Childhood Acute Lymphoblastic Leukemia Treatment Protocol Moscow-Berlin 2015 (ALL-MB 2015)

Study Overview
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Brief Summary
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QUESTIONS AND OBJECTIVES OF ALL-MB 2015 STUDY Will the new risk group stratification (especially of T-ALL) to improve overall and event-free survival? Will the new protocol is effective and feasible in patients older than 15 years, and especially in young adults? Whether the intermittent dexamethasone administration in induction will result in a decrease in toxicity and mortality without loss of efficacy? Whether the methylprednisolone administration as basic glucocorticoids during induction, consolidation and maintenance therapy will lead to decrease of severe infections and early mortality rate, improve survival and therapy compliance in adolescents and young adults with B-precursor ALL? Whether the administration of Bortezomib in patients with B-precursor ALL with initial WBC≥100,000/µl will improve treatment outcome? Whether the administration of Idarubicin instead Daunorubicin in low-risk T-ALL patients and two-phase induction in intermediate-risk T-ALL patients will reduce relapse rate and improve survival?

Official Title
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Moscow-Berlin 2015 Multicenter Randomized Study for Treatment of Acute Lymphoblastic Leukemia in Children, Adolescents and Young Adults

Conditions
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Childhood Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: Dexamethasone continuous
* Drug: Dexamethasone intermittent
* Drug: Dexamethasone
* Drug: Methylprednisolone
* Drug: Daunorubicin
* Drug: Idarubicin
* Drug: Bortezomib
* Drug: Second phase of induction
* Drug: Standard induction therapy
* Drug: Standard consolidation therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age at diagnosis at 1 to 50 years. The start of induction therapy within a time interval of study recruitment phase. The diagnosis of ALL is to be proved by the morphological, cytochemical, and immunological analysis of tumor cells in bone marrow (see Diagnostics). Patients with B-cell (Burkitt) ALL are excluded. Informed consent of the patient parents (guardians) to be treated in one of the clinics included in this multicenter study. Exclusion Criteria: ALL is a second malignancies; The disease is a relapse of previously misdiagnosed and, therefore, inadequately treated ALL; There is severe concomitant disease, which significantly impedes chemotherapy protocol (such as multiple malformations, heart diseases, metabolic disorders, etc.); There is a lack of important data needed for the exact adherence to the cytostatic therapy according to a specific chemotherapy protocol (differential diagnosis of ALL-AML (acute myeloid leukemia) is not possible, stratification according to therapeutic group is not possible); The patient was treated before for a long time with cytotoxic drugs; There were treatment deviations not covered by the protocol and/or not due to side effects of treatment and/or complications of the disease

