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)

Acute Myeloid Leukemia Clinical Trial

Official title:

A Multi-center, Randomized, Double-blind, Placebo-controlled Phase III Trial of the FLT3 Inhibitor Gilteritinib Administered as Maintenance Therapy Following Allogeneic Transplant for Patients With FLT3/ITD AML

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02997202
• Other study ID #: 2215-CL-0304
• Secondary ID: 2016-001061-83BM
• Status: Completed
• Phase: Phase 3
• Start date: June 7, 2017
• Est. completion date: May 9, 2023

Study information

• Verified date: March 2024
• Source: Astellas Pharma Inc
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 356
• Est. completion date: May 9, 2023
• Est. primary completion date: March 1, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Registration Inclusion Criteria

• Participant is considered a suitable candidate for HCT and has an acceptable source of allogeneic donor stem cells, as defined per institutional practice (allogeneic HCT for any donor source [matched sibling, unrelated donor (URD), mismatched URD, related haploidentical, or umbilical cord blood] and any graft source [umbilical cord, BM, peripheral blood (PB)], and any conditioning [myeloablative conditioning (MAC), reduced intensity conditioning (RIC), or non-myeloablative conditioning (NMA)] will be permitted).

• Participant is considered a legal adult by local regulation at the time of signing informed consent form (ICF).

• Participant consents to allow access to diagnostic BM aspirate or PB sample and/or the DNA derived from that sample, if available, that may be used to validate a companion diagnostic that is being developed in parallel with gilteritinib.

• Participant has confirmed, morphologically documented AML in CR1. For the purposes of registration, CR1 will be defined as < 5% blasts in the BM with no morphologic characteristics of acute leukemia (e.g., Auer Rods) in the BM with no evidence of extramedullary disease such as central nervous system involvement or granulocytic sarcoma.

• Participant has not received more than 2 cycles of induction chemotherapy to achieve CR1. The induction cycles can be the same regimen or different regimens. The regimen(s) may contain conventional agents, investigational agents, or a combination of both.

• Participants with CR with incomplete count recovery (CRp or CRi) are allowed. Incomplete platelet recovery (CRp) is defined as CR with platelet count < 100 x 109/L. Incomplete blood count recovery (CRi) is defined as CR with residual neutropenia < 1 x 109/L with or without complete platelet recovery. Red blood cell count (RBC) and platelet transfusion independence is not required.

• The maximum time allowed from establishment of CR1 to registration is 12 months.

• Participant has presence of the FLT3/ITD activating mutation in the BM or PB as determined by the local institution at diagnosis.

• Participant must meet the following criteria as indicated on the clinical laboratory tests:

• Serum creatinine within normal range, or if serum creatinine outside normal range, then glomerular filtration rate (GFR) > 40 mL/min/1.73m2 as calculated with the Cockcroft-Gault equation with adjustment if total body weight is = 125% of ideal body weight.

• Total bilirubin (TBL) = 2.5 mg/dL, except for participants with Gilbert's syndrome.

• Serum AST and/or alanine aminotransferase (ALT) < 3 x institutional upper limit of normal (ULN).

• Participant has left ventricular ejection fraction at rest = 40%.

• Participant has diffusing capacity of the lung for carbon monoxide (DLCO) (corrected for hemoglobin) = 50% predicted and/or forced expiratory volume in 1 second (FEV1) = 50% predicted.

• Female participants must either:

• Be of non-childbearing potential:

• postmenopausal (defined as at least 1 year without menses) prior to screening or

• documented as surgically sterilized (at least 1 month prior to the screening visit)

• Or, if of childbearing potential,

• Agree not to try to become pregnant during the study for 6 months after the final study drug administration

• And have a negative serum pregnancy test at screening

• And, if heterosexually active, agree to consistently use highly effective contraception per locally accepted standards in addition to a barrier method starting at screening and throughout the study period and for 6 months after the final study drug administration.

