Clincosm LogoSign in Get a demo

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

Sponsor
Astellas Pharma Global Development, Inc. (Industry)
Overall Status
Active, not recruiting
CT.gov ID
NCT02421939
Collaborator
(none)
371
Enrollment
126
Locations
2
Arms
93.3
Anticipated Duration (Months)
2.9
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease Intervention/Treatment Phase
  • 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)
 Phase 3

Detailed Description

Participants considered an adult according to local regulations at the time of signing informed consent may participate in this study. Participants will be randomized in a 2:1 ratio to receive ASP2215 or salvage chemotherapy. Participants 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 participant; 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. Participants will be administered treatment over continuous 28-day cycles.

After treatment discontinuation, participants 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 participant 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 participant's end-of-treatment visit.

Study Design

Study Type:
Interventional
Actual Enrollment :
371 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
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
Actual Study Start Date :
Oct 20, 2015
Actual Primary Completion Date :
Sep 17, 2018
Anticipated Study Completion Date :
Jul 31, 2023

Arms and Interventions

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

    Outcome Measures

    Primary Outcome Measures

    1. Duration of Overall Survival (OS) [From randomization until the data cut-off date of 17 Sep 2018, median time of follow-up for OS was 17.8 months]

      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 by the cutoff date. 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.

    2. Percentage of Participants With Complete Remission and Complete Remission With Partial Hematological Recovery (CR/CRh) in the Gilteritinib Arm [From randomization until the data cut-off date 04 Aug 2017, the 142 patients included in the primary analysis of CR/CRh rate were followed up at least 112 days]

      The CR/CRh rate was defined as the number of participants who achieved either CR or CRh at any of the postbaseline visits divided by the number of participants in the analysis population.

    Secondary Outcome Measures

    1. Duration of Event-Free Survival (EFS) [From randomization until the data cut-off date of 17 Sep 2018, median time of follow-up for OS was 17.8 months]

      EFS was defined as the time from the date of randomization until the date of documented relapse (excluding relapse after PR), treatment failure or death from any cause within 30 days after the last dose of study drug, whichever occurred first (earliest of [relapse date, treatment failure date, death date] - randomization date + 1). If a participant experienced relapse or death within 30 days after the last dose of study drug, the participant was defined as having an EFS event related to either "relapse" or "death", and the event date was the date of relapse or death. For a participant who was not known to have had a relapse or treatment failure or death event, EFS was censored at the date of last relapse-free disease assessment (last relapse-free disease assessment date - randomization date + 1). Data was estimated based on Kaplan-Meier estimates.

    2. Percentage of Participants With Complete Remission (CR) Rate [From randomization until the data cut-off date of 17 Sep 2018, all participants included in the primary analysis of CR rate were followed up at least 6 months]

      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.

    3. Duration of Leukemia-Free Survival (LFS) [From randomization until the data cut-off date of 17 Sep 2018, median time of follow-up for OS was 17.8 months]

      The LFS was defined as the time from the date of first CRc until the date of documented relapse (excluding relapse from PR) or death for participants who achieved CRc (relapse date or death date - first CRc disease assessment date + 1). For a participant who was not known to have relapsed or died, LFS was censored on the date of last relapse-free disease assessment date (last relapse-free disease assessment date - first CRc disease assessment date + 1). For a participant who was not known to have relapsed or died, LFS was censored on the date of last relapse-free disease assessment date (last relapse-free disease assessment date - first CRc disease assessment date + 1).

    4. Duration of Remission [From randomization until the data cut-off date of 17 Sep 2018, median time of follow-up for OS was 17.8 months]

      Duration of remission included duration of composite complete remission (CRc), duration of complete remission (CR)/ complete remission with partial hematologic recovery (CRh), duration of CRh, duration of CR and duration of response (CRc + partial remission (PR). The duration of response was defined as the time from the date of either first CRc or PR until the date of documented relapse (i.e., the date of first NR after CRc or PR) for participants who achieved CRc or PR (relapse date - first CRc or PR disease assessment date + 1). Participants who died without report of relapse were considered nonevents and censored at their last relapse-free disease assessment date (last relapse-free disease assessment date - first CRc or PR disease assessment date + 1). Other participants who did not relapse during the study were considered nonevents and censored at the last relapse-free assessment date. Duration of CR was only applicable to participants with best overall response of CR.

    5. Percentage of Participants With Composite Complete Remission (CRc Rate) [From randomization until the data cut-off date of 17 Sep 2018, median time of follow-up for OS was 17.8 months]

      CRc rate was defined as the number of participants who achieved the best response of CRc (CR,complete remission with incomplete platelet recovery (CRp) or complete remission with incomplete hematologic recovery (CRi) divided by the number of participants in the analysis population.

    6. Percentage of Participants Who Underwent Hematopoietic Stem Cell Transplant [From randomization until the data cut-off date of 17 Sep 2018, median time of follow-up for OS was 17.8 months]

      Transplantation rate is defined as the percentage of participants undergoing Hematopoietic stem cell transplant (HSCT) during the study period.

    7. Change From Baseline in Brief Fatigue Inventory (BFI) [Baseline and cycle 1, day 8 and cycle 2 day 1 (up to data cut off date of 17 Sep 2018)]

      The Brief Fatigue Inventory (BFI) is 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 ask 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 ask 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 global BFI score will be calculated only if at least 5 of the 9 items are answered. A higher BFI fatigue score indicates worse outcome.

    8. Percentage of Participants With Complete Remission (CR) With Partial Hematological Recovery (CRh) [From randomization until the data cut-off date of 17 Sep 2018, median time of follow-up for OS was 17.8 months]

      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.

    9. Percentage of Participants Who Achieved Transfusion Conversion and Maintenance [From randomization until the data cut-off date of 17 Sep 2018, median treatment duration for gilteritinib was (126.00 [4.0, 885.0]) days versus salvage chemotherapy 28.0 [5.0, 217.0] days)]

      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.

