Clinical Trials /

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:

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), 2) time from HCT to randomization (30-60 days vs. 61-90 days) and 3) presence or
      absence of 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 hematologic recovery (CRi) is defined as CR with residual
                  neutropenia < 1 x 109/L with or without complete platelet recovery. 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).

               -  Serum potassium and magnesium greater than the institutional lower limit of
                  normal (LLN).

          -  Participant has left ventricular ejection fraction at rest ≥ 40%.

          -  Participant has diffusing capacity of the lung for carbon monoxide (DLCO) (corrected
             for hemoglobin), forced expiratory volume in 1 second (FEV1), and forced vital
             capacity (FVC) > 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 through 60 days 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 60 days after the
                  final study drug administration.

          -  Female participants must agree not to breastfeed or donate ova at screening and
             throughout the study period and for 60 days 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 starting at screening and throughout the study period and for 120 days
             after the final study drug administration.

          -  Male participants must not donate sperm starting at screening and throughout the study
             period and for 120 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 stem cell infusion.

          -  Participant has an ANC ≥ 500/μL and platelets ≥ 20000/μL in the absence of platelet
             transfusion within the prior 7 days.

          -  Participant has no use of investigational agents within the prior 4 weeks.

          -  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 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 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 greater than the institutional LLN.

          -  Participant has no need for supplemental oxygen with the exception of using previously
             existing non-invasive continuous positive airway pressure (CPAP) at night

          -  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 immunosuppression in terms of increase of corticosteroids or
                  addition of new agent / modality in prior 2 weeks (note that increasing
                  calcineurin inhibitors or sirolimus to achieve therapeutic trough levels is
                  allowed)

          -  Participant has no use of any experimental therapies for acute GVHD in the prior 4
             weeks. If unsure of the definition of "experimental", discussion with one of the
             protocol chairs is encouraged.

          -  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
             CYP3A4.

          -  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).

          -  Participant has long QT Syndrome at screening.

          -  Participant has a known infection with human immunodeficiency virus (HIV) as
             determined by serology or nucleic acid amplification test (NAAT).

          -  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. Participants who
             have had past exposure and have no detectable virus either through spontaneous
             clearance or treatment are eligible.

          -  Participant with uncontrolled infections will be excluded. 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.

          -  Female participants who are 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
             CYP3A4.

          -  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).

          -  Participant with uncontrolled infections will be excluded. 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, 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. 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.
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.
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.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Astellas Pharma Global Development, Inc.

Trial Keywords

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

Last Updated

September 12, 2017