A Randomized Phase II Study of Venetoclax and HMA-Based Therapies for the Treatment of Older and Unfit Adults With Newly Diagnosed FLT3-Mutated Acute Myeloid Leukemia (AML): A MyeloMATCH Treatment Trial
Summary
This phase II MyeloMATCH treatment trial compares the usual treatment of azacitidine and venetoclax to the combination treatment of azacitidine, venetoclax and gilteritinib in treating older and unfit patients with acute myeloid leukemia and FLT3 mutations. Azacitidine is a drug that is absorbed into DNA and leads to the activation of cancer suppressor genes, which are genes that help control cell growth. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Gilteritinib is in a class of medications called kinase inhibitors. It works by blocking the action of a certain naturally occurring substance that may be needed to help cancer cells multiply. This study may help doctors find out if these different approaches are better than the usual approaches. To decide if they are better, the study doctors are looking to see if the study drugs lead to a higher percentage of patients achieving a deeper remission compared to the usual approach.
Detailed description
PRIMARY OBJECTIVE: I. To compare the achievement rate of measured residual disease negative (MRDneg) complete remission (CR) of either triplet regimen to azacitidine and venetoclax alone within 4 cycles of therapy. SECONDARY OBJECTIVES: I. To compare the achievement rate of MRDneg CR/complete remission with incomplete count recovery (CRi)/complete remission with partial hematologic recovery (CRh) of either triplet regimen to azacitidine and venetoclax alone within 4 cycles of therapy. II. To determine the safety and tolerability of the combination of gilteritinib, azacitidine, and venetoclax, if both of the triplet regimens show superiority to the azacitidine plus venetoclax regimen. III. To determine the optimal sequence and duration of gilteritinib, when added to azacitidine and venetoclax if both of the triplet regimens show superiority to the azacitidine plus venetoclax regimen. IV. To estimate the rates of complete remission (CR), complete remission with incomplete count recovery (CRi), and complete remission with partial hematologic recovery (CRh), morphologic leukemia-free state (MLFS), event-free survival (EFS), and overall survival (OS) of the combination of gilteritinib, azacitidine, and venetoclax versus azacitidine and venetoclax alone. EXPLORATORY OBJECTIVES: I. To establish the degree reduction in FLT3- internal tandem duplication (ITD) mutation burden after 2 and 4 cycles of therapy using a highly sensitive next-generation sequencing (NGS) MRD assay and compare the median reduction in the investigational regimens among patients with CR/CRi/CRh to that of control regimen. II. To determine if the degree of FLT3 ITD reduction is associated with the duration of remission. III. To monitor which mutations are present at the time of relapse. IV. To monitor which co-mutations at presentation are associated with lack of response to these regimens. V. To determine if the FLT3 AR /variant allele frequency (VAF) is associated with response to the regimens. OUTLINE: Patients are randomized to 1 of 3 regimens. REGIMEN 1: INDUCTION: Patients receive azacitidine intravenously (IV) or subcutaneously (SC) on days 1-7 of each cycle and venetoclax orally (PO) on days 1-28 of each cycle. Treatment repeats every 28 days for up to 2 cycles or until patient achieves remission, whichever comes first, in the absence of disease progression or unacceptable toxicity. CONSOLIDATION: Patients receive azacitidine IV or SC on days 1-7 and venetoclax PO on days 1-28 of each cycle. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity. REGIMEN 2: INDUCTION: Patients receive azacitidine IV or SC on days 1-7 and venetoclax and gilteritinib PO on days 1-28 of each cycle. Treatment repeats every 28 days for up to 2 cycles or until patient achieves remission, whichever comes first, in the absence of disease progression or unacceptable toxicity. CONSOLIDATION: Patients receive azacitidine IV or SC on days 1-5, venetoclax PO on days 1-7 and gilteritinib PO on days 1-28 of each cycle. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity. REGIMEN 3: INDUCTION: Patients receive azacitidine IV or SC on days 1-7 and venetoclax PO on days 1-28, and gilteritinib PO on days 8-21 of each cycle. Treatment repeats every 28 days for up to 2 cycles or until patient achieves remission, whichever comes first, in the absence of disease progression or unacceptable toxicity. CONSOLIDATION: Patients receive azacitidine IV or SC on days 1-5, venetoclax PO on days 1-14 and gilteritinib PO on days 8-21 of each cycle. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity. All patients undergo bone marrow biopsy and aspiration as well as blood sample collection on the trial. After completion of study treatment, patients are followed up every 3 months if patient is \< 2 years from first registration, and every 6 months if patient is 2-5 years from first registration. All patients, including those who discontinue protocol therapy early, are followed for response until progression, even if non-protocol therapy is initiated, and for survival for 10 years from the date of randomization.