    10. Number of Participants With Adverse Events [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)]

      A treatment-emergent adverse event (TEAE) was defined as an AE observed after starting administration of the study drug (gilteritinib or salvage chemotherapy). If the AE occurred on day 1 and the onset check box was marked "Onset after first dose of study drug" or the onset check box was left blank, then the AE was considered treatment emergent. If the AE occurred on day 1 and the onset check box was marked "Onset before first dose of study drug", then the AE was not considered treatment emergent. Majority of salvage chemotherapy participants finished the study by cycle 2 of treatment, the duration of exposure was longer in the gilteritinib arm compared with the salvage chemotherapy arm (126.00 [4.0, 885.0] days versus 28.0 [5.0, 217.0] days). The NCI-CTCAE is defined as National Cancer Institute-Common Terminology Criteria for Adverse Events.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Site US10011 Birmingham Alabama United States 35294-0006
    2 Site US10012 Los Angeles California United States 90095-1752
    3 Site US10076 Orange California United States 92868
    4 Site US10073 San Francisco California United States 94143
    5 Site US10067 New Haven Connecticut United States 06504
    6 Site US10045 Gainesville Florida United States 32610
    7 Site US10081 Atlanta Georgia United States 30342
    8 Site US10006 Chicago Illinois United States 60637
    9 Site US10075 Westwood Kansas United States 66205
    10 Site US10074 Louisville Kentucky United States 40202
    11 Site US10048 New Orleans Louisiana United States 70112
    12 Site US10005 Baltimore Maryland United States 21201
    13 Site US10034 Boston Massachusetts United States 02114
    14 Site US10022 Boston Massachusetts United States 02215
    15 Site US10085 Boston Massachusetts United States 02215
    16 Site US10087 Detroit Michigan United States 48201
    17 Site US10057 Minneapolis Minnesota United States 55455
    18 Site US10023 Lebanon New Hampshire United States 03756-1000
    19 Site US10027 Hackensack New Jersey United States 07601
    20 Site US10077 New Brunswick New Jersey United States 08903
    21 Site US10001 Buffalo New York United States 14263
    22 Site US10037 New York New York United States 10029
    23 Site US10008 New York New York United States 10032
    24 Site US10013 New York New York United States 10065
    25 Site US10072 New York New York United States 10065
    26 Site US10046 Syracuse New York United States 13210
    27 Site US10024 Durham North Carolina United States 27710
    28 Site US10078 Winston-Salem North Carolina United States 27157
    29 Site US10044 Cleveland Ohio United States 44106
    30 Site US10084 Columbus Ohio United States 43210
    31 Site US10058 Oklahoma City Oklahoma United States 73104
    32 Site US10041 Hershey Pennsylvania United States 17033
    33 Site US10010 Philadelphia Pennsylvania United States 19104
    34 Site US10080 Philadelphia Pennsylvania United States 19107
    35 Site US10014 Charleston South Carolina United States 29425
    36 Site US10063 Nashville Tennessee United States 37232-0656
    37 Site US10035 Milwaukee Wisconsin United States 53226
    38 Site BE32002 Yvoir Belgium 5530
    39 Site CA15004 Edmonton Alberta Canada T6G 2G3
    40 Site CA15001 Hamilton Ontario Canada L8V 1C3
    41 Site CA15015 Toronto Ontario Canada M5G 2M9
    42 Site CA15003 Montreal Quebec Canada H1T 2M4
    43 Site FR33013 Brest France 29609
    44 Site FR33002 Le Chesnay Cedex France 78157
    45 Site FR33010 Lille France 59037
    46 Site FR33009 Pessac France 33604
    47 Site FR33014 Rennes France 35033
    48 Site FR33008 Toulouse France 31059
    49 Site DE49009 Dresden Germany 01307
    50 Site DE49011 Leipzig Germany 04103
    51 Site DE49003 Marburg Germany 35043
    52 Site DE49002 Munchen Germany 81737
    53 Site DE49010 Tubingen Germany 72076
    54 Site IL97201 Ashkelon Israel 78278
    55 Site IL97209 Haifa Israel 31096
    56 Site IL97203 Jerusalem Israel 91031
    57 Site IL97210 Jerusalem Israel 91120
    58 Site IL97206 Petah Tikva Israel 49100
    59 Site IL97208 Rehovot Israel 76100
    60 Site IT39005 Bologna Italy 40138
    61 Site IT39010 Brescia Italy 25126
    62 Site IT39001 Milan Italy 20132
    63 Site IT39004 Palermo Italy 90146
    64 Site IT39011 Pavia Italy 27100
    65 Site IT39007 Roma Italy 00189
    66 Site IT39002 Varese Italy 21100
    67 Site JP81002 Nagoya Aichi Japan
    68 Site JP81010 Narita Chiba Japan
    69 Site JP81026 Yoshida-gun Fukui Japan
    70 Site JP81016 Sapporo Hokkaido Japan
    71 Site JP81018 Kobe Hyogo Japan
    72 Site JP81017 Tsukuba Ibaraki Japan
    73 Site JP81009 Isehara Kanagawa Japan
    74 Site JP81006 Yokohama Kanagawa Japan
    75 Site JP81012 Sendai Miyagi Japan
    76 Site JP81007 Kurashiki Okayama Japan
    77 Site JP81014 Osakasayama Osaka Japan
    78 Site JP81020 Kawagoe Saitama Japan
    79 Site JP81027 Shimotsuke Tochigi Japan
    80 Site JP81005 Chuo-ku Tokyo Japan
    81 Site JP81004 Shinagawa-ku Tokyo Japan
    82 Site JP81022 Shinjuku-ku Tokyo Japan
    83 Site JP81023 Akita Japan
    84 Site JP81021 Aomori Japan
    85 Site JP81013 Kumamoto Japan
    86 Site JP81025 Kyoto Japan
    87 Site JP81008 Nagasaki Japan
    88 Site JP81024 Okayama Japan
    89 Site JP81011 Osaka Japan
    90 Site KR82005 Suwon-si Gyeonggi-do Korea, Republic of 443380
    91 Site KR82010 Busan Korea, Republic of 602739
    92 Site KR82009 Goyang Korea, Republic of 602-715
    93 Site KR82003 Jeollanam-do Korea, Republic of 519-809
    94 Site KR82007 Seoul Korea, Republic of 110-744
    95 Site KR82004 Seoul Korea, Republic of 120-752
    96 Site KR82001 Seoul Korea, Republic of 135710
    97 Site KR82002 Seoul Korea, Republic of 137701
    98 Site KR82008 Seoul Korea, Republic of 138-736
    99 Site KR82011 Seoul Korea, Republic of 156-707
    100 Site PL48002 Gdansk Poland 80-952
    101 Site PL48005 Opole Poland 45-372
    102 Site PL48004 Wroclaw Poland 50-367
    103 Site ES34009 Badalona Spain 08025
    104 Site ES34011 Barcelona Spain 08035
    105 Site ES34012 Barcelona Spain 08036
    106 Site ES34010 Barcelona Spain 08916
    107 Site ES34016 Girona Spain 17007
    108 Site ES34005 L'Hospitalet de Llobregat Spain 08907
    109 Site ES34014 Salamanca Spain 37007
    110 Site ES34017 Valencia Spain 46026
    111 Site TW88606 Kaohsiung Taiwan 112
    112 Site TW88604 Kaohsiung Taiwan 83301
    113 Site TW88609 Taichung City Taiwan 40705
    114 Site TW88608 Taichung Taiwan 404
    115 Site TW88601 Tainan Taiwan 704
    116 Site TW88603 Taipei Taiwan 10002
    117 Site TW88610 Taipei Taiwan 10449
    118 Site TW88611 Taipei Taiwan 112
    119 Site TW88602 Taipei Taiwan 114
    120 Site TW88605 Taoyuan Taiwan 33305
    121 Site TR90001 Ankara Turkey 06100
    122 Site TR90004 Ankara Turkey 06500
    123 Site GB44014 Bournemouth United Kingdom BH7 7DW
    124 Site GB44013 Harrow United Kingdom HA1 3UJ
    125 Site GB44003 Manchester United Kingdom M13 9WL
    126 Site GB44015 Plymouth United Kingdom PL6 8DH

    Sponsors and Collaborators

    • Astellas Pharma Global Development, Inc.

    Investigators

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

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Astellas Pharma Global Development, Inc.
    ClinicalTrials.gov Identifier:
    NCT02421939
    Other Study ID Numbers:
    • 2215-CL-0301
    • 2015-000140-42
    First Posted:
    Apr 21, 2015
    Last Update Posted:
    Aug 11, 2022
    Last Verified:
    Aug 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Astellas Pharma Global Development, Inc.
    ASP2215
    Relapsed Acute Myeloid Leukemia
    FLT3 Mutation
    gilteritinib
    Refractory Acute Myeloid Leukemia
    Acute Myeloid Leukemia (AML)
    XOSPATA®
    Additional relevant MeSH terms:
    Leukemia
    Leukemia, Myeloid
    Leukemia, Myeloid, Acute
    Cytarabine
    Fludarabine
    Etoposide
    Azacitidine
    Mitoxantrone
    Idarubicin
    Lenograstim

    Study Results

    Participant Flow

    Recruitment Details Participants were recruited from approximately 140 centers in North America, Europe, Asia and the rest of the world and randomized in a 2:1 ratio to receive gilteritinib or salvage chemotherapy. Participants had FMS-like tyrosine kinase 3 (FLT3) mutations and relapsed or refractory acute myeloid leukemia (AML) after first-line therapy.
    Pre-assignment Detail Participants entered the screening period up to 14 days prior to the start of treatment. Prior to randomization, the investigator preselected a salvage chemotherapy for each participant. The randomization was stratified by response to first-line AML therapy and preselected salvage chemotherapy. Treatment was given over continuous 28-day cycles.
    Arm/Group Title Gilteritinib Salvage Chemotherapy
    Arm/Group Description 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. 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.
    Period Title: Overall Study
    STARTED 247 124
    Treated 246 109
    COMPLETED 38 0
    NOT COMPLETED 209 124

