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A Study of ASP2215 (Gilteritinib), Administered as Maintenance Therapy Following Induction/Consolidation Therapy for Subjects With FMS-like Tyrosine Kinase 3 (FLT3/ITD) Acute Myeloid Leukemia (AML) in First Complete Remission

NCT02927262

Description:

The purpose of this study is to compare relapse-free survival (RFS) between subjects with FMS-like tyrosine kinase 3 (FLT3) / internal tandem duplication (ITD) acute myeloid leukemia (AML) in first complete remission (CR1) and who are randomized to receive gilteritinib or placebo beginning after completion of induction/consolidation chemotherapy for a two-year period.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study of ASP2215 (Gilteritinib), Administered as Maintenance Therapy Following Induction/Consolidation Therapy for Subjects With FMS-like Tyrosine Kinase 3 (FLT3/ITD) Acute Myeloid Leukemia (AML) in First Complete Remission
  • Official Title: A Phase 3 Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of the FLT3 Inhibitor Gilteritinib (ASP2215) Administered as Maintenance Therapy Following Induction/Consolidation Therapy for Subjects With FLT3/ITD AML in First Complete Remission

Clinical Trial IDs

  • ORG STUDY ID: 2215-CL-0302
  • SECONDARY ID: 2016-001643-39
  • NCT ID: NCT02927262

Conditions

  • Acute Myeloid Leukemia (AML)
  • Acute Myeloid Leukemia With FMS-like Tyrosine Kinase (FLT3) / Internal Tandem Duplication (ITD) Mutation

Interventions

DrugSynonymsArms
gilteritinibASP2215ASP2215
PlaceboPlacebo

Purpose

The purpose of this study is to compare relapse-free survival (RFS) between subjects with FMS-like tyrosine kinase 3 (FLT3) / internal tandem duplication (ITD) acute myeloid leukemia (AML) in first complete remission (CR1) and who are randomized to receive gilteritinib or placebo beginning after completion of induction/consolidation chemotherapy for a two-year period.

Detailed Description

      Subjects in CR1 will be approached for this study after induction/consolidation therapy is
      complete and a decision not to proceed with transplantation is made or a suitable donor could
      not be identified. Subjects will be randomized in a 2:1 ratio to receive gilteritinib or
      placebo. Subjects will enter the screening period up to 14 days prior to the start of
      treatment. Subjects will be administered treatment over continuous 28-day cycles. After
      treatment discontinuation, subjects will have a 30-day follow-up visit for safety, after
      which the subjects will enter the long-term follow up period for collection of subsequent AML
      treatment, remission status, and survival (cause of death and date of death). Gilteritinib or
      placebo will be given daily for up to 2 years. Subjects will be followed for up to 3 years
      from the subjects 30-day follow up, or until 80% of the subjects have an RFS event, whichever
      comes first. Study drug will not be provided during the follow-up period.
    

Trial Arms

NameTypeDescriptionInterventions
ASP2215ExperimentalSubjects will be treated with ASP2215 once daily (continuously for up to 2 years).
  • gilteritinib
PlaceboPlacebo ComparatorSubjects will be treated with matching placebo tablets once daily (continuously for up to 2 years).
  • Placebo

Eligibility Criteria

        Inclusion Criteria:

          -  Subject is considered an adult according to local regulation at the time of obtaining
             consent form (ICF).

          -  Subject consents to allow access to subject's diagnostic bone marrow aspirate or
             peripheral blood sample and/or the DNA derived from that sample, if available, that
             may be used to validate a companion diagnostic test that is being developed in
             parallel with gilteritinib.

          -  Subject has confirmed morphologically documented AML, excluding acute promyelocytic
             leukemia (APL), in CR1 (including CRp and CRi). For the purposes of enrollment, CR
             will be defined as < 5% blasts in the bone marrow with no morphologic characteristics
             of acute leukemia (e.g., Auer rods) in the bone marrow with no evidence of
             extramedullary disease such as central nervous system involvement or granulocytic
             sarcoma.

          -  Subject will not proceed with transplantation as either a decision not to proceed with
             transplantation has been made either on the recommendation of the treating physician
             or by the patient or a suitable donor could not be identified.

          -  Subject is < 2 months from the start of the last cycle of consolidation and should
             have completed the recommended number of consolidations per local practice.

          -  Subject has had no use of investigational agents, with the exception of FLT3
             inhibiting agents during induction and/or consolidation therapy, within the prior 4
             weeks.

          -  Subject has had presence of the FLT3/ITD activating mutation in the bone marrow or
             peripheral blood as determined by the local institution at diagnosis.

          -  Subject has an ECOG performance status 0 to 2.

          -  Subject must meet the following criteria as indicated on the clinical laboratory
             tests:

               -  Serum creatinine ≤ 1.5 x institutional upper limit of normal (ULN), or if serum
                  creatinine outside normal range, then glomerular filtration rate (GFR) > 40
                  mL/min/1.73m^2 as calculated with the 4-parameter Modification of Diet in Renal
                  Disease (MDRD) equation.

               -  Serum total bilirubin ≤ 2.5 mg/dL (43 μmol/L), except for subjects with Gilbert's
                  syndrome.

               -  Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x
                  ULN.

               -  Serum potassium and serum magnesium ≥ institutional lower limit of normal (LLN).

               -  Absolute neutrophil count (ANC) ≥ 500/μl and platelets ≥ 20000/μl (unsupported by
                  transfusions).

          -  Subject is suitable for oral administration of study drug.

          -  Female subject must either:

               -  Be of nonchildbearing potential:

               -  Postmenopausal (defined as at least 1 year without any menses) prior to
                  screening, or

               -  Documented surgically sterile or status posthysterectomy (at least 1 month prior
                  to screening)

               -  Or, if of childbearing potential,

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

               -  And have a negative urine or 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.

          -  Female subject must agree not to breastfeed starting at screening and throughout the
             study period, and for 2 months and 1 week after the final study drug administration.

          -  Female subject must not donate ova starting at screening and throughout the study
             period, and for 6 months after the final study drug administration.

          -  Male subject and subject's female partners who are of childbearing potential must be
             using highly effective contraception per locally accepted standards (in addition to a
             barrier method) starting at screening and continue throughout the study period and for
             4 months and 1 week after the final study drug administration.

          -  Male subject must not donate sperm starting at screening and throughout the study
             period and for 4 months and 1 week after the final study drug administration.

          -  Subject agrees not to participate in another interventional study while on treatment.

        Exclusion Criteria:

          -  Subject has had prior allogeneic transplant.

          -  Subject has QTcF interval > 450 msec (average of triplicate determinations based on
             central reading).

          -  Subject with Long QT Syndrome.

          -  Subject with hypokalemia and hypomagnesemia at screening (defined as values below
             LLN).

          -  Subject has clinically active central nervous system leukemia.

          -  Subject is known to have human immunodeficiency virus infection.

          -  Subject has active hepatitis B or C.

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

          -  Subject has progressing infection 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.

          -  Subject has uncontrolled angina, severe uncontrolled ventricular arrhythmias,
             electrocardiographic evidence of acute ischemia, congestive heart failure New York
             Heart Association (NYHA) class 3 or 4 or subject has a history of congestive heart
             failure NYHA class 3 or 4 in the past, unless a screening echocardiogram or multigated
             acquisition (MUGA) scan performed within 1 month prior to study entry results in a
             left ventricular ejection fraction that is ≥ 45%.

          -  Subject requires treatment with concomitant drugs that are strong inducers of
             cytochrome P450 (CYP) 3A.

          -  Subject requires treatment with concomitant drugs that are strong inhibitors or
             inducers of P-glycoprotein (P-gp) with the exception of drugs that are considered
             absolutely essential for the care of the subject.

          -  Subject 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 subject.

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

          -  Subject has prior malignancies, except resected basal cell carcinoma 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.

          -  Subject has any condition which makes the subject unsuitable for study participation.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Relapse-free Survival (RFS)
Time Frame:Up to 61 months
Safety Issue:
Description:RFS is defined as the time from the date of randomization until the date of documented relapse or death from any cause, whichever occurs first. Relapse after Complete Remission (CR) (including Complete Remission with incomplete Platelet recovery (CRp) and Complete Remission with incomplete hematologic recovery (CRi)), is defined as bone marrow blasts 5% or higher (not attributable to regenerating bone marrow), any circulating blasts, any extra-medullary blast foci as per Revised International Working Group (IWG) criteria. Relapse events will be adjudicated by an independent review committee and will be used in the efficacy assessments, unless specifically stated otherwise.

Secondary Outcome Measures

Measure:Overall Survival (OS)
Time Frame:Up to 61 months
Safety Issue:
Description:OS is defined as the time from the date of randomization until the date of death from any cause. For surviving subjects, non-events will be censored at the date of last known date alive.
Measure:Event-free survival (EFS)
Time Frame:Up to 61 months
Safety Issue:
Description:EFS is defined as the time from the date of randomization until the date of documented relapse or discontinuation of the treatment, or initiation of other anti-leukemic treatment or death from any cause, whichever occurs first.
Measure:Minimal Residual Disease (MRD)
Time Frame:Up to 61 months
Safety Issue:
Description:MRD will be measured from bone marrow samples. FLT3/ITD mutation ratio will be measured in relation to total FLT3. Changes in FLT3/ITD mutation ratio will be compared with baseline/screening samples.
Measure:Safety assessed by Adverse Events (AEs)
Time Frame:Up to 61 months
Safety Issue:
Description:
Measure:Number of participants with abnormal laboratory values and/or adverse events related to treatment
Time Frame:Up to 61 months
Safety Issue:
Description:
Measure:Number of participants with abnormal vital signs and/or adverse events related to treatment
Time Frame:Up to 61 months
Safety Issue:
Description:
Measure:Safety assessed by electrocardiograms (ECGs)
Time Frame:Up to 61 months
Safety Issue:
Description:The 12-lead ECGs will be recorded in triplicate (3 separate ECGs, 10 minutes resting prior to first ECG and at least 5 minutes apart per time point) and transmitted electronically for central reading. The mean of the triplicate ECG from central read should be used for all final treatment decisions and AE reporting.
Measure:Number of participants with physical exam abnormalities and/or adverse events related to treatment
Time Frame:Up to 61 months
Safety Issue:
Description:
Measure:Eastern Cooperative Oncology Group (ECOG) performance status score
Time Frame:Up to 24 months
Safety Issue:
Description:ECOG performance status measured on 6 point scale to assess participant's performance status. 0=Fully active, able to carry on all pre-disease activities without restriction; 1=Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature; 2= Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours; 3=Capable of only limited self-care, confined to bed or chair more than 50% of waking hours; 4=Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair; 5=Dead.

Details

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

Trial Keywords

  • Acute myeloid leukemia
  • First Complete Remission
  • gilteritinib
  • FLT3/ITD
  • AML
  • ASP2215

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