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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT03007147
Other study ID # AALL1631
Secondary ID NCI-2016-01588AA
Status Recruiting
Phase Phase 3
First received
Last updated
Start date August 8, 2017
Est. completion date September 30, 2027

Study information

Verified date April 2024
Source Children's Oncology Group
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

This randomized phase III trial studies how well imatinib mesylate works in combination with two different chemotherapy regimens in treating patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (ALL). Imatinib mesylate has been shown to improve outcomes in children and adolescents with Philadelphia chromosome positive (Ph+) ALL when given with strong chemotherapy, but the combination has many side effects. This trial is testing whether a different chemotherapy regimen may work as well as the stronger one but have fewer side effects when given with imatinib. The trial is also testing how well the combination of chemotherapy and imatinib works in another group of patients with a type of ALL that is similar to Ph+ ALL. This type of ALL is called "ABL-class fusion positive ALL", and because it is similar to Ph+ ALL, is thought it will respond well to the combination of agents used to treat Ph+ ALL.


Description:

PRIMARY OBJECTIVE: I. To compare disease-free survival (DFS) of standard risk (SR) pediatric Philadelphia chromosome (Ph)+ acute lymphoblastic leukemia (ALL) treated with continuous imatinib mesylate (imatinib) combined with either a high-risk Children's Oncology Group (COG) ALL chemotherapy backbone or the more intensive European (Es)PhALL chemotherapy backbone. SECONDARY OBJECTIVES: I. To compare DFS of SR pediatric Ph+ and ABL-class fusion positive ALL patients treated with continuous imatinib combined with either a high-risk COG-ALL chemotherapy backbone or the more intensive EsPhALL chemotherapy backbone. II. To determine the feasibility of administration of imatinib after allogeneic hematopoietic stem cell transplantation (HSCT) in high risk Ph+ ALL patients. III. To determine event-free survival (EFS) of HR pediatric Ph+ ALL patients treated with EsPhALL chemotherapy, HSCT in first complete remission and post-HSCT imatinib. IV. To compare rates of grade 3 or higher infections in standard risk (SR) Ph+ ALL patients between the two randomized arms. V. To evaluate event free survival (EFS) and overall survival (OS) of all eligible Ph+ALL patients enrolled on the study. VI. To evaluate OS in SR Ph+ ALL patients. VII. To evaluate OS in HR Ph+ ALL patients. VIII. To evaluate EFS and OS of all eligible ABL-class fusion positive ALL patients enrolled on the study. EXPLORATORY OBJECTIVES: I. To describe the toxicities associated with post-HSCT administration of imatinib in HR Ph+ALL patients. II. To evaluate the long-term toxicities in SR Ph+ ALL patients treated with chemotherapy plus imatinib (no transplant), overall and between both randomized arms. III. To determine prognostic significance of minimal residual disease (MRD) in Ph+ ALL at various time points during therapy. IIIa. To evaluate MRD in HR patients just prior to HSCT and then at regular intervals post-HSCT and explore the association of these measurements with long-term outcome. IIIb. To evaluate concordance of MRD assessments made by IGH-T cell receptor (TCR) polymerase chain reaction (PCR) assay and next generation sequencing (NGS) assays. IV. To determine prognostic significance of IKZF1 gene aberrations and deletions in Ph+ ALL. V. To determine frequency and prognostic significance of p190 and p210 BCR-ABL1 fusion variants in pediatric Ph+ ALL. VI. To measure adherence to oral chemotherapeutic agents (imatinib, 6-mercaptopurine, and methotrexate) during the maintenance phase in SR Ph+ ALL patients. VIa. To identify factors associated with poor adherence. VIb. To determine association between relapse risk and adherence to each oral chemotherapeutic agent (separately and combined). VII. To measure adherence to imatinib after allogeneic HSCT in HR Ph+ ALL patients and identify factors associated with poor adherence. VIII. To compare DFS of SR ABL-class fusion positive ALL patients treated with continuous imatinib combined with either a high-risk COG-ALL chemotherapy backbone or the more intensive EsPhALL chemotherapy backbone. OUTLINE: INDUCTION IA PART 1: Patients receive induction IA according to standard of care on days 1-14. INDUCTION IA PART 2: Patients receive imatinib mesylate orally (PO) once daily (QD) or twice daily (BID) on days 15-33, prednisolone PO twice daily (BID) or methylprednisolone intravenously (IV) on days 15-28, vincristine sulfate IV over 1 minute on days 15 and 22, daunorubicin hydrochloride IV over 1-15 minutes on days 15 and 22, and methotrexate intrathecally (IT) on day 29. INDUCTION IB: Patients receive imatinib mesylate PO QD or BID on days 1-35, cyclophosphamide IV over 30-60 minutes on days 1 and 28, mercaptopurine PO on days 1-28, cytarabine IV or subcutaneously (SC) on days 3-6, 10-13, 17-20, and 24-27, and methotrexate IT on days 10 and 24. POST-INDUCTION THERAPY: Patients classified as standard risk are randomized to 1 of 2 arms. Patients with high risk are assigned to Arm C. ARM A: CONSOLIDATION BLOCK 1: Patients receive imatinib mesylate PO QD or BID on days 1-21, methotrexate IT, cytarabine IT, and therapeutic hydrocortisone IT on day 1, high dose methotrexate IV over 24 hours on day 1, vincristine sulfate IV over 1 minute on days 1 and 6, dexamethasone PO BID or IV on days 1-5, cyclophosphamide IV over 30-60 minutes on days 2-4, leucovorin calcium PO or IV on days 3 and 4, high dose cytarabine IV over 3 hours and pegaspargase or calaspargase pegol IV over 1-2 hours on day 5, and filgrastim SC on days 7-11 in the absence of disease progression or unexpected toxicity. CONSOLIDATION BLOCK 2: Patients receive imatinib mesylate PO QD or BID on days 1-21, methotrexate IT, cytarabine IT, and therapeutic hydrocortisone IT on day 1, high dose methotrexate IV over 24 hours on day 1, dexamethasone PO BID or IV on days 1-5, vincristine sulfate IV over 1 minute on days 1 and 6, ifosfamide IV over 1 hour on days 2-4, leucovorin calcium PO or IV on days 3 and 4, dexrazoxane hydrochloride IV over 5-15 minutes and daunorubicin hydrochloride IV over 1-15 minutes