    Baseline Characteristics

    Arm/Group Title Gilteritinib Salvage Chemotherapy Total
    Arm/Group Description 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. 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. Total of all reporting groups
    Overall Participants 247 124 371
    Age (Years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Years]
    59
    (14.6)
    57.6
    (14.8)
    58.5
    (14.7)
    Sex: Female, Male (Count of Participants)
    Female
    131
    53%
    70
    56.5%
    201
    54.2%
    Male
    116
    47%
    54
    43.5%
    170
    45.8%
    Race/Ethnicity, Customized (Count of Participants)
    WHITE
    145
    58.7%
    75
    60.5%
    220
    59.3%
    ASIAN
    69
    27.9%
    33
    26.6%
    102
    27.5%
    BLACK OR AFRICAN AMERICAN
    14
    5.7%
    7
    5.6%
    21
    5.7%
    NATIVE HAWAIIAN OR OTHER PACIFIC ISLANDER
    1
    0.4%
    0
    0%
    1
    0.3%
    AMERICAN INDIAN OR ALASKA NATIVE
    0
    0%
    0
    0%
    0
    0%
    UNKNOWN
    4
    1.6%
    4
    3.2%
    8
    2.2%
    OTHER
    5
    2%
    1
    0.8%
    6
    1.6%
    MISSING
    9
    3.6%
    4
    3.2%
    13
    3.5%
    Ethnicity (Count of Participants)
    NOT HISPANIC OR LATINO
    221
    89.5%
    116
    93.5%
    337
    90.8%
    HISPANIC OR LATINO
    12
    4.9%
    2
    1.6%
    14
    3.8%
    UNKNOWN
    3
    1.2%
    2
    1.6%
    5
    1.3%
    MISSING
    11
    4.5%
    4
    3.2%
    15
    4%
    Cytogenic Risk Status (Count of Participants)
    INTERMEDIATE
    182
    73.7%
    89
    71.8%
    271
    73%
    UNFAVORABLE
    26
    10.5%
    11
    8.9%
    37
    10%
    FAVORABLE
    4
    1.6%
    1
    0.8%
    5
    1.3%
    OTHER
    35
    14.2%
    23
    18.5%
    58
    15.6%
    Baseline Eastern Cooperative Oncology Group (ECOG) (Count of Participants)
    0-1
    206
    83.4%
    105
    84.7%
    311
    83.8%
    >=2
    41
    16.6%
    19
    15.3%
    60
    16.2%
    FLT3 Mutation Status by Central Testing by FLT3 CDx (Count of Participants)
    FLT3-ITD Alone
    215
    87%
    113
    91.1%
    328
    88.4%
    FLT3-TKD Alone
    21
    8.5%
    10
    8.1%
    31
    8.4%
    FLT3-ITD and FLT3-TKD
    7
    2.8%
    0
    0%
    7
    1.9%
    Others (Unknown/Missing/Negative)
    4
    1.6%
    1
    0.8%
    5
    1.3%
    Prior Use of FLT3 Inhibitor (Count of Participants)
    No
    215
    87%
    110
    88.7%
    325
    87.6%
    Yes
    32
    13%
    14
    11.3%
    46
    12.4%
    Region (Count of Participants)
    NORTH AMERICA
    114
    46.2%
    52
    41.9%
    166
    44.7%
    EUROPE
    68
    27.5%
    43
    34.7%
    111
    29.9%
    ASIA
    65
    26.3%
    29
    23.4%
    94
    25.3%
    Baseline Body Surface Area (BSA) (m^2) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [m^2]
    1.815
    (0.281)
    1.777
    (0.257)
    1.8
    (0.272)
    Baseline Height (centimeter (cm)) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [centimeter (cm)]
    167.25
    (10.31)
    166.39
    (10.63)
    166.95
    (10.41)
    Baseline Weight (kilogram (kg)) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [kilogram (kg)]
    72.79
    (20.47)
    69.91
    (19.73)
    71.82
    (20.25)
    Response to First Line Therapy (Count of Participants)
    Primary refractory without HSCT
    98
    39.7%
    48
    38.7%
    146
    39.4%
    Relapse within 6 months after CRc and no HSCT
    67
    27.1%
    34
    27.4%
    101
    27.2%
    Relapse after 6 months after CRc and no HSCT
    34
    13.8%
    17
    13.7%
    51
    13.7%
    Relapse within 6 months after allogeneic HSCT
    31
    12.6%
    17
    13.7%
    48
    12.9%
    Relapse after 6 months after allogeneic HSCT
    17
    6.9%
    8
    6.5%
    25
    6.7%
    Preselected Salvage Chemotherapy (Count of Participants)
    High intensity chemotherapy
    149
    60.3%
    75
    60.5%
    224
    60.4%
    Low intensity chemotherapy
    98
    39.7%
    49
    39.5%
    147
    39.6%
    Response to First Line Therapy-Preselected Salvage Chemotherapy (Count of Participants)
    Primary refractory w/o HSCT, high intensity (IT)
    57
    23.1%
    28
    22.6%
    85
    22.9%
    Primary refractory w/o HSCT, low IT
    41
    16.6%
    20
    16.1%
    61
    16.4%
    Relapse w/I 6 mths after CRc and no HSCT, high IT
    40
    16.2%
    21
    16.9%
    61
    16.4%
    Relapse w/I 6 mths after CRc and no HSCT low IT
    27
    10.9%
    13
    10.5%
    40
    10.8%
    Relapse after 6 mths after CRc and no HSCT high IT
    23
    9.3%
    11
    8.9%
    34
    9.2%
    Relapse w/I 6 mths after allogeneic HSCT low IT
    16
    6.5%
    9
    7.3%
    25
    6.7%
    Relapse w/I 6 mths after allogeneic HSCT high IT
    15
    6.1%
    8
    6.5%
    23
    6.2%
    Relapse after 6 mths after allogeneic HSCT high IT
    14
    5.7%
    7
    5.6%
    21
    5.7%
    Relapse after 6 mths after CRc and no HSCT low IT
    11
    4.5%
    6
    4.8%
    17
    4.6%
    Relapse after 6 mths after allogeneic HSCT low IT
    3
    1.2%
    1
    0.8%
    4
    1.1%

    Outcome Measures

    1. Primary Outcome
    Title Duration of Overall Survival (OS)
    Description 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 by the cutoff date. 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.
    Time Frame From randomization until the data cut-off date of 17 Sep 2018, median time of follow-up for OS was 17.8 months

    Outcome Measure Data

    Analysis Population Description
    The analysis population was the Intention to Treatment (ITT) which consisted of all randomized participants.
    Arm/Group Title Gilteritinib Salvage Chemotherapy
    Arm/Group Description 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. 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.
    Measure Participants 247 124
    Median (95% Confidence Interval) [Months]
    9.3
    5.6
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Gilteritinib, Salvage Chemotherapy
    Comments Stratified analysis where tratification factors were response to first-line AML therapy and preselected salvage chemotherapy per IRT.
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0004
    Comments 1-sided P-value
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.637
    Confidence Interval (2-Sided) 95%
    0.490 to 0.830
    Parameter Dispersion Type:
    Value:
    Estimation Comments Based on Cox proportional hazards model. Assuming proportional hazards, an HR of < 1 indicates a reduction in the hazard rate in favor of the gilteritinib arm
    2. Primary Outcome
    Title Percentage of Participants With Complete Remission and Complete Remission With Partial Hematological Recovery (CR/CRh) in the Gilteritinib Arm
    Description The CR/CRh rate was defined as the number of participants who achieved either CR or CRh at any of the postbaseline visits divided by the number of participants in the analysis population.
    Time Frame From randomization until the data cut-off date 04 Aug 2017, the 142 patients included in the primary analysis of CR/CRh rate were followed up at least 112 days

    Outcome Measure Data

    Analysis Population Description
    The analysis population was the response analysis set (RAS) which consisted of participants who were who were at least 112 days past the first dose of gilteritinib or randomization (for participants who did not receive gilteritinib). The participants were analyzed based on the randomized treatments.
    Arm/Group Title Gilteritinib
    Arm/Group Description 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.
    Measure Participants 142
    CR/CRh rate
    28.2
    11.4%
    CR rate
    19.0
    7.7%
    CRh rate
    9.2
    3.7%
    3. Secondary Outcome
    Title Duration of Event-Free Survival (EFS)
    Description EFS was defined as the time from the date of randomization until the date of documented relapse (excluding relapse after PR), treatment failure or death from any cause within 30 days after the last dose of study drug, whichever occurred first (earliest of [relapse date, treatment failure date, death date] - randomization date + 1). If a participant experienced relapse or death within 30 days after the last dose of study drug, the participant was defined as having an EFS event related to either "relapse" or "death", and the event date was the date of relapse or death. For a participant who was not known to have had a relapse or treatment failure or death event, EFS was censored at the date of last relapse-free disease assessment (last relapse-free disease assessment date - randomization date + 1). Data was estimated based on Kaplan-Meier estimates.
    Time Frame From randomization until the data cut-off date of 17 Sep 2018, median time of follow-up for OS was 17.8 months

    Outcome Measure Data

    Analysis Population Description
    The analysis population was the ITT.
    Arm/Group Title Gilteritinib Salvage Chemotherapy
    Arm/Group Description 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. 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.
    Measure Participants 189 62
    Median (95% Confidence Interval) [Months]
    2.8
    0.7
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Gilteritinib, Salvage Chemotherapy
    Comments Stratification factors were response to first-line AML therapy and preselected salvage chemotherapy per IRT
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0415
    Comments 1-sided P-value
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.793
    Confidence Interval (2-Sided) 95%
    0.577 to 1.089
    Parameter Dispersion Type:
    Value:
    Estimation Comments Based on the Cox proportional hazards model. Assuming proportional hazards, an HR of < 1 indicates a reduction in the hazard rate in favor of the gilteritinib arm.
    4. Secondary Outcome
    Title Percentage of Participants With Complete Remission (CR) Rate
    Description 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.
    Time Frame From randomization until the data cut-off date of 17 Sep 2018, all participants included in the primary analysis of CR rate were followed up at least 6 months

    Outcome Measure Data

    Analysis Population Description
    The analysis population was the ITT.
    Arm/Group Title Gilteritinib Salvage Chemotherapy
    Arm/Group Description 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. 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.
    Measure Participants 247 124
    Number (95% Confidence Interval) [Percentage of participants]
    21.1
    8.5%
    10.5
    8.5%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Gilteritinib, Salvage Chemotherapy
    Comments Based on stratified Cochran-Mantel-Haenszel test. Stratification factors were response to first-line AML therapy and preselected salvage chemotherapy per IRT. Treatment difference = gilteritinib -chemotherapy.
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0106
    Comments Stratified P-value
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Adjusted Treatment Difference
    Estimated Value 10.6
    Confidence Interval (2-Sided) 95%
    2.8 to 18.4
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    5. Secondary Outcome
    Title Duration of Leukemia-Free Survival (LFS)
    Description The LFS was defined as the time from the date of first CRc until the date of documented relapse (excluding relapse from PR) or death for participants who achieved CRc (relapse date or death date - first CRc disease assessment date + 1). For a participant who was not known to have relapsed or died, LFS was censored on the date of last relapse-free disease assessment date (last relapse-free disease assessment date - first CRc disease assessment date + 1). For a participant who was not known to have relapsed or died, LFS was censored on the date of last relapse-free disease assessment date (last relapse-free disease assessment date - first CRc disease assessment date + 1).
    Time Frame From randomization until the data cut-off date of 17 Sep 2018, median time of follow-up for OS was 17.8 months

