A Study of ASP2215 Versus Salvage Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FMS-like Tyrosine Kinase (FLT3) Mutation
Condition: Leukemia, Acute Myeloid (AML)
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
Intervention: gilteritinib; LoDAC (Low Dose Cytarabine); Azacitidine; MEC (Mitoxantrone, Etoposide, Cytarabine); FLAG-IDA (Granulocyte-Colony Stimulating Factor (G-CSF), Fludarabine, Cytarabine, Idarubicin)
Intervention description: tablet, oral; subcutaneous (SC) or intravenous (IV) injection; SC or IV injection; IV injection; SC (G-CSF) and IV (Fludarabine, Cytarabine, Idarubicin) injection
Intervention MeSH terms: Cytarabine; Fludarabine; Etoposide; Azacitidine; Mitoxantrone; Idarubicin; Lenograstim
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 371.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: ASP2215; Relapsed Acute Myeloid Leukemia; FLT3 Mutation; gilteritinib; Refractory Acute Myeloid Leukemia; Acute Myeloid Leukemia (AML); XOSPATA®

Summary:

      The purpose of this study is to determine the clinical benefit of ASP2215 therapy in
      participants 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 participants.

      This study will also determine the overall efficacy in event-free survival (EFS) and complete
      remission (CR) rate of ASP2215 compared to salvage chemotherapy.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Participant 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.

          -  Participant 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. Participant did not achieve complete remission/complete remission with
                  incomplete hematologic recovery/complete remission with incomplete platelet
                  recovery (CR/CRi/CRp) under initial therapy. A Participant 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 Participant 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. Participant 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.

          -  Participant is positive for FLT3 mutation in bone marrow or whole blood as determined
             by the central lab. A Participant 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. Participants 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.

          -  Participant has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.

          -  Participant is eligible for pre-selected salvage chemotherapy.

          -  Participant 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.

          -  Participant is suitable for oral administration of study drug.

          -  Female Participant 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 Participant must agree not to breastfeed at Screening and throughout the study
             period and for 60 days after the final study drug administration.

          -  Female Participant must not donate ova starting at Screening and throughout the study
             period and for 180 days after the final study drug administration.

          -  Male Participant 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 Participant must not donate sperm starting at Screening and throughout the study
             period and 120 days after the final study drug administration.

          -  Participant agrees not to participate in another interventional study while on
             treatment.

        Exclusion Criteria:

          -  Participant was diagnosed as acute promyelocytic leukemia (APL).

          -  Participant has BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast
             crisis).

          -  Participant has AML secondary to prior chemotherapy for other neoplasms (except for
             MDS).

          -  Participant is in second or later hematologic relapse or has received salvage therapy
             for refractory disease

          -  Participant has clinically active central nervous system leukemia.

          -  Participant has been diagnosed with another malignancy, unless disease-free for at
             least 5 years. Participants 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.
             Participants 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.

          -  Participant 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).

          -  Participant has clinically significant abnormality of coagulation profile, such as
             disseminated intravascular coagulation (DIC).

          -  Participant has had major surgery within 4 weeks prior to the first study dose.

          -  Participant has radiation therapy within 4 weeks prior to the first study dose.

          -  Participant has congestive heart failure New York Heart Association (NYHA) class 3 or
             4, or Participant 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%.

          -  Participant requires treatment with concomitant drugs that are strong inducers of
             cytochrome P450 (CYP)3A.

          -  Participants with mean of triplicate Fridericia-corrected QT interval (QTcF) > 450 ms
             at Screening based on central reading.

          -  Participants with Long QT Syndrome at Screening.

          -  Participants with hypokalemia and hypomagnesemia at Screening (defined as values below
             lower limit of normal [LLN]).

          -  Participant 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.

          -  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 subject.

          -  Participant has an active uncontrolled infection.

          -  Participant is known to have human immunodeficiency virus infection.

          -  Participant has active hepatitis B or C, or other active hepatic disorder.

          -  Participant has any condition which makes the Participant unsuitable for study
             participation.

          -  Participant has active clinically significant GVHD or is on treatment with systemic
             corticosteroids for GVHD.

          -  Participant has an FLT3 mutation other than the following: FLT3-ITD, FLT3-TKD/D835 or
             FLT3-TKD/I836.