on day 5, pegaspargase or calaspargase pegol IV over 1-2 hours on day 6, and filgrastim SC on days 7-11 in the absence of disease progression or unexpected toxicity. CONSOLIDATION BLOCK 3: Patients receive imatinib mesylate PO QD or BID on days 1-21, high dose cytarabine IV over 3 hours on days 1-3, dexamethasone PO BID or IV on days 1-5, etoposide IV over 1-2 hours on days 3-5, methotrexate IT, cytarabine IT, and therapeutic hydrocortisone IT on day 5, pegaspargase or calaspargase pegol IV over 1-2 hours on day 6, and filgrastim SC on days 7-11 in the absence of disease progression or unexpected toxicity. DELAYED INTENSIFICATION 1 PART 1: Patients receive imatinib mesylate PO QD or BID on days 1-35, methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine sulfate IV over 1 minute, dexrazoxane hydrochloride IV over 5-15 minutes, and doxorubicin IV over 1-15 minutes on days 8, 15, 22, and 29, and pegaspargase or calaspargase pegol IV over 1-2 hours on day 8 in the absence of disease progression or unexpected toxicity. DELAYED INTENSIFICATION 1 PART 2: Patients receive imatinib mesylate PO QD on days 36-63, cyclophosphamide IV over 30-60 minutes on day 36, thioguanine PO on days 36-49, cytarabine IV over 1-30 minutes or SC on days 38-41 and 45-48, and methotrexate IT on days 38 and 45in the absence of disease progression or unexpected toxicity. INTERIM MAINTENANCE: Patients receive imatinib mesylate PO QD or BID on days 1-28, methotrexate PO on days 1, 8, 15, and 22, and mercaptopurine PO on days 1-28 in the absence of disease progression or unexpected toxicity. DELAYED INTENSIFICATION 2 PART 1: Patients receive imatinib mesylate PO QD or BID on days 1-35, methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine sulfate IV over 1 minute, dexrazoxane hydrochloride IV over 5-15 minutes, and doxorubicin IV over 1-15 minutes on days 8, 15, 22, and 29, and pegaspargase or calaspargase pegol IV over 1-2 hours on day 8 in the absence of disease progression or unexpected toxicity. DELAYED INTENSIFICATION 2 PART 2: Patients receive imatinib mesylate PO QD on days 36-49, cyclophosphamide IV over 30-60 minutes on day 36, thioguanine PO on days 36-49, cytarabine IV over 1-30 minutes or SC on days 36-39 and 43-46, and methotrexate IT on days 36 and 43 in the absence of disease progression or unexpected toxicity. MAINTENANCE: Patients receive imatinib mesylate PO QD or BID on days 1-84, methotrexate PO once weekly (QW) and IT on days 1 and 43 of cycles 1, 2, and 3, and mercaptopurine PO on days 1-84. Cycles with imatinib mesylate and mercaptopurine repeat every 84 days for up to 104 weeks from the start of Induction IA in the absence of disease progression or unexpected toxicity. ARM B: INTERIM MAINTENANCE: Patients receive imatinib mesylate PO QD or BID on days 1-63, vincristine sulfate IV over 1 minute and high dose methotrexate IV over 24 hours on days 1, 15, 29, and 43, leucovorin calcium PO or IV on days 3-4, 17-18, 31-32, and 45-46, mercaptopurine PO on days 1-56, and methotrexate IT on days 1 and 29 in the absence of disease progression or unexpected toxicity. DELAYED INTENSIFICATION PART 1: Patients receive imatinib mesylate PO QD or BID on days 1-28, methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine sulfate IV over 1 minute, dexrazoxane hydrochloride IV over 5-15 minutes, and doxorubicin IV over 1-15 minutes on days 1, 8, and 15, and pegaspargase or calaspargase pegol IV over 1-2 hours or IM on day 4 in the absence of disease progression or unexpected toxicity. DELAYED INTENSIFICATION PART 2: Patients receive imatinib mesylate PO QD on days 29-56, cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on days 29-42, cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39, methotrexate IT on days 29 and 36, vincristine sulfate IV over 1 minute on days 43 and 50, and pegaspargase or calaspargase pegol IV over 1-2 hours on day 43 in the absence of disease progression or unexpected toxicity. INTERIM MAINTENANCE WITH CAPIZZI METHOTREXATE: Patients receive imatinib mesylate PO QD or BID on days 1-56, vincristine sulfate IV over 1 minute and methotrexate IV over 2-15 minutes on days 1, 11, 21, 31, and 41, methotrexate IT on days 1 and 31, and pegaspargase or calaspargase pegol IV over 1-2 hours on days 2 and 22 in the absence of disease progression or unexpected toxicity. MAINTENANCE: Patients receive imatinib mesylate PO QD or BID on days 1-84, vincristine sulfate IV over 1 minute on days 1, 29, and 57, prednisolone PO BID (or methylprednisolone IV for cycle 1 and 2) on days 1-5, 29-33, and 57-61, mercaptopurine PO on days 1-84, methotrexate PO QW, and methotrexate IT on day 1 (and day 29 for cycle 1 and 2). Cycles repeat every 84 days for up to 104 weeks from the start of Induction IA in the absence of disease progression or unexpected toxicity. ARM C: CONSOLIDATION BLOCK 1: Patients receive imatinib mesylate, methotrexate, cytarabine, therapeutic hydrocortisone, high dose methotrexate, vincristine sulfate, dexamethasone, leucovorin calcium, high dose cytarabine, and pegaspargase or calaspargase pegol as in Arm A Consolidation Block 1, and filgrastim SC on day 7 in the absence of disease progression or unexpected toxicity. CONSOLIDATION BLOCK 2: Patients receive imatinib mesylate, methotrexate, cytarabine, therapeutic hydrocortisone, high dose methotrexate, dexamethasone, vincristine sulfate, ifosfamide, leucovorin calcium, dexrazoxane hydrochloride, daunorubicin hydrochloride, pegaspargase or calaspargase pegol, and filgrastim as Arm A Consolidation Block 2 in the absence of disease progression or unexpected toxicity. CONSOLIDATION BLOCK 3: Patients receive imatinib mesylate, dexamethasone, etoposide, methotrexate, cytarabine, therapeutic hydrocortisone, pegaspargase or calaspargase pegol, and filgrastim as in Arm A Consolidation Block 3, and high dose cytarabine IV over 3 hours on days 1-2 in the absence of disease progression or unexpected toxicity. HSCT: Patients undergo HSCT on day 0. Patients who do not proceed to HSCT receive Delayed Intensification 1, Interim Maintenance, Delayed Intensification 2, and Maintenance as in Arm A. POST-HSCT: Patients receive imatinib mesylate PO QD or BID starting on days 56-365 in the in the absence of disease progression or unexpected toxicity. After completion of study treatment, patients are followed up every year for 3 years.


