Clinical trial NCT02997202: 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)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Acute Myeloid Leukemia
Keywords: Gilteritinib
ASP2215
Safety and Efficacy
Acute Myeloid Leukemia
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: Blood and Marrow Transplant Clinical Trials Network
First posted: 2016-12-19
Enrollment: 356
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study was to compare relapse-free survival between participants with FLT3/ITD AML in first morphologic complete remission (CR1) who underwent hematopoietic stem cell transplant (HCT) and were 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) undergone allogeneic hematopoietic stem cell transplant (HCT) were randomized to receive gilteritinib or placebo 30 to 90 days after HCT for a two year period. Participants wiere 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Relapse-free Survival (RFS)
timeFrame: From the date of randomization up to 64 months and 22 days
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: From the date of randomization up to 64 months and 22 day
measure: Number of Participants With Treatment Emergent Adverse Events (TEAE)
timeFrame: From the date of randomization through 30 days after the last dose, up to 25 months and 22 days
measure: Karnofsky Performance Status Scores
timeFrame: Baseline, month 24
measure: Percentage of Participants With Non-relapse Mortality (NRM)
timeFrame: From the date of randomization up to 64 months and 22 days
measure: Event-free Survival (EFS)
timeFrame: From the date of randomization up to 64 months and 22 days
measure: Percentage of Participants With Treatment Emergent Acute Graft vs. Host Disease (aGVHD)
timeFrame: From the date of randomization up to 6 months
measure: Percentage of Participants With Treatment Emergent Chronic GVHD at 12 Months
timeFrame: From the date of randomization up to 12 months
measure: Percentage of Participants With Treatment Emergent Chronic GVHD at 24 Months
timeFrame: From the date of randomization up to 24 months
measure: Percentage of Participants With FMS-like Tyrosine Kinase 3/Internal Tandem Duplication (FLT3/ITD) Minimal Residual Disease (MRD)
timeFrame: From the date of randomization up to 64 months and 22 days
measure: Percentage of Participants With Relapse
timeFrame: From the date of randomization up to 64 months and 22 days
measure: Percentage of Participants With Treatment Emergent Infection by Severity.
timeFrame: From the date of randomization through 30 days after the last dose, up to 25 months and 22 days
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Mayo Clinic
state: Arizona
city: Scottsdale
country: United States
facility: Virginia G Piper Cancer Center
state: Arizona
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Stanford
country: United States
facility: Stanford University
state: California
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Atlanta
country: United States
facility: Northside
state: Georgia
city: Augusta
country: United States
facility: Augusta University
state: Georgia
city: Chicago
country: United States
facility: Northwestern Memorial Hospital
state: Illinois
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Maywood
country: United States
facility: Loyola University Medical Center
state: Illinois
city: Indianapolis
country: United States
facility: Indiana Blood and Marrow Transplant
state: Indiana
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Baltimore
country: United States
facility: University of Maryland Medical Systems
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Worcester
country: United States
facility: University of Massachusetts
state: Massachusetts
city: Detroit
country: United States
facility: Karmanos Cancer Center
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota School of Medicine
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University in St. Louis
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: New York
country: United States
facility: Memorial Sloan Kettering
state: New York
city: New York
country: United States
facility: Weill Cornell Medical Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Health
state: North Carolina
city: Cleveland
country: United States
facility: University Hospitals of Cleveland Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: Ohio State University, The
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute
state: Utah
city: Salt Lake City
country: United States
facility: Intermountain BMT
state: Utah
