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

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ClinicalTrials.gov Identifier: NCT02421939

Recruitment Status : Active, not recruiting

First Posted : April 21, 2015

Results First Posted : October 17, 2019

Last Update Posted : March 23, 2021

Sponsor:

Information provided by (Responsible Party):

Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition	Leukemia, Acute Myeloid (AML)
Interventions	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)
Enrollment	371

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 Details	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 (...	Participants received 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 ^[1]	38	0
Not Completed	209	124
Reason Not Completed
Progressive disease	70	16
Lack of Efficacy	21	31
Death	36	10
Disease relapse	33	2
Adverse Event	28	5
Withdrawal by Subject	5	24
Physician Decision	11	11
Completed 1 or 2 chemo cycles with CRs	0	19
Miscellaneous	4	5
Protocol deviation	1	1
[1] Participants still on treatment. Last assessment of remission status at the end of treatment visit.

Baseline Characteristics

Arm/Group Title		Gilteritinib	Salvage Chemotherapy	Total
Arm/Group Description		Participants received 120 mg dose (...	Participants received chemotherapy ...	Total of all reporting groups
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 Number of Baseline Participants		247	124	371
Baseline Analysis Population Description		...
Baseline Analysis Population Description		The analysis population was the Intention to Treatment (ITT), which consisted of all randomized participants.
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	247 participants	124 participants	371 participants
		59 (14.6)	57.6 (14.8)	58.5 (14.7)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	247 participants	124 participants	371 participants
	Female	131 53.0%	70 56.5%	201 54.2%
	Male	116 47.0%	54 43.5%	170 45.8%
Race/Ethnicity, Customized Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	247 participants	124 participants	371 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 0.0%	1 0.3%
	AMERICAN INDIAN OR ALASKA NATIVE	0 0.0%	0 0.0%	0 0.0%
	UNKNOWN	4 1.6%	4 3.2%	8 2.2%
	OTHER	5 2.0%	1 0.8%	6 1.6%
	MISSING	9 3.6%	4 3.2%	13 3.5%
Ethnicity Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	247 participants	124 participants	371 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 4.0%
Cytogenic Risk Status ^[1] Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	247 participants	124 participants	371 participants
	INTERMEDIATE	182 73.7%	89 71.8%	271 73.0%
	UNFAVORABLE	26 10.5%	11 8.9%	37 10.0%
	FAVORABLE	4 1.6%	1 0.8%	5 1.3%
	OTHER	35 14.2%	23 18.5%	58 15.6%
		[1] Measure Description: The category of "Other" includes those with cytogenetic risk status that cannot be categorized as favorable, intermediate or unfavorable.
Baseline Eastern Cooperative Oncology Group (ECOG) ^[1] Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	247 participants	124 participants	371 participants
	0-1	206 83.4%	105 84.7%	311 83.8%
	>=2	41 16.6%	19 15.3%	60 16.2%
		[1] Measure Description: ECOG performance status is a scale used to assess impact on daily activities. It is based on the investigator assessment. Scores range from 0 to 5, with 0-signifying fully active participant; 1-restricted in physically strenuous activity; 2-ambulatory and capable of all self-care, unable to work; 3-capable of only limited self-care, confined to bed more than 50% of waking hours; 4-completely disabled and 5-dead. Negative numerical score indicates an improvement and positive numerical score indicates a decline in participant's daily activities, indicating disease progression.
FLT3 Mutation Status by Central Testing by FLT3 CDx Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	247 participants	124 participants	371 participants
	FLT3-ITD Alone	215 87.0%	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 0.0%	7 1.9%
	Others (Unknown/Missing/Negative)	4 1.6%	1 0.8%	5 1.3%
Prior Use of FLT3 Inhibitor ^[1] Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	247 participants	124 participants	371 participants
	No	215 87.0%	110 88.7%	325 87.6%
	Yes	32 13.0%	14 11.3%	46 12.4%
		[1] Measure Description: Prior use of FLT3 inhibitor is defined as 'Yes' if participants received prior AML therapy of midostaurin, sorafenib or quizartinib; otherwise, prior use of FLT3 inhibitor is assigned as No.
Region Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	247 participants	124 participants	371 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) ^[1] Mean (Standard Deviation) Unit of measure: M^2
	Number Analyzed	199 participants	122 participants	321 participants
		1.815 (0.281)	1.777 (0.257)	1.8 (0.272)
		[1] Measure Analysis Population Description: The analysis population was the ITT, with available data.
Baseline Height ^[1] Mean (Standard Deviation) Unit of measure: Centimeter (cm)
	Number Analyzed	234 participants	123 participants	357 participants
		167.25 (10.31)	166.39 (10.63)	166.95 (10.41)
		[1] Measure Analysis Population Description: The analysis population was the ITT, with available data.
Baseline Weight ^[1] Mean (Standard Deviation) Unit of measure: Kilogram (kg)
	Number Analyzed	243 participants	124 participants	367 participants
		72.79 (20.47)	69.91 (19.73)	71.82 (20.25)
		[1] Measure Analysis Population Description: The analysis population was the ITT, with available data.
Response to First Line Therapy ^[1] Measure Type: Count of Participants Unit of measure: Participants
Primary refractory without HSCT	Number Analyzed	247 participants	124 participants	371 participants
Primary refractory without HSCT		98 39.7%	48 38.7%	146 39.4%
Relapse within 6 months after CRc and no HSCT	Number Analyzed	247 participants	124 participants	371 participants
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	Number Analyzed	247 participants	124 participants	371 participants
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	Number Analyzed	247 participants	124 participants	371 participants
Relapse within 6 months after allogeneic HSCT		31 12.6%	17 13.7%	48 12.9%
Relapse after 6 months after allogeneic HSCT	Number Analyzed	247 participants	124 participants	371 participants
Relapse after 6 months after allogeneic HSCT		17 6.9%	8 6.5%	25 6.7%
		[1] Measure Description: Baseline stratification factors.
Preselected Salvage Chemotherapy ^[1] Measure Type: Count of Participants Unit of measure: Participants
High intensity chemotherapy	Number Analyzed	247 participants	124 participants	371 participants
High intensity chemotherapy		149 60.3%	75 60.5%	224 60.4%
Low intensity chemotherapy	Number Analyzed	247 participants	124 participants	371 participants
Low intensity chemotherapy		98 39.7%	49 39.5%	147 39.6%
		[1] Measure Description: Baseline stratification factors.
Response to First Line Therapy-Preselected Salvage Chemotherapy ^[1] Measure Type: Count of Participants Unit of measure: Participants
Primary refractory w/o HSCT, high intensity (IT)	Number Analyzed	247 participants	124 participants	371 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	Number Analyzed	247 participants	124 participants	371 participants
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	Number Analyzed	247 participants	124 participants	371 participants
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	Number Analyzed	247 participants	124 participants	371 participants
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	Number Analyzed	247 participants	124 participants	371 participants
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	Number Analyzed	247 participants	124 participants	371 participants
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	Number Analyzed	247 participants	124 participants	371 participants
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	Number Analyzed	247 participants	124 participants	371 participants
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	Number Analyzed	247 participants	124 participants	371 participants
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	Number Analyzed	247 participants	124 participants	371 participants
Relapse after 6 mths after allogeneic HSCT low IT		3 1.2%	1 0.8%	4 1.1%
		[1] Measure Description: Baseline stratification factors. HSCT is hematopoietic stem cell transplant. CRc is composite complete remission.

Outcome Measures

1.Primary Outcome


Title	Duration of Overall Survival (OS)
Description	Overall survival was defined as the time from the date of randomizatio...
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 (...	Participants received 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.
Overall Number of Participants Analyzed	247	124
Median (95% Confidence Interval) Unit of Measure: Months
	9.3 (7.7 to 10.7)	5.6 (4.7 to 7.3)

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	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0004
	Comments	1-sided P-value
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.637
	Confidence Interval	(2-Sided) 95% 0.490 to 0.830
	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...
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 (...
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.
Overall Number of Participants Analyzed	142
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: Percentage of participants
CR/CRh rate	28.2 (20.9 to 36.3)
CR rate	19.0 (12.9 to 26.4)
CRh rate	9.2 (5.0 to 15.1)

3.Secondary Outcome


Title	Duration of Event-Free Survival (EFS)
Description	EFS was defined as the time from the date of randomization until the d...
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 (...	Participants received 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.
Overall Number of Participants Analyzed	189	62
Median (95% Confidence Interval) Unit of Measure: Months
	2.8 (1.4 to 3.7)	0.7 ^[1] (0.2 to NA)

[1]

Not estimable. Data could not be estimated due to low number of events.

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	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0415
	Comments	1-sided P-value
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.793
	Confidence Interval	(2-Sided) 95% 0.577 to 1.089
	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...
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 (...	Participants received 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.
Overall Number of Participants Analyzed	247	124
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: Percentage of participants
	21.1 (16.1 to 26.7)	10.5 (5.7 to 17.3)

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	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0106
	Comments	Stratified P-value
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Adjusted Treatment Difference
	Estimated Value	10.6
	Confidence Interval	(2-Sided) 95% 2.8 to 18.4
	Estimation Comments	[Not Specified]

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 d...
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 (...	Participants received 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.
Overall Number of Participants Analyzed	134	27
Median (95% Confidence Interval) Unit of Measure: Months
	4.4 (3.6 to 5.2)	6.7 (2.1 to 8.5)

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	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.6654
	Comments	Unstratified p-value
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.889
	Confidence Interval	(2-Sided) 95% 0.506 to 1.563
	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 remissio...
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 (...	Participants received 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.
Overall Number of Participants Analyzed	52	13
Median (95% Confidence Interval) Unit of Measure: Months
	14.8 ^[1] (11.0 to NA)	1.8 ^[1] (NA to NA)

[1]

Not estimable. Data could not be estimated due to low number of events.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gilteritinib, Salvage Chemotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.1189
	Comments	Unstratified
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.206
	Confidence Interval	(2-Sided) 95% 0.022 to 1.886
	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 be...
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 (...	Participants received 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.
Overall Number of Participants Analyzed	247	124
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: Percentage of participants
	54.3 (47.8 to 60.6)	21.8 (14.9 to 30.1)

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	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Unstratified 2-sided P-value
	Method	2-sided Fisher's exact test
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	32.5
	Confidence Interval	(2-Sided) 95% 22.3 to 42.6
	Estimation Comments	[Not Specified]

8.Secondary Outcome


Title	Percentage of Participants Who Underwent Hematopoietic Stem Cell Transplant
Description	Transplantation rate is defined as the percentage of participants unde...
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 (...	Participants received 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.
Overall Number of Participants Analyzed	247	124
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: Percentage of participants
	25.5 (20.2 to 31.4)	15.3 (9.5 to 22.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gilteritinib, Salvage Chemotherapy
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]