Recruitment information / eligibility

Status Recruiting
Enrollment 475
Est. completion date September 30, 2027
Est. primary completion date September 30, 2027
Accepts healthy volunteers No
Gender All
Age group 1 Year to 21 Years
Eligibility Inclusion Criteria: - For patients enrolled on APEC14B1 prior to enrollment on AALL1631, the required diagnostic bone marrow sample has been fulfilled - For patients who have not previously enrolled on APEC14B1 prior to enrollment on AALL1631, a baseline diagnostic sample (or peripheral blood sample with blasts if marrow sample unavailable) must be available to develop an MRD probe - In addition, laboratory reports detailing evidence of BCR-ABL1 fusion or ABL-class fusion must be submitted for rapid central review within 72 hours of study enrollment - >= 1 year (365 days) and =< 21 years at ALL diagnosis - Ph+ (BCR-ABL1 fusion): newly diagnosed de novo ALL (B-ALL or T-ALL) or mixed phenotypic acute leukemia (MPAL meeting 2016 World Health Organization [WHO] definition) with definitive evidence of BCR-ABL1 fusion by karyotype, fluorescence in situ hybridization (FISH) and/or molecular methodologies - ABL-class fusion: newly diagnosed B-ALL with definitive evidence of ABL-class fusions. ABL-class fusions are defined as those involving the following genes: ABL1, ABL2, CSF1R, PDGFRB, PDGFRA. Methods of detection include fluorescence in-situ hybridization (FISH, e.g. using break-apart or colocalization signals probes), multiplex or singleplex reverse-transcription polymerase chain reaction (RT-PCR), whole transcriptome or panel-based ribonucleic acid (RNA)-sequencing (e.g. TruSight RNA Pan-Cancer Panel; Illumina, San Diego, CA, USA or similar) - Ph+ patients must have previously started Induction therapy, which includes vincristine, a corticosteroid, pegaspargase, with or without anthracycline, and/or other standard cytotoxic chemotherapy - Ph+ patients have not received more than 14 days of multiagent Induction therapy beginning with the first dose of vinCRIStine - Ph+ patients may have started imatinib prior to study entry but have not received more than 14 days of imatinib - ABL-class fusion patients must have previously completed the 4 or 5 weeks of multiagent Induction chemotherapy (Induction IA phase) - ABL-class fusion patients may have started imatinib during Induction IA, at the same time of or after the first vinCRIStine dose - Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2 - Direct bilirubin =< 2.0 mg/dL - Shortening fraction of >= 27% by echocardiogram - Ejection fraction of >= 50% by radionuclide angiogram or echocardiogram - Corrected QT interval, QTc < 480 msec - Note: Repeat echocardiogram and electrocardiogram are not required if they were performed at or after initial ALL diagnosis, before study enrollment - Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or serum creatinine within normal limits based on age/gender, as follows: - 1 to < 2 years: maximum serum creatinine 0.6 mg/dL (both male and female) - 2 to < 6 years: maximum serum creatinine 0.8 mg/dL (both male and female) - 6 to < 10 years: maximum serum creatinine 1 mg/dL (both male and female) - 10 to < 13 years: maximum serum creatinine 1.2 mg/dL (both male and female) - 13 to < 16 years: maximum serum creatinine 1.5 mg/dL (male), 1.4 mg/dL (female) - >= 16 years: maximum serum creatinine 1.7 mg/dL (male), 1.4 mg/dL (female) Exclusion Criteria: - Known history of chronic myelogenous leukemia (CML) - ALL developing after a previous cancer treated with cytotoxic chemotherapy - Active, uncontrolled infection, or active systemic illness that requires ongoing vasopressor support or mechanical ventilation - Down syndrome - Pregnancy and breast feeding - Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs; a pregnancy test is required for female patients of childbearing potential - Lactating females who plan to breastfeed their infants - Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of treatment according to protocol - Patients with congenital long QT syndrome, history of ventricular arrhythmias or heart block - Prior treatment with dasatinib, or any TKI other than imatinib

