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A Study of ASP2215 Versus Salvage Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FMS-like Tyrosine Kinase (FLT3) Mutation

NCT02421939

Description:

The purpose of this study is to determine the clinical benefit of ASP2215 therapy in patients with FMS-like tyrosine kinase (FLT3) mutated acute myeloid leukemia (AML) who are refractory to or have relapsed after first-line AML therapy as shown with overall survival (OS) compared to salvage chemotherapy, and to determine the efficacy of ASP2215 therapy as assessed by the rate of complete remission and complete remission with partial hematological recovery (CR/CRh) in these patients. This study will also determine the overall efficacy in event-free survival (EFS) and complete remission (CR) rate of ASP2215 compared to salvage chemotherapy.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Active, not recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: A Study of ASP2215 Versus Salvage Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FMS-like Tyrosine Kinase (FLT3) Mutation
  • Official Title: A Phase 3 Open-Label, Multicenter, Randomized Study of ASP2215 Versus Salvage Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FLT3 Mutation

Clinical Trial IDs

  • ORG STUDY ID: 2215-CL-0301
  • SECONDARY ID: 2015-000140-42
  • NCT ID: NCT02421939

Conditions

  • Leukemia, Acute Myeloid (AML)

Interventions

DrugSynonymsArms
gilteritinibASP2215ASP2215
LoDAC (Low Dose Cytarabine)Salvage chemotherapy
AzacitidineSalvage chemotherapy
MEC (Mitoxantrone, Etoposide, Cytarabine)Salvage chemotherapy
FLAG-IDA (Granulocyte-Colony Stimulating Factor (G-CSF), Fludarabine, Cytarabine, Idarubicin)Salvage chemotherapy

Purpose

The purpose of this study is to determine the clinical benefit of ASP2215 therapy in patients with FMS-like tyrosine kinase (FLT3) mutated acute myeloid leukemia (AML) who are refractory to or have relapsed after first-line AML therapy as shown with overall survival (OS) compared to salvage chemotherapy, and to determine the efficacy of ASP2215 therapy as assessed by the rate of complete remission and complete remission with partial hematological recovery (CR/CRh) in these patients. This study will also determine the overall efficacy in event-free survival (EFS) and complete remission (CR) rate of ASP2215 compared to salvage chemotherapy.

Detailed Description

      Subjects considered an adult according to local regulations at the time of signing informed
      consent may participate in this study. Subjects will be randomized in a 2:1 ratio to receive
      ASP2215 or salvage chemotherapy. Subjects will enter the screening period up to 14 days prior
      to the start of treatment. Prior to randomization, a salvage chemotherapy regimen will be
      pre-selected for each subject; options will include low-dose cytarabine (LoDAC), azacitidine,
      mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC), or fludarabine, cytarabine,
      and granulocyte colony-stimulating factor (G-CSF) with idarubicin (FLAG-IDA). The
      randomization will be stratified by response to first-line therapy and pre-selected salvage
      chemotherapy. Subjects will be administered treatment over continuous 28-day cycles.

      After treatment discontinuation, subjects will have a pre-hematopoietic stem cell transplant
      (HSCT)/end-of-treatment visit within 7 days after treatment discontinuation, followed by a
      30-day follow-up for safety, in which a telephone contact with the subject is sufficient
      unless any assessment must be repeated for resolution of treatment-related adverse events
      (AEs). After that, long term follow-up will be done every 3 months up to 3 years from the
      subject's end-of-treatment visit.
    

Trial Arms

NameTypeDescriptionInterventions
ASP2215ExperimentalAdministered once daily
  • gilteritinib
Salvage chemotherapyActive ComparatorOptions for salvage chemotherapy are limited to the following: Low- Dose Cytarabine (LoDAC), Azacitidine, MEC Induction Chemotherapy, FLAG-IDA Induction Chemotherapy
  • LoDAC (Low Dose Cytarabine)
  • Azacitidine
  • MEC (Mitoxantrone, Etoposide, Cytarabine)
  • FLAG-IDA (Granulocyte-Colony Stimulating Factor (G-CSF), Fludarabine, Cytarabine, Idarubicin)

Eligibility Criteria

        Inclusion Criteria:

          -  Subject has a diagnosis of primary acute myeloid leukemia (AML) or AML secondary to
             myelodysplastic syndrome (MDS) according to WHO classification (2008) as determined by
             pathology review at the treating institute.

          -  Subject is refractory to or relapsed after first-line AML therapy (with or without
             hematopoietic stem cell transplant (HSCT)).

               -  Refractory to first-line AML therapy is defined as:

                  1. Subject did not achieve complete remission/complete remission with incomplete
                  hematologic recovery/complete remission with incomplete platelet recovery
                  (CR/CRi/CRp) under initial therapy. A subject eligible for standard therapy must
                  receive at least one cycle of an anthracycline containing induction block in
                  standard dose for the selected induction regimen. A subject not eligible for
                  standard therapy must have received at least one complete block of induction
                  therapy seen as the optimum choice of therapy to induce remission for this
                  subject.

               -  Untreated first hematologic relapse is defined as:

                    1. Subject must have achieved a CR/CRi/CRp (criteria as defined by [Cheson et
                       al, 2003], see Section 5.3) with first line treatment and has hematologic
                       relapse.

          -  Subject is positive for FLT3 mutation in bone marrow or whole blood as determined by
             the central lab. A subject with rapidly proliferative disease and unable to wait for
             the central lab results can be enrolled based on a local test performed after
             completion of the last interventional treatment. Subjects can be enrolled from a local
             test result if they have any of the following FLT3 mutations: FLT3 internal tandem
             duplication (ITD), FLT3 tyrosine kinase domain (TKD)/D835 or FLT3- TKD/I836.

          -  Subject has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.

          -  Subject is eligible for pre-selected salvage chemotherapy.

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

               -  Serum aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x upper limit
                  of normal (ULN)

               -  Serum total bilirubin ≤ 1.5 x ULN

               -  Serum creatinine ≤ 1.5 x ULN or an estimated glomerular filtration rate of > 50
                  mL/min as calculated by the Modification of Diet in Renal Disease equation.

          -  Subject is suitable for oral administration of study drug.

          -  Female subject must either:

               -  Be of non-child bearing potential:

                    1. post-menopausal (defined as at least 1 year without any menses) prior to
                       Screening, or

                    2. documented as surgically sterile (at least 1 month prior to Screening)

               -  Or, if of childbearing potential,

                    1. Agree not to try to become pregnant during the study and for 180 days after
                       the final study administration

                    2. And have a negative urine pregnancy test at Screening

                    3. 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 180 days after
                       the final study drug administration.

          -  Female subject must agree not to breastfeed at Screening and throughout the study
             period and for 60 days after the final study drug administration.

          -  Female subject must not donate ova starting at Screening and throughout the study
             period and for 180 days after the final study drug administration.

          -  Male subject and their 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 120 days
             after the final study drug administration.

          -  Male subject must not donate sperm starting at Screening and throughout the study
             period and 120 days after the final study drug administration.

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

        Exclusion Criteria:

          -  Subject was diagnosed as acute promyelocytic leukemia (APL).

          -  Subject has BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast crisis).

          -  Subject has AML secondary to prior chemotherapy for other neoplasms (except for MDS).

          -  Subject is in second or later hematologic relapse or has received salvage therapy for
             refractory disease

          -  Subject has clinically active central nervous system leukemia.

          -  Subject has been diagnosed with another malignancy, unless disease-free for at least 5
             years. Subjects with treated nonmelanoma skin cancer, in situ carcinoma or cervical
             intraepithelial neoplasia, regardless of the disease-free duration, are eligible for
             this study if definitive treatment for the condition has been completed. Subjects with
             organ-confined prostate cancer with no evidence of recurrent or progressive disease
             are eligible if hormonal therapy has been initiated or the malignancy has been
             surgically removed or treated with definitive radiotherapy.

          -  Subject has received prior treatment with ASP2215 or other FLT3 inhibitors (with the
             exception of sorafenib and midostaurin used in first-line therapy regimen as part of
             induction, consolidation, and/or maintenance).

          -  Subject has clinically significant abnormality of coagulation profile, such as
             disseminated intravascular coagulation (DIC).

          -  Subject has had major surgery within 4 weeks prior to the first study dose.

          -  Subject has radiation therapy within 4 weeks prior to the first study dose.

          -  Subject has congestive heart failure New York Heart Association (NYHA) class 3 or 4,
             or subject with a history of congestive heart failure NYHA class 3 or 4 in the past,
             unless a screening echocardiogram performed within 3 months 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.

          -  Subjects with mean of triplicate Fridericia-corrected QT interval (QTcF) > 450 ms at
             Screening based on central reading.

          -  Subjects with Long QT Syndrome at Screening.

          -  Subjects with hypokalemia and hypomagnesemia at Screening (defined as values below
             lower limit of normal [LLN]).

          -  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 an active uncontrolled infection.

          -  Subject is known to have human immunodeficiency virus infection.

          -  Subject has active hepatitis B or C, or other active hepatic disorder.

          -  Subject has any condition which makes the subject unsuitable for study participation.

          -  Subject has active clinically significant GVHD or is on treatment with systemic
             corticosteroids for GVHD.

          -  Subject has an FLT3 mutation other than the following: FLT3-ITD, FLT3-TKD/D835 or
             FLT3-TKD/I836.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Survival (OS)
Time Frame:up to 30 months
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Event-free survival
Time Frame:up to 49 months
Safety Issue:
Description:
Measure:Complete remission rate
Time Frame:up to 36 months
Safety Issue:
Description:
Measure:Leukemia-free survival
Time Frame:up to 49 months
Safety Issue:
Description:
Measure:Duration of remission
Time Frame:up to 36 months
Safety Issue:
Description:
Measure:Composite complete remission rate
Time Frame:up to 36 months
Safety Issue:
Description:Complete remission (CR) + Complete remission with incomplete hematologic recovery (Cri) + Complete remission with incomplete platelet recovery (CRp)
Measure:Transplantation rate
Time Frame:up to 49 months
Safety Issue:
Description:Transplantation rate is defined as the percentage of subjects undergoing Hematopoietic stem cell transplant (HSCT) during the study period.
Measure:Brief Fatigue Inventory
Time Frame:up to 36 months
Safety Issue:
Description:The Brief Fatigue Inventory (BFI) is used to assess the severity of fatigue and the impact of fatigue on daily functioning in patients with fatigue due to cancer and cancer treatment. The BFI short form has 9 items and a 24-hour recall. A global fatigue score is computed by averaging the 9 items.
Measure:Complete remission with partial hematological recovery (CRh) rate
Time Frame:up to 36 months
Safety Issue:
Description:
Measure:Transfusion conversion rate
Time Frame:up to 36 months
Safety Issue:
Description:
Measure:Transfusion maintenance rate
Time Frame:up to 36 months
Safety Issue:
Description:

Details

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

Trial Keywords

  • ASP2215
  • Relapsed Acute Myeloid Leukemia
  • FLT3 Mutation
  • gilteritinib
  • Refractory Acute Myeloid Leukemia
  • Acute Myeloid Leukemia (AML)

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