    Outcome Measure Data

    Analysis Population Description
    The analysis population was the ITT, with participants with best response of CRc.
    Arm/Group Title Gilteritinib Salvage Chemotherapy
    Arm/Group Description 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. 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.
    Measure Participants 134 27
    Median (95% Confidence Interval) [Months]
    4.4
    6.7
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Gilteritinib, Salvage Chemotherapy
    Comments The LFS was analyzed for participants who achieved remission using the stratified log-rank test with strata to control for response to first-line AML therapy and preselected salvage chemotherapy. Duration of LFS was based on Kaplan-Meier estimates.
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.6654
    Comments Unstratified p-value
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.889
    Confidence Interval (2-Sided) 95%
    0.506 to 1.563
    Parameter Dispersion Type:
    Value:
    Estimation Comments Based on the Cox proportional hazards model. Assuming proportional hazards, an HR of < 1 indicates a reduction in the hazard rate in favor of the gilteritinib arm.
    6. Secondary Outcome
    Title Duration of Remission
    Description Duration of remission included duration of composite complete remission (CRc), duration of complete remission (CR)/ complete remission with partial hematologic recovery (CRh), duration of CRh, duration of CR and duration of response (CRc + partial remission (PR). The duration of response was defined as the time from the date of either first CRc or PR until the date of documented relapse (i.e., the date of first NR after CRc or PR) for participants who achieved CRc or PR (relapse date - first CRc or PR disease assessment date + 1). Participants who died without report of relapse were considered nonevents and censored at their last relapse-free disease assessment date (last relapse-free disease assessment date - first CRc or PR disease assessment date + 1). Other participants who did not relapse during the study were considered nonevents and censored at the last relapse-free assessment date. Duration of CR was only applicable to participants with best overall response of CR.
    Time Frame From randomization until the data cut-off date of 17 Sep 2018, median time of follow-up for OS was 17.8 months

    Outcome Measure Data

    Analysis Population Description
    The analysis population was the ITT, Duration of CR was only applicable to participants with best overall response of CR.
    Arm/Group Title Gilteritinib Salvage Chemotherapy
    Arm/Group Description 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. 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.
    Measure Participants 52 13
    Median (95% Confidence Interval) [Months]
    14.8
    1.8
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Gilteritinib, Salvage Chemotherapy
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.1189
    Comments Unstratified
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.206
    Confidence Interval (2-Sided) 95%
    0.022 to 1.886
    Parameter Dispersion Type:
    Value:
    Estimation Comments Based on Cox proportional hazards model. Assuming proportional hazards, a hazard ratio < 1 indicates a reduction in hazard rate in favor of gilteritinib arm.
    7. Secondary Outcome
    Title Percentage of Participants With Composite Complete Remission (CRc Rate)
    Description CRc rate was defined as the number of participants who achieved the best response of CRc (CR,complete remission with incomplete platelet recovery (CRp) or complete remission with incomplete hematologic recovery (CRi) divided by the number of participants in the analysis population.
    Time Frame From randomization until the data cut-off date of 17 Sep 2018, median time of follow-up for OS was 17.8 months

    Outcome Measure Data

    Analysis Population Description
    The analysis population was the ITT.
    Arm/Group Title Gilteritinib Salvage Chemotherapy
    Arm/Group Description 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. 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.
    Measure Participants 247 124
    Number (95% Confidence Interval) [Percentage of participants]
    54.3
    22%
    21.8
    17.6%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Gilteritinib, Salvage Chemotherapy
    Comments Treatment difference = gilteritinib - chemotherapy. The 95% CIs were asymptotic confidence limits using the normal approximation to the binomial distribution.
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Unstratified 2-sided P-value
    Method 2-sided Fisher's exact test
    Comments
    Method of Estimation Estimation Parameter Treatment difference
    Estimated Value 32.5
    Confidence Interval (2-Sided) 95%
    22.3 to 42.6
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    8. Secondary Outcome
    Title Percentage of Participants Who Underwent Hematopoietic Stem Cell Transplant
    Description Transplantation rate is defined as the percentage of participants undergoing Hematopoietic stem cell transplant (HSCT) during the study period.
    Time Frame From randomization until the data cut-off date of 17 Sep 2018, median time of follow-up for OS was 17.8 months

    Outcome Measure Data

    Analysis Population Description
    The analysis population is the ITT.
    Arm/Group Title Gilteritinib Salvage Chemotherapy
    Arm/Group Description 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. 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.
    Measure Participants 247 124
    Number (95% Confidence Interval) [Percentage of participants]
    25.5
    10.3%
    15.3
    12.3%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Gilteritinib, Salvage Chemotherapy
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0333
    Comments Unstratified 2-sided P-value.
    Method 2-sided Fisher's exact test
    Comments Treatment difference = gilteritinib - chemotherapy.
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value 10.2
    Confidence Interval (2-Sided) 95%
    1.2 to 19.1
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    9. Secondary Outcome
    Title Change From Baseline in Brief Fatigue Inventory (BFI)
    Description The Brief Fatigue Inventory (BFI) is 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 ask 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 ask 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 global BFI score will be calculated only if at least 5 of the 9 items are answered. A higher BFI fatigue score indicates worse outcome.
    Time Frame Baseline and cycle 1, day 8 and cycle 2 day 1 (up to data cut off date of 17 Sep 2018)

    Outcome Measure Data

    Analysis Population Description
    The analysis population was the ITT, with participants with data at baseline.
    Arm/Group Title Gilteritinib Salvage Chemotherapy
    Arm/Group Description 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. 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.
    Measure Participants 227 97
    Cycle 1 day 8 (C1D8)
    -0.4
    (2.1)
    1.0
    (2.3)
    Cycle 2 day 1 (C2D1)
    0.0
    (2.6)
    0.4
    (2.8)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Gilteritinib, Salvage Chemotherapy
    Comments C1D8: Using analysis of covariance (ANCOVA) including treatment as a fixed factor, baseline score, response to first-line AML therapy and preselected salvage chemotherapy per IRT as covariates. Least Square (LS) Mean difference was estimated using chemotherapy as control.
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0000
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value -1.2567
    Confidence Interval () %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Gilteritinib, Salvage Chemotherapy
    Comments C2D1: Using analysis of covariance (ANCOVA) including treatment as a fixed factor, baseline score, response to first-line AML therapy and preselected salvage chemotherapy per IRT as covariates. Least Square (LS) Mean difference was estimated using chemotherapy as control.
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.8037
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 0.1574
    Confidence Interval () %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    10. Secondary Outcome
    Title Percentage of Participants With Complete Remission (CR) With Partial Hematological Recovery (CRh)
    Description 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.
    Time Frame From randomization until the data cut-off date of 17 Sep 2018, median time of follow-up for OS was 17.8 months

    Outcome Measure Data

    Analysis Population Description
    The analysis population was the ITT.
    Arm/Group Title Gilteritinib Salvage Chemotherapy
    Arm/Group Description 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. 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.
    Measure Participants 247 124
    Number (95% Confidence Interval) [Percentage of participants]
    34.0
    13.8%
    15.3
    12.3%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Gilteritinib, Salvage Chemotherapy
    Comments Based on a stratified Cochran-Mantel-Haenszel test. Stratification factors were response to first-line AML therapy and preselected salvage chemotherapy per IRT. Pooled strata were used as shown in Table 12.3.3.2. Treatment differences were adjusted based on pooled strata. Treatment difference = gilteritinib 120 mg - chemotherapy.
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0171
    Comments Stratified 1-sided P-value.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Adjusted Treatment Difference,
    Estimated Value 18.6
    Confidence Interval (2-Sided) 95%
    9.8 to 27.4
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    11. Secondary Outcome
    Title Percentage of Participants Who Achieved Transfusion Conversion and Maintenance
    Description 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.
    Time Frame From randomization until the data cut-off date of 17 Sep 2018, median treatment duration for gilteritinib was (126.00 [4.0, 885.0]) days versus salvage chemotherapy 28.0 [5.0, 217.0] days)