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
	Estimation Comments	[Not Specified]

9.Secondary Outcome


Title	Change From Baseline in Brief Fatigue Inventory (BFI)
Description	The Brief Fatigue Inventory (BFI) is a screening tool designed to asse...
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 (...	Participants received 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.
Overall Number of Participants Analyzed		227	97
Mean (Standard Deviation) Unit of Measure: Units on a scale
Cycle 1 day 8 (C1D8)	Number Analyzed	191 participants	73 participants
Cycle 1 day 8 (C1D8)		-0.4 (2.1)	1.0 (2.3)
Cycle 2 day 1 (C2D1)	Number Analyzed	206 participants	15 participants
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	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0000
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-1.2567
	Estimation Comments	[Not Specified]

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	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.8037
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.1574
	Estimation Comments	[Not Specified]

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...
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 (...	Participants received 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.
Overall Number of Participants Analyzed	247	124
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: Percentage of participants
	34.0 (28.1 to 40.3)	15.3 (9.5 to 22.9)

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	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.0171
	Comments	Stratified 1-sided P-value.
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Adjusted Treatment Difference,
	Estimated Value	18.6
	Confidence Interval	(2-Sided) 95% 9.8 to 27.4
	Estimation Comments	[Not Specified]

11.Secondary Outcome


Title	Percentage of Participants Who Achieved Transfusion Conversion and Maintenance
Description	Transfusion conversion & maintenance rate was defined for gilterit...
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 (...
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.
Overall Number of Participants Analyzed	246
Measure Type: Number Unit of Measure: Percentage of participants
Baseline Independent/ Post baseline Independent	59.2
Baseline Independent/Post baseline Dependent	24.5
Baseline Independent/Post baseline Not Evaluable	16.3
Baseline Dependent/Post baseline Independent	34.5
Baseline Dependent/Post baseline Dependent	55.8
Baseline Dependent/Post baseline Not Evaluable	9.6

12.Secondary Outcome


Title	Number of Participants With Adverse Events
Description	A treatment-emergent adverse event (TEAE) was defined as an AE observe...
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 (...	Participants received 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.
Overall Number of Participants Analyzed	246	109
Measure Type: Count of Participants Unit of Measure: Participants
Drug-related TEAE	206 83.7%	71 65.1%
Serious TEAE	205 83.3%	34 31.2%
Drug-related serious TEAE	88 35.8%	16 14.7%
TEAE leading to death	71 28.9%	16 14.7%
Drug-related TEAE leading to death	10 4.1%	5 4.6%
TEAE leading to withdrawal of treatment	58 23.6%	13 11.9%
Drug-related TEAE lead withdrawal of treatment	27 11.0%	5 4.6%
NCI-CTCAE Grade 3 or higher TEAE	236 95.9%	94 86.2%
Drug-related Grade 3 or higher TEAE	153 62.2%	57 52.3%
Death	170 69.1%	81 74.3%

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	[Not Specified]

