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Clinical Trial Results:
A Phase 1b/2 Study of the Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of the Selective SYK Inhibitor Lanraplenib (LANRA) in Combination with the FLT3 Inhibitor Gilteritinib, in Patients with FLT3-mutated Relapsed or Refractory AML

Summary
EudraCT number	2022-001279-15
Trial protocol	ES
Global end of trial date	09 Apr 2024

Results information
Results version number	v1(current)
This version publication date	27 Jul 2024
First version publication date	27 Jul 2024
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

KB-LANRA-1001

ISRCTN number

US NCT number

NCT05028751

WHO universal trial number (UTN)

Other trial identifiers

IND: 156759

Sponsor organisation name

Kronos Bio, Inc.

Sponsor organisation address

1300 So. El Camino Real, Suite 400, San Mateo, CA, United States, 94402

Public contact

VP, Corporate Affairs,, Kronos Bio, Inc., +1 16507815200, media@kronