A Trial of the FMS-like Tyrosine Kinase 3 (FLT3) Inhibitor Gilteritinib Administered as Maintenance Therapy Following Allogeneic Transplant for Patients With FLT3/Internal Tandem Duplication (ITD) Acute Myeloid Leukemia (AML)
- Registration Number
- NCT02997202
- Lead Sponsor
- Astellas Pharma Global Development, Inc.
- Brief Summary
The purpose of this study is to compare relapse-free survival between participants with FLT3/ITD AML in first morphologic complete remission (CR1) who undergo hematopoietic stem cell transplant (HCT) and are randomized to receive gilteritinib or placebo beginning after the time of engraftment for a two year period.
- Detailed Description
Participants with FLT3/ITD AML in first morphologic complete remission (CR1) undergoing allogeneic hematopoietic stem cell transplant (HCT) will be randomized to receive gilteritinib or placebo 30 to 90 days after HCT for a two year period. Participants will be stratified according to: 1) conditioning regimen intensity (myeloablative vs. reduced intensity/non-myeloablative), 2) time from first day of hematopoietic cell infusion to randomization (30-60 days vs. 61-90 days) and 3) presence vs absence of or unknown minimal residual disease (MRD) from the most recent pre-registration bone marrow (BM) aspirate.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 356
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Gilteritinib gilteritinib Participants received gilteritinib 120 milligrams (mg) (three tablets of 40 mg) orally, once daily (QD) for up to 2 years or until a protocol-defined discontinuation criterion was met. Placebo Placebo Participants received gilteritinib matching placebo orally, QD for up to 2 years or until a protocol-defined discontinuation criterion was met.
- Primary Outcome Measures
Name Time Method Relapse-free Survival (RFS) From the date of randomization up to 64 months and 22 days RFS was defined as the time from the date of randomization until the date of documented morphological relapse, or death from any cause, whichever occurred first. Morphological relapse was defined as documentation of any of the following events:
* BM blasts ≥ 5% (not attributable to regenerating BM)
* Any circulating blasts (not attributable to regenerating BM or growth factors)
* Presence of extramedullary blast foci per Revised International Working Group (RIWG) criteria
* The earliest date of any of the relapse event was used for RFS.
- Secondary Outcome Measures
Name Time Method Overall Survival (OS) From the date of randomization up to 64 months and 22 day OS was defined as the time from randomization until the date of death from any cause (death date - first dose date + 1). For a Participant who were not known to have died by the end of study follow-up, OS was censored at the date of last contact (date of last contact - first dose date + 1).
Number of Participants With Treatment Emergent Adverse Events (TEAE) From the date of randomization through 30 days after the last dose, up to 25 months and 22 days An Adverse event (AE) was any untoward medical occurrence in a participant administered a study drug, and which did not have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease (new or exacerbated) temporally associated with the use of a medicinal product, whether considered related to the medicinal product.
TEAE defined as an AE event observed through 30 days after the last dose.Karnofsky Performance Status Scores Baseline, month 24 KPS scores of participants were reported. KPS was a standard way of measuring ability of cancer participants to perform ordinary tasks. It was 11 level score which ranged between 0-100%. 100 =Normal, no complaints, no evidence of disease 90 =Able to carry on normal activity, minor signs or symptoms of disease 80 =Normal activity with effort, some signs or symptoms of disease 70 =Care for self, unable to carry on normal activity or to do work 60 =Required occasional assistance but was able to care for most of his needs 50 =Required considerable assistance \& frequent medical care 40 =Disabled, required special care \& assistance 30 = Severely disabled, hospitalization indicated, although death not imminent 20 =Very sick, hospitalization necessary, active supportive treatment necessary 10 =moribund fatal processes progressing rapidly 0 =Dead.
Percentage of Participants With Non-relapse Mortality (NRM) From the date of randomization up to 64 months and 22 days NRM was defined as death from any cause other than relapse or disease progression (DP). Relapse was defined as documentation of any of the following events:
* BM blasts ≥ 5% (not attributable to regenerating BM)
* Any circulating blasts (not attributable to regenerating BM or growth factors)
* Presence of extramedullary blast foci per RIWG criteria
* The earliest date of any of the relapse event were used for RFS. DP: \>=20% increase in sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline, sum must also be absolute increase of \>=5 mm. Unequivocal progression of existing non-target lesions. Appearance of at least 1 new lesion. Incidence of NRM was estimated using the cumulative incidence function, treating relapse/progression as a competing risk.Event-free Survival (EFS) From the date of randomization up to 64 months and 22 days EFS: Time from date of randomization until documented relapse, or premature discontinuation of treatment or initiation of other anti-leukemic treatment or death from any cause, whichever occurred first.