• For United Kingdom sites:

• Highly effective forms of birth control include:

• Consistent and correct usage of established hormonal contraceptives that inhibit ovulation

• Established intrauterine device (IUD) or intrauterine system (IUS)

• Female participants must agree not to breastfeed or donate ova throughout the study drug treatment period and for 6 months after the final study drug administration.

• Male participants (even if surgically sterilized), and partners who are women of childbearing potential must be using highly effective contraception in addition to a barrier method throughout the study drug treatment period and for 127 days after the final study drug administration.

• For United Kingdom sites:

• Highly effective forms of birth control include:

• Consistent and correct usage of established hormonal contraceptives that inhibit ovulation

• Established IUD or IUS

• Vasectomy (A vasectomy is a highly effective contraception method provided the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used.)

• Male is sterile due to a bilateral orchiectomy

• Male participants must not donate sperm throughout the study drug treatment period and for 127 days after the final study drug administration.

• Participant is able to take an oral medication.

• Participant agrees not to participate in another interventional study while on treatment.

Randomization Inclusion Criteria

• Participant is = 30 days and = 90 days from hematopoietic cell infusion.

• Participant has achieved engraftment. Engraftment is defined as ANC = 500 cells/µL and platelets = 20000/µL on 3 consecutive measurements (each occurring at least 1 day apart). The participant must not have had a platelet transfusion within 7 days prior to the first measurement.

• Participant has confirmed ongoing morphologically documented AML in CR1. For the purposes of randomization, CR1 will be defined as < 5% blasts with no morphologic characteristics of acute leukemia (e.g., Auer Rods) in the BM with no evidence of extramedullary disease such as central nervous system involvement or granulocytic sarcoma.

• Participant meets the following criteria as indicated on the clinical laboratory tests:

• Serum creatinine within normal range, or if serum creatinine outside normal range, then GFR > 40 mL/min/1.73m2 as calculated with the Cockcroft-Gault equation with adjustment if total body weight is = 125% of ideal body weight.

• TBL < 2.5 mg/dL, except for participants with Gilbert's syndrome.

• Serum AST and/or ALT < 3 x institutional ULN.

• Serum potassium and magnesium = the institutional lower limit of normal (LLN).

• If the participant has developed overall grades II-IV acute GVHD, the following criteria must be met to be randomized:

• No requirement of > 0.5 mg/kg of prednisone (or equivalent) daily dose within 1 week of randomization

• No escalation of systemic immunosuppression in terms of increase of corticosteroids or addition of new agent / modality within 2 weeks of randomization. (Note that increasing calcineurin inhibitors or sirolimus to achieve therapeutic trough levels is allowed.) Topical skin and topical gastrointestinal steroids are allowed.

• Participant is able to take oral medication.

Registration Exclusion Criteria

• Participant has had a prior allogeneic transplant.

• Participant has Karnofsky performance status score < 70% .

• Participant requires treatment with concomitant drugs that are strong inducers of CYP3A within 14 days of start of study drug.

• Participant requires treatment with concomitant drugs that target serotonin 5-hydroxytryptamine receptor 1 (5HT1R) or 5-hydroxytryptamine receptor 2B (5HT2BR) or sigma nonspecific receptor with the exception of drugs that are considered absolutely essential for the care of the participant.

• Participant has a Fridericia-corrected QT interval (QTcF) > 450 msec (average of triplicate determinations) per central read.

• Participant has long QT Syndrome at screening.

• Participant has a known infection with human immunodeficiency virus (HIV).

• Participant has active hepatitis B infection as determined by NAAT or surface antigen assay. Participants who have acquired immunity from past exposure (HBcAb positive / HBsAb positive / HBsAg negative) are eligible.

• Participant has active hepatitis C infection as determined by NAAT. NAAT must be performed if the participant has positive serology for hepatitis C. Participants who have had past exposure and have no detectable virus either through spontaneous clearance or treatment are eligible.