Study Design


Related Conditions & MeSH terms


Intervention

Procedure:
Allogeneic Hematopoietic Stem Cell Transplantation
Undergo HSCT
Drug:
Calaspargase Pegol
Given IV
Cyclophosphamide
Given IV
Cytarabine
Given IV, SC, or IT
Daunorubicin Hydrochloride
Given IV
Dexamethasone
Given PO or IV
Dexrazoxane Hydrochloride
Given IV
Doxorubicin
Given IV
Etoposide
Given IV
Biological:
Filgrastim
Given IV
Drug:
Ifosfamide
Given IV
Imatinib Mesylate
Given PO
Other:
Laboratory Biomarker Analysis
Correlative studies
Drug:
Leucovorin Calcium
Given PO or IV
Mercaptopurine
Given PO
Mercaptopurine
Given PO
Methotrexate
Given IT
Methylprednisolone
Given IV
Pegaspargase
Given IV
Prednisolone
Given PO
Other:
Questionnaire Administration
Ancillary studies
Drug:
Therapeutic Hydrocortisone
Given IT
Thioguanine
Given PO
Vincristine Sulfate
Given IV

Locations

Country Name City State
Australia John Hunter Children's Hospital Hunter Regional Mail Centre New South Wales
Australia Perth Children's Hospital Perth Western Australia
Australia Princess Margaret Hospital for Children Perth Western Australia
Australia Sydney Children's Hospital Randwick New South Wales
Australia Queensland Children's Hospital South Brisbane Queensland
Australia The Children's Hospital at Westmead Westmead New South Wales
Austria St. Anna Children's Hospital Vienna
Belgium Hospitals Leuven Leuven Flemish Brabant
Canada Alberta Children's Hospital Calgary Alberta
Canada University of Alberta Hospital Edmonton Alberta
Canada IWK Health Centre Halifax Nova Scotia
Canada McMaster Children's Hospital at Hamilton Health Sciences Hamilton Ontario
Canada Kingston Health Sciences Centre Kingston Ontario
Canada Children's Hospital London Ontario
Canada Centre Hospitalier Universitaire Sainte-Justine Montreal Quebec
Canada The Montreal Children's Hospital of the MUHC Montreal Quebec
Canada Children's Hospital of Eastern Ontario Ottawa Ontario
Canada CHU de Quebec-Centre Hospitalier de l'Universite Laval (CHUL) Quebec
Canada Jim Pattison Children's Hospital Saskatoon Saskatchewan
Canada Saskatoon Cancer Centre Saskatoon Saskatchewan
Canada Centre Hospitalier Universitaire de Sherbrooke-Fleurimont Sherbrooke Quebec
Canada Hospital for Sick Children Toronto Ontario
Canada British Columbia Children's Hospital Vancouver British Columbia
Canada CancerCare Manitoba Winnipeg Manitoba
Chile Hospital Roberto del Rio-Universidad de Chile Santiago
Czechia University Hospital Motol Praha
Finland Tampere University Hospital Tampere
France CHU Hopital Sud Rennes
Germany Universitätsklinik Eppendorf Hamburg
Germany University Medical Center chleswig- Campus Kiel Kiel Schleswig-Holstein
Hong Kong Hong Kong Children's Hospital Kowloon Bay Kowloon
Israel Schneider Children's Medical Center of Israe Petah-Tikva Central District
Italy Clinica Pediatrica Università Milano-Bicocca Ospedale S. Gerardo/Fondazione MBBM Monza
Netherlands Princess Máxima Center for Pediatric Oncology Utrecht
New Zealand Christchurch Hospital Christchurch
New Zealand Starship Children's Hospital Grafton Auckland
Puerto Rico HIMA San Pablo Oncologic Hospital Caguas
Puerto Rico San Jorge Children's Hospital San Juan
Puerto Rico University Pediatric Hospital San Juan
Saudi Arabia King Faisal Specialist Hospital and Research Centre Riyadh
Sweden Skane University Hospital Lund Scania
Switzerland University Children's Hospital Zurich
United States Children's Hospital Medical Center of Akron Akron Ohio
United States Albany Medical Center Albany New York
United States Presbyterian Hospital Albuquerque New Mexico
United States University of New Mexico Cancer Center Albuquerque New Mexico
United States Lehigh Valley Hospital-Cedar Crest Allentown Pennsylvania
United States Texas Tech University Health Sciences Center-Amarillo Amarillo Texas
United States Providence Alaska Medical Center Anchorage Alaska
United States C S Mott Children's Hospital Ann Arbor Michigan
United States Mission Hospital Asheville North Carolina
United States Children's Healthcare of Atlanta - Egleston Atlanta Georgia
United States Augusta University Medical Center Augusta Georgia
United States Children's Hospital Colorado Aurora Colorado
United States Dell Children's Medical Center of Central Texas Austin Texas
United States Johns Hopkins University/Sidney Kimmel Cancer Center Baltimore Maryland
United States Sinai Hospital of Baltimore Baltimore Maryland
United States Eastern Maine Medical Center Bangor Maine
United States Walter Reed National Military Medical Center Bethesda Maryland
United States Children's Hospital of Alabama Birmingham Alabama
United States Saint Luke's Cancer Institute - Boise Boise Idaho
United States Dana-Farber Cancer Institute Boston Massachusetts
United States Massachusetts General Hospital Cancer Center Boston Massachusetts
United States Tufts Children's Hospital Boston Massachusetts
United States Montefiore Medical Center - Moses Campus Bronx New York
United States Maimonides Medical Center Brooklyn New York
United States Roswell Park Cancer Institute Buffalo New York
United States University of Vermont and State Agricultural College Burlington Vermont
United States UNC Lineberger Comprehensive Cancer Center Chapel Hill North Carolina
United States Medical University of South Carolina Charleston South Carolina
United States Carolinas Medical Center/Levine Cancer Institute Charlotte North Carolina
United States Novant Health Presbyterian Medical Center Charlotte North Carolina