Arms & interventions
- DrugAzacitidine
Given IV or SC
- ProcedureBiospecimen Collection
Undergo blood sample collection
- ProcedureBone Marrow Aspiration
Undergo bone marrow biopsy and aspiration
- ProcedureBone Marrow Biopsy
Undergo bone marrow biopsy and aspiration
- DrugGilteritinib
Given PO
- DrugVenetoclax
Given PO
Outcome measures
Primary
Rate of measured residual disease (MRD) negative complete remission (CR)
Will be assessed by multiparameter flow cytometry at a level of ≤ 1 residual blast / 1,000 leukocytes (≤ 10\^-3).
Time frame: Up to 4 cycles of treatment
Secondary
Overall survival
Time frame: Time between randomization and death from any cause, assessed up to 10 years
Event-free survival
Time frame: Time from randomization to failure to achieve complete remission (CR), CR with incomplete count recovery, and CR with partial hematologic recovery, or to relapse after CR/CRi/CRh or to death in remission, assessed up to 10 years
Incidence of adverse events
Time frame: Up to 10 years
Eligibility criteria
Study locations (221)
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, 35233
Banner University Medical Center - Tucson
Tucson, Arizona, 85719
University of Arizona Cancer Center-North Campus
Tucson, Arizona, 85719
University of Arkansas for Medical Sciences
Little Rock, Arkansas, 72205
Alta Bates Summit Medical Center-Herrick Campus
Berkeley, California, 94704
Kaiser Permanente Dublin
Dublin, California, 94568
Kaiser Permanente-Fremont
Fremont, California, 94538
Kaiser Permanente Fresno Orchard Plaza
Fresno, California, 93720
Kaiser Permanente-Fresno
Fresno, California, 93720
Cedars-Sinai Medical Center
Los Angeles, California, 90048
Kaiser Permanente- Modesto MOB II
Modesto, California, 95356
Kaiser Permanente-Modesto
Modesto, California, 95356
Kaiser Permanente-Oakland
Oakland, California, 94611
Kaiser Permanente-Roseville
Roseville, California, 95661
Kaiser Permanente Downtown Commons
Sacramento, California, 95814
University of California Davis Comprehensive Cancer Center
Sacramento, California, 95817
Kaiser Permanente-South Sacramento
Sacramento, California, 95823
Kaiser Permanente-San Francisco
San Francisco, California, 94115
UCSF Medical Center-Parnassus
San Francisco, California, 94143
Kaiser Permanente-Santa Teresa-San Jose
San Jose, California, 95119
Kaiser Permanente San Leandro
San Leandro, California, 94577
Mills Health Center
San Mateo, California, 94401
Kaiser San Rafael-Gallinas
San Rafael, California, 94903
Kaiser Permanente Medical Center - Santa Clara
Santa Clara, California, 95051
Kaiser Permanente-Santa Rosa
Santa Rosa, California, 95403
Kaiser Permanente-South San Francisco
South San Francisco, California, 94080
Kaiser Permanente-Vallejo
Vallejo, California, 94589
Kaiser Permanente-Walnut Creek
Walnut Creek, California, 94596
Yale University
New Haven, Connecticut, 06520
Veterans Affairs Connecticut Healthcare System-West Haven Campus
West Haven, Connecticut, 06516
UF Health Cancer Institute - Gainesville
Gainesville, Florida, 32610
Miami Cancer Institute
Miami, Florida, 33176
Phoebe Putney Memorial Hospital
Albany, Georgia, 31701
