
• Study Completion (Estimated): July 14, 2028
• Last Updated: April 6, 2025

Record last verified: 2025-04

Locations

IT (31); SL (3); AU (2); CH (9); CZ (8); IL (6); DE (51)