A Study to Investigate Blinatumomab in Combination With Chemotherapy in Patients With Newly Diagnosed B-Lymphoblastic Leukemia
Phase 3 – large-scale trial before approval
Conditions:
B Acute Lymphoblastic Leukemia
B Lymphoblastic Lymphoma
Down Syndrome
Sponsor: National Cancer Institute (NCI)
trial.available_in:
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Overview
This phase III trial studies how well blinatumomab works in combination with chemotherapy in treating patients with newly diagnosed, standard risk B-lymphoblastic leukemia or B-lymphoblastic lymphoma with or without Down syndrome. Monoclonal antibodies, such as blinatumomab, may induce changes in the body's immune system and may interfere with the ability of cancer cells to grow and spread. Chemotherapy drugs, such as vincristine, dexamethasone, prednisone, prednisolone, pegaspargase, methotrexate, cytarabine, mercaptopurine, doxorubicin, cyclophosphamide, and thioguanine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Leucovorin decreases the toxic effects of methotrexate. Giving monoclonal antibody therapy with chemotherapy may kill more cancer cells. Giving blinatumomab and combination chemotherapy may work better than combination chemotherapy alone in treating patients with B-ALL. This trial also assigns patients into different chemotherapy treatment regimens based on risk (the chance of cancer returning after treatment). Treating patients with chemotherapy based on risk may help doctors decide which patients can best benefit from which chemotherapy treatment regimens.
Description
PRIMARY OBJECTIVES:
I. To determine in a randomized manner if the addition of 2 cycles of blinatumomab to standard therapy improves disease-free survival (DFS) in patients with standard risk (SR) B-ALL and higher risk features (SR-High), and patients with standard-risk average (SR-Avg) B-ALL who are negative for minimal residual disease (MRD) by flow cytometry but have detectable or indeterminate MRD as measured by high-throughput sequencing (HTS) at end of induction (EOI).
II. To confirm that boys in the standard-risk favorable (SR-Fav) subset of B-ALL, with or without Down syndrome (DS), will maintain a 5-year DFS of greater than 93% when treated with a standard chemotherapy regimen with a treatment duration of 2 years from the start of interim maintenance I (IM1).
SECONDARY OBJECTIVES:
I. To describe the DFS for patients with SR-Avg B-ALL who are negative for MRD measured by flow cytometry and HTS at EOI when treated with standard chemotherapy with a treatment duration of 2 years from the start of IM1, regardless of sex.
II. To describe the DFS for patients with standard-risk favorable (SR-Fav) B-ALL when treated with a standard chemotherapy regimen.
III. To determine if patients with DS-High achieve a reduction of treatment-related mortality (TRM) after replacement of intensive elements of standard chemotherapy (omission of anthracyclines in induction, omission of the second month of delayed intensification \[DI\]) with 3 cycles of blinatumomab.
IV. To describe the DFS characterized by the replacement of intensive elements of standard chemotherapy with 3 cycles of blinatumomab in patients with DS-High B ALL.
V. To describe the DFS for patients with localized (Murphy stage I and II) B lymphoblastic lymphoma (B-LLy) receiving standard risk B-ALL therapy.
VI. To compare the change in neurocognitive functioning, as measured by the CogState Cognitive Composite, from baseline to end-of-therapy among patients with ALL ages 4- \< 10 years at the time of diagnosis between children from poor families (defined as presence of household material hardship \[HMH\], including either food, housing or energy insecurity) and non-poor families (absence of HMH).
VII. To describe the impact of blinatumomab on caregiver burden and patient/proxy-reported symptoms among a subset of children enrolled in the HMH and neurocognitive outcome study.
VII. To evaluate available peripheral blood (PB) samples at EOI using HTS MRD and compare the results against bone marrow (BM) results.
IX. To evaluate available end of Consolidation (EOC) BM samples using HTS in patients who were Day 29 MRD positive by flow cytometry and who have submitted EOC BM flow cytometry results.
EXPLORATORY OBJECTIVES:
I. To explore adaptive and innate immune functions and host genetic factors associated with severe infectious complications in children with DS B-ALL.
II. To explore the impact of acute lymphoblastic leukemia (ALL) and its therapy on neurocognitive, functional, and quality
Who can participate
Inclusion Criteria:
* All B-ALL patients must be enrolled on APEC14B1 and consented to Eligibility Screening (Part A) prior to treatment and enrollment on AALL1731. APEC 14B1 is not a requirement for B-LLy patients. B-LLy patients may directly enroll on AALL1731.