Augusta University Medical Center
Augusta, Georgia, 30912
Hawaii Cancer Care Inc - Waterfront Plaza
Honolulu, Hawaii, 96813
Straub Clinic and Hospital
Honolulu, Hawaii, 96813
Kaiser Permanente Moanalua Medical Center
Honolulu, Hawaii, 96819
Hawaii Cancer Care - Westridge
‘Aiea, Hawaii, 96701
Pali Momi Medical Center
‘Aiea, Hawaii, 96701
Saint Alphonsus Cancer Care Center-Boise
Boise, Idaho, 83706
Saint Luke's Cancer Institute - Boise
Boise, Idaho, 83712
Saint Alphonsus Cancer Care Center-Caldwell
Caldwell, Idaho, 83605
Kootenai Health - Coeur d'Alene
Coeur d'Alene, Idaho, 83814
Saint Luke's Cancer Institute - Fruitland
Fruitland, Idaho, 83619
Saint Luke's Cancer Institute - Meridian
Meridian, Idaho, 83642
Saint Alphonsus Cancer Care Center-Nampa
Nampa, Idaho, 83687
Saint Luke's Cancer Institute - Nampa
Nampa, Idaho, 83687
Kootenai Clinic Cancer Services - Post Falls
Post Falls, Idaho, 83854
Kootenai Clinic Cancer Services - Sandpoint
Sandpoint, Idaho, 83864
Northwestern University
Chicago, Illinois, 60611
University of Illinois
Chicago, Illinois, 60612
Carle at The Riverfront
Danville, Illinois, 61832
Cancer Care Specialists of Illinois - Decatur
Decatur, Illinois, 62526
Decatur Memorial Hospital
Decatur, Illinois, 62526
Northwestern Medicine Cancer Center Kishwaukee
DeKalb, Illinois, 60115
Carle Physician Group-Effingham
Effingham, Illinois, 62401
Crossroads Cancer Center
Effingham, Illinois, 62401
NorthShore University HealthSystem-Evanston Hospital
Evanston, Illinois, 60201
Northwestern Medicine Cancer Center Delnor
Geneva, Illinois, 60134
NorthShore University HealthSystem-Glenbrook Hospital
Glenview, Illinois, 60026
Northwestern Medicine Glenview Outpatient Center
Glenview, Illinois, 60026
Northwestern Medicine Grayslake Outpatient Center
Grayslake, Illinois, 60030
NorthShore University HealthSystem-Highland Park Hospital
Highland Park, Illinois, 60035
Edward Hines Jr VA Hospital
Hines, Illinois, 60141
Northwestern Medicine Lake Forest Hospital
Lake Forest, Illinois, 60045
Carle Physician Group-Mattoon/Charleston
Mattoon, Illinois, 61938
Loyola University Medical Center
Maywood, Illinois, 60153
Cancer Care Center of O'Fallon
O'Fallon, Illinois, 62269
Northwestern Medicine Orland Park
Orland Park, Illinois, 60462
Memorial Hospital East
Shiloh, Illinois, 62269
Southern Illinois University School of Medicine
Springfield, Illinois, 62702
Springfield Clinic
Springfield, Illinois, 62702
Springfield Memorial Hospital
Springfield, Illinois, 62781
Carle Cancer Center
Urbana, Illinois, 61801
Northwestern Medicine Cancer Center Warrenville
Warrenville, Illinois, 60555
Indiana University/Melvin and Bren Simon Cancer Center
Indianapolis, Indiana, 46202
University of Iowa/Holden Comprehensive Cancer Center
Iowa City, Iowa, 52242
University of Kansas Clinical Research Center
Fairway, Kansas, 66205
University of Kansas Cancer Center
Kansas City, Kansas, 66160
University of Kansas Hospital-Indian Creek Campus
Overland Park, Kansas, 66211
Cotton O'Neil Cancer Center / Stormont Vail Health
Topeka, Kansas, 66606
University of Kansas Hospital-Westwood Cancer Center