Arm/Group Title	Gilteritinib		Salvage Chemotherapy
Arm/Group Description	Participants received 120 mg dose (...		Participants received 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 (%)		Affected / at Risk (%)
Total	170/246 (69.11%)		81/109 (74.31%)
Serious Adverse Events Serious Adverse Events
	Gilteritinib		Salvage Chemotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	205/246 (83.33%)		34/109 (31.19%)
Blood and lymphatic system disorders
Anaemia ^† 1	8/246 (3.25%)	10	0/109 (0.00%)	0
Aplasia pure red cell ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Autoimmune haemolytic anaemia ^† 1	1/246 (0.41%)	3	0/109 (0.00%)	0
Bone marrow failure ^† 1	1/246 (0.41%)	2	0/109 (0.00%)	0
Disseminated intravascular coagulation ^† 1	2/246 (0.81%)	2	0/109 (0.00%)	0
Febrile neutropenia ^† 1	76/246 (30.89%)	112	9/109 (8.26%)	15
Haemolytic anaemia ^† 1	2/246 (0.81%)	2	0/109 (0.00%)	0
Leukocytosis ^† 1	2/246 (0.81%)	2	1/109 (0.92%)	1
Neutropenia ^† 1	3/246 (1.22%)	4	1/109 (0.92%)	1
Pancytopenia ^† 1	4/246 (1.63%)	4	0/109 (0.00%)	0
Thrombocytopenia ^† 1	4/246 (1.63%)	4	1/109 (0.92%)	1
Cardiac disorders
Acute coronary syndrome ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Angina pectoris ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Atrial fibrillation ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Cardiac arrest ^† 1	4/246 (1.63%)	5	0/109 (0.00%)	0
Cardiac failure ^† 1	3/246 (1.22%)	3	0/109 (0.00%)	0
Cardiac failure congestive ^† 1	2/246 (0.81%)	3	0/109 (0.00%)	0
Cardio-respiratory arrest ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Myocardial infarction ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Myocarditis ^† 1	2/246 (0.81%)	2	0/109 (0.00%)	0
Pericardial effusion ^† 1	3/246 (1.22%)	5	0/109 (0.00%)	0
Pericardial haemorrhage ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Pericarditis ^† 1	3/246 (1.22%)	3	0/109 (0.00%)	0
Sinus tachycardia ^† 1	1/246 (0.41%)	1	1/109 (0.92%)	1
Supraventricular tachycardia ^† 1	2/246 (0.81%)	2	0/109 (0.00%)	0
Congenital, familial and genetic disorders
Hamartoma ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Eye disorders
Ocular hyperaemia ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Vision blurred ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Gastrointestinal disorders
Abdominal pain ^† 1	2/246 (0.81%)	2	0/109 (0.00%)	0
Anal fissure ^† 1	1/246 (0.41%)	2	0/109 (0.00%)	0
Colitis ^† 1	2/246 (0.81%)	3	0/109 (0.00%)	0
Diarrhoea ^† 1	10/246 (4.07%)	13	0/109 (0.00%)	0
Diarrhoea haemorrhagic ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Dysphagia ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Enterocolitis ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Gastritis ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Gastrointestinal haemorrhage ^† 1	1/246 (0.41%)	1	1/109 (0.92%)	2
Gastrooesophageal reflux disease ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Haematemesis ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Haematochezia ^† 1	1/246 (0.41%)	2	0/109 (0.00%)	0
Haemorrhoids ^† 1	2/246 (0.81%)	2	0/109 (0.00%)	0
Ileus ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Intestinal ischaemia ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Large intestine perforation ^† 1	2/246 (0.81%)	4	0/109 (0.00%)	0
Lower gastrointestinal haemorrhage ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Melaena ^† 1	1/246 (0.41%)	1	1/109 (0.92%)	1
Mouth haemorrhage ^† 1	2/246 (0.81%)	2	0/109 (0.00%)	0
Nausea ^† 1	2/246 (0.81%)	2	0/109 (0.00%)	0
Pancreatitis ^† 1	3/246 (1.22%)	4	0/109 (0.00%)	0
Proctalgia ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Stomatitis ^† 1	1/246 (0.41%)	1	1/109 (0.92%)	1
Stomatitis necrotising ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Tongue haematoma ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Vomiting ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
General disorders
Asthenia ^† 1	3/246 (1.22%)	3	0/109 (0.00%)	0
Chills ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Death ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Face oedema ^† 1	2/246 (0.81%)	2	0/109 (0.00%)	0
Fatigue ^† 1	4/246 (1.63%)	4	1/109 (0.92%)	1
Generalised oedema ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Influenza like illness ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Mucosal haemorrhage ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Mucosal inflammation ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Multiple organ dysfunction syndrome ^† 1	1/246 (0.41%)	1	1/109 (0.92%)	1
Oedema ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Pyrexia ^† 1	32/246 (13.01%)	43	1/109 (0.92%)	2
Hepatobiliary disorders
Cholecystitis ^† 1	2/246 (0.81%)	2	0/109 (0.00%)	0
Drug-induced liver injury ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Hepatic function abnormal ^† 1	1/246 (0.41%)	7	0/109 (0.00%)	0
Hepatotoxicity ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Immune system disorders
Acute graft versus host disease in intestine ^† 1	1/246 (0.41%)	2	0/109 (0.00%)	0
Anaphylactic reaction ^† 1	3/246 (1.22%)	3	0/109 (0.00%)	0
Drug hypersensitivity ^† 1	1/246 (0.41%)	2	0/109 (0.00%)	0
