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

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

QUESTIONS AND OBJECTIVES OF ALL-MB 2015 STUDY

1. Will the new risk group stratification (especially of T-ALL) to improve overall and event-free survival?
2. Will the new protocol is effective and feasible in patients older than 15 years, and especially in young adults?
3. Whether the intermittent dexamethasone administration in induction will result in a decrease in toxicity and mortality without loss of efficacy?
4. 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?
5. Whether the administration of Bortezomib in patients with B-precursor ALL with initial WBC≥100,000/µl will improve treatment outcome?
6. 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?

Study Overview

• Status: Recruiting
• Conditions: Childhood Acute Lymphoblastic Leukemia
• Intervention / Treatment: Drug: Dexamethasone intermittent; Drug: Dexamethasone continuous; Drug: Dexamethasone; Drug: Methylprednisolone; Drug: Idarubicin; Drug: Daunorubicin; Drug: Second phase of induction; Drug: Standard induction therapy; Drug: Standard consolidation therapy; Drug: Bortezomib

• Study Type: Interventional
• Enrollment (Anticipated): 4000
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Alexander I. Karachunskiy, Professor, MD; Phone Number: +7-926-218-84-09; Email: info@mbstudy.net
• Study Contact Backup: Name: Julia V. Roumiantseva, MD. PhD; Phone Number: +7-903-730-39-78; Email: j.roumiantseva@mbstudy.net

Study Locations

• Armenia
  • Ereván, Armenia
    • Completed
    • prof. R.O.Eolyan Hematology Center
• Belarus
  • Gomel, Belarus
    • Recruiting
    • Republican Research and Practical Center of Radiation Medicine and Human Ecology
  • Minsk, Belarus
    • Recruiting
    • Republic Research and Practical Center of Pediatric Oncology, Hematology and Immunology
  • Mogilev, Belarus
    • Recruiting
    • Mogilev Regional Children's Hospital
• Kyrgyzstan
  • Bishkek, Kyrgyzstan
    • Completed
    • National Oncology and Hematology Center, Ministry of Health of the Kyrgyz Republic
• Russian Federation
  • Arkhangelsk, Russian Federation
    • Recruiting
    • Arkhangelsk Regional Clinical Children's Hospital
  • Astrakhan, Russian Federation
    • Recruiting
    • Regional Clinical Children's Hospital
  • Barnaul, Russian Federation
    • Recruiting
    • Altay Regional Clinical Children's Hospital
  • Blagoveshchensk, Russian Federation
    • Recruiting
    • Amur Regional Clinical Children's Hospital
  • Bryansk, Russian Federation
    • Recruiting
    • Bryansk Regional Children's Hospital
  • Chelyabinsk, Russian Federation
    • Recruiting
    • Chelyabinsk Regional Clinical Children's Hospital
  • Chita, Russian Federation
    • Recruiting
    • Transbaikal Regional Oncology Dispensary
  • Irkutsk, Russian Federation
    • Recruiting
    • Irkutsk Regional Children Clinical Hospital
  • Ivanovo, Russian Federation
    • Recruiting
    • Ivanovo Regional Clinical Hospital
  • Izhevsk, Russian Federation
    • Recruiting
    • Republic Clinical Children's Hospital
  • Khabarovsk, Russian Federation
    • Recruiting
    • Regional Clinical Children's Hospital
  • Kirov, Russian Federation
    • Recruiting
    • Kirov Research Institute of Hematology and Blood Transfusion
  • Krasnodar, Russian Federation
    • Recruiting
    • Regional Clinical Children's Hospital
  • Krasnoyarsk, Russian Federation
    • Recruiting
    • Krasnoyarsk Territorial Clinical Children's Hospital
  • Kurgan, Russian Federation
    • Recruiting
    • Kurgan Regional Clinical Children's Hospital
  • Kursk, Russian Federation
    • Recruiting
    • Regional Clinical Children's Hospital
  • Lipetsk, Russian Federation
    • Recruiting
    • Regional Children's Hospital
  • Makhachkala, Russian Federation
    • Recruiting
    • Republic Children's Clinical Hospital
  • Moscow, Russian Federation
    • Recruiting
    • Morozov Children's Municipal Clinical Hospital
  • Moscow, Russian Federation
    • Recruiting
    • Research Institute of Pediatric Hematology, Oncology and Immunology named after Dmitry Rogachev
  • Moscow, Russian Federation
    • Recruiting
    • Russian Children's Clinical Hospital
  • Murmansk, Russian Federation
    • Recruiting
    • Murmansk Clinical Children's Hospital
  • Nal'chik, Russian Federation
    • Recruiting
    • Republic Clinical Children's Hospital
  • Nizhnevartovsk, Russian Federation
    • Recruiting
    • Nizhnevartovsk Regional Clinical Children's Hospital
  • Nizhny Novgorod, Russian Federation
    • Recruiting
    • Regional Clinical Children's Hospital
  • Novokuznetsk, Russian Federation
    • Recruiting
    • Novokuznetsk Municipal Clinical Children's Hospital N4
  • Novosibirsk, Russian Federation
    • Recruiting
    • Novosibirsk Central District Clinical Hospital
  • Orenburg, Russian Federation
    • Recruiting
    • Orenburg Regional Clinical Oncology Dispensary
  • Orël, Russian Federation
    • Recruiting
    • Regional Clinical Children's Hospital
  • Perm, Russian Federation
    • Recruiting
    • Perm Territorial Clinical Children's Hospital
  • Rostov-on-Don, Russian Federation
    • Recruiting
    • Regional Clinical Children's Hospital
  • Rostov-on-Don, Russian Federation
    • Recruiting
    • Rostov Research Institute of Oncology
  • Ryazan, Russian Federation
    • Recruiting
    • N. Dmitrieva Ryazan Regional Clinical Children's Hospital
  • Saint Petersburg, Russian Federation
    • Recruiting
    • Almazov National Medical Research Center
  • Saint Petersburg, Russian Federation
    • Recruiting
    • Children's Municipal Hospital N1
  • Saint Petersburg, Russian Federation
    • Recruiting
    • Municipal Clinical Hospital N31
  • Saint Petersburg, Russian Federation
    • Recruiting
    • N.N.Petrov National Medical Research Oncology Center
  • Saint Petersburg, Russian Federation
    • Recruiting
    • R. Gorbacheva Research Institute of Pediatric Hematology and Transfusiology; Pavlov First Saint-Petersburg State Medical University
  • Samara, Russian Federation
    • Recruiting
    • Municipal Clinical Children's Hospital N1
  • Stavropol, Russian Federation
    • Recruiting
    • Regional Children's Clinical Hospital
  • Surgut, Russian Federation
    • Completed
    • Surgut Regional Clinical Hospital
  • Syktyvkar, Russian Federation
    • Recruiting
    • Republic Clinical Children's Hospital
  • Tomsk, Russian Federation
    • Recruiting
    • Tomsk Regional Clinical Hospital
  • Tula, Russian Federation
    • Recruiting
    • Tula Regional Clinical Children's Hospital
  • Ulan-Ude, Russian Federation
    • Recruiting
    • Republic Clinical Children's Hospital
  • Ulyanovsk, Russian Federation
    • Recruiting
    • Ulyanovsk Regional Children's Clinical Hospital
  • Vladivostok, Russian Federation
    • Recruiting
    • Regional Children's Clinical Hospital N1, Territorial Children's Hematological Center
  • Vologda, Russian Federation
    • Recruiting
    • Vologda Regional Clinical Children's Hospital
  • Voronezh, Russian Federation
    • Recruiting
    • Voronezh Regional Clinical Children's Hospital N1
  • Yakutsk, Russian Federation
    • Recruiting
    • Republic Hospital N1 - National Medicine Centre
  • Yaroslavl, Russian Federation
    • Recruiting
    • Regional Clinical Children's Hospital
  • Yekaterinburg, Russian Federation
    • Recruiting
    • Regional Clinical Children's Hospital N1; Children Oncology and hematology Center
• Uzbekistan
  • Tashkent, Uzbekistan
    • Recruiting
    • Research Institute of Hematology and Blood Transfusion