Westwood, Kansas, 66205
University of Kentucky/Markey Cancer Center
Lexington, Kentucky, 40536
The James Graham Brown Cancer Center at University of Louisville
Louisville, Kentucky, 40202
UofL Health Medical Center Northeast
Louisville, Kentucky, 40245
LSU Health Baton Rouge-North Clinic
Baton Rouge, Louisiana, 70805
Our Lady of the Lake Physician Group
Baton Rouge, Louisiana, 70808
Our Lady of The Lake
Baton Rouge, Louisiana, 70808
MaineHealth Cancer Care and IV Therapy - Brunswick
Brunswick, Maine, 04011
Mid Coast Hospital
Brunswick, Maine, 04011
MaineHealth Maine Medical Center - Portland
Portland, Maine, 04102
MaineHealth Maine Medical Center- Scarborough
Scarborough, Maine, 04074
MaineHealth Cancer Care and IV Therapy - South Portland
South Portland, Maine, 04106
Walter Reed National Military Medical Center
Bethesda, Maryland, 20889-5600
Tufts Medical Center
Boston, Massachusetts, 02111
Beth Israel Deaconess Medical Center
Boston, Massachusetts, 02215
Dana-Farber Cancer Institute
Boston, Massachusetts, 02215
Lahey Hospital and Medical Center
Burlington, Massachusetts, 01805
Lahey Clinic Peabody
Peabody, Massachusetts, 01960
Trinity Health IHA Medical Group Hematology Oncology - Brighton
Brighton, Michigan, 48114
Trinity Health IHA Medical Group Hematology Oncology - Canton
Canton, Michigan, 48188
Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital
Chelsea, Michigan, 48118
Henry Ford Macomb Hospital-Clinton Township
Clinton Township, Michigan, 48038
Henry Ford Hospital
Detroit, Michigan, 48202
Cancer Hematology Centers - Flint
Flint, Michigan, 48503
Genesee Hematology Oncology PC
Flint, Michigan, 48503
Genesys Hurley Cancer Institute
Flint, Michigan, 48503
Hurley Medical Center
Flint, Michigan, 48503
Allegiance Health
Jackson, Michigan, 49201
Trinity Health Saint Mary Mercy Livonia Hospital
Livonia, Michigan, 48154
Henry Ford Medical Center-Columbus
Novi, Michigan, 48377
Trinity Health Saint Joseph Mercy Oakland Hospital
Pontiac, Michigan, 48341
Henry Ford West Bloomfield Hospital
West Bloomfield, Michigan, 48322
Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus
Ypsilanti, Michigan, 48197
Mercy Hospital
Coon Rapids, Minnesota, 55433
Essentia Health - Deer River Clinic
Deer River, Minnesota, 56636
Essentia Health Cancer Center
Duluth, Minnesota, 55805
Fairview Southdale Hospital
Edina, Minnesota, 55435
Essentia Health Hibbing Clinic
Hibbing, Minnesota, 55746
Abbott-Northwestern Hospital
Minneapolis, Minnesota, 55407
Park Nicollet Clinic - Saint Louis Park
Saint Louis Park, Minnesota, 55416
Regions Hospital
Saint Paul, Minnesota, 55101
United Hospital
Saint Paul, Minnesota, 55102
Essentia Health Sandstone
Sandstone, Minnesota, 55072
Essentia Health Virginia Clinic
Virginia, Minnesota, 55792
Baptist Memorial Hospital and Cancer Center-Golden Triangle
Columbus, Mississippi, 39705
Baptist Cancer Center-Grenada
Grenada, Mississippi, 38901
Baptist Memorial Hospital and Cancer Center-Union County
New Albany, Mississippi, 38652
Baptist Memorial Hospital and Cancer Center-Oxford
Oxford, Mississippi, 38655
Baptist Memorial Hospital and Cancer Center-Desoto