• Participant has an uncontrolled infection. If a bacterial or viral infection is present, the participant must be receiving definitive therapy and have no signs of progressing infection for 72 hours prior to registration. If a fungal infection is present, the participant must be receiving definitive systemic anti-fungal therapy and have no signs of progressing infection for 1 week prior to registration.

• Progressing infection is defined as hemodynamic instability attributable to sepsis or new symptoms, worsening physical signs or radiographic findings attributable to infection.

• Persisting fever without other signs or symptoms will not be interpreted as progressing infection.

• Participant has had a myocardial infarction within 6 months prior to registration or New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia.

• Participant has a serious medical or psychiatric illness likely to interfere with participation in this clinical study.

• Participant is breast feeding or pregnant.

• Participant has prior malignancies, except lobular breast carcinoma in situ, fully resected basal cell or squamous cell carcinoma of skin or treated cervical carcinoma in situ.

Cancer treated with curative intent = 5 years previously will be allowed. Cancer treated with curative intent < 5 years previously will not be allowed.

Randomization Exclusion Criteria

• Participant requires treatment with concomitant drugs that are strong inducers of CYP3A within 14 days of starting study drug.

• Participant requires treatment with concomitant drugs that target serotonin 5HT1R or 5HT2BR or sigma nonspecific receptor with the exception of drugs that are considered by the investigator to be absolutely essential for the care of the participant and for which no acceptable alternative exists.

• Participant has a QTcF interval > 450 msec (average of triplicate determinations) by central read.

• Participant has a need for supplemental oxygen with the exception of using previously existing non-invasive continuous positive airway pressure (CPAP) at night.

• Participant has used investigational agents within 4 weeks of randomization.

• Participant has used experimental therapy for acute GVHD within 4 weeks of randomization. If unsure of the definition of "experimental", discussion with one of the protocol chairs is recommended.

• Participant has an uncontrolled infection. If a bacterial or viral infection is present, the participant must be receiving definitive therapy and have no signs of progressing infection for 72 hours prior to randomization. If a fungal infection is present, the participant must be receiving definitive systemic anti-fungal therapy and have no signs of progressing infection for 1 week prior to randomization.

• Progressing infection is defined as hemodynamic instability attributable to sepsis or new symptoms, worsening physical signs or radiographic findings attributable to infection.

• Persisting fever without other signs or symptoms will not be interpreted as progressing infection.

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• gilteritinib
oral
• Placebo
oral