* Age at diagnosis:
* Patients must be \>= 365 days and \< 10 years of age (B-ALL patients without DS).
* Patients must be \>= 365 days and =\< 31 years of age (B-ALL patients with DS).
* Patients must be \>= 365 days and =\< 31 years of age (B-LLy patients with or without DS).
* B-ALL patients without DS must have an initial white blood cell count \< 50,000/uL (performed within 7 days prior to enrollment).
* B-ALL patients with DS are eligible regardless of the presenting white blood cell count (WBC) (performed within 7 days prior to enrollment).
* Patient has newly diagnosed B-cell ALL, with or without Down syndrome: \> 25% blasts on a bone marrow (BM) aspirate;
* OR if a BM aspirate is not obtained or is not diagnostic of B-ALL, the diagnosis can be established by a pathologic diagnosis of B-ALL on a BM biopsy;
* OR a complete blood count (CBC) documenting the presence of at least 1,000/uL circulating leukemic cells;
* OR patient has newly diagnosed B-cell LLy Murphy stages I or II, with or without Down syndrome.
* Note: For B-LLy patients with tissue available for flow cytometry, the criterion for diagnosis should be analogous to B-ALL. For tissue processed by other means (i.e., paraffin blocks), the methodology and criteria for immunophenotypic analysis to establish the diagnosis of B-LLy defined by the submitting institution will be accepted (diagnostic biopsy for B-LLy must be performed within 14 days prior to enrollment).
* All patients and/or their parents or legal guardians must sign a written informed consent.
* All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met.
Exclusion Criteria:
* Patient must not have secondary ALL that developed after treatment of a prior malignancy with cytotoxic chemotherapy. Note: patients with Down syndrome with a prior history of transient myeloproliferative disease (TMD) are not considered to have had a prior malignancy. They would therefore be eligible whether or not the TMD was treated with cytarabine.
* With the exception of steroid pretreatment or the administration of intrathecal cytarabine, patients must not have received any prior cytotoxic chemotherapy for either the current diagnosis of B ALL or B LLy or for any cancer diagnosed prior to initiation of protocol therapy on AALL1731.
* For patients receiving steroid pretreatment, the following additional exclusion criteria apply:
* Non-DS B-ALL patients must not have received steroids for more than 24 hours in the 2 weeks prior to diagnosis without a CBC obtained within 3 days prior to initiation of the steroids.
* DS and non-DS B-LLy patients must not have received \> 48 hours of oral or IV steroids within 4 weeks of diagnosis.
* Patients who have received \> 72 hours of hydroxyurea within 1 week (7 days) prior to the start of systemic protocol therapy.
* B-ALL patients who do not have sufficient diagnostic bone marrow submitted for APEC14B1 diagnostic testing and who do not have a peripheral blood sample submitted containing \> 1,000/uL circulating leukemia cells.
* Patient must not have acute undifferentiated leukemia (AUL).
* Non-DS B-ALL patients with central nervous system \[CNS\]3 leukemia (CNS status must be known prior to enrollment).
* Note: DS patients with CNS3 disease are eligible but will be assigned to the DS-High B-ALL arm. CNS status must be determined based on a sample obtained prior to administration of any systemic or intrathecal chemotherapy, except for steroid pretreatment.
* Non-DS B-ALL patients with testicular leukemia. (Note: DS patients with testicular disease are eligible but will be assigned to the DS-High B-ALL arm).
* For LLy patients, the following additional exclusion criteria apply:
* T-Lymphoblastic Lymphoma.
* Morphologically unclassifiable lymphoma.
* Absence of both B-cell and T-cell phenotype markers in a case submitted as lymphoblastic lymphoma.
* CNS positive disease or testicular involvement.
* M2 (5% - 25% blasts) or M3 (\> 25% blasts) marrow.
* Patients with known Charcot-Marie-Tooth disease.
* Patients with known MYC translocation associated with mature (Burkitt) B-cell ALL, regardless of blast immunophenotype.
* Patients requiring radiation at diagnosis.
* 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 their study participation.