Southhaven, Mississippi, 38671
Siteman Cancer Center at Saint Peters Hospital
City of Saint Peters, Missouri, 63376
Siteman Cancer Center at West County Hospital
Creve Coeur, Missouri, 63141
Washington University School of Medicine
St Louis, Missouri, 63110
Siteman Cancer Center-South County
St Louis, Missouri, 63129
Siteman Cancer Center at Christian Hospital
St Louis, Missouri, 63136
Community Hospital of Anaconda
Anaconda, Montana, 59711
Billings Clinic Cancer Center
Billings, Montana, 59101
Bozeman Health Deaconess Hospital
Bozeman, Montana, 59715
Benefis Sletten Cancer Institute
Great Falls, Montana, 59405
Logan Health Medical Center
Kalispell, Montana, 59901
Community Medical Center
Missoula, Montana, 59804
OptumCare Cancer Care at Charleston
Las Vegas, Nevada, 89102
OptumCare Cancer Care at Fort Apache
Las Vegas, Nevada, 89183
Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center
Lebanon, New Hampshire, 03756
Memorial Sloan Kettering Basking Ridge
Basking Ridge, New Jersey, 07920
Saint Barnabas Medical Center
Livingston, New Jersey, 07039
Monmouth Medical Center
Long Branch, New Jersey, 07740
Memorial Sloan Kettering Monmouth
Middletown, New Jersey, 07748
Memorial Sloan Kettering Bergen
Montvale, New Jersey, 07645
Rutgers Cancer Institute of New Jersey
New Brunswick, New Jersey, 08903
The Valley Hospital - Luckow Pavilion
Paramus, New Jersey, 07652
Valley Health System Ridgewood Campus
Ridgewood, New Jersey, 07450
Community Medical Center
Toms River, New Jersey, 08755
University of New Mexico Cancer Center
Albuquerque, New Mexico, 87106
Roswell Park Cancer Institute
Buffalo, New York, 14263
Memorial Sloan Kettering Commack
Commack, New York, 11725
Northwell Health/Center for Advanced Medicine
Lake Success, New York, 11042
North Shore University Hospital
Manhasset, New York, 11030
Memorial Sloan Kettering Cancer Center
New York, New York, 10065
University of Rochester
Rochester, New York, 14642
Stony Brook University Medical Center
Stony Brook, New York, 11794
State University of New York Upstate Medical University
Syracuse, New York, 13210
UNC Lineberger Comprehensive Cancer Center
Chapel Hill, North Carolina, 27599
Carolinas Medical Center/Levine Cancer Institute
Charlotte, North Carolina, 28203
Duke University Medical Center
Durham, North Carolina, 27710
East Carolina University
Greenville, North Carolina, 27834
Wake Forest University Health Sciences
Winston-Salem, North Carolina, 27157
Case Western Reserve University
Cleveland, Ohio, 44106
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, 43210
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, 73104
Providence Newberg Medical Center
Newberg, Oregon, 97132
Saint Alphonsus Cancer Care Center-Ontario
Ontario, Oregon, 97914
Providence Willamette Falls Medical Center
Oregon City, Oregon, 97045
Providence Portland Medical Center
Portland, Oregon, 97213
Providence Saint Vincent Medical Center
Portland, Oregon, 97225
Lehigh Valley Hospital-Cedar Crest
Allentown, Pennsylvania, 18103
Geisinger Medical Center
Danville, Pennsylvania, 17822
Penn State Milton S Hershey Medical Center