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dexa intermittent<br>Induction therapy with intermittent Dexamethasone administration (1-15 days - 6 mg/m2, 15-22 day - pause, 22-29 days - 6 mg/m2). | Drug: Dexamethasone intermittent<br>* 6 mg/m2, per os, in two divided doses per day q12 hours. Days: 1-14 (dose in the first few days is depending on the total tumor mass) and 22-28; days 15-21 - pause. From day 29 the dose of dexamethasone is reducing: days 29-30 - 3 mg/m2, days 31-32 - 1.5 mg/m2, then dexamethasone is discontinued completely.<br>|
| Active Comparator: Dexa constant<br>Induction therapy with continuous Dexamethasone administration (6 mg/m2 1-29 days). | Drug: Dexamethasone continuous<br>* 6 mg/m2, per os, in two divided doses per day q12 hours. 1-28 day (dose in the first few days is depending on the total tumor mass). From day 29 the dose of dexamethasone is reducing: days 29-31 - 3 mg/m2, days 32-34 - 1.5 mg/m2, days 35-36 - 0.75 mg/m2; then dexamethasone is discontinued completely.<br>|
| Active Comparator: Dexa<br>Therapy with Dexamethasone (6 mg/m2) as basic glucocorticoid preparation. | Drug: Dexamethasone<br>* Induction: 6 mg/m2, per os, in two divided doses per day q12 hours. 1-28 day (dose in the first few days is depending on the total tumor mass). From day 29 the dose of dexamethasone is reducing: days 29-31 - 3 mg/m2, days 32-34 - 1.5 mg/m2, days 35-36 - 0.75 mg/m2; then dexamethasone is discontinued completely. Consolidation: 6 mg/m2 per os, in two divided doses per day q12 hours. Weeks 13-14 (days 85-98), weeks 21-22 (days 141-154), weeks 29-30 (days 197-210), weeks 37-38 (days 253-260), weeks 45-46 (days 309-316), weeks 53-54 (days 365-372). Maintenance therapy: 6 mg/m2, per os, in two divided doses per day q12 hours, for 10 days followed by quick discontinuation during 3 days. Weeks 61-62, 69-70, 77-78, 85-86, 93-94.<br>|
| Experimental: Medrol<br>Therapy with Methylprednisolone (60 mg/m2) as basic glucocorticoid preparation. | Drug: Methylprednisolone<br>* Induction: 60 mg/m2, per os, in two divided doses per day q12 hours. 1-28 day (dose in the first few days is depending on the total tumor mass). From day 29 the dose of dexamethasone is reducing: days 29-31 - 30 mg/m2, days 32-34 - 15 mg/m2, days 35-36 - 8 mg/m2; then methylprednisolone is discontinued completely. Consolidation: 60 mg/m2 per os, in two divided doses per day q12 hours. Weeks 13-14 (days 85-98), weeks 21-22 (days 141-154), weeks 29-30 (days 197-210), weeks 37-38 (days 253-260), weeks 45-46 (days 309-316), weeks 53-54 (days 365-372). Maintenance therapy: 60 mg/m2, per os, in two divided doses per day q12 hours, for 10 days followed by quick discontinuation during 3 days. Weeks 61-62, 69-70, 77-78, 85-86, 93-94.<br>|
| Experimental: IDA<br>Induction and consolidation therapy with Idarubicin | Drug: Idarubicin<br>* Induction: 10 mg/m2, intravenously, for 6 hours on days 8 and 22. Consolidation: 8 mg/m2, intravenously, for 6 hours on days 44, 65 (consolidation S1); 107, 121 (consolidation S2); and 163 (consolidation S3).<br>|
| Active Comparator: DNR<br>Induction and consolidation therapy with Daunorubicin | Drug: Daunorubicin<br>* Induction: 45 mg/m2, intravenously, for 6 hours on days 8 and 22. Consolidation: 30 mg/m2, intravenously, for 6 hours on days 44, 65 (consolidation S1); 107, 121 (consolidation S2); and 163 (consolidation S3).<br>|
| Experimental: Protocol Ib+<br>Two-phase induction therapy (additional second phase of induction - protocol Ib) | Drug: Second phase of induction<br>* Cyclophosphamide (1,000 mg/m2, intravenously, for 1 hour - days 43 and 71); Cytarabine (75 mg/m2/day, intravenously, bolus injection. Four blocks of 4 days each, days 46-48, 52-55, 59-62, and 66-69); 6-mercaptopurine (60 mg/m2/day, per os, days 43-71); Triple intrathecal therapy (days 52 and 66)<br>|
| Active Comparator: Protocol Ib-<br>Standard induction therapy (without second phase) | Drug: Standard induction therapy<br>* Dexamethasone (6 mg/m2, p/o; 1-29 days); Daunorubicin (45 mg/m2, i.v.; day 8 and 22); Vincristine (1.5 mg/m2, i.v.; days 8, 15, 22, 29 and 36); Triple intrathecal therapy (Methotrexate/Cytarabine/Prednisone; days 0/1, 8, 15, 22, 29 and 36)<br>|
| Active Comparator: Bortezomib-<br>Consolidation therapy without Bortezomib | Drug: Standard consolidation therapy<br>* Consolidation consists of 3 phases: S1, S2 and S3. Each phase is a 6-week therapy with 6-mercaptopurine (50 mg/m2 per day, daily, orally), methotrexate (30 мг/м2, i.m., weekly) and L-asparaginase (10 000 U/m2, i.m., weekly), followed by 2 weeks of re-induction with Vincristine (1.5 mg/m2, i.v., days 1 and 8 of reinduction) plus Dexamethasone (6 mg/m2, p/o, daily, for 10 days followed by quick discontinuation during 3 days). Daunorubicin (30 mg/м2, i.v., N2 during S1, N2 during S2 and N1 during S3). Triple intrathecal therapy (Methotrexate/Cytarabine/Prednisone) N12 (4 injections per each phase)<br>|
| Experimental: Bortezomib+<br>Consolidation therapy with Bortezomib 1.3 mg/m2 N12 (N4 in each reinduction) | Drug: Bortezomib<br>* 1.3 mg/м2, intravenously, bolus injection. Days 85, 89, 92, 96 (consolidation S1); 141, 145, 148, 152 (consolidation S2) and 197, 201, 204, 208 (consolidation S3).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival |  | 3 years, 5 years and 10 years after study start | 
| Overall survival |  | 3 years, 5 years and 10 years after study start | 
| Cumulative incidence of relapse |  | 3 years, 5 years and 10 years after study start | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Early death rate |  | 3 years, 5 years and 10 years after study start | 
| Remission death rate |  | 3 years, 5 years and 10 years after study start | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute lymphoblastic leukemia, children, adolescents, treatment