Relapse was defined as documentation of any of following events:
* BM blasts ≥ 5% (not attributable to regenerating BM)
* Any circulating blasts (not attributable to regenerating BM or growth factors)
* Presence of extramedullary blast foci per RIWG criteria
* The earliest date of any of relapse event were used for RFS.
Anti-leukemic treatment was defined as hypomethylating agents, chemotherapy, oral anticancer agents, Donor lymphocyte infusion (DLI) or cellular therapies given because of detectable disease, not meeting R-IWG criteria for relapse.Percentage of Participants With Treatment Emergent Acute Graft vs. Host Disease (aGVHD) From the date of randomization up to 6 months The cumulative incidence at 6 months after randomization of grades II-IV and grades III-IV aGVHD were reported, treating death prior to aGVHD as the competing risk. It was graded according to diagnosis and severity scoring used by the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). The acute GVHD algorithm calculated the grade based on the organ (skin, gastrointestinal (GI)and liver) stage and etiology/biopsy reported on the weekly GVHD form. Grade I aGVHD was defined as Skin stage of 1-2 and stage 0 for both GI and liver organs. Grade II aGVHD was stage 3 of skin, or stage 1 of GI, or stage 1 of liver. Grade III is stage 2-4 for GI, or stage 2-3 of liver. Grade IV was stage 4 of skin, or stage 4 of liver. Grade IV was the worst outcome. Treatment emergent was defined as an event observed through 30 days after the last dose.
Percentage of Participants With Treatment Emergent Chronic GVHD at 12 Months From the date of randomization up to 12 months Chronic GVHD was graded according to diagnosis and severity scoring from the National Institute of Health (NIH) 2014 Consensus Criteria. Eight organs - skin, mouth, liver, upper and lower gastrointestinal, esophagus, lung, eye, and joint/fascia were scored on a 0-3 scale to reflect degree of chronic GVHD involvement, where 0 = no involvement/no symptoms \& 3 indicated the worst symptom. This system staged severity in each individual organ, and then a global score defined as mild, moderate or severe, based on number of organs involved and organ severity score was calculated. The cumulative incidence of chronic GVHD (mild, moderate, severe) at 12 months after randomization was reported, treating death prior to chronic GVHD as the competing risk. Treatment emergent was defined as an event observed through 30 days after the last dose.
Percentage of Participants With Treatment Emergent Chronic GVHD at 24 Months From the date of randomization up to 24 months Chronic GVHD was graded according to diagnosis and severity scoring from the NIH 2014 Consensus Criteria. Eight organs- skin, mouth, liver, upper and lower gastrointestinal, esophagus, lung, eye, and joint/fascia are scored on a 0-3 scale to reflect degree of chronic GVHD involvement where 0 = no involvement/no symptoms \& 3 indicated the worst symptom. This system staged severity in each individual organ, and then a global score defined as mild, moderate or severe, based on number of organs involved and organ severity score was calculated. The cumulative incidence of chronic GVHD (mild, moderate, severe) at 24 months after randomization was reported, treating death prior to chronic GVHD as the competing risk. Treatment emergent was defined as an event observed through 30 days after the last dose.
Percentage of Participants With FMS-like Tyrosine Kinase 3/Internal Tandem Duplication (FLT3/ITD) Minimal Residual Disease (MRD) From the date of randomization up to 64 months and 22 days The presence of MRD was considered Detectable in participants who were FLT3/ITD MRD undetectable prior to randomization if log10-transformed overall FLT3/ITD mutation ratio greater than -4 otherwise presence of MRD was considered Not Detectable. Participants who had detectable FLT3/ITD MRD prior to randomization were considered eradicated if log10-transformed overall FLT3/ITD mutation ratio ≤ -4. Incidence of MRD Eradication and Detection were estimated using the cumulative incidence function, treating death during MRD assessment period without documentation of MRD event as competing risk.