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 months to 48 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

10

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dexa intermittent; 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; 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.
Active Comparator: Dexa constant; Induction therapy with continuous Dexamethasone administration (6 mg/m2 1-29 days).	Drug: Dexamethasone continuous; 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.
Active Comparator: Dexa; Therapy with Dexamethasone (6 mg/m2) as basic glucocorticoid preparation.	Drug: Dexamethasone; 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.
Experimental: Medrol; Therapy with Methylprednisolone (60 mg/m2) as basic glucocorticoid preparation.	Drug: Methylprednisolone; 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.
Experimental: IDA; Induction and consolidation therapy with Idarubicin	Drug: Idarubicin; 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).
Active Comparator: DNR; Induction and consolidation therapy with Daunorubicin	Drug: Daunorubicin; 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).
Experimental: Protocol Ib+; Two-phase induction therapy (additional second phase of induction - protocol Ib)	Drug: Second phase of induction; 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)
Active Comparator: Protocol Ib-; Standard induction therapy (without second phase)	Drug: Standard induction therapy; 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)
Active Comparator: Bortezomib-; Consolidation therapy without Bortezomib	Drug: Standard consolidation therapy; 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)
Experimental: Bortezomib+; Consolidation therapy with Bortezomib 1.3 mg/m2 N12 (N4 in each reinduction)	Drug: Bortezomib; 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).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Federal Research Institute of Pediatric Hematology, Oncology and Immunology
• Investigators: Principal Investigator: Alexander I. Karachunskiy, Professor, MD, Research Institute of Pediatric Hematology, Oncology and Immunology

Publications and helpful links

Helpful Links

• Study web-site

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2015
• Primary Completion (Anticipated): November 1, 2020
• Study Completion (Anticipated): November 1, 2025

Study Registration Dates

• First Submitted: December 27, 2017
• First Submitted That Met QC Criteria: December 27, 2017
• First Posted (Actual): January 4, 2018

Study Record Updates

• Last Update Posted (Actual): February 5, 2020
• Last Update Submitted That Met QC Criteria: February 4, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: Acute lymphoblastic leukemia, children, adolescents, treatment
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protease Inhibitors; Neuroprotective Agents; Protective Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Dexamethasone; Dexamethasone acetate; Methylprednisolone; BB 1101; Bortezomib; Daunorubicin; Idarubicin
• Other Study ID Numbers: ALL-MB 2015

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No