    Outcome Measure Data

    Analysis Population Description
    The analysis population was the ITT, with participants who had evaluable postbaseline transfusion status.
    Arm/Group Title Gilteritinib
    Arm/Group Description 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.
    Measure Participants 246
    Baseline Independent/ Post baseline Independent
    59.2
    24%
    Baseline Independent/Post baseline Dependent
    24.5
    9.9%
    Baseline Independent/Post baseline Not Evaluable
    16.3
    6.6%
    Baseline Dependent/Post baseline Independent
    34.5
    14%
    Baseline Dependent/Post baseline Dependent
    55.8
    22.6%
    Baseline Dependent/Post baseline Not Evaluable
    9.6
    3.9%
    12. Secondary Outcome
    Title Number of Participants With Adverse Events
    Description A treatment-emergent adverse event (TEAE) was defined as an AE observed after starting administration of the study drug (gilteritinib or salvage chemotherapy). If the AE occurred on day 1 and the onset check box was marked "Onset after first dose of study drug" or the onset check box was left blank, then the AE was considered treatment emergent. If the AE occurred on day 1 and the onset check box was marked "Onset before first dose of study drug", then the AE was not considered treatment emergent. Majority of salvage chemotherapy participants finished the study by cycle 2 of treatment, the duration of exposure was longer in the gilteritinib arm compared with the salvage chemotherapy arm (126.00 [4.0, 885.0] days versus 28.0 [5.0, 217.0] days). The NCI-CTCAE is defined as National Cancer Institute-Common Terminology Criteria for Adverse Events.
    Time Frame 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)

    Outcome Measure Data

    Analysis Population Description
    The analysis population was the safety analysis set (SAF), which consisted of participants who received who received at least 1 dose of study drug (gilteritinib or salvage chemotherapy).
    Arm/Group Title Gilteritinib Salvage Chemotherapy
    Arm/Group Description 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. 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.
    Measure Participants 246 109
    Drug-related TEAE
    206
    83.4%
    71
    57.3%
    Serious TEAE
    205
    83%
    34
    27.4%
    Drug-related serious TEAE
    88
    35.6%
    16
    12.9%
    TEAE leading to death
    71
    28.7%
    16
    12.9%
    Drug-related TEAE leading to death
    10
    4%
    5
    4%
    TEAE leading to withdrawal of treatment
    58
    23.5%
    13
    10.5%
    Drug-related TEAE lead withdrawal of treatment
    27
    10.9%
    5
    4%
    NCI-CTCAE Grade 3 or higher TEAE
    236
    95.5%
    94
    75.8%
    Drug-related Grade 3 or higher TEAE
    153
    61.9%
    57
    46%
    Death
    170
    68.8%
    81
    65.3%