Percentage of Participants With Relapse From the date of randomization up to 64 months and 22 days Cumulative incidence of relapse was reported, treating death in remission as a competing risk. Relapse was defined as documentation of any of the following events:
* BM blasts ≥ 5% (not attributable to regenerating BM)
* Any circulating blasts (not attributable to regenerating BM or growth factors)
* Presence of extramedullary blast foci per RIWG criteria
* The earliest date of any of the relapse event were used for RFS.Percentage of Participants With Treatment Emergent Infection by Severity. From the date of randomization through 30 days after the last dose, up to 25 months and 22 days Severity of Infection was assessed based on the following criteria:
Grade 1-Mild Asymptomatic or mild symptoms, clinical or diagnostic observations noted intervention not indicated.
Grade 2-Moderate Local or noninvasive intervention indicated. Grade 3-Severe Medically significant but not immediately life threatening, hospitalization or prolonged hospitalization. Grade 4-Life Threatening Life threatening consequences, urgent intervention indicated.
Grade 5-Death related to the AE. Cumulative incidence of grade 3 to 5 infections were reported, treating death (grade 5) as a competing event. Treatment emergent was defined as an event observed through 30 days after the last dose.
Trial Locations
- Locations (117)
Site IT39009
🇮🇹Genova, Italy
Site DE49007
🇩🇪Mainz, Germany
Site IT39004
🇮🇹Udine, Italy
Site TW88603
🇨🇳Taichung, Taiwan
Site TW88602
🇨🇳Taipei, Taiwan
Site TW88605
🇨🇳Taoyuan, Taiwan
Site GB44010
🇬🇧Birmingham, United Kingdom
Site GB44009
🇬🇧Glasgow, United Kingdom
University of Wisconsin Hospital and Clinics
🇺🇸Madison, Wisconsin, United States
Site GR30004
🇬🇷Athens, Greece
Site GR30001
🇬🇷Thessaloniki, Greece
Site JP81012
🇯🇵Nishinomiya, Hyogo, Japan
Site KR82004
🇰🇷Seoul, Korea, Republic of
Site JP81008
🇯🇵Shimotsuke, Tochigi, Japan
Site NZ64001
🇳🇿Grafton, New Zealand
Site DE49005
🇩🇪Hamburg, Germany
Site JP81007
🇯🇵Yokohama, Kanagawa, Japan
Site JP81017
🇯🇵Okayama, Japan
Site BE32003
🇧🇪Bruxelles, Belgium
Site IT39002
🇮🇹Milano, Italy
Site IT39007
🇮🇹Milano, Italy
Site AU61002
🇦🇺Melbourne, Australia
Site KR82001
🇰🇷Seoul, Korea, Republic of
Site JP81018
🇯🇵Sapporo, Hokkaido, Japan
Site JP81006
🇯🇵Suita, Osaka, Japan
Site AU61001
🇦🇺Liverpool, Australia
Site CA15004
🇨🇦Hamilton, Canada
Site PL48004
🇵🇱Warszawa, Poland
Site DE49004
🇩🇪Münster, Germany
Site IT39006
🇮🇹Bologna, Italy
Site AU61004
🇦🇺Westmead, Australia
Site JP81014
🇯🇵Anjo, Aichi, Japan
Site ES34007
🇪🇸Santander, Spain
Washington University in St. Louis
🇺🇸Saint Louis, Missouri, United States
Site FR33007
🇫🇷Lille, France
Site FR33008
🇫🇷Pessac, France
Site DE49003
🇩🇪Halle (Saale), Germany
Site BE32004
🇧🇪Gent, Belgium
Site IT39005
🇮🇹Bergamo, Italy
Site FR33005
🇫🇷Paris, France
Site JP81001
🇯🇵Fukuoka, Japan
Site ES34002
🇪🇸Valencia, Spain
Site FR33010
🇫🇷Vandoeuvre-Les-Nancy, France
Site JP81021
🇯🇵Kobe, Hyogo, Japan
Site DE49006
🇩🇪Köln, Germany
Site JP81005
🇯🇵Osaka, Japan
Site KR82003
🇰🇷Seoul, Korea, Republic of
Site JP81003
🇯🇵Fukuoka, Japan
Site ES34005
🇪🇸Barcelona, Spain
Site JP81011
🇯🇵Nagoya, Aichi, Japan
Site JP81015
🇯🇵Kyoto, Japan
Site GB44001
🇬🇧Sutton, United Kingdom
Site GB44004
🇬🇧London, United Kingdom
Emory University
🇺🇸Atlanta, Georgia, United States
Northside
🇺🇸Atlanta, Georgia, United States
Augusta University