Interventions
Asparaginase Erwinia chrysanthemi
DRUG
Blinatumomab
BIOLOGICAL
Cyclophosphamide
DRUG
Cytarabine
DRUG
Dexamethasone
DRUG
Doxorubicin Hydrochloride
DRUG
Leucovorin Calcium
DRUG
Mercaptopurine
DRUG
Mercaptopurine Oral Suspension
DRUG
Methotrexate
DRUG
Pegaspargase
DRUG
Prednisolone
DRUG
Prednisone
DRUG
Radiation Therapy
RADIATION
Radiation Therapy
RADIATION
Thioguanine
DRUG
Vincristine Sulfate
DRUG
Locations
228
Australia (7)
Monash Medical Center-Clayton Campus
Clayton , Victoria
John Hunter Children's Hospital
Hunter Regional Mail Centre , New South Wales
Women's and Children's Hospital-Adelaide
North Adelaide , South Australia
Royal Children's Hospital
Parkville , Victoria
Perth Children's Hospital
Perth , Western Australia
Queensland Children's Hospital
South Brisbane , Queensland
The Children's Hospital at Westmead
Westmead , New South Wales
Canada (16)
Alberta Children's Hospital
Calgary , Alberta
University of Alberta Hospital
Edmonton , Alberta
IWK Health Centre
Halifax , Nova Scotia
McMaster Children's Hospital at Hamilton Health Sciences
Hamilton , Ontario
Kingston Health Sciences Centre
Kingston , Ontario
Children's Hospital
London , Ontario
The Montreal Children's Hospital of the MUHC
Montreal , Quebec
Children's Hospital of Eastern Ontario
Ottawa , Ontario
CHU de Quebec-Centre Hospitalier de l'Universite Laval (CHUL)
Québec
Jim Pattison Children's Hospital
Saskatoon , Saskatchewan
Saskatoon Cancer Centre
Saskatoon , Saskatchewan
Centre Hospitalier Universitaire de Sherbrooke-Fleurimont
Sherbrooke , Quebec
Janeway Child Health Centre
St. John's , Newfoundland and Labrador
Hospital for Sick Children
Toronto , Ontario
British Columbia Children's Hospital
Vancouver , British Columbia
CancerCare Manitoba
Winnipeg , Manitoba
New Zealand (2)
Christchurch Hospital
Christchurch
Starship Children's Hospital
Grafton , Auckland
Puerto Rico (2)
HIMA San Pablo Oncologic Hospital
Caguas
University Pediatric Hospital
San Juan
United States (201)
Children's Hospital Medical Center of Akron
Akron , Ohio
Albany Medical Center
Albany , New York
Presbyterian Hospital
Albuquerque , New Mexico
University of New Mexico Cancer Center
Albuquerque , New Mexico
Lehigh Valley Hospital-Cedar Crest
Allentown , Pennsylvania
Texas Tech University Health Sciences Center-Amarillo
Amarillo , Texas
Providence Alaska Medical Center
Anchorage , Alaska
C S Mott Children's Hospital
Ann Arbor , Michigan
Mission Hospital
Asheville , North Carolina
Children's Healthcare of Atlanta - Arthur M Blank Hospital
Atlanta , Georgia
Augusta University Medical Center
Augusta , Georgia
Children's Hospital Colorado
Aurora , Colorado
Dell Children's Medical Center of Central Texas
Austin , Texas
University of Maryland/Greenebaum Cancer Center
Baltimore , Maryland
Sinai Hospital of Baltimore
Baltimore , Maryland
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore , Maryland
Eastern Maine Medical Center
Bangor , Maine
Walter Reed National Military Medical Center
Bethesda , Maryland
Children's Hospital of Alabama
Birmingham , Alabama
Saint Luke's Cancer Institute - Boise
Boise , Idaho
Tufts Children's Hospital
Boston , Massachusetts
Massachusetts General Hospital Cancer Center
Boston , Massachusetts
Dana-Farber Cancer Institute
Boston , Massachusetts
Maimonides Medical Center
Brooklyn , New York
University of Vermont and State Agricultural College
Burlington , Vermont
UNC Lineberger Comprehensive Cancer Center
Chapel Hill , North Carolina
Medical University of South Carolina
Charleston , South Carolina
West Virginia University Charleston Division
Charleston , West Virginia
Carolinas Medical Center/Levine Cancer Institute
Charlotte , North Carolina
Novant Health Presbyterian Medical Center
Charlotte , North Carolina
University of Virginia Cancer Center
Charlottesville , Virginia
T C Thompson Children's Hospital
Chattanooga , Tennessee
Lurie Children's Hospital-Chicago
Chicago , Illinois
University of Illinois
Chicago , Illinois
University of Chicago Comprehensive Cancer Center
Chicago , Illinois
Cincinnati Children's Hospital Medical Center
Cincinnati , Ohio
Rainbow Babies and Childrens Hospital
Cleveland , Ohio
Cleveland Clinic Foundation
Cleveland , Ohio
University of Missouri Children's Hospital