    Adverse Events

    Time Frame 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)
    Adverse Event Reporting Description
    Arm/Group Title Gilteritinib Salvage Chemotherapy
    Arm/Group Description 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. 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.
    All Cause Mortality
    Gilteritinib Salvage Chemotherapy
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 170/246 (69.1%) 81/109 (74.3%)
    Serious Adverse Events
    Gilteritinib Salvage Chemotherapy
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 205/246 (83.3%) 34/109 (31.2%)
    Blood and lymphatic system disorders
    Anaemia 8/246 (3.3%) 10 0/109 (0%) 0
    Aplasia pure red cell 1/246 (0.4%) 1 0/109 (0%) 0
    Autoimmune haemolytic anaemia 1/246 (0.4%) 3 0/109 (0%) 0
    Bone marrow failure 1/246 (0.4%) 2 0/109 (0%) 0
    Disseminated intravascular coagulation 2/246 (0.8%) 2 0/109 (0%) 0
    Febrile neutropenia 76/246 (30.9%) 112 9/109 (8.3%) 15
    Haemolytic anaemia 2/246 (0.8%) 2 0/109 (0%) 0
    Leukocytosis 2/246 (0.8%) 2 1/109 (0.9%) 1
    Neutropenia 3/246 (1.2%) 4 1/109 (0.9%) 1
    Pancytopenia 4/246 (1.6%) 4 0/109 (0%) 0
    Thrombocytopenia 4/246 (1.6%) 4 1/109 (0.9%) 1
    Cardiac disorders
    Acute coronary syndrome 1/246 (0.4%) 1 0/109 (0%) 0
    Angina pectoris 1/246 (0.4%) 1 0/109 (0%) 0
    Atrial fibrillation 1/246 (0.4%) 1 0/109 (0%) 0
    Cardiac arrest 4/246 (1.6%) 5 0/109 (0%) 0
    Cardiac failure 3/246 (1.2%) 3 0/109 (0%) 0
    Cardiac failure congestive 2/246 (0.8%) 3 0/109 (0%) 0
    Cardio-respiratory arrest 1/246 (0.4%) 1 0/109 (0%) 0
    Myocardial infarction 1/246 (0.4%) 1 0/109 (0%) 0
    Myocarditis 2/246 (0.8%) 2 0/109 (0%) 0
    Pericardial effusion 3/246 (1.2%) 5 0/109 (0%) 0
    Pericardial haemorrhage 1/246 (0.4%) 1 0/109 (0%) 0
    Pericarditis 3/246 (1.2%) 3 0/109 (0%) 0
    Sinus tachycardia 1/246 (0.4%) 1 1/109 (0.9%) 1
    Supraventricular tachycardia 2/246 (0.8%) 2 0/109 (0%) 0
    Congenital, familial and genetic disorders
    Hamartoma 1/246 (0.4%) 1 0/109 (0%) 0
    Eye disorders
    Ocular hyperaemia 1/246 (0.4%) 1 0/109 (0%) 0
    Vision blurred 1/246 (0.4%) 1 0/109 (0%) 0
    Gastrointestinal disorders
    Abdominal pain 2/246 (0.8%) 2 0/109 (0%) 0
    Anal fissure 1/246 (0.4%) 2 0/109 (0%) 0
    Colitis 2/246 (0.8%) 3 0/109 (0%) 0
    Diarrhoea 10/246 (4.1%) 13 0/109 (0%) 0
    Diarrhoea haemorrhagic 1/246 (0.4%) 1 0/109 (0%) 0
    Dysphagia 1/246 (0.4%) 1 0/109 (0%) 0
    Enterocolitis 1/246 (0.4%) 1 0/109 (0%) 0
    Gastritis 1/246 (0.4%) 1 0/109 (0%) 0
    Gastrointestinal haemorrhage 1/246 (0.4%) 1 1/109 (0.9%) 2
    Gastrooesophageal reflux disease 1/246 (0.4%) 1 0/109 (0%) 0
    Haematemesis 1/246 (0.4%) 1 0/109 (0%) 0
    Haematochezia 1/246 (0.4%) 2 0/109 (0%) 0
    Haemorrhoids 2/246 (0.8%) 2 0/109 (0%) 0
    Ileus 1/246 (0.4%) 1 0/109 (0%) 0
    Intestinal ischaemia 1/246 (0.4%) 1 0/109 (0%) 0
    Large intestine perforation 2/246 (0.8%) 4 0/109 (0%) 0
    Lower gastrointestinal haemorrhage 1/246 (0.4%) 1 0/109 (0%) 0
    Melaena 1/246 (0.4%) 1 1/109 (0.9%) 1
    Mouth haemorrhage 2/246 (0.8%) 2 0/109 (0%) 0
    Nausea 2/246 (0.8%) 2 0/109 (0%) 0
    Pancreatitis 3/246 (1.2%) 4 0/109 (0%) 0
    Proctalgia 1/246 (0.4%) 1 0/109 (0%) 0
    Stomatitis 1/246 (0.4%) 1 1/109 (0.9%) 1
    Stomatitis necrotising 1/246 (0.4%) 1 0/109 (0%) 0
    Tongue haematoma 1/246 (0.4%) 1 0/109 (0%) 0
    Vomiting 1/246 (0.4%) 1 0/109 (0%) 0
    General disorders
    Asthenia 3/246 (1.2%) 3 0/109 (0%) 0
    Chills 1/246 (0.4%) 1 0/109 (0%) 0
    Death 1/246 (0.4%) 1 0/109 (0%) 0
    Face oedema 2/246 (0.8%) 2 0/109 (0%) 0
    Fatigue 4/246 (1.6%) 4 1/109 (0.9%) 1
    Generalised oedema 1/246 (0.4%) 1 0/109 (0%) 0
    Influenza like illness 1/246 (0.4%) 1 0/109 (0%) 0
    Mucosal haemorrhage 1/246 (0.4%) 1 0/109 (0%) 0
    Mucosal inflammation 1/246 (0.4%) 1 0/109 (0%) 0
    Multiple organ dysfunction syndrome 1/246 (0.4%) 1 1/109 (0.9%) 1
    Oedema 1/246 (0.4%) 1 0/109 (0%) 0
    Pyrexia 32/246 (13%) 43 1/109 (0.9%) 2
    Hepatobiliary disorders
    Cholecystitis 2/246 (0.8%) 2 0/109 (0%) 0
    Drug-induced liver injury 1/246 (0.4%) 1 0/109 (0%) 0
    Hepatic function abnormal 1/246 (0.4%) 7 0/109 (0%) 0
    Hepatotoxicity 1/246 (0.4%) 1 0/109 (0%) 0
    Immune system disorders
    Acute graft versus host disease in intestine 1/246 (0.4%) 2 0/109 (0%) 0
    Anaphylactic reaction 3/246 (1.2%) 3 0/109 (0%) 0
    Drug hypersensitivity 1/246 (0.4%) 2 0/109 (0%) 0
    Graft versus host disease 1/246 (0.4%) 1 0/109 (0%) 0
    Graft versus host disease in gastrointestinal tract 1/246 (0.4%) 1 0/109 (0%) 0
    Infections and infestations
    Abscess bacterial 1/246 (0.4%) 1 0/109 (0%) 0
    Adenoviral upper respiratory infection 1/246 (0.4%) 1 0/109 (0%) 0
    Anal abscess 0/246 (0%) 0 1/109 (0.9%) 1
    Bacteraemia 10/246 (4.1%) 11 1/109 (0.9%) 1
    Bacterial colitis 1/246 (0.4%) 2 0/109 (0%) 0
    Bacterial infection 1/246 (0.4%) 1 0/109 (0%) 0
    Bacterial sepsis 1/246 (0.4%) 1 0/109 (0%) 0
    Bronchitis 4/246 (1.6%) 5 0/109 (0%) 0
    Bronchopulmonary aspergillosis 2/246 (0.8%) 4 0/109 (0%) 0
    Catheter site infection 1/246 (0.4%) 1 0/109 (0%) 0
    Cellulitis 6/246 (2.4%) 6 0/109 (0%) 0
    Clostridium difficile colitis 2/246 (0.8%) 2 0/109 (0%) 0
    Clostridium difficile infection 4/246 (1.6%) 4 0/109 (0%) 0
    Cytomegalovirus infection 1/246 (0.4%) 2 0/109 (0%) 0
    Device related infection 4/246 (1.6%) 4 1/109 (0.9%) 1
    Diarrhoea infectious 1/246 (0.4%) 1 0/109 (0%) 0
    Endocarditis 1/246 (0.4%) 2 0/109 (0%) 0
    Enterococcal bacteraemia 1/246 (0.4%) 1 0/109 (0%) 0
    Enterococcal sepsis 1/246 (0.4%) 1 0/109 (0%) 0
    Enterocolitis infectious 4/246 (1.6%) 5 0/109 (0%) 0
    Epstein-Barr viraemia 1/246 (0.4%) 1 0/109 (0%) 0
    Escherichia bacteraemia 2/246 (0.8%) 4 0/109 (0%) 0
    Escherichia sepsis 1/246 (0.4%) 1 0/109 (0%) 0
    Escherichia urinary tract infection 3/246 (1.2%) 3 1/109 (0.9%) 1
    Eye infection 1/246 (0.4%) 1 0/109 (0%) 0
    Eye infection bacterial 1/246 (0.4%) 1 0/109 (0%) 0
    Haemophilus infection 0/246 (0%) 0 1/109 (0.9%) 1
    Hepatic infection 1/246 (0.4%) 1 0/109 (0%) 0
    Infection 1/246 (0.4%) 3 1/109 (0.9%) 2
    Infectious colitis 1/246 (0.4%) 1 0/109 (0%) 0
    Influenza 3/246 (1.2%) 3 1/109 (0.9%) 2
    Klebsiella bacteraemia 0/246 (0%) 0 1/109 (0.9%) 1
    Leptotrichia infection 1/246 (0.4%) 1 0/109 (0%) 0
    Lower respiratory tract infection 2/246 (0.8%) 3 0/109 (0%) 0
    Lower respiratory tract infection bacterial 1/246 (0.4%) 1 0/109 (0%) 0
    Lower respiratory tract infection fungal 2/246 (0.8%) 2 0/109 (0%) 0
    Lung infection 14/246 (5.7%) 17 5/109 (4.6%) 6
    Oesophageal infection 1/246 (0.4%) 1 0/109 (0%) 0
    Otitis externa 1/246 (0.4%) 1 0/109 (0%) 0
    Parotitis 1/246 (0.4%) 1 0/109 (0%) 0
    Periorbital infection 1/246 (0.4%) 1 0/109 (0%) 0
    Pneumonia 26/246 (10.6%) 40 4/109 (3.7%) 6
    Pneumonia fungal 2/246 (0.8%) 2 0/109 (0%) 0
    Pneumonia respiratory syncytial viral 1/246 (0.4%) 1 0/109 (0%) 0
    Pneumonia viral 1/246 (0.4%) 1 0/109 (0%) 0
    Pseudomonal bacteraemia 2/246 (0.8%) 2 0/109 (0%) 0
    Pseudomonal sepsis 1/246 (0.4%) 1 0/109 (0%) 0
    Pulmonary mycosis 1/246 (0.4%) 1 0/109 (0%) 0
    Respiratory syncytial virus infection 1/246 (0.4%) 1 0/109 (0%) 0