🇺🇸Augusta, Georgia, United States
Johns Hopkins Hospital
🇺🇸Baltimore, Maryland, United States
Ohio State University, The
🇺🇸Columbus, Ohio, United States
University of Pennsylvania
🇺🇸Philadelphia, Pennsylvania, United States
West Virginia University Hospital
🇺🇸Morgantown, West Virginia, United States
University Hospitals of Cleveland Medical Center
🇺🇸Cleveland, Ohio, United States
Northwestern Memorial Hospital
🇺🇸Chicago, Illinois, United States
Rush University Medical Center
🇺🇸Chicago, Illinois, United States
Cleveland Clinic
🇺🇸Cleveland, Ohio, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Beth Israel Deaconess Medical Center
🇺🇸Boston, Massachusetts, United States
Dana Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Fred Hutchinson Cancer Research Center
🇺🇸Seattle, Washington, United States
University of Miami
🇺🇸Miami, Florida, United States
Indiana Blood and Marrow Transplant
🇺🇸Indianapolis, Indiana, United States
University of Maryland Medical Systems
🇺🇸Baltimore, Maryland, United States
Site GR30003
🇬🇷Rio, Greece
Site JP81004
🇯🇵Chuo-ku, Tokyo, Japan
Site JP81013
🇯🇵Bunkyo-ku, Tokyo, Japan
Site JP81020
🇯🇵Shinjuku-ku, Tokyo, Japan
Baylor College of Medicine
🇺🇸Houston, Texas, United States
University of California San Francisco
🇺🇸San Francisco, California, United States
Karmanos Cancer Center
🇺🇸Detroit, Michigan, United States
University of Minnesota School of Medicine
🇺🇸Minneapolis, Minnesota, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
Vanderbilt University Medical Center
🇺🇸Nashville, Tennessee, United States
Huntsman Cancer Institute
🇺🇸Salt Lake City, Utah, United States
Intermountain BMT
🇺🇸Salt Lake City, Utah, United States
Site DK45002
🇩🇰Arhus, Denmark
Site DK45001
🇩🇰Copenhagen, Denmark
University of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States
Oregon Health and Science University
🇺🇸Portland, Oregon, United States
Site CA15003
🇨🇦Montreal, Canada
Site GB44002
🇬🇧Manchester, United Kingdom
University of Nebraska Medical Center
🇺🇸Omaha, Nebraska, United States
Medical College of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
Mayo Clinic
🇺🇸Rochester, Minnesota, United States
Site DE49002
🇩🇪Düsseldorf, Germany
Site JP81010
🇯🇵Sendai, Miyagi, Japan
Site NZ64002
🇳🇿Christchurch, New Zealand
Site FR33004
🇫🇷Lyon, France
Site ES34004
🇪🇸Barcelona, Spain
Virginia G Piper Cancer Center
🇺🇸Scottsdale, Arizona, United States
Stanford University
🇺🇸Stanford, California, United States
Site ES34006
🇪🇸Salamanca, Spain
Loyola University Medical Center
🇺🇸Maywood, Illinois, United States
University of Massachusetts
🇺🇸Worcester, Massachusetts, United States
Weill Cornell Medical Center
🇺🇸New York, New York, United States
Memorial Sloan Kettering
🇺🇸New York, New York, United States
Site IT39011
🇮🇹Pescara, Italy
Site IT39003
🇮🇹Roma, Italy
Site JP81002
🇯🇵Isehara, Kanagawa, Japan
Site JP81016
🇯🇵Minato-ku, Tokyo, Japan
Site KR82005
🇰🇷Seoul, Korea, Republic of
Site KR82002
🇰🇷Seoul, Korea, Republic of
Site GB44003
🇬🇧Bristol, United Kingdom
H. Lee Moffitt Cancer Center
🇺🇸Tampa, Florida, United States
Wake Forest Baptist Health
🇺🇸Winston-Salem, North Carolina, United States
Yale University School of Medicine
🇺🇸New Haven, Connecticut, United States
University of Florida
🇺🇸Gainesville, Florida, United States
University of North Carolina
🇺🇸Chapel Hill, North Carolina, United States
University of Kansas Medical Center
🇺🇸Kansas City, Kansas, United States