Columbia , Missouri
Prisma Health Richland Hospital
Columbia , South Carolina
Nationwide Children's Hospital
Columbus , Ohio
Driscoll Children's Hospital
Corpus Christi , Texas
Medical City Dallas Hospital
Dallas , Texas
UT Southwestern/Simmons Cancer Center-Dallas
Dallas , Texas
Geisinger Medical Center
Danville , Pennsylvania
Dayton Children's Hospital
Dayton , Ohio
Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center
Denver , Colorado
Blank Children's Hospital
Des Moines , Iowa
Children's Hospital of Michigan
Detroit , Michigan
Henry Ford Health Saint John Hospital
Detroit , Michigan
Kaiser Permanente Downey Medical Center
Downey , California
City of Hope Comprehensive Cancer Center
Duarte , California
Duke University Medical Center
Durham , North Carolina
Michigan State University
East Lansing , Michigan
El Paso Children's Hospital
El Paso , Texas
Inova Fairfax Hospital
Falls Church , Virginia
Sanford Broadway Medical Center
Fargo , North Dakota
Broward Health Medical Center
Fort Lauderdale , Florida
Golisano Children's Hospital of Southwest Florida
Fort Myers , Florida
Cook Children's Medical Center
Fort Worth , Texas
UF Health Cancer Institute - Gainesville
Gainesville , Florida
Corewell Health Grand Rapids Hospitals - Helen DeVos Children's Hospital
Grand Rapids , Michigan
Saint Vincent Hospital Cancer Center Green Bay
Green Bay , Wisconsin
East Carolina University
Greenville , North Carolina
BI-LO Charities Children's Cancer Center
Greenville , South Carolina
Hackensack University Medical Center
Hackensack , New Jersey
Connecticut Children's Medical Center
Hartford , Connecticut
Penn State Children's Hospital
Hershey , Pennsylvania
Memorial Regional Hospital/Joe DiMaggio Children's Hospital
Hollywood , Florida
Kapiolani Medical Center for Women and Children
Honolulu , Hawaii
Tripler Army Medical Center
Honolulu , Hawaii
Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
Houston , Texas
M D Anderson Cancer Center
Houston , Texas
Edwards Comprehensive Cancer Center
Huntington , West Virginia
Riley Hospital for Children
Indianapolis , Indiana
Ascension Saint Vincent Indianapolis Hospital
Indianapolis , Indiana
University of Iowa/Holden Comprehensive Cancer Center
Iowa City , Iowa
University of Mississippi Medical Center
Jackson , Mississippi
Nemours Children's Clinic-Jacksonville
Jacksonville , Florida
Bronson Methodist Hospital
Kalamazoo , Michigan
Children's Mercy Hospitals and Clinics
Kansas City , Missouri
East Tennessee Childrens Hospital
Knoxville , Tennessee
University Medical Center of Southern Nevada
Las Vegas , Nevada
Sunrise Hospital and Medical Center
Las Vegas , Nevada
Alliance for Childhood Diseases/Cure 4 the Kids Foundation
Las Vegas , Nevada
Summerlin Hospital Medical Center
Las Vegas , Nevada
Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center
Lebanon , New Hampshire
University of Kentucky/Markey Cancer Center
Lexington , Kentucky
Arkansas Children's Hospital
Little Rock , Arkansas
Loma Linda University Medical Center
Loma Linda , California
Miller Children's and Women's Hospital Long Beach
Long Beach , California
Children's Hospital Los Angeles
Los Angeles , California
Cedars Sinai Medical Center
Los Angeles , California
Mattel Children's Hospital UCLA
Los Angeles , California
Norton Children's Hospital
Louisville , Kentucky
Palms West Radiation Therapy
Loxahatchee Groves , Florida
Covenant Children's Hospital
Lubbock , Texas
UMC Cancer Center / UMC Health System
Lubbock , Texas
Atrium Health Navicent
Macon , Georgia
Valley Children's Hospital
Madera , California
University of Wisconsin Carbone Cancer Center - University Hospital
Madison , Wisconsin
Marshfield Medical Center-Marshfield
Marshfield , Wisconsin
Loyola University Medical Center
Maywood , Illinois
Vannie Cook Children's Clinic
McAllen , Texas
Banner Children's at Desert
Mesa , Arizona
University of Miami Miller School of Medicine-Sylvester Cancer Center
Miami , Florida
Nicklaus Children's Hospital
Miami , Florida
Miami Cancer Institute
Miami , Florida
Children's Hospital of Wisconsin
Milwaukee , Wisconsin
NYU Langone Hospital - Long Island
Mineola , New York
Children's Hospitals and Clinics of Minnesota - Minneapolis
Minneapolis , Minnesota
University of Minnesota/Masonic Cancer Center