Locations

Country	Name	City	State
Australia	Site AU61001	Liverpool
Australia	Site AU61002	Melbourne
Australia	Site AU61004	Westmead
Belgium	Site BE32003	Bruxelles
Belgium	Site BE32004	Gent
Canada	Site CA15004	Hamilton
Canada	Site CA15003	Montreal
Denmark	Site DK45002	Arhus
Denmark	Site DK45001	Copenhagen
France	Site FR33007	Lille
France	Site FR33004	Lyon
France	Site FR33005	Paris
France	Site FR33008	Pessac
France	Site FR33010	Vandoeuvre-Les-Nancy
Germany	Site DE49002	Düsseldorf
Germany	Site DE49003	Halle (Saale)
Germany	Site DE49005	Hamburg
Germany	Site DE49006	Köln
Germany	Site DE49007	Mainz
Germany	Site DE49004	Münster
Greece	Site GR30004	Athens
Greece	Site GR30003	Rio
Greece	Site GR30001	Thessaloniki
Italy	Site IT39005	Bergamo
Italy	Site IT39006	Bologna
Italy	Site IT39009	Genova
Italy	Site IT39002	Milano
Italy	Site IT39007	Milano
Italy	Site IT39011	Pescara
Italy	Site IT39003	Roma
Italy	Site IT39004	Udine
Japan	Site JP81014	Anjo	Aichi
Japan	Site JP81013	Bunkyo-ku	Tokyo
Japan	Site JP81004	Chuo-ku	Tokyo
Japan	Site JP81001	Fukuoka
Japan	Site JP81003	Fukuoka
Japan	Site JP81002	Isehara	Kanagawa
Japan	Site JP81021	Kobe	Hyogo
Japan	Site JP81015	Kyoto
Japan	Site JP81016	Minato-ku	Tokyo
Japan	Site JP81011	Nagoya	Aichi
Japan	Site JP81012	Nishinomiya	Hyogo
Japan	Site JP81017	Okayama
Japan	Site JP81005	Osaka
Japan	Site JP81018	Sapporo	Hokkaido
Japan	Site JP81010	Sendai	Miyagi
Japan	Site JP81008	Shimotsuke	Tochigi
Japan	Site JP81020	Shinjuku-ku	Tokyo
Japan	Site JP81006	Suita	Osaka
Japan	Site JP81007	Yokohama	Kanagawa
Korea, Republic of	Site KR82001	Seoul
Korea, Republic of	Site KR82002	Seoul
Korea, Republic of	Site KR82003	Seoul
Korea, Republic of	Site KR82004	Seoul
Korea, Republic of	Site KR82005	Seoul
New Zealand	Site NZ64002	Christchurch
New Zealand	Site NZ64001	Grafton
Poland	Site PL48004	Warszawa
Spain	Site ES34004	Barcelona
Spain	Site ES34005	Barcelona
Spain	Site ES34006	Salamanca
Spain	Site ES34007	Santander
Spain	Site ES34002	Valencia
Taiwan	Site TW88603	Taichung
Taiwan	Site TW88602	Taipei
Taiwan	Site TW88605	Taoyuan
United Kingdom	Site GB44010	Birmingham
United Kingdom	Site GB44003	Bristol
United Kingdom	Site GB44009	Glasgow
United Kingdom	Site GB44004	London
United Kingdom	Site GB44002	Manchester
United Kingdom	Site GB44001	Sutton
United States	Emory University	Atlanta	Georgia
United States	Northside	Atlanta	Georgia
United States	Augusta University	Augusta	Georgia
United States	Johns Hopkins Hospital	Baltimore	Maryland
United States	University of Maryland Medical Systems	Baltimore	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	University of North Carolina	Chapel Hill	North Carolina
United States	Northwestern Memorial Hospital	Chicago	Illinois
United States	Rush University Medical Center	Chicago	Illinois
United States	Cleveland Clinic	Cleveland	Ohio
United States	University Hospitals of Cleveland Medical Center	Cleveland	Ohio
United States	Ohio State University, The	Columbus	Ohio
United States	Karmanos Cancer Center	Detroit	Michigan
United States	Duke University Medical Center	Durham	North Carolina
United States	University of Florida	Gainesville	Florida
United States	Baylor College of Medicine	Houston	Texas
United States	Indiana Blood and Marrow Transplant	Indianapolis	Indiana
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	University of Wisconsin Hospital and Clinics	Madison	Wisconsin
United States	Loyola University Medical Center	Maywood	Illinois
United States	University of Miami	Miami	Florida
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	University of Minnesota School of Medicine	Minneapolis	Minnesota
United States	West Virginia University Hospital	Morgantown	West Virginia
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Yale University School of Medicine	New Haven	Connecticut
United States	Memorial Sloan Kettering	New York	New York
United States	Weill Cornell Medical Center	New York	New York
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	Mayo Clinic	Phoenix	Arizona
United States	Oregon Health and Science University	Portland	Oregon
United States	Mayo Clinic	Rochester	Minnesota
United States	Washington University in St. Louis	Saint Louis	Missouri
United States	Huntsman Cancer Institute	Salt Lake City	Utah
United States	Intermountain BMT	Salt Lake City	Utah
United States	University of California San Francisco	San Francisco	California
United States	Virginia G Piper Cancer Center	Scottsdale	Arizona
United States	Fred Hutchinson Cancer Research Center	Seattle	Washington
United States	Stanford University	Stanford	California
United States	H. Lee Moffitt Cancer Center	Tampa	Florida
United States	Wake Forest Baptist Health	Winston-Salem	North Carolina
United States	University of Massachusetts	Worcester	Massachusetts