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Morgantown
country: United States
facility: West Virginia University Hospital
state: West Virginia
city: Madison
country: United States
facility: University of Wisconsin Hospital and Clinics
state: Wisconsin
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Liverpool
country: Australia
facility: Site AU61001
city: Melbourne
country: Australia
facility: Site AU61002
city: Westmead
country: Australia
facility: Site AU61004
city: Bruxelles
country: Belgium
facility: Site BE32003
city: Gent
country: Belgium
facility: Site BE32004
city: Hamilton
country: Canada
facility: Site CA15004
city: Montreal
country: Canada
facility: Site CA15003
city: Arhus
country: Denmark
facility: Site DK45002
city: Copenhagen
country: Denmark
facility: Site DK45001
city: Lille
country: France
facility: Site FR33007
city: Lyon
country: France
facility: Site FR33004
city: Paris
country: France
facility: Site FR33005
city: Pessac
country: France
facility: Site FR33008
city: Vandoeuvre-Les-Nancy
country: France
facility: Site FR33010
city: Düsseldorf
country: Germany
facility: Site DE49002
city: Halle (Saale)
country: Germany
facility: Site DE49003
city: Hamburg
country: Germany
facility: Site DE49005
city: Köln
country: Germany
facility: Site DE49006
city: Mainz
country: Germany
facility: Site DE49007
city: Münster
country: Germany
facility: Site DE49004
city: Athens
country: Greece
facility: Site GR30004
city: Rio
country: Greece
facility: Site GR30003
city: Thessaloniki
country: Greece
facility: Site GR30001
city: Bergamo
country: Italy
facility: Site IT39005
city: Bologna
country: Italy
facility: Site IT39006
city: Genova
country: Italy
facility: Site IT39009
city: Milano
country: Italy
facility: Site IT39002
city: Milano
country: Italy
facility: Site IT39007
city: Pescara
country: Italy
facility: Site IT39011
city: Roma
country: Italy
facility: Site IT39003
city: Udine
country: Italy
facility: Site IT39004
city: Anjo
country: Japan
facility: Site JP81014
state: Aichi
city: Nagoya
country: Japan
facility: Site JP81011
state: Aichi
city: Sapporo
country: Japan
facility: Site JP81018
state: Hokkaido
city: Kobe
country: Japan
facility: Site JP81021
state: Hyogo
city: Nishinomiya
country: Japan
facility: Site JP81012
state: Hyogo
city: Isehara
country: Japan
facility: Site JP81002
state: Kanagawa
city: Yokohama
country: Japan
facility: Site JP81007
state: Kanagawa
city: Sendai
country: Japan
facility: Site JP81010
state: Miyagi
city: Suita
country: Japan
facility: Site JP81006
state: Osaka
city: Shimotsuke
country: Japan
facility: Site JP81008
state: Tochigi
city: Bunkyo-ku
country: Japan
facility: Site JP81013
state: Tokyo
city: Chuo-ku
country: Japan
facility: Site JP81004
state: Tokyo
city: Minato-ku
country: Japan
facility: Site JP81016
state: Tokyo
city: Shinjuku-ku
country: Japan
facility: Site JP81020
state: Tokyo
city: Fukuoka
country: Japan
facility: Site JP81001
city: Fukuoka
country: Japan
facility: Site JP81003
city: Kyoto
country: Japan
facility: Site JP81015
city: Okayama
country: Japan
facility: Site JP81017
city: Osaka
country: Japan
facility: Site JP81005
city: Seoul
country: Korea, Republic of
facility: Site KR82001
city: Seoul
country: Korea, Republic of
facility: Site KR82002
city: Seoul
country: Korea, Republic of
facility: Site KR82003
city: Seoul
country: Korea, Republic of
facility: Site KR82004
city: Seoul
country: Korea, Republic of
facility: Site KR82005
city: Christchurch
country: New Zealand
facility: Site NZ64002
city: Grafton
country: New Zealand
facility: Site NZ64001
city: Warszawa
country: Poland
facility: Site PL48004
city: Barcelona
country: Spain
facility: Site ES34004
city: Barcelona
country: Spain
facility: Site ES34005
city: Salamanca
country: Spain
facility: Site ES34006
city: Santander
country: Spain
facility: Site ES34007
city: Valencia
country: Spain
facility: Site ES34002
city: Taichung
country: Taiwan
facility: Site TW88603
city: Taipei
country: Taiwan
facility: Site TW88602
city: Taoyuan
country: Taiwan
facility: Site TW88605
city: Birmingham
country: United Kingdom
facility: Site GB44010
city: Bristol
country: United Kingdom
facility: Site GB44003
city: Glasgow
country: United Kingdom
facility: Site GB44009
city: London
country: United Kingdom
facility: Site GB44004
city: Manchester
country: United Kingdom
facility: Site GB44002
city: Sutton
country: United Kingdom
facility: Site GB44001
Study officials:
affiliation: Astellas Pharma Global Development, Inc.
name: Senior Medical Director
role: STUDY_DIRECTOR
References: