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

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

The purpose of this study was to determine the clinical benefit of ASP2215 therapy in participants with FMS-like tyrosine kinase (FLT3) mutated acute myeloid leukemia (AML) who were refractory to or had relapsed after first-line AML therapy as shown with overall survival (OS) compared to salvage chemotherapy, and determined 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 also determined the overall efficacy in event-free survival (EFS) and complete remission (CR) rate of ASP2215 compared to salvage chemotherapy.

Study Overview

• Status: Completed
• Conditions: Leukemia, Acute Myeloid (AML)
• Intervention / Treatment: Drug: gilteritinib; Drug: LoDAC (Low Dose Cytarabine); Drug: Azacitidine; Drug: MEC (Mitoxantrone, Etoposide, Cytarabine); Drug: FLAG-IDA (Granulocyte-Colony Stimulating Factor (G-CSF), Fludarabine, Cytarabine, Idarubicin)

Detailed Description

Participants considered an adult according to local regulations at the time of signing informed consent participated in this study. Participants were randomized in a 2:1 ratio to receive ASP2215 or salvage chemotherapy. Participants entered the screening period up to 14 days prior to the start of treatment. Prior to randomization, a salvage chemotherapy regimen was pre-selected for each participant; options included 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 was stratified by response to first-line therapy and pre-selected salvage chemotherapy. Participants were administered treatment over continuous 28-day cycles. After treatment discontinuation, participants had 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 participant was sufficient unless any assessment had to be repeated for resolution of treatment-related adverse events (AEs). After that, long term follow-up was done every 3 months up to 3 years from the participant's end-of-treatment visit.

• Study Type: Interventional
• Enrollment (Actual): 371
• Phase: Phase 3

Expanded Access

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Contacts and Locations

Study Locations

• Belgium
  • Yvoir, Belgium, 5530
    • Site BE32002
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2G3
      • Site CA15004
  • Ontario
    • Hamilton, Ontario, Canada, L8V 1C3
      • Site CA15001
    • Toronto, Ontario, Canada, M5G 2M9
      • Site CA15015
  • Quebec
    • Montreal, Quebec, Canada, H1T 2M4
      • Site CA15003
• France
  • Brest, France, 29609
    • Site FR33013
  • Le Chesnay, France, 78157
    • Site FR33002
  • Lille, France, 59037
    • Site FR33010
  • Pessac, France, 33604
    • Site FR33009
  • Rennes, France, 35033
    • Site FR33014
  • Toulouse, France, 31059
    • Site FR33008
• Germany
  • Dresden, Germany, 01307
    • Site DE49009
  • Leipzig, Germany, 04103
    • Site DE49011
  • Marburg, Germany, 35043
    • Site DE49003
  • München, Germany, 81737
    • Site DE49002
  • Tübingen, Germany, 72076
    • Site DE49010
• Israel
  • Ashkelon, Israel, 78278
    • Site IL97201
  • Haifa, Israel, 31096
    • Site IL97209
  • Jerusalem, Israel, 91031
    • Site IL97203
  • Jerusalem, Israel, 91120
    • Site IL97210
  • Petah Tikva, Israel, 49100
    • Site IL97206
  • Rehovot, Israel, 76100
    • Site IL97208
• Italy
  • Bologna, Italy, 40138
    • Site IT39005
  • Brescia, Italy, 25126
    • Site IT39010
  • Milan, Italy, 20132
    • Site IT39001
  • Palermo, Italy, 90146
    • Site IT39004
  • Pavia, Italy, 27100
    • Site IT39011
  • Roma, Italy, 00189
    • Site IT39007
  • Varese, Italy, 21100
    • Site IT39002
• Japan
  • Akita, Japan
    • Site JP81023
  • Aomori, Japan
    • Site JP81021
  • Kumamoto, Japan
    • Site JP81013
  • Kyoto, Japan
    • Site JP81025
  • Nagasaki, Japan
    • Site JP81008
  • Okayama, Japan
    • Site JP81024
  • Osaka, Japan
    • Site JP81011
  • Aichi-ken
    • Nagoya, Aichi-ken, Japan
      • Site JP81002
  • Chiba
    • Narita, Chiba, Japan
      • Site JP81010
  • Fukui
    • Yoshida-gun, Fukui, Japan
      • Site JP81026
  • Hokkaido
    • Sapporo, Hokkaido, Japan
      • Site JP81016
  • Hyōgo
    • Kobe, Hyōgo, Japan
      • Site JP81018
  • Ibaraki
    • Tsukuba, Ibaraki, Japan
      • Site JP81017
  • Kanagawa
    • Isehara, Kanagawa, Japan
      • Site JP81009
    • Yokohama, Kanagawa, Japan
      • Site JP81006
  • Miyagi
    • Sendai, Miyagi, Japan
      • Site JP81012
  • Okayama-ken
    • Kurashiki, Okayama-ken, Japan
      • Site JP81007
  • Osaka
    • Sayama, Osaka, Japan
      • Site JP81014
  • Saitama
    • Kawagoe, Saitama, Japan
      • Site JP81020
  • Tochigi
    • Shimotsuke, Tochigi, Japan
      • Site JP81027
  • Tokyo
    • Chuo-ku, Tokyo, Japan
      • Site JP81005
    • Shinagawa-ku, Tokyo, Japan
      • Site JP81004
    • Shinjuku-ku, Tokyo, Japan
      • Site JP81022
• Poland
  • Gdansk, Poland, 80-952
    • Site PL48002
  • Opole, Poland, 45-372
    • Site PL48005
  • Wroclaw, Poland, 50-367
    • Site PL48004
• South Korea
  • Busan, South Korea, 602739
    • Site KR82010
  • Goyang, South Korea, 602-715
    • Site KR82009
  • Jeollanam-do, South Korea, 519-809
    • Site KR82003
  • Seoul, South Korea, 110-744
    • Site KR82007
  • Seoul, South Korea, 120-752
    • Site KR82004
  • Seoul, South Korea, 135710
    • Site KR82001
  • Seoul, South Korea, 137701
    • Site KR82002
  • Seoul, South Korea, 138-736
    • Site KR82008
  • Seoul, South Korea, 156-707
    • Site KR82011
  • Gyeonggi-do
    • Suwon, Gyeonggi-do, South Korea, 443380
      • Site KR82005
• Spain
  • Badalona, Spain, 08025
    • Site ES34009
  • Barcelona, Spain, 08035
    • Site ES34011
  • Barcelona, Spain, 08036
    • Site ES34012
  • Barcelona, Spain, 08916
    • Site ES34010
  • Girona, Spain, 17007
    • Site ES34016
  • L'Hospitalet de Llobregat, Spain, 08907
    • Site ES34005
  • Salamanca, Spain, 37007
    • Site ES34014
  • Valencia, Spain, 46026
    • Site ES34017
• Taiwan
  • Kaohsiung City, Taiwan, 112
    • Site TW88606
  • Kaohsiung City, Taiwan, 83301
    • Site TW88604
  • Taichung, Taiwan, 404
    • Site TW88608
  • Taichung, Taiwan, 40705
    • Site TW88609
  • Tainan, Taiwan, 704
    • Site TW88601
  • Taipei, Taiwan, 10002
    • Site TW88603
  • Taipei, Taiwan, 10449
    • Site TW88610
  • Taipei, Taiwan, 112
    • Site TW88611
  • Taipei, Taiwan, 114
    • Site TW88602
  • Taoyuan District, Taiwan, 33305
    • Site TW88605
• Turkey (Türkiye)
  • Ankara, Turkey (Türkiye), 06100
    • Site TR90001
  • Ankara, Turkey (Türkiye), 06500
    • Site TR90004
• United Kingdom
  • Bournemouth, United Kingdom, BH7 7DW
    • Site GB44014
  • Harrow, United Kingdom, HA1 3UJ
    • Site GB44013
  • Manchester, United Kingdom, M13 9WL
    • Site GB44003
  • Plymouth, United Kingdom, PL6 8DH
    • Site GB44015
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294-0006
      • Site US10011
  • California
    • Los Angeles, California, United States, 90095-1752
      • Site US10012
    • Orange, California, United States, 92868
      • Site US10076
    • San Francisco, California, United States, 94143
      • Site US10073
  • Connecticut
    • New Haven, Connecticut, United States, 06504
      • Site US10067
  • Florida
    • Gainesville, Florida, United States, 32610
      • Site US10045
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Site US10081
  • Illinois
    • Chicago, Illinois, United States, 60637
      • Site US10006
  • Kansas
    • Westwood, Kansas, United States, 66205
      • Site US10075
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Site US10074
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Site US10048
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Site US10005
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Site US10034
    • Boston, Massachusetts, United States, 02215
      • Site US10022
    • Boston, Massachusetts, United States, 02215
      • Site US10085
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Site US10087
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Site US10057
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756-1000
      • Site US10023
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Site US10027
    • New Brunswick, New Jersey, United States, 08903
      • Site US10077
  • New York
    • Buffalo, New York, United States, 14263
      • Site US10001
    • New York, New York, United States, 10029
      • Site US10037
    • New York, New York, United States, 10032
      • Site US10008
    • New York, New York, United States, 10065
      • Site US10013
    • New York, New York, United States, 10065
      • Site US10072
    • Syracuse, New York, United States, 13210
      • Site US10046
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Site US10024
    • Winston-Salem, North Carolina, United States, 27157
      • Site US10078
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Site US10044
    • Columbus, Ohio, United States, 43210
      • Site US10084
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Site US10058
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Site US10041
    • Philadelphia, Pennsylvania, United States, 19104
      • Site US10010
    • Philadelphia, Pennsylvania, United States, 19107
      • Site US10080
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Site US10014
  • Tennessee
    • Nashville, Tennessee, United States, 37232-0656
      • Site US10063
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Site US10035

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Gilteritinib; Participants received 120 mg dose (3 tablets of 40 mg) orally once a day in continuous 28-day cycles, at least 2 hours after or 1 hour before food. Gilteritinib treatment continued until participants met one of the treatment discontinuation criteria.	Drug: gilteritinib; tablet, oral; Other Names: ASP2215; XOSPATA®
Active Comparator: Salvage Chemotherapy; Participants received chemotherapy in 28-day cycles. Participants on Low-Dose Cytarabine (LoDAC) received 20 mg of cytarabine twice daily by subcutaneous (SC) or intravenous (IV) injection for 10 days. Participants on azacitidine received 75 mg/m^2 daily by SC or IV injection for 7 days. Participants on LoDAC or azacitidine treatment continued until they met discontinuation criteria. Participants on MEC chemotherapy received mitoxantrone 8 mg/m^2 daily by IV for 5 days, etoposide 100 mg/m^2 daily by IV for 5 days and cytarabine 1000 mg/m^2 daily by IV for 5 days (days 1-5). Participants on FLAG-IDA chemotherapy received G-CSF 300 μg/m^2 daily by SC/IV for 5 days (days 1-5), fludarabine 30 mg/m^2 daily by IV for 5 days (days 2-6), cytarabine 2000 mg/m^2 daily by IV for 5 days (days 2-6) and idarubicin 10 mg/m^2 daily by IV for 3 days (days 2-4). Participants receiving MEC or FLAG-IDA received 1 cycle of therapy and were assessed for response on or after day 15.	Drug: LoDAC (Low Dose Cytarabine); subcutaneous (SC) or intravenous (IV) injection; Drug: Azacitidine; SC or IV injection; Drug: MEC (Mitoxantrone, Etoposide, Cytarabine); IV injection; Drug: FLAG-IDA (Granulocyte-Colony Stimulating Factor (G-CSF), Fludarabine, Cytarabine, Idarubicin); SC (G-CSF) and IV (Fludarabine, Cytarabine, Idarubicin) injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Overall Survival (OS)	Overall survival was defined as the time from the date of randomization until the date of death from any cause (death date - randomization date + 1). For a participant who was not known to have died by the end of study follow-up, OS was censored at the date of last contact (date of last contact - randomized date + 1). The date of last contact was the latest date that the participant was known to be alive. The last contact date was derived for participants alive at the analysis cutoff date. Survival rate and 95% CI were estimated using the Kaplan-Meier method and the Greenwood formula.	From randomization to until the date of death from any cause (median time of follow-up for OS was 17.8 months)
Percentage of Participants With Complete Remission and Complete Remission With Partial Hematological Recovery (CR/CRh) in the Gilteritinib Arm	The CR/CRh rate was defined as the number of participants who achieved either CR or CRh divided by the number of participants in the analysis population. CR: For participants to be classified as being in CR at, they must have had bone marrow regenerating normal hematopoietic cells and achieved a morphologic leukemia-free state and must had an ANC ≥ 1 x 10^9/L and platelet count ≥ 100 x 10^9/L and normal marrow differential with < 5% blasts, and they were RBC and platelet transfusion independent (defined as 1 week without RBC transfusion and 1 week without platelet transfusion). There was no evidence of extramedullary leukemia. CRh: Participants were classified as CRh if they had marrow blasts < 5%, partial hematologic recovery ANC ≥ 0.5 x 10^9/L and platelets ≥ 50 x 10^9/L, no evidence of extramedullary leukemia and could not be classified as CR.	From the date of randomization up to at least 112 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Event-Free Survival (EFS)	EFS: time from randomization date up to date of documented relapse (excluding relapse after PR)/ treatment failure (failure to achieve CR, CRp, CRi /PR) /death, whichever occurred first. Relapse: leukemic blasts in peripheral blood 5/ ≥ 25% blasts in bone marrow (BM) aspirate due to no other cause/reappearance/new appearance of extramedullary leukemia. CR: BM regenerating normal hematopoietic cells, morphologic leukemia-free state, ANC ≥1x10^9/L, platelet count ≥100x10^9/L, normal marrow differential with <5% blasts, and RBC/platelet transfusion independent with no extramedullary leukemia. CRp: achieved CR except incomplete platelet recovery (<100x 0^9/L). CRi: criteria for CR fulfilled except incomplete hematological recovery with residual neutropenia <1x10^9/L with /without complete platelet recovery. PR: BM regenerating normal hematopoietic cells, peripheral recovery, no circulating blasts and decrease of 50% blasts in with total blasts between 5% -25% or, 5% if Auer rods present.	From the date of randomization until the date of documented relapse, treatment failure or death from any cause (median time of follow-up was 17.8 months)
Percentage of Participants With Complete Remission (CR) Rate	The CR rate was defined as the number of participants who achieved the best response of CR divided by the number of participants in the analysis population. CR: For participants to be classified as being in CR, they must have had bone marrow regenerating normal hematopoietic cells and achieved a morphologic leukemia-free state and must had an ANC ≥ 1 x 10^9/L and platelet count ≥ 100 x 10^9/L and normal marrow differential with < 5% blasts, and they were RBC and platelet transfusion independent (defined as 1 week without RBC transfusion and 1 week without platelet transfusion). There was no evidence of extramedullary leukemia.	From the date of randomization up to at least 6 months
Duration of Leukemia-Free Survival (LFS)	LFS: time from the date of first CRc until the date of documented relapse or death for subjects who achieve CRc. For a subject who is not known to have relapsed or died, LFS is censored on the date of last relapse-free disease assessment date. CRc: achieved CR, CRp or CRi. Relapse: leukemic blasts in peripheral blood/ ≥ 25% blasts in bone marrow (BM) aspirate not due to any other cause/reappearance/new appearance of extramedullary leukemia. CR: BM regenerating normal hematopoietic cells, morphologic leukemia-free state, ANC ≥ 1 x 10^9/L, platelet count ≥ 100 x 10^9/L, normal marrow differential with < 5% blasts, and RBC/platelet transfusion independent with no extramedullary leukemia. CRp: achieved CR except incomplete platelet recovery (< 100 x 10^9/L). CRi : criteria for CR fulfilled except incomplete hematological recovery with residual neutropenia < 1 x 10^9/L with /without complete platelet recovery..	From the date of first CRc until the date of documented relapse or death for participants who achieved CRc (median time of follow-up was 17.8 months)
Duration of Remission	Duration of remission included duration of CRc, CR/CRh, CRh, CR, CRi, CRp (defined as the time from the date of first CRc until the date of first documented relapse for participants who achieved CRc, CR/CRh, CRh, CR, CRi, CRp respectively) and duration of response (CRc + PR). CRc: achieved CR, CRp or CRi at the visit. CR: BM regenerating normal hematopoietic cells, morphologic leukemia-free state, ANC ≥1x10^9/L, platelet count ≥100x10^9/L, normal marrow differential with <5% blasts, and RBC/platelet transfusion independent with no extramedullary leukemia. CRp: achieved CR except incomplete platelet recovery (<100x 0^9/L). CRi: criteria for CR fulfilled except incomplete hematological recovery with residual neutropenia <1x10^9/L with /without complete platelet recovery. PR: BM regenerating normal hematopoietic cells, peripheral recovery, no circulating blasts and decrease of 50% blasts in with total blasts between 5% -25% or, 5% if Auer rods present.	From the date of first response until the date of documented relapse for participants who achieved CRc or PR (median time of follow-up was 17.8 months)
Percentage of Participants With Composite Complete Remission (CRc Rate)	CRc rate: Number of participants with best response of CRc (CR,complete remission with incomplete platelet recovery [CRp] or complete remission with incomplete hematologic recovery [CRi]) divided by number of participants in the analysis population. CRc : Participants who achieved CR, CRp or CRi at a post-baseline visit. CR: Participants having bone marrow regenerating normal hematopoietic cells, a morphologic leukemia-free state, an ANC ≥ 1 x 10^9/L and platelet count ≥ 100 x 10^9/L, normal marrow differential with < 5% blasts, and being RBC and platelet transfusion independent with no evidence of extramedullary leukemia at a post-baseline visit. CRp: Participants achieving CR except for incomplete platelet recovery (< 100 x 10^9/L) at a post-baseline visit. CRi : Participants, who fulfilled all criteria for CR except incomplete hematological recovery with residual neutropenia < 1 x 10^9/L with or without complete platelet recovery at a post-baseline visit.	From the date of randomization up to at least 6 months
Percentage of Participants Who Underwent Hematopoietic Stem Cell Transplant	Transplantation rate is defined as the percentage of participants undergoing Hematopoietic stem cell transplant (HSCT) during the study period.	From the date of randomization until end of study (median time of follow-up was 17.8 months)
Change From Baseline in Brief Fatigue Inventory (BFI)	The Brief Fatigue Inventory (BFI) was a screening tool designed to assess the severity and impact of fatigue on daily functioning of participants with cancer during the 24 hours. There are 9 items on the scale. The first three questions asked participants to rate their fatigues on a scale from 0 (no fatigue) - 10 (as bad as you can imagine), with higher scores indicating worse outcome. The remaining six questions asked participants to rate how much fatigue has interfered with their daily activities on a scale from 0 (Does not interfere) to 10 (Completely interferes). A global fatigue score can be obtained by averaging all the items on the BFI. The total score range is 0-10 with a higher BFI fatigue score indicates worse outcome. The global BFI score was calculated only if at least 5 of the 9 items are answered.	Baseline, Cycle 1 Day 8 and Cycle 2 Day 1
Percentage of Participants With Complete Remission (CR) With Partial Hematological Recovery (CRh)	CRh rate was defined as the number of participants who achieved CRh at any of the postbaseline visits and did not have a best response of CR divided by the number of participants in the analysis population. CR: For participants to be classified as being in CR at a post-baseline visit, they must have had bone marrow regenerating normal hematopoietic cells and achieved a morphologic leukemia-free state and must had an ANC ≥ 1 x 10^9/L and platelet count ≥ 100 x 10^9/L and normal marrow differential with < 5% blasts, and they were RBC and platelet transfusion independent (defined as 1 week without RBC transfusion and 1 week without platelet transfusion). There was no evidence of extramedullary leukemia. CRh: At a post baseline visit, participantss were classified as CRh if they had marrow blasts < 5%, partial hematologic recovery ANC ≥ 0.5 x 10^9/L and platelets ≥ 50 x 10^9/L, no evidence of extramedullary leukemia and could not be classified as CR.	From the date of randomization up to at least 6 months
Percentage of Participants Who Achieved Transfusion Conversion and Maintenance	Transfusion conversion & maintenance rate was defined for gilteritinib arm. Participants were classified as transfusion independent if there were no RBC or platelet transfusions within 28 days prior to the first dose to 28 days after the first dose; otherwise they were classified as transfusion dependent at baseline. Participants were considered independent postbaseline if they had 1 consecutive 8 week period without any RBC or platelet transfusion from 29 days after the first dose until the last dose date. For participants who were on treatment ≤ 4 weeks or > 4 weeks but < 12 weeks and there was no RBC or platelet transfusion within postbaseline period, they were considered not evaluable; otherwise, they were considered postbaseline transfusion dependent. Transfusion conversion rate was defined for participants who had evaluable postbaseline transfusion status. Transfusion status (independent vs. dependent) at baseline and postbaseline was reported in a 2 by 2 contingency table.	From 29 days post first dose of study drug until last dose(median treatment duration was (126.00 [4.0, 885.0])
Number of Participants With Treatment Emergent Adverse Events	An AE was defined as any untoward medical occurrence in a participant, temporally associated with the use of study drug, whether or not related to it. It could be any unfavorable/unintended sign (including abnormal laboratory finding), symptom, or disease (new/exacerbated) temporally associated with use of the study drug. A treatment-emergent adverse event (TEAE) : AEs observed after starting administration of study drug (gilteritinib or salvage chemotherapy). Serious AEs (SAEs): AEs which caused death, were life-threatening, resulted in persistent/significant disability/incapacity or disruption of the ability to conduct normal life functions, congenital anomaly, birth defect, required inpatient hospitalization/led to prolongation of hospitalization. Based on national cancer institute common terminology criteria (NCI-CTCAE), AEs were graded as grade 1=mild, grade 2=moderate, grade 3 =severe or medically significant, grade 4 =life threatening, grade 5 =death related to AE	From first dose of study drug up to 30 days after the last dose of study drug (median treatment duration for gilteritinib was (126.00 [4.0, 885.0]) days versus salvage chemotherapy 28.0 [5.0, 217.0] days)

Collaborators and Investigators

• Sponsor: Astellas Pharma Global Development, Inc.
• Investigators: Study Director: Executive Medical Director, Astellas Pharma Global Development, Inc.

Publications and helpful links

General Publications

• Smith CC, Levis MJ, Perl AE, Hill JE, Rosales M, Bahceci E. Molecular profile of FLT3-mutated relapsed/refractory patients with AML in the phase 3 ADMIRAL study of gilteritinib. Blood Adv. 2022 Apr 12;6(7):2144-2155. doi: 10.1182/bloodadvances.2021006489.
• Perl AE, Larson RA, Podoltsev NA, Strickland S, Wang ES, Atallah E, Schiller GJ, Martinelli G, Neubauer A, Sierra J, Montesinos P, Recher C, Yoon SS, Hosono N, Onozawa M, Chiba S, Kim HJ, Hasabou N, Lu Q, Tiu R, Levis MJ. Follow-up of patients with R/R FLT3-mutation-positive AML treated with gilteritinib in the phase 3 ADMIRAL trial. Blood. 2022 Jun 9;139(23):3366-3375. doi: 10.1182/blood.2021011583.
• Ritchie EK, Cella D, Fabbiano F, Pigneux A, Kanda Y, Ivanescu C, Pandya BJ, Shah MV. Patient-reported outcomes from the phase 3 ADMIRAL trial in patients with FLT3-mutated relapsed/refractory AML. Leuk Lymphoma. 2023 May;64(5):938-950. doi: 10.1080/10428194.2023.2186731. Epub 2023 Apr 5.
• Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, Montesinos P, Baer MR, Larson RA, Ustun C, Fabbiano F, Erba HP, Di Stasi A, Stuart R, Olin R, Kasner M, Ciceri F, Chou WC, Podoltsev N, Recher C, Yokoyama H, Hosono N, Yoon SS, Lee JH, Pardee T, Fathi AT, Liu C, Hasabou N, Liu X, Bahceci E, Levis MJ. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N Engl J Med. 2019 Oct 31;381(18):1728-1740. doi: 10.1056/NEJMoa1902688.

Helpful Links

• Link to results and other applicable study documents on the Astellas Clinical Trials website
• Link to plain language summary of the study on the Trial Results Summaries website

Study record dates

Study Major Dates

• Study Start (Actual): October 20, 2015
• Primary Completion (Actual): September 17, 2018
• Study Completion (Actual): February 25, 2025

Study Registration Dates

• First Submitted: April 16, 2015
• First Submitted That Met QC Criteria: April 16, 2015
• First Posted (Estimated): April 21, 2015

Study Record Updates

• Last Update Posted (Estimated): December 4, 2025
• Last Update Submitted That Met QC Criteria: November 27, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: Acute Myeloid Leukemia (AML); gilteritinib; ASP2215; Relapsed Acute Myeloid Leukemia; FLT3 Mutation; Refractory Acute Myeloid Leukemia; XOSPATA®
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia, Myeloid; Leukemia; Hemic and Lymphatic Diseases; Leukemia, Myeloid, Acute; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides; Hydrocarbons; Hydrocarbons, Cyclic; Biological Factors; Carbohydrates; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Glucosides; Glycosides; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Aza Compounds; Nucleosides; Ribonucleosides; Intercellular Signaling Peptides and Proteins; Arabinonucleosides; Anthracyclines; Naphthacenes; Aminoglycosides; Glycoproteins; Glycoconjugates; Daunorubicin; Anthraquinones; Anthrones; Anthracenes; Quinones; Colony-Stimulating Factors; Hematopoietic Cell Growth Factors; Cytokines; Cytarabine; Etoposide; Azacitidine; Mitoxantrone; Idarubicin; fludarabine; Granulocyte Colony-Stimulating Factor; gilteritinib
• Other Study ID Numbers: 2215-CL-0301; 2015-000140-42 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Access to anonymized individual participant level data collected during the study, in addition to study-related supporting documentation, is planned for studies conducted with approved product indications and formulations, as well as products terminated during development. Studies conducted with product indications or formulations that remain active in development are assessed after study completion to determine if Individual Participant Data can be shared. Further details on Astellas' data sharing policy can be found at https://www.clinicaltrials.astellas.com/transparency/.
• IPD Sharing Time Frame: Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable) and is available as long as Astellas has legal authority to provide the data.
• IPD Sharing Access Criteria: Researchers must submit a proposal to conduct a scientifically relevant analysis of the study data. The research proposal is reviewed by an Independent Research Panel. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No