    Respiratory tract infection 4/246 (1.6%) 6 0/109 (0%) 0
    Scrotal infection 1/246 (0.4%) 1 0/109 (0%) 0
    Sepsis 18/246 (7.3%) 23 7/109 (6.4%) 11
    Septic shock 9/246 (3.7%) 15 1/109 (0.9%) 1
    Sinusitis 3/246 (1.2%) 4 0/109 (0%) 0
    Sinusitis fungal 1/246 (0.4%) 2 0/109 (0%) 0
    Skin infection 4/246 (1.6%) 7 0/109 (0%) 0
    Soft tissue infection 1/246 (0.4%) 1 0/109 (0%) 0
    Staphylococcal bacteraemia 6/246 (2.4%) 6 0/109 (0%) 0
    Staphylococcal infection 2/246 (0.8%) 2 0/109 (0%) 0
    Streptococcal bacteraemia 3/246 (1.2%) 4 0/109 (0%) 0
    Systemic bacterial infection 1/246 (0.4%) 2 0/109 (0%) 0
    Systemic mycosis 1/246 (0.4%) 2 0/109 (0%) 0
    Tooth abscess 0/246 (0%) 0 1/109 (0.9%) 1
    Tooth infection 2/246 (0.8%) 2 0/109 (0%) 0
    Upper respiratory tract infection 3/246 (1.2%) 4 0/109 (0%) 0
    Urinary tract infection 2/246 (0.8%) 2 0/109 (0%) 0
    Urinary tract infection bacterial 2/246 (0.8%) 2 1/109 (0.9%) 1
    Urinary tract infection enterococcal 1/246 (0.4%) 1 0/109 (0%) 0
    Viral upper respiratory tract infection 2/246 (0.8%) 3 0/109 (0%) 0
    Vulval cellulitis 1/246 (0.4%) 1 0/109 (0%) 0
    Wound infection 1/246 (0.4%) 1 0/109 (0%) 0
    Injury, poisoning and procedural complications
    Accidental overdose 1/246 (0.4%) 1 0/109 (0%) 0
    Anaphylactic transfusion reaction 1/246 (0.4%) 1 0/109 (0%) 0
    Ankle fracture 1/246 (0.4%) 1 0/109 (0%) 0
    Fall 8/246 (3.3%) 8 1/109 (0.9%) 1
    Hip fracture 1/246 (0.4%) 2 0/109 (0%) 0
    Infusion related reaction 2/246 (0.8%) 2 0/109 (0%) 0
    Joint dislocation 1/246 (0.4%) 1 0/109 (0%) 0
    Patella fracture 1/246 (0.4%) 2 0/109 (0%) 0
    Subarachnoid haemorrhage 1/246 (0.4%) 1 0/109 (0%) 0
    Subdural haematoma 2/246 (0.8%) 2 0/109 (0%) 0
    Subdural haemorrhage 0/246 (0%) 0 1/109 (0.9%) 1
    Toxicity to various agents 1/246 (0.4%) 1 0/109 (0%) 0
    Investigations
    Alanine aminotransferase increased 13/246 (5.3%) 17 0/109 (0%) 0
    Aspartate aminotransferase increased 10/246 (4.1%) 14 0/109 (0%) 0
    Blood alkaline phosphatase increased 1/246 (0.4%) 1 0/109 (0%) 0
    Blood bilirubin increased 2/246 (0.8%) 2 0/109 (0%) 0
    Blood creatine phosphokinase increased 2/246 (0.8%) 2 0/109 (0%) 0
    Blood creatinine increased 1/246 (0.4%) 1 0/109 (0%) 0
    Blood fibrinogen decreased 1/246 (0.4%) 1 0/109 (0%) 0
    Blood pressure decreased 0/246 (0%) 0 1/109 (0.9%) 1
    Ejection fraction decreased 0/246 (0%) 0 1/109 (0.9%) 1
    Electrocardiogram QT prolonged 2/246 (0.8%) 3 0/109 (0%) 0
    Gamma-glutamyltransferase increased 1/246 (0.4%) 1 0/109 (0%) 0
    General physical condition abnormal 1/246 (0.4%) 1 0/109 (0%) 0
    Liver function test increased 1/246 (0.4%) 1 0/109 (0%) 0
    Menstruation normal 1/246 (0.4%) 1 0/109 (0%) 0
    Neutrophil count decreased 4/246 (1.6%) 6 0/109 (0%) 0
    Norovirus test positive 1/246 (0.4%) 1 0/109 (0%) 0
    Platelet count decreased 5/246 (2%) 11 0/109 (0%) 0
    Transaminases increased 1/246 (0.4%) 1 0/109 (0%) 0
    White blood cell count decreased 1/246 (0.4%) 1 0/109 (0%) 0
    White blood cell count increased 1/246 (0.4%) 1 0/109 (0%) 0
    Metabolism and nutrition disorders
    Decreased appetite 2/246 (0.8%) 2 0/109 (0%) 0
    Dehydration 2/246 (0.8%) 2 0/109 (0%) 0
    Failure to thrive 1/246 (0.4%) 1 0/109 (0%) 0
    Hyperglycaemia 0/246 (0%) 0 1/109 (0.9%) 2
    Hyperphosphataemia 1/246 (0.4%) 1 0/109 (0%) 0
    Hypoglycaemia 1/246 (0.4%) 1 0/109 (0%) 0
    Hypokalaemia 0/246 (0%) 0 1/109 (0.9%) 1
    Hyponatraemia 2/246 (0.8%) 3 0/109 (0%) 0
    Hyponatraemic syndrome 1/246 (0.4%) 1 0/109 (0%) 0
    Hypophosphataemia 1/246 (0.4%) 1 0/109 (0%) 0
    Metabolic acidosis 1/246 (0.4%) 1 0/109 (0%) 0
    Tumour lysis syndrome 1/246 (0.4%) 1 2/109 (1.8%) 2
    Musculoskeletal and connective tissue disorders
    Arthralgia 3/246 (1.2%) 3 0/109 (0%) 0
    Arthritis 2/246 (0.8%) 2 0/109 (0%) 0
    Back pain 1/246 (0.4%) 1 0/109 (0%) 0
    Bone pain 1/246 (0.4%) 1 0/109 (0%) 0
    Joint effusion 1/246 (0.4%) 1 0/109 (0%) 0
    Joint swelling 1/246 (0.4%) 1 0/109 (0%) 0
    Muscular weakness 1/246 (0.4%) 1 0/109 (0%) 0
    Myositis 3/246 (1.2%) 3 0/109 (0%) 0
    Osteoarthritis 1/246 (0.4%) 1 0/109 (0%) 0
    Pain in extremity 0/246 (0%) 0 1/109 (0.9%) 1
    Pain in jaw 1/246 (0.4%) 1 0/109 (0%) 0
    Soft tissue necrosis 1/246 (0.4%) 1 0/109 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia 33/246 (13.4%) 38 4/109 (3.7%) 6
    Acute myeloid leukaemia recurrent 7/246 (2.8%) 9 0/109 (0%) 0
    Cancer pain 1/246 (0.4%) 1 0/109 (0%) 0
    Central nervous system leukaemia 2/246 (0.8%) 2 0/109 (0%) 0
    Gastric cancer 1/246 (0.4%) 1 0/109 (0%) 0
    Leukaemia cutis 2/246 (0.8%) 2 0/109 (0%) 0
    Leukaemia recurrent 1/246 (0.4%) 1 1/109 (0.9%) 2
    Malignant neoplasm progression 0/246 (0%) 0 1/109 (0.9%) 2
    Neoplasm malignant 1/246 (0.4%) 1 0/109 (0%) 0
    Oesophageal carcinoma 1/246 (0.4%) 1 0/109 (0%) 0
    Soft tissue sarcoma 1/246 (0.4%) 1 0/109 (0%) 0
    Squamous cell carcinoma 0/246 (0%) 0 1/109 (0.9%) 2
    Nervous system disorders
    Amnesia 0/246 (0%) 0 1/109 (0.9%) 1
    Brain oedema 2/246 (0.8%) 2 0/109 (0%) 0
    Cerebellar haemorrhage 1/246 (0.4%) 1 0/109 (0%) 0
    Cerebral haemorrhage 3/246 (1.2%) 3 0/109 (0%) 0
    Cerebral infarction 0/246 (0%) 0 1/109 (0.9%) 1
    Cerebrovascular accident 1/246 (0.4%) 1 0/109 (0%) 0
    Cognitive disorder 1/246 (0.4%) 1 0/109 (0%) 0
    Depressed level of consciousness 2/246 (0.8%) 2 0/109 (0%) 0
    Dizziness 1/246 (0.4%) 1 0/109 (0%) 0
    Haemorrhage intracranial 1/246 (0.4%) 1 0/109 (0%) 0
    Haemorrhagic stroke 0/246 (0%) 0 1/109 (0.9%) 1
    Headache 5/246 (2%) 5 0/109 (0%) 0
    Hemiplegia 1/246 (0.4%) 1 0/109 (0%) 0
    Hydrocephalus 1/246 (0.4%) 1 0/109 (0%) 0
    Posterior reversible encephalopathy syndrome 1/246 (0.4%) 1 0/109 (0%) 0
    Presyncope 1/246 (0.4%) 1 0/109 (0%) 0
    Seizure 2/246 (0.8%) 2 0/109 (0%) 0
    Somnolence 1/246 (0.4%) 1 0/109 (0%) 0
    Syncope 7/246 (2.8%) 8 0/109 (0%) 0
    Tremor 1/246 (0.4%) 1 0/109 (0%) 0
    Psychiatric disorders
    Confusional state 1/246 (0.4%) 1 0/109 (0%) 0
    Depression 0/246 (0%) 0 1/109 (0.9%) 1
    Hallucination 1/246 (0.4%) 1 0/109 (0%) 0
    Mania 1/246 (0.4%) 1 0/109 (0%) 0
    Mental status changes 1/246 (0.4%) 1 0/109 (0%) 0
    Renal and urinary disorders
    Acute kidney injury 16/246 (6.5%) 20 4/109 (3.7%) 5
    Haematuria 1/246 (0.4%) 1 0/109 (0%) 0
    Renal impairment 1/246 (0.4%) 1 0/109 (0%) 0
    Reproductive system and breast disorders
    Pelvic pain 1/246 (0.4%) 1 0/109 (0%) 0
    Vaginal haemorrhage 1/246 (0.4%) 1 0/109 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome 4/246 (1.6%) 4 0/109 (0%) 0
    Acute respiratory failure 2/246 (0.8%) 2 1/109 (0.9%) 1
    Aspiration 1/246 (0.4%) 1 0/109 (0%) 0
    Cough 2/246 (0.8%) 2 0/109 (0%) 0
    Dyspnoea 10/246 (4.1%) 10 2/109 (1.8%) 2
    Hypoxia 4/246 (1.6%) 4 2/109 (1.8%) 2
    Interstitial lung disease 1/246 (0.4%) 1 0/109 (0%) 0
    Lung disorder 1/246 (0.4%) 1 0/109 (0%) 0
    Organising pneumonia 2/246 (0.8%) 3 0/109 (0%) 0
    Oropharyngeal pain 1/246 (0.4%) 1 0/109 (0%) 0
    Pleural effusion 2/246 (0.8%) 3 0/109 (0%) 0
    Pneumomediastinum 1/246 (0.4%) 1 0/109 (0%) 0
    Pneumonia aspiration 2/246 (0.8%) 3 0/109 (0%) 0
    Pneumothorax 1/246 (0.4%) 1 0/109 (0%) 0
    Productive cough 1/246 (0.4%) 1 0/109 (0%) 0