Graft versus host disease ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Graft versus host disease in gastrointestinal tract ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Infections and infestations
Abscess bacterial ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Adenoviral upper respiratory infection ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Anal abscess ^† 1	0/246 (0.00%)	0	1/109 (0.92%)	1
Bacteraemia ^† 1	10/246 (4.07%)	11	1/109 (0.92%)	1
Bacterial colitis ^† 1	1/246 (0.41%)	2	0/109 (0.00%)	0
Bacterial infection ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Bacterial sepsis ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Bronchitis ^† 1	4/246 (1.63%)	5	0/109 (0.00%)	0
Bronchopulmonary aspergillosis ^† 1	2/246 (0.81%)	4	0/109 (0.00%)	0
Catheter site infection ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Cellulitis ^† 1	6/246 (2.44%)	6	0/109 (0.00%)	0
Clostridium difficile colitis ^† 1	2/246 (0.81%)	2	0/109 (0.00%)	0
Clostridium difficile infection ^† 1	4/246 (1.63%)	4	0/109 (0.00%)	0
Cytomegalovirus infection ^† 1	1/246 (0.41%)	2	0/109 (0.00%)	0
Device related infection ^† 1	4/246 (1.63%)	4	1/109 (0.92%)	1
Diarrhoea infectious ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Endocarditis ^† 1	1/246 (0.41%)	2	0/109 (0.00%)	0
Enterococcal bacteraemia ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Enterococcal sepsis ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Enterocolitis infectious ^† 1	4/246 (1.63%)	5	0/109 (0.00%)	0
Epstein-Barr viraemia ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Escherichia bacteraemia ^† 1	2/246 (0.81%)	4	0/109 (0.00%)	0
Escherichia sepsis ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Escherichia urinary tract infection ^† 1	3/246 (1.22%)	3	1/109 (0.92%)	1
Eye infection ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Eye infection bacterial ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Haemophilus infection ^† 1	0/246 (0.00%)	0	1/109 (0.92%)	1
Hepatic infection ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Infection ^† 1	1/246 (0.41%)	3	1/109 (0.92%)	2
Infectious colitis ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Influenza ^† 1	3/246 (1.22%)	3	1/109 (0.92%)	2
Klebsiella bacteraemia ^† 1	0/246 (0.00%)	0	1/109 (0.92%)	1
Leptotrichia infection ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Lower respiratory tract infection ^† 1	2/246 (0.81%)	3	0/109 (0.00%)	0
Lower respiratory tract infection bacterial ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Lower respiratory tract infection fungal ^† 1	2/246 (0.81%)	2	0/109 (0.00%)	0
Lung infection ^† 1	14/246 (5.69%)	17	5/109 (4.59%)	6
Oesophageal infection ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Otitis externa ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Parotitis ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Periorbital infection ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Pneumonia ^† 1	26/246 (10.57%)	40	4/109 (3.67%)	6
Pneumonia fungal ^† 1	2/246 (0.81%)	2	0/109 (0.00%)	0
Pneumonia respiratory syncytial viral ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Pneumonia viral ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Pseudomonal bacteraemia ^† 1	2/246 (0.81%)	2	0/109 (0.00%)	0
Pseudomonal sepsis ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Pulmonary mycosis ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Respiratory syncytial virus infection ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Respiratory tract infection ^† 1	4/246 (1.63%)	6	0/109 (0.00%)	0
Scrotal infection ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Sepsis ^† 1	18/246 (7.32%)	23	7/109 (6.42%)	11
Septic shock ^† 1	9/246 (3.66%)	15	1/109 (0.92%)	1
Sinusitis ^† 1	3/246 (1.22%)	4	0/109 (0.00%)	0
Sinusitis fungal ^† 1	1/246 (0.41%)	2	0/109 (0.00%)	0
Skin infection ^† 1	4/246 (1.63%)	7	0/109 (0.00%)	0
Soft tissue infection ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Staphylococcal bacteraemia ^† 1	6/246 (2.44%)	6	0/109 (0.00%)	0
Staphylococcal infection ^† 1	2/246 (0.81%)	2	0/109 (0.00%)	0
Streptococcal bacteraemia ^† 1	3/246 (1.22%)	4	0/109 (0.00%)	0
Systemic bacterial infection ^† 1	1/246 (0.41%)	2	0/109 (0.00%)	0
Systemic mycosis ^† 1	1/246 (0.41%)	2	0/109 (0.00%)	0
Tooth abscess ^† 1	0/246 (0.00%)	0	1/109 (0.92%)	1
Tooth infection ^† 1	2/246 (0.81%)	2	0/109 (0.00%)	0
Upper respiratory tract infection ^† 1	3/246 (1.22%)	4	0/109 (0.00%)	0
Urinary tract infection ^† 1	2/246 (0.81%)	2	0/109 (0.00%)	0
Urinary tract infection bacterial ^† 1	2/246 (0.81%)	2	1/109 (0.92%)	1
Urinary tract infection enterococcal ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Viral upper respiratory tract infection ^† 1	2/246 (0.81%)	3	0/109 (0.00%)	0
Vulval cellulitis ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Wound infection ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Injury, poisoning and procedural complications
Accidental overdose ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Anaphylactic transfusion reaction ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Ankle fracture ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Fall ^† 1	8/246 (3.25%)	8	1/109 (0.92%)	1
Hip fracture ^† 1	1/246 (0.41%)	2	0/109 (0.00%)	0
Infusion related reaction ^† 1	2/246 (0.81%)	2	0/109 (0.00%)	0
Joint dislocation ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Patella fracture ^† 1	1/246 (0.41%)	2	0/109 (0.00%)	0
Subarachnoid haemorrhage ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Subdural haematoma ^† 1	2/246 (0.81%)	2	0/109 (0.00%)	0
Subdural haemorrhage ^† 1	0/246 (0.00%)	0	1/109 (0.92%)	1
Toxicity to various agents ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Investigations
Alanine aminotransferase increased ^† 1	13/246 (5.28%)	17	0/109 (0.00%)	0
Aspartate aminotransferase increased ^† 1	10/246 (4.07%)	14	0/109 (0.00%)	0
Blood alkaline phosphatase increased ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Blood bilirubin increased ^† 1	2/246 (0.81%)	2	0/109 (0.00%)	0
Blood creatine phosphokinase increased ^† 1	2/246 (0.81%)	2	0/109 (0.00%)	0
Blood creatinine increased ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Blood fibrinogen decreased ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Blood pressure decreased ^† 1	0/246 (0.00%)	0	1/109 (0.92%)	1
Ejection fraction decreased ^† 1	0/246 (0.00%)	0	1/109 (0.92%)	1
Electrocardiogram QT prolonged ^† 1	2/246 (0.81%)	3	0/109 (0.00%)	0
Gamma-glutamyltransferase increased ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
General physical condition abnormal ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Liver function test increased ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Menstruation normal ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Neutrophil count decreased ^† 1	4/246 (1.63%)	6	0/109 (0.00%)	0
Norovirus test positive ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Platelet count decreased ^† 1	5/246 (2.03%)	11	0/109 (0.00%)	0
Transaminases increased ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
White blood cell count decreased ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
White blood cell count increased ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Metabolism and nutrition disorders
Decreased appetite ^† 1	2/246 (0.81%)	2	0/109 (0.00%)	0
Dehydration ^† 1	2/246 (0.81%)	2	0/109 (0.00%)	0
Failure to thrive ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Hyperglycaemia ^† 1	0/246 (0.00%)	0	1/109 (0.92%)	2
Hyperphosphataemia ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Hypoglycaemia ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Hypokalaemia ^† 1	0/246 (0.00%)	0	1/109 (0.92%)	1
Hyponatraemia ^† 1	2/246 (0.81%)	3	0/109 (0.00%)	0
Hyponatraemic syndrome ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Hypophosphataemia ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Metabolic acidosis ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Tumour lysis syndrome ^† 1	1/246 (0.41%)	1	2/109 (1.83%)	2
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	3/246 (1.22%)	3	0/109 (0.00%)	0
Arthritis ^† 1	2/246 (0.81%)	2	0/109 (0.00%)	0
Back pain ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Bone pain ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Joint effusion ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Joint swelling ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Muscular weakness ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Myositis ^† 1	3/246 (1.22%)	3	0/109 (0.00%)	0
Osteoarthritis ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Pain in extremity ^† 1	0/246 (0.00%)	0	1/109 (0.92%)	1
Pain in jaw ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Soft tissue necrosis ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia ^† 1	33/246 (13.41%)	38	4/109 (3.67%)	6
Acute myeloid leukaemia recurrent ^† 1	7/246 (2.85%)	9	0/109 (0.00%)	0
Cancer pain ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Central nervous system leukaemia ^† 1	2/246 (0.81%)	2	0/109 (0.00%)	0
Gastric cancer ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Leukaemia cutis ^† 1	2/246 (0.81%)	2	0/109 (0.00%)	0
Leukaemia recurrent ^† 1	1/246 (0.41%)	1	1/109 (0.92%)	2
Malignant neoplasm progression ^† 1	0/246 (0.00%)	0	1/109 (0.92%)	2
Neoplasm malignant ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Oesophageal carcinoma ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Soft tissue sarcoma ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Squamous cell carcinoma ^† 1	0/246 (0.00%)	0	1/109 (0.92%)	2
Nervous system disorders
Amnesia ^† 1	0/246 (0.00%)	0	1/109 (0.92%)	1
Brain oedema ^† 1	2/246 (0.81%)	2	0/109 (0.00%)	0
Cerebellar haemorrhage ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Cerebral haemorrhage ^† 1	3/246 (1.22%)	3	0/109 (0.00%)	0
Cerebral infarction ^† 1	0/246 (0.00%)	0	1/109 (0.92%)	1
Cerebrovascular accident ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Cognitive disorder ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Depressed level of consciousness ^† 1	2/246 (0.81%)	2	0/109 (0.00%)	0
Dizziness ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Haemorrhage intracranial ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Haemorrhagic stroke ^† 1	0/246 (0.00%)	0	1/109 (0.92%)	1
Headache ^† 1	5/246 (2.03%)	5	0/109 (0.00%)	0
Hemiplegia ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Hydrocephalus ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Posterior reversible encephalopathy syndrome ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Presyncope ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Seizure ^† 1	2/246 (0.81%)	2	0/109 (0.00%)	0
Somnolence ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Syncope ^† 1	7/246 (2.85%)	8	0/109 (0.00%)	0
Tremor ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Psychiatric disorders
Confusional state ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Depression ^† 1	0/246 (0.00%)	0	1/109 (0.92%)	1
Hallucination ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Mania ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Mental status changes ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Renal and urinary disorders
Acute kidney injury ^† 1	16/246 (6.50%)	20	4/109 (3.67%)	5
Haematuria ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Renal impairment ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Reproductive system and breast disorders
Pelvic pain ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Vaginal haemorrhage ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome ^† 1	4/246 (1.63%)	4	0/109 (0.00%)	0
Acute respiratory failure ^† 1	2/246 (0.81%)	2	1/109 (0.92%)	1
Aspiration ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Cough ^† 1	2/246 (0.81%)	2	0/109 (0.00%)	0
Dyspnoea ^† 1	10/246 (4.07%)	10	2/109 (1.83%)	2
Hypoxia ^† 1	4/246 (1.63%)	4	2/109 (1.83%)	2
Interstitial lung disease ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Lung disorder ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Organising pneumonia ^† 1	2/246 (0.81%)	3	0/109 (0.00%)	0
Oropharyngeal pain ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Pleural effusion ^† 1	2/246 (0.81%)	3	0/109 (0.00%)	0
Pneumomediastinum ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Pneumonia aspiration ^† 1	2/246 (0.81%)	3	0/109 (0.00%)	0
Pneumothorax ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Productive cough ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Pulmonary alveolar haemorrhage ^† 1	0/246 (0.00%)	0	1/109 (0.92%)	1
Pulmonary embolism ^† 1	2/246 (0.81%)	2	0/109 (0.00%)	0
Pulmonary haemorrhage ^† 1	0/246 (0.00%)	0	1/109 (0.92%)	1
Pulmonary hypertension ^† 1	2/246 (0.81%)	2	0/109 (0.00%)	0
Respiratory failure ^† 1	7/246 (2.85%)	8	3/109 (2.75%)	5
Skin and subcutaneous tissue disorders
Acute febrile neutrophilic dermatosis ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Dermatitis bullous ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Drug eruption ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Petechiae ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Psoriasis ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Skin necrosis ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Swelling face ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Toxic skin eruption ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Vascular disorders
Deep vein thrombosis ^† 1	0/246 (0.00%)	0	1/109 (0.92%)	1
Embolism ^† 1	3/246 (1.22%)	3	1/109 (0.92%)	1
Haematoma ^† 1	3/246 (1.22%)	5	0/109 (0.00%)	0
Haemorrhage ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Hypertension ^† 1	1/246 (0.41%)	1	1/109 (0.92%)	1
Hypotension ^† 1	6/246 (2.44%)	6	1/109 (0.92%)	1
Orthostatic hypotension ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
Venous thrombosis ^† 1	1/246 (0.41%)	1	0/109 (0.00%)	0
1 Term from vocabulary, MedDRA 19.1 † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Gilteritinib		Salvage Chemotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	242/246 (98.37%)		103/109 (94.50%)
Blood and lymphatic system disorders
Anaemia ^† 1	110/246 (44.72%)	471	38/109 (34.86%)	80
Disseminated intravascular coagulation ^† 1	7/246 (2.85%)	8	6/109 (5.50%)	6
Febrile neutropenia ^† 1	57/246 (23.17%)	72	32/109 (29.36%)	37
Neutropenia ^† 1	31/246 (12.60%)	105	16/109 (14.68%)	18
Thrombocytopenia ^† 1	62/246 (25.20%)	294	17/109 (15.60%)	41
Cardiac disorders
Tachycardia ^† 1	12/246 (4.88%)	13	7/109 (6.42%)	7
Eye disorders
Dry eye ^† 1	24/246 (9.76%)	25	3/109 (2.75%)	3
Retinal haemorrhage ^† 1	19/246 (7.72%)	22	2/109 (1.83%)	2
Vision blurred ^† 1	20/246 (8.13%)	22	1/109 (0.92%)	1
Gastrointestinal disorders
Abdominal pain ^† 1	36/246 (14.63%)	42	16/109 (14.68%)	17
Constipation ^† 1	76/246 (30.89%)	94	16/109 (14.68%)	18
Diarrhoea ^† 1	79/246 (32.11%)	123	32/109 (29.36%)	37
Dry mouth ^† 1	20/246 (8.13%)	21	3/109 (2.75%)	3
Dyspepsia ^† 1	13/246 (5.28%)	16	7/109 (6.42%)	7
Mouth ulceration ^† 1	13/246 (5.28%)	14	2/109 (1.83%)	2
Nausea ^† 1	79/246 (32.11%)	120	36/109 (33.03%)	41
Stomatitis ^† 1	34/246 (13.82%)	44	15/109 (13.76%)	19
Vomiting ^† 1	53/246 (21.54%)	79	15/109 (13.76%)	16
General disorders
Asthenia ^† 1	36/246 (14.63%)	50	10/109 (9.17%)	11
Chills ^† 1	22/246 (8.94%)	32	8/109 (7.34%)	9
Fatigue ^† 1	70/246 (28.46%)	98	14/109 (12.84%)	17
Mucosal inflammation ^† 1	13/246 (5.28%)	13	9/109 (8.26%)	11
Oedema ^† 1	15/246 (6.10%)	18	3/109 (2.75%)	3
Oedema peripheral ^† 1	59/246 (23.98%)	77	13/109 (11.93%)	19
Pain ^† 1	17/246 (6.91%)	21	1/109 (0.92%)	1
Pyrexia ^† 1	89/246 (36.18%)	136	31/109 (28.44%)	57
Immune system disorders
Graft versus host disease ^† 1	13/246 (5.28%)	18	1/109 (0.92%)	1