Minneapolis , Minnesota
USA Health Strada Patient Care Center
Mobile , Alabama
West Virginia University Healthcare
Morgantown , West Virginia
Morristown Medical Center
Morristown , New Jersey
The Children's Hospital at TriStar Centennial
Nashville , Tennessee
Vanderbilt University/Ingram Cancer Center
Nashville , Tennessee
Jersey Shore Medical Center
Neptune City , New Jersey
Saint Peter's University Hospital
New Brunswick , New Jersey
Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital
New Brunswick , New Jersey
Yale University
New Haven , Connecticut
The Steven and Alexandra Cohen Children's Medical Center of New York
New Hyde Park , New York
Children's Hospital New Orleans
New Orleans , Louisiana
Ochsner Medical Center Jefferson
New Orleans , Louisiana
Laura and Isaac Perlmutter Cancer Center at NYU Langone
New York , New York
Mount Sinai Hospital
New York , New York
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
New York , New York
Memorial Sloan Kettering Cancer Center
New York , New York
NYP/Weill Cornell Medical Center
New York , New York
Newark Beth Israel Medical Center
Newark , New Jersey
Children's Hospital of The King's Daughters
Norfolk , Virginia
Advocate Children's Hospital-Oak Lawn
Oak Lawn , Illinois
UCSF Benioff Children's Hospital Oakland
Oakland , California
Kaiser Permanente-Oakland
Oakland , California
University of Oklahoma Health Sciences Center
Oklahoma City , Oklahoma
Children's Hospital and Medical Center of Omaha
Omaha , Nebraska
University of Nebraska Medical Center
Omaha , Nebraska
Children's Hospital of Orange County
Orange , California
AdventHealth Orlando
Orlando , Florida
Arnold Palmer Hospital for Children
Orlando , Florida
Nemours Children's Hospital
Orlando , Florida
Lucile Packard Children's Hospital Stanford University
Palo Alto , California
Advocate Children's Hospital-Park Ridge
Park Ridge , Illinois
Saint Joseph's Regional Medical Center
Paterson , New Jersey
Sacred Heart Hospital
Pensacola , Florida
Saint Jude Midwest Affiliate
Peoria , Illinois
Children's Hospital of Philadelphia
Philadelphia , Pennsylvania
Saint Christopher's Hospital for Children
Philadelphia , Pennsylvania
Phoenix Childrens Hospital
Phoenix , Arizona
Children's Hospital of Pittsburgh of UPMC
Pittsburgh , Pennsylvania
Legacy Emanuel Children's Hospital
Portland , Oregon
Oregon Health and Science University
Portland , Oregon
Naval Medical Center - Portsmouth
Portsmouth , Virginia
Rhode Island Hospital
Providence , Rhode Island
Renown Regional Medical Center
Reno , Nevada
VCU Massey Comprehensive Cancer Center
Richmond , Virginia
Carilion Children's
Roanoke , Virginia
Mayo Clinic in Rochester
Rochester , Minnesota
University of Rochester
Rochester , New York
Corewell Health Children's
Royal Oak , Michigan
Sutter Medical Center Sacramento
Sacramento , California
University of California Davis Comprehensive Cancer Center
Sacramento , California
Primary Children's Hospital
Salt Lake City , Utah
Children's Hospital of San Antonio
San Antonio , Texas
Methodist Children's Hospital of South Texas
San Antonio , Texas
University of Texas Health Science Center at San Antonio
San Antonio , Texas
Rady Children's Hospital - San Diego
San Diego , California
Naval Medical Center -San Diego
San Diego , California
UCSF Medical Center-Mission Bay
San Francisco , California
Santa Barbara Cottage Hospital
Santa Barbara , California
Memorial Health University Medical Center
Savannah , Georgia
Maine Children's Cancer Program
Scarborough , Maine
Seattle Children's Hospital
Seattle , Washington
Sanford USD Medical Center - Sioux Falls
Sioux Falls , South Dakota
Providence Sacred Heart Medical Center and Children's Hospital
Spokane , Washington
Southern Illinois University School of Medicine
Springfield , Illinois
Baystate Medical Center
Springfield , Massachusetts
Cardinal Glennon Children's Medical Center
St Louis , Missouri
Washington University School of Medicine
St Louis , Missouri
Mercy Hospital Saint Louis
St Louis , Missouri
Johns Hopkins All Children's Hospital
St. Petersburg , Florida
Stony Brook University Medical Center
Stony Brook , New York
State University of New York Upstate Medical University
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