Sponsors (3)

Lead Sponsor	Collaborator
Astellas Pharma Global Development, Inc.	Blood and Marrow Transplant Clinical Trials Network, National Heart, Lung, and Blood Institute (NHLBI)

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  Denmark,  France,  Germany,  Greece,  Italy,  Japan,  Korea, Republic of,  New Zealand,  Poland,  Spain,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Relapse-free survival	Relapse-free survival (RFS) will be measured from time of randomization to either morphological relapse or death, whichever comes first. Morphological relapse will be defined as bone marrow (BM) blasts 5% or higher (not attributable to regenerating BM), any circulating blasts (not attributable to regenerating BM or growth factors), or any extra-medullary blast foci as per Revised International Working Group (R-IWG) criteria.	96 months
Secondary	Safety and tolerability assessed by incidence and severity of adverse events	All grade = 3 toxicities according to CTCAE (Common Terminology Criteria for Adverse Events) version 4.03 will be tabulated for each treatment arm. The proportion of participants developing grade = 3 AE across treatment arms will be compared. In addition, the incidence of all grade 1 to 4 toxicities according to CTCAE version 4.03 will be tabulated for each treatment arm and compared. Clinical laboratory evaluations and change from baseline will be described and compared. Electrocardiogram (ECG) results and change from baseline will be described and compared. Karnofsky Performance Status scores will be described and compared. The duration of drug use and dose of drug use will also be compared.	25 months (24 months + 30 days)
Secondary	Overall Survival (OS)	Time to OS is defined as the time to death from any cause after randomization. For surviving participants, non-events will be censored at the last known alive date.	66 months (5.5 years)
Secondary	Non-relapse Mortality	An event for this endpoint is death without evidence of disease progression or recurrence.	66 months (5.5 years)
Secondary	Event-free Survival (EFS) at 12 months	The cumulative incidence at 12 months after randomization of EFS will be described and compared.	12 months
Secondary	Event-free Survival (EFS) at 24 months	The cumulative incidence at 24 months after randomization of EFS will be described and compared.	24 months
Secondary	Cumulative Incidence of Acute Graft vs. Host Disease (GVHD)	The cumulative incidence at 6 months after randomization of grades II-IV and grades III-IV acute GVHD will be described and compared. Acute GVHD will be graded according to diagnosis and severity scoring used by the Blood and Marrow Transplant Clinical Trial Network (BMT CTN).	6 months
Secondary	Cumulative Incidence of Chronic GVHD at 12 months	The cumulative incidence at 12 months after randomization of chronic GVHD will be described and compared. Chronic GVHD will be graded according to diagnosis and severity scoring from the NIH 2014 Consensus Criteria.	12 months
Secondary	Cumulative Incidence of Chronic GVHD at 24 months	The cumulative incidence at 24 months after randomization of chronic GVHD will be described and compared. Chronic GVHD will be graded according to diagnosis and severity scoring from the NIH 2014 Consensus Criteria.	24 months
Secondary	The cumulative incidence of detection of FLT3/ITD MRD	The cumulative incidence of detection of FLT3/ITD MRD in participants who are FLT3/ITD MRD undetectable prior to randomization will be described. Similarly, the pattern of eradication of FLT3/ITD MRD in participants who have detectable FLT3/ITD MRD prior to randomization will be described.	24 months
Secondary	Incidence of Severity of Infection	The cumulative incidence of CTCAE grades 3 to 5 infection in participants will be described and compared.	25 months (24 months + 30 days)