Infections and infestations
Cellulitis ^† 1	15/246 (6.10%)	17	1/109 (0.92%)	2
Lung infection ^† 1	14/246 (5.69%)	15	0/109 (0.00%)	0
Pneumonia ^† 1	23/246 (9.35%)	26	5/109 (4.59%)	5
Sinusitis ^† 1	13/246 (5.28%)	18	2/109 (1.83%)	3
Upper respiratory tract infection ^† 1	19/246 (7.72%)	32	3/109 (2.75%)	3
Injury, poisoning and procedural complications
Allergic transfusion reaction ^† 1	10/246 (4.07%)	17	7/109 (6.42%)	13
Contusion ^† 1	14/246 (5.69%)	16	3/109 (2.75%)	3
Fall ^† 1	18/246 (7.32%)	27	1/109 (0.92%)	1
Investigations
Alanine aminotransferase increased ^† 1	99/246 (40.24%)	230	10/109 (9.17%)	20
Aspartate aminotransferase increased ^† 1	96/246 (39.02%)	237	13/109 (11.93%)	21
Blood alkaline phosphatase increased ^† 1	55/246 (22.36%)	112	2/109 (1.83%)	2
Blood bilirubin increased ^† 1	21/246 (8.54%)	68	7/109 (6.42%)	9
Blood creatine phosphokinase increased ^† 1	33/246 (13.41%)	94	0/109 (0.00%)	0
Blood creatinine increased ^† 1	29/246 (11.79%)	64	4/109 (3.67%)	4
Blood lactate dehydrogenase increased ^† 1	22/246 (8.94%)	33	5/109 (4.59%)	5
Electrocardiogram QT prolonged ^† 1	16/246 (6.50%)	19	0/109 (0.00%)	0
International normalised ratio increased ^† 1	13/246 (5.28%)	17	5/109 (4.59%)	6
Neutrophil count decreased ^† 1	40/246 (16.26%)	161	12/109 (11.01%)	28
Platelet count decreased ^† 1	53/246 (21.54%)	245	28/109 (25.69%)	76
Weight decreased ^† 1	13/246 (5.28%)	21	3/109 (2.75%)	4
Weight increased ^† 1	13/246 (5.28%)	17	2/109 (1.83%)	6
White blood cell count decreased ^† 1	34/246 (13.82%)	127	19/109 (17.43%)	27
Metabolism and nutrition disorders
Decreased appetite ^† 1	44/246 (17.89%)	52	20/109 (18.35%)	22
Dehydration ^† 1	13/246 (5.28%)	15	1/109 (0.92%)	1
Hyperglycaemia ^† 1	36/246 (14.63%)	62	13/109 (11.93%)	18
Hyperkalaemia ^† 1	22/246 (8.94%)	32	1/109 (0.92%)	1
Hyperuricaemia ^† 1	23/246 (9.35%)	30	2/109 (1.83%)	2
Hypoalbuminaemia ^† 1	32/246 (13.01%)	64	7/109 (6.42%)	11
Hypocalcaemia ^† 1	47/246 (19.11%)	110	6/109 (5.50%)	14
Hypokalaemia ^† 1	71/246 (28.86%)	183	33/109 (30.28%)	48
Hypomagnesaemia ^† 1	39/246 (15.85%)	67	12/109 (11.01%)	15
Hyponatraemia ^† 1	32/246 (13.01%)	78	6/109 (5.50%)	7
Hypophosphataemia ^† 1	40/246 (16.26%)	69	5/109 (4.59%)	5
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	28/246 (11.38%)	42	6/109 (5.50%)	8
Back pain ^† 1	29/246 (11.79%)	32	13/109 (11.93%)	13
Muscular weakness ^† 1	19/246 (7.72%)	22	1/109 (0.92%)	2
Myalgia ^† 1	35/246 (14.23%)	45	4/109 (3.67%)	4
Pain in extremity ^† 1	36/246 (14.63%)	44	8/109 (7.34%)	11
Nervous system disorders
Dizziness ^† 1	48/246 (19.51%)	64	2/109 (1.83%)	2
Dysgeusia ^† 1	25/246 (10.16%)	28	5/109 (4.59%)	5
Headache ^† 1	61/246 (24.80%)	87	16/109 (14.68%)	18
Paraesthesia ^† 1	21/246 (8.54%)	25	0/109 (0.00%)	0
Psychiatric disorders
Anxiety ^† 1	19/246 (7.72%)	21	1/109 (0.92%)	1
Depression ^† 1	11/246 (4.47%)	12	7/109 (6.42%)	7
Insomnia ^† 1	40/246 (16.26%)	44	6/109 (5.50%)	6
Renal and urinary disorders
Haematuria ^† 1	19/246 (7.72%)	21	5/109 (4.59%)	6
Respiratory, thoracic and mediastinal disorders
Cough ^† 1	70/246 (28.46%)	96	11/109 (10.09%)	13
Dyspnoea ^† 1	50/246 (20.33%)	67	7/109 (6.42%)	8
Dyspnoea exertional ^† 1	15/246 (6.10%)	18	0/109 (0.00%)	0
Epistaxis ^† 1	42/246 (17.07%)	51	8/109 (7.34%)	8
Nasal congestion ^† 1	17/246 (6.91%)	20	1/109 (0.92%)	1
Oropharyngeal pain ^† 1	21/246 (8.54%)	24	8/109 (7.34%)	8
Pleural effusion ^† 1	16/246 (6.50%)	17	2/109 (1.83%)	3
Productive cough ^† 1	16/246 (6.50%)	20	2/109 (1.83%)	2
Skin and subcutaneous tissue disorders
Dry skin ^† 1	15/246 (6.10%)	19	3/109 (2.75%)	3
Erythema ^† 1	13/246 (5.28%)	16	4/109 (3.67%)	4
Pruritus ^† 1	24/246 (9.76%)	29	3/109 (2.75%)	3
Rash ^† 1	36/246 (14.63%)	48	10/109 (9.17%)	10
Rash maculo-papular ^† 1	10/246 (4.07%)	13	6/109 (5.50%)	6
Vascular disorders
Hypertension ^† 1	33/246 (13.41%)	56	10/109 (9.17%)	10
Hypotension ^† 1	38/246 (15.45%)	44	7/109 (6.42%)	8
1 Term from vocabulary, MedDRA 19.1 † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

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Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

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

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Name/Title:	Clinical Trial Disclosure
Organization:	Astellas Pharma Global Development, Inc.
Phone:	800-888-7704
EMail:	astellas.resultsdisclosure@astellas.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, Montesinos P, Baer MR, Larson RA, Ustun C, Fabbiano F, Erba HP, Di Stasi A, Stuart R, Olin R, Kasner M, Ciceri F, Chou WC, Podoltsev N, Recher C, Yokoyama H, Hosono N, Yoon SS, Lee JH, Pardee T, Fathi AT, Liu C, Hasabou N, Liu X, Bahceci E, Levis MJ. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N Engl J Med. 2019 Oct 31;381(18):1728-1740. doi: 10.1056/NEJMoa1902688.

Layout table for additonal information

Responsible Party:	Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )
ClinicalTrials.gov Identifier:	NCT02421939
Other Study ID Numbers:	2215-CL-0301 2015-000140-42 ( EudraCT Number )
First Submitted:	April 16, 2015
First Posted:	April 21, 2015
Results First Submitted:	September 12, 2019
Results First Posted:	October 17, 2019
Last Update Posted:	March 23, 2021

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