Hershey, Pennsylvania, 17033-0850
University of Pennsylvania/Abramson Cancer Center
Philadelphia, Pennsylvania, 19104
University of Pittsburgh Cancer Institute (UPCI)
Pittsburgh, Pennsylvania, 15232
Reading Hospital
West Reading, Pennsylvania, 19611
Geisinger Wyoming Valley/Henry Cancer Center
Wilkes-Barre, Pennsylvania, 18711
Rhode Island Hospital
Providence, Rhode Island, 02903
Prisma Health Cancer Institute - Spartanburg
Boiling Springs, South Carolina, 29316
Medical University of South Carolina
Charleston, South Carolina, 29425
Prisma Health Cancer Institute - Easley
Easley, South Carolina, 29640
Prisma Health Cancer Institute - Butternut
Greenville, South Carolina, 29605
Prisma Health Cancer Institute - Faris
Greenville, South Carolina, 29605
Prisma Health Cancer Institute - Eastside
Greenville, South Carolina, 29615
Prisma Health Cancer Institute - Greer
Greer, South Carolina, 29650
Prisma Health Cancer Institute - Seneca
Seneca, South Carolina, 29672
Baptist Memorial Hospital and Cancer Center-Collierville
Collierville, Tennessee, 38017
University of Tennessee - Knoxville
Knoxville, Tennessee, 37920
Baptist Memorial Hospital and Cancer Center-Memphis
Memphis, Tennessee, 38120
Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
Houston, Texas, 77030
Ben Taub General Hospital
Houston, Texas, 77030
Huntsman Cancer Institute/University of Utah
Salt Lake City, Utah, 84112
George E Wahlen Department of Veterans Affairs Medical Center
Salt Lake City, Utah, 84148
University of Vermont Medical Center
Burlington, Vermont, 05401
University of Vermont and State Agricultural College
Burlington, Vermont, 05405
University of Virginia Cancer Center
Charlottesville, Virginia, 22908
VCU Massey Comprehensive Cancer Center
Richmond, Virginia, 23298
Swedish Cancer Institute-Edmonds
Edmonds, Washington, 98026
Swedish Cancer Institute-Issaquah
Issaquah, Washington, 98029
Fred Hutchinson Cancer Center
Seattle, Washington, 98109
Swedish Medical Center-First Hill
Seattle, Washington, 98122
University of Washington Medical Center - Montlake
Seattle, Washington, 98195
ThedaCare Regional Cancer Center
Appleton, Wisconsin, 54911
Duluth Clinic Ashland
Ashland, Wisconsin, 54806
Saint Vincent Hospital Cancer Center Green Bay
Green Bay, Wisconsin, 54301
Saint Vincent Hospital Cancer Center at Saint Mary's
Green Bay, Wisconsin, 54303
Gundersen Lutheran Medical Center
La Crosse, Wisconsin, 54601
William S Middleton VA Medical Center
Madison, Wisconsin, 53705
University of Wisconsin Carbone Cancer Center - Eastpark Medical Center
Madison, Wisconsin, 53718
University of Wisconsin Carbone Cancer Center - University Hospital
Madison, Wisconsin, 53792
Medical College of Wisconsin
Milwaukee, Wisconsin, 53226
Saint Vincent Hospital Cancer Center at Oconto Falls
Oconto Falls, Wisconsin, 54154
Saint Vincent Hospital Cancer Center at Sheboygan
Sheboygan, Wisconsin, 53081
Marshfield Medical Center-River Region at Stevens Point
Stevens Point, Wisconsin, 54482
Saint Vincent Hospital Cancer Center at Sturgeon Bay
Sturgeon Bay, Wisconsin, 54235-1495
Marshfield Medical Center - Weston
Weston, Wisconsin, 54476