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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)

NCT02997202

Description:

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.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Active, not recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: 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

Clinical Trial IDs

  • ORG STUDY ID: 2215-CL-0304
  • SECONDARY ID: 2016-001061-83
  • SECONDARY ID: BMT CTN 1506
  • NCT ID: NCT02997202

Conditions

  • Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
gilteritinibGilteritinib
PlaceboPlacebo

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
GilteritinibExperimentalParticipants will take gilteritinib once daily for continuous daily dosing.
  • gilteritinib
PlaceboPlacebo ComparatorParticipants will take placebo once daily for continuous daily dosing.
  • Placebo

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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Relapse-free survival
Time Frame:84 months
Safety Issue:
Description:Relapse-free survival (RFS) will be measured from time of randomization to either leukemia relapse or death, whichever comes first. Leukemia 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.

Secondary Outcome Measures

Measure:Safety and tolerability assessed by incidence and severity of adverse events
Time Frame:24 months
Safety Issue:
Description: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.
Measure:Overall Survival (OS)
Time Frame:84 months
Safety Issue:
Description: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.
Measure:Non-relapse Mortality
Time Frame:84 months
Safety Issue:
Description:An event for this endpoint is death without evidence of disease progression or recurrence.
Measure:Event-free Survival (EFS) at 12 months
Time Frame:12 months
Safety Issue:
Description:The cumulative incidence at 12 months after randomization of EFS will be described and compared.
Measure:Event-free Survival (EFS) at 24 months
Time Frame:24 months
Safety Issue:
Description:The cumulative incidence at 24 months after randomization of EFS will be described and compared.
Measure:Cumulative Incidence of Acute Graft vs. Host Disease (GVHD)
Time Frame:6 months
Safety Issue:
Description: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).
Measure:Cumulative Incidence of Chronic GVHD at 12 months
Time Frame:12 months
Safety Issue:
Description: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.
Measure:Cumulative Incidence of Chronic GVHD at 24 months
Time Frame:24 months
Safety Issue:
Description: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.
Measure:The cumulative incidence of detection of FLT3/ITD MRD
Time Frame:24 months
Safety Issue:
Description: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.
Measure:Incidence of Severity of Infection
Time Frame:28 months
Safety Issue:
Description:The cumulative incidence of CTCAE grades 3 to 5 infection in participants will be described and compared.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Astellas Pharma Global Development, Inc.

Trial Keywords

  • Gilteritinib
  • ASP2215
  • Safety and Efficacy
  • Acute Myeloid Leukemia

Last Updated

May 10, 2021