United States University of Virginia Cancer Center Charlottesville Virginia
United States T C Thompson Children's Hospital Chattanooga Tennessee
United States Lurie Children's Hospital-Chicago Chicago Illinois
United States University of Chicago Comprehensive Cancer Center Chicago Illinois
United States University of Illinois Chicago Illinois
United States Cincinnati Children's Hospital Medical Center Cincinnati Ohio
United States Cleveland Clinic Foundation Cleveland Ohio
United States Rainbow Babies and Childrens Hospital Cleveland Ohio
United States Columbia Regional Columbia Missouri
United States Prisma Health Richland Hospital Columbia South Carolina
United States Nationwide Children's Hospital Columbus Ohio
United States Driscoll Children's Hospital Corpus Christi Texas
United States Medical City Dallas Hospital Dallas Texas
United States UT Southwestern/Simmons Cancer Center-Dallas Dallas Texas
United States Geisinger Medical Center Danville Pennsylvania
United States Dayton Children's Hospital Dayton Ohio
United States Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center Denver Colorado
United States Blank Children's Hospital Des Moines Iowa
United States Ascension Saint John Hospital Detroit Michigan
United States Children's Hospital of Michigan Detroit Michigan
United States Kaiser Permanente Downey Medical Center Downey California
United States City of Hope Comprehensive Cancer Center Duarte California
United States Duke University Medical Center Durham North Carolina
United States Michigan State University Clinical Center East Lansing Michigan
United States El Paso Children's Hospital El Paso Texas
United States Inova Fairfax Hospital Falls Church Virginia
United States Sanford Broadway Medical Center Fargo North Dakota
United States Broward Health Medical Center Fort Lauderdale Florida
United States Golisano Children's Hospital of Southwest Florida Fort Myers Florida
United States Cook Children's Medical Center Fort Worth Texas
United States University of Florida Health Science Center - Gainesville Gainesville Florida
United States Helen DeVos Children's Hospital at Spectrum Health Grand Rapids Michigan
United States Saint Vincent Hospital Cancer Center Green Bay Green Bay Wisconsin
United States BI-LO Charities Children's Cancer Center Greenville South Carolina
United States East Carolina University Greenville North Carolina
United States Hackensack University Medical Center Hackensack New Jersey
United States Connecticut Children's Medical Center Hartford Connecticut
United States Penn State Children's Hospital Hershey Pennsylvania
United States Memorial Regional Hospital/Joe DiMaggio Children's Hospital Hollywood Florida
United States Kapiolani Medical Center for Women and Children Honolulu Hawaii
United States Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center Houston Texas
United States M D Anderson Cancer Center Houston Texas
United States Edwards Comprehensive Cancer Center Huntington West Virginia
United States Ascension Saint Vincent Indianapolis Hospital Indianapolis Indiana
United States Riley Hospital for Children Indianapolis Indiana
United States University of Iowa/Holden Comprehensive Cancer Center Iowa City Iowa
United States University of Mississippi Medical Center Jackson Mississippi
United States Nemours Children's Clinic-Jacksonville Jacksonville Florida
United States Bronson Methodist Hospital Kalamazoo Michigan
United States Children's Mercy Hospitals and Clinics Kansas City Missouri
United States East Tennessee Childrens Hospital Knoxville Tennessee
United States Alliance for Childhood Diseases/Cure 4 the Kids Foundation Las Vegas Nevada
United States Summerlin Hospital Medical Center Las Vegas Nevada
United States Sunrise Hospital and Medical Center Las Vegas Nevada
United States University Medical Center of Southern Nevada Las Vegas Nevada
United States Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center Lebanon New Hampshire
United States University of Kentucky/Markey Cancer Center Lexington Kentucky
United States Arkansas Children's Hospital Little Rock Arkansas
United States Loma Linda University Medical Center Loma Linda California
United States Miller Children's and Women's Hospital Long Beach Long Beach California
United States Cedars Sinai Medical Center Los Angeles California
United States Children's Hospital Los Angeles Los Angeles California
United States Norton Children's Hospital Louisville Kentucky
United States Palms West Radiation Therapy Loxahatchee Groves Florida
United States Covenant Children's Hospital Lubbock Texas
United States UMC Cancer Center / UMC Health System Lubbock Texas
United States Medical Center of Central Georgia Macon Georgia
United States Valley Children's Hospital Madera California
United States University of Wisconsin Carbone Cancer Center Madison Wisconsin
United States Marshfield Medical Center-Marshfield Marshfield Wisconsin
United States Banner Children's at Desert Mesa Arizona
United States Miami Cancer Institute Miami Florida
United States Nicklaus Children's Hospital Miami Florida
United States University of Miami Miller School of Medicine-Sylvester Cancer Center Miami Florida
United States Children's Hospital of Wisconsin Milwaukee Wisconsin
United States NYU Winthrop Hospital Mineola New York
United States Children's Hospitals and Clinics of Minnesota - Minneapolis Minneapolis Minnesota
United States University of Minnesota/Masonic Cancer Center Minneapolis Minnesota
United States USA Health Strada Patient Care Center Mobile Alabama
United States West Virginia University Healthcare Morgantown West Virginia
United States Morristown Medical Center Morristown New Jersey
United States The Children's Hospital at TriStar Centennial Nashville Tennessee
United States Vanderbilt University/Ingram Cancer Center Nashville Tennessee
United States Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital New Brunswick New Jersey
United States Saint Peter's University Hospital New Brunswick New Jersey
United States Yale University New Haven Connecticut
United States The Steven and Alexandra Cohen Children's Medical Center of New York New Hyde Park New York
United States Ochsner Medical Center Jefferson New Orleans Louisiana
United States Laura and Isaac Perlmutter Cancer Center at NYU Langone New York New York
United States Memorial Sloan Kettering Cancer Center New York New York
United States Mount Sinai Hospital New York New York
United States NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center New York New York
United States Newark Beth Israel Medical Center Newark New Jersey
United States Children's Hospital of The King's Daughters Norfolk Virginia
United States Advocate Children's Hospital-Oak Lawn Oak Lawn Illinois
United States Kaiser Permanente-Oakland Oakland California
United States UCSF Benioff Children's Hospital Oakland Oakland California
United States University of Oklahoma Health Sciences Center Oklahoma City Oklahoma
United States Children's Hospital and Medical Center of Omaha Omaha Nebraska
United States University of Nebraska Medical Center Omaha Nebraska
United States Children's Hospital of Orange County Orange California
United States AdventHealth Orlando Orlando Florida
United States Arnold Palmer Hospital for Children Orlando Florida
United States Nemours Children's Hospital Orlando Florida
United States Lucile Packard Children's Hospital Stanford University Palo Alto California
United States Advocate Children's Hospital-Park Ridge Park Ridge Illinois
United States Saint Joseph's Regional Medical Center Paterson New Jersey
United States Sacred Heart Hospital Pensacola Florida
United States Saint Jude Midwest Affiliate Peoria Illinois
United States Children's Hospital of Philadelphia Philadelphia Pennsylvania
United States Saint Christopher's Hospital for Children Philadelphia Pennsylvania
United States Phoenix Childrens Hospital Phoenix Arizona
United States Children's Hospital of Pittsburgh of UPMC Pittsburgh Pennsylvania
United States Legacy Emanuel Children's Hospital Portland Oregon
United States Oregon Health and Science University Portland Oregon
United States Naval Medical Center - Portsmouth Portsmouth Virginia
United States Rhode Island Hospital Providence Rhode Island
United States Renown Regional Medical Center Reno Nevada
United States Virginia Commonwealth University/Massey Cancer Center Richmond Virginia
United States Carilion Children's Roanoke Virginia
United States Mayo Clinic in Rochester Rochester Minnesota
United States University of Rochester Rochester New York
United States Beaumont Children's Hospital-Royal Oak Royal Oak Michigan
United States University of California Davis Comprehensive Cancer Center Sacramento California
United States Mercy Hospital Saint Louis Saint Louis Missouri
United States Washington University School of Medicine Saint Louis Missouri
United States Johns Hopkins All Children's Hospital Saint Petersburg Florida
United States Primary Children's Hospital Salt Lake City Utah
United States Children's Hospital of San Antonio San Antonio Texas
United States Methodist Children's Hospital of South Texas San Antonio Texas
United States University of Texas Health Science Center at San Antonio San Antonio Texas
United States Rady Children's Hospital - San Diego San Diego California
United States UCSF Medical Center-Mission Bay San Francisco California
United States Memorial Health University Medical Center Savannah Georgia
United States Maine Children's Cancer Program Scarborough Maine
United States Seattle Children's Hospital Seattle Washington
United States Sanford USD Medical Center - Sioux Falls Sioux Falls South Dakota
United States Providence Sacred Heart Medical Center and Children's Hospital Spokane Washington
United States Southern Illinois University School of Medicine Springfield Illinois
United States Stony Brook University Medical Center Stony Brook New York
United States State University of New York Upstate Medical University Syracuse New York
United States Madigan Army Medical Center Tacoma Washington
United States Mary Bridge Children's Hospital and Health Center Tacoma Washington
United States Saint Joseph's Hospital/Children's Hospital-Tampa Tampa Florida
United States Tampa General Hospital Tampa Florida
United States Scott and White Memorial Hospital Temple Texas
United States ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital Toledo Ohio
United States Banner University Medical Center - Tucson Tucson Arizona
United States New York Medical College Valhalla New York
United States Children's National Medical Center Washington District of Columbia
United States MedStar Georgetown University Hospital Washington District of Columbia
United States Saint Mary's Hospital West Palm Beach Florida
United States Alfred I duPont Hospital for Children Wilmington Delaware
United States Wake Forest University Health Sciences Winston-Salem North Carolina
United States UMass Memorial Medical Center - University Campus Worcester Massachusetts

Sponsors (3)

Lead Sponsor Collaborator
Children's Oncology Group EsPhALL Network/ BFM Study Group, National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Canada,  Chile,  Czechia,  Finland,  France,  Germany,  Hong Kong,  Israel,  Italy,  Netherlands,  New Zealand,  Puerto Rico,  Saudi Arabia,  Sweden,  Switzerland, 

Outcome

Type Measure Description Time frame Safety issue
Other Incidence of toxicities associated with post-HSCT administration of imatinib mesylate Evaluated according to NCI CTCAE version 5.0. Frequencies of target toxicities in high risk patients after the initiation of post-HSCT imatinib mesylate will be described. For the high risk patients, the specific targeted toxicities will include grade 4 neutropenia, grade 4 thrombocytopenia, grade 3 or higher bilirubin, grade 4 or higher transaminitis, and grade 3 or higher infection. Up to 2 years
Other Incidence of long-term toxicities in patients treated with chemotherapy plus imatinib mesylate (no transplant) in both arms Evaluated according to NCI CTCAE version 5.0. Frequencies of long-term toxicities will be described and differences between randomized arms will be explored. Specific long-term toxicities to be explored include cardiac (echocardiographic abnormalities, including decreased left ventricular (LV) function and decreased LV wall thickness), growth (linear height, bone age), and second malignant neoplasm. Up to 3 years
Other MRD measured by IGH-T cell receptor (TCR) polymerase chain reaction (PCR) and next generation sequencing (NGS) assay For all patients, frequencies and prognostic significance (DFS, EFS, OS) will be explored for MRD levels (i.e., MRD negative, detectable at < 5 x 10^-4, and dectectable at >= 5 x 10^-4) at end of Induction IB. Up to 6 months
Other MRD in high risk Ph+ patients measured by IGH-TCR PCR and NGS assay The outcome of high risk Ph+ patients will be described, including proportion of patients who achieve MRD-negativity just prior to HSCT, and at regular intervals post-HSCT. Associations between these findings and long-term outcomes (e.g., OS, DFS) will be explored. Up to 3 years
Other MRD assessments made by IGH-TCR PCR assay and NGS assay Concordance of MRD assessments made by IGH-TCR PCR assay and NGS assay will be described and evaluated. Scatter plots and diagrams will be used to examine agreements and patterns of agreement or any differences found. Concordance will be explored both for the overall cohort, as well as by risk group. The increased sensitivity of the NGS will be closely examined to find cases where the MRD levels are detectable by NGS but undetectable by PCR, as well as cases in which one test yields results and the other does not (test failure). Prognostic relationships on outcomes for these subjects will be inspected. Up to 3 years
Other IKZF1 gene aberrations and deletions For both standard risk and high risk groups, frequencies and prognostic significance (OS, DFS) will be explored for IKZF1 gene aberrations and deletions. Up to 3 years
Other Frequency of p190 and p210 BCR-ABL1 fusion variants For both standard risk and high risk groups, frequencies and prognostic significance (OS, DFS) will be explored for p190 and p210 BCR-ABL1 fusion variants in pediatric Ph+ ALL. Up to 3 years
Other Adherence to oral chemotherapeutic agents in standard risk Ph+ ALL patients Adherence to imatinib mesylate, 6-mercaptopurine, and methotrexate will be evaluated in COG-enrolled participants using an electronic monitoring device. Adherence rate will be computed for each month of adherence monitoring. Longitudinal binomial regression will be conducted using generalized estimating equation methods by modeling monthly adherence rate as an unstructured mean model using five indicator variables of time for the study months. Time in months will also be treated as a continuous variable to explore temporal trends in adherence rate. Compound symmetry will be assumed as the working correlation matrix over time. Covariates that will be considered for adjustment include those hypothesized to be predictors of adherence, annual household income, parental education, time since start of maintenance, risk classification for ALL, and imatinib, 6-mercaptopurine (6MP), and methotrexate dose-intensity. Up to 2 years
Other Adherence to imatinib mesylate after allogeneic HSCT in high risk Ph+ ALL patients Longitudinal binomial regression will be conducted using generalized estimating equation methods by modeling monthly adherence rate as an unstructured mean model using five indicator variables of time for the study months. Time in months will also be treated as a continuous variable to explore temporal trends in adherence rate. Compound symmetry will be assumed as the working correlation matrix over time. Covariates that will be considered for adjustment include those hypothesized to be predictors of adherence, annual household income, parental education, time since start of maintenance, risk classification for ALL, and imatinib, 6MP, and methotrexate dose-intensity. Up to 2 years
Primary Disease free survival (DFS) of Randomized Arms (standard risk [SR] Philadelphia chromosome [Ph+] acute lymphoblastic leukemia [ALL] patients) Three-year DFS and 95% confidence intervals (CI) of SR Ph+ ALL patients treated continuous imatinib mesylate with high risk Children's Oncology Group (COG)-ALL chemotherapy backbone or more intensive European (Es)PhALL chemotherapy backbone. Up to 3 years
Secondary DFS on Randomized Arms (SR Ph+ ALL and ABL-class fusion positive patients) Three-year DFS (time from randomization to relapse, second malignancy, or death in complete remission) and 95% CI of SR pediatric Ph+ and ABL-class fusion positive patients treated with continuous imatinib combined with either a high-risk COG-ALL chemotherapy backbone or the more intensive EsPhALL chemotherapy backbone. Up to 3 years
Secondary Feasibility of post hematopoietic stem cell transplantation (HSCT) imatinib mesylate administration after allogenic HSCT in high risk Ph+ ALL patients The proportion of patients who receive at least 75% of intended doses. Up to 2 years
Secondary Event free survival (EFS) of high risk pediatric Ph+ ALL patients treated with EsPhALL chemotherapy, HSCT in first complete remission, and post-HSCT imatinib mesylate Three-year EFS and 95% CI for high risk pediatric Ph+ ALL patients treated with EsPhALL chemotherapy, HSCT in first complete remission, and post-HSCT imatinib mesylate. EFS is defined as the time from the date of bone marrow for minimal residual disease (MRD) assessment at end-IB to first event (resistant disease [MRD >= 10-2 or morphologic residual disease at end of consolidation block 3], relapse, progressive disease [i.e., MRD >= 10-2 at two post-HSCT time points separated by at least 2 weeks], second malignancy, or death in complete remission), or time to last follow-up for patients without events. Up to 3 years
Secondary Incidence of grade 3 or higher infections in standard risk Ph+ ALL patients in the two randomized arms Evaluated according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The rate of infections during the post IB/pre-maintenance phases of treatment will be described for each randomization group. Up to 3 years
Secondary EFS of all Ph+ patients Three-year EFS and 95% CI for Ph+ ALL patients. EFS here is defined as the time from enrollment until resistant disease, relapse, progressive disease post-HSCT, second malignant, or death, whichever occurs first. Up to 3 years
Secondary Overall survival (OS) of all Ph+ patients Three-year OS and 95% CI for Ph+ ALL patients. OS is defined as the time from study enrollment to death from any cause. Up to 3 years
Secondary OS of SR Ph+ patients Three-year OS (time from randomization to death from any cause) and 95% CI of SR pediatric Ph+ patients Up to 3 years
Secondary OS of SR Ph+ patients by randomization group Three-year OS (time from randomization to death from any cause) and 95% CI of SR pediatric Ph+ patients by randomization group: treated with continuous imatinib combined with either a high-risk COG-ALL chemotherapy backbone or the more intensive EsPhALL chemotherapy backbone. Up to 3 years
Secondary OS of high risk Ph+ patients Three-year OS (time from the date of MRD assessment at end-IB to death from any cause) and 95% CI of HR pediatric Ph+ patients. Up to 3 years
Secondary EFS of all eligibility ABL-class fusion positive ALL patients Three-year EFS (time from enrollment until resistant disease, relapse, progressive disease post-HSCT, second malignancy, or death, whichever occurs first) and 95% CI of ABL-class fusion positive patients. Up to 3 years
Secondary OS of all eligibility ABL-class fusion positive ALL patients Three-year OS (the time from study enrollment to death from any cause) and 95% CI of ABL-class fusion positive patients. Up to 3 years
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