    Pulmonary alveolar haemorrhage 0/246 (0%) 0 1/109 (0.9%) 1
    Pulmonary embolism 2/246 (0.8%) 2 0/109 (0%) 0
    Pulmonary haemorrhage 0/246 (0%) 0 1/109 (0.9%) 1
    Pulmonary hypertension 2/246 (0.8%) 2 0/109 (0%) 0
    Respiratory failure 7/246 (2.8%) 8 3/109 (2.8%) 5
    Skin and subcutaneous tissue disorders
    Acute febrile neutrophilic dermatosis 1/246 (0.4%) 1 0/109 (0%) 0
    Dermatitis bullous 1/246 (0.4%) 1 0/109 (0%) 0
    Drug eruption 1/246 (0.4%) 1 0/109 (0%) 0
    Petechiae 1/246 (0.4%) 1 0/109 (0%) 0
    Psoriasis 1/246 (0.4%) 1 0/109 (0%) 0
    Skin necrosis 1/246 (0.4%) 1 0/109 (0%) 0
    Swelling face 1/246 (0.4%) 1 0/109 (0%) 0
    Toxic skin eruption 1/246 (0.4%) 1 0/109 (0%) 0
    Vascular disorders
    Deep vein thrombosis 0/246 (0%) 0 1/109 (0.9%) 1
    Embolism 3/246 (1.2%) 3 1/109 (0.9%) 1
    Haematoma 3/246 (1.2%) 5 0/109 (0%) 0
    Haemorrhage 1/246 (0.4%) 1 0/109 (0%) 0
    Hypertension 1/246 (0.4%) 1 1/109 (0.9%) 1
    Hypotension 6/246 (2.4%) 6 1/109 (0.9%) 1
    Orthostatic hypotension 1/246 (0.4%) 1 0/109 (0%) 0
    Venous thrombosis 1/246 (0.4%) 1 0/109 (0%) 0
    Other (Not Including Serious) Adverse Events
    Gilteritinib Salvage Chemotherapy
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 242/246 (98.4%) 103/109 (94.5%)
    Blood and lymphatic system disorders
    Anaemia 110/246 (44.7%) 471 38/109 (34.9%) 80
    Disseminated intravascular coagulation 7/246 (2.8%) 8 6/109 (5.5%) 6
    Febrile neutropenia 57/246 (23.2%) 72 32/109 (29.4%) 37
    Neutropenia 31/246 (12.6%) 105 16/109 (14.7%) 18
    Thrombocytopenia 62/246 (25.2%) 294 17/109 (15.6%) 41
    Cardiac disorders
    Tachycardia 12/246 (4.9%) 13 7/109 (6.4%) 7
    Eye disorders
    Dry eye 24/246 (9.8%) 25 3/109 (2.8%) 3
    Retinal haemorrhage 19/246 (7.7%) 22 2/109 (1.8%) 2
    Vision blurred 20/246 (8.1%) 22 1/109 (0.9%) 1
    Gastrointestinal disorders
    Abdominal pain 36/246 (14.6%) 42 16/109 (14.7%) 17
    Constipation 76/246 (30.9%) 94 16/109 (14.7%) 18
    Diarrhoea 79/246 (32.1%) 123 32/109 (29.4%) 37
    Dry mouth 20/246 (8.1%) 21 3/109 (2.8%) 3
    Dyspepsia 13/246 (5.3%) 16 7/109 (6.4%) 7
    Mouth ulceration 13/246 (5.3%) 14 2/109 (1.8%) 2
    Nausea 79/246 (32.1%) 120 36/109 (33%) 41
    Stomatitis 34/246 (13.8%) 44 15/109 (13.8%) 19
    Vomiting 53/246 (21.5%) 79 15/109 (13.8%) 16
    General disorders
    Asthenia 36/246 (14.6%) 50 10/109 (9.2%) 11
    Chills 22/246 (8.9%) 32 8/109 (7.3%) 9
    Fatigue 70/246 (28.5%) 98 14/109 (12.8%) 17
    Mucosal inflammation 13/246 (5.3%) 13 9/109 (8.3%) 11
    Oedema 15/246 (6.1%) 18 3/109 (2.8%) 3
    Oedema peripheral 59/246 (24%) 77 13/109 (11.9%) 19
    Pain 17/246 (6.9%) 21 1/109 (0.9%) 1
    Pyrexia 89/246 (36.2%) 136 31/109 (28.4%) 57
    Immune system disorders
    Graft versus host disease 13/246 (5.3%) 18 1/109 (0.9%) 1
    Infections and infestations
    Cellulitis 15/246 (6.1%) 17 1/109 (0.9%) 2
    Lung infection 14/246 (5.7%) 15 0/109 (0%) 0
    Pneumonia 23/246 (9.3%) 26 5/109 (4.6%) 5
    Sinusitis 13/246 (5.3%) 18 2/109 (1.8%) 3
    Upper respiratory tract infection 19/246 (7.7%) 32 3/109 (2.8%) 3
    Injury, poisoning and procedural complications
    Allergic transfusion reaction 10/246 (4.1%) 17 7/109 (6.4%) 13
    Contusion 14/246 (5.7%) 16 3/109 (2.8%) 3
    Fall 18/246 (7.3%) 27 1/109 (0.9%) 1
    Investigations
    Alanine aminotransferase increased 99/246 (40.2%) 230 10/109 (9.2%) 20
    Aspartate aminotransferase increased 96/246 (39%) 237 13/109 (11.9%) 21
    Blood alkaline phosphatase increased 55/246 (22.4%) 112 2/109 (1.8%) 2
    Blood bilirubin increased 21/246 (8.5%) 68 7/109 (6.4%) 9
    Blood creatine phosphokinase increased 33/246 (13.4%) 94 0/109 (0%) 0
    Blood creatinine increased 29/246 (11.8%) 64 4/109 (3.7%) 4
    Blood lactate dehydrogenase increased 22/246 (8.9%) 33 5/109 (4.6%) 5
    Electrocardiogram QT prolonged 16/246 (6.5%) 19 0/109 (0%) 0
    International normalised ratio increased 13/246 (5.3%) 17 5/109 (4.6%) 6
    Neutrophil count decreased 40/246 (16.3%) 161 12/109 (11%) 28
    Platelet count decreased 53/246 (21.5%) 245 28/109 (25.7%) 76
    Weight decreased 13/246 (5.3%) 21 3/109 (2.8%) 4
    Weight increased 13/246 (5.3%) 17 2/109 (1.8%) 6
    White blood cell count decreased 34/246 (13.8%) 127 19/109 (17.4%) 27
    Metabolism and nutrition disorders
    Decreased appetite 44/246 (17.9%) 52 20/109 (18.3%) 22
    Dehydration 13/246 (5.3%) 15 1/109 (0.9%) 1
    Hyperglycaemia 36/246 (14.6%) 62 13/109 (11.9%) 18
    Hyperkalaemia 22/246 (8.9%) 32 1/109 (0.9%) 1
    Hyperuricaemia 23/246 (9.3%) 30 2/109 (1.8%) 2
    Hypoalbuminaemia 32/246 (13%) 64 7/109 (6.4%) 11
    Hypocalcaemia 47/246 (19.1%) 110 6/109 (5.5%) 14
    Hypokalaemia 71/246 (28.9%) 183 33/109 (30.3%) 48
    Hypomagnesaemia 39/246 (15.9%) 67 12/109 (11%) 15
    Hyponatraemia 32/246 (13%) 78 6/109 (5.5%) 7
    Hypophosphataemia 40/246 (16.3%) 69 5/109 (4.6%) 5
    Musculoskeletal and connective tissue disorders
    Arthralgia 28/246 (11.4%) 42 6/109 (5.5%) 8
    Back pain 29/246 (11.8%) 32 13/109 (11.9%) 13
    Muscular weakness 19/246 (7.7%) 22 1/109 (0.9%) 2
    Myalgia 35/246 (14.2%) 45 4/109 (3.7%) 4
    Pain in extremity 36/246 (14.6%) 44 8/109 (7.3%) 11
    Nervous system disorders
    Dizziness 48/246 (19.5%) 64 2/109 (1.8%) 2
    Dysgeusia 25/246 (10.2%) 28 5/109 (4.6%) 5
    Headache 61/246 (24.8%) 87 16/109 (14.7%) 18
    Paraesthesia 21/246 (8.5%) 25 0/109 (0%) 0
    Psychiatric disorders
    Anxiety 19/246 (7.7%) 21 1/109 (0.9%) 1
    Depression 11/246 (4.5%) 12 7/109 (6.4%) 7
    Insomnia 40/246 (16.3%) 44 6/109 (5.5%) 6
    Renal and urinary disorders
    Haematuria 19/246 (7.7%) 21 5/109 (4.6%) 6
    Respiratory, thoracic and mediastinal disorders
    Cough 70/246 (28.5%) 96 11/109 (10.1%) 13
    Dyspnoea 50/246 (20.3%) 67 7/109 (6.4%) 8
    Dyspnoea exertional 15/246 (6.1%) 18 0/109 (0%) 0
    Epistaxis 42/246 (17.1%) 51 8/109 (7.3%) 8
    Nasal congestion 17/246 (6.9%) 20 1/109 (0.9%) 1
    Oropharyngeal pain 21/246 (8.5%) 24 8/109 (7.3%) 8
    Pleural effusion 16/246 (6.5%) 17 2/109 (1.8%) 3
    Productive cough 16/246 (6.5%) 20 2/109 (1.8%) 2
    Skin and subcutaneous tissue disorders
    Dry skin 15/246 (6.1%) 19 3/109 (2.8%) 3
    Erythema 13/246 (5.3%) 16 4/109 (3.7%) 4
    Pruritus 24/246 (9.8%) 29 3/109 (2.8%) 3
    Rash 36/246 (14.6%) 48 10/109 (9.2%) 10
    Rash maculo-papular 10/246 (4.1%) 13 6/109 (5.5%) 6
    Vascular disorders
    Hypertension 33/246 (13.4%) 56 10/109 (9.2%) 10
    Hypotension 38/246 (15.4%) 44 7/109 (6.4%) 8

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    Institute and/or Principal Investigator may publish trial data generated at their specific study site after Sponsor publication of the multi-center data. Sponsor must receive a site's manuscript prior to publication for review and comment as specified in the Investigator Agreement.

    Results Point of Contact

    Name/Title Clinical Trial Disclosure
    Organization Astellas Pharma Global Development, Inc.
    Phone 800-888-7704
    Email astellas.resultsdisclosure@astellas.com
    Responsible Party:
    Astellas Pharma Global Development, Inc.
    ClinicalTrials.gov Identifier:
    NCT02421939
    Other Study ID Numbers:
    • 2215-CL-0301
    • 2015-000140-42
    First Posted:
    Apr 21, 2015
    Last Update Posted:
    Aug 11, 2022
    Last Verified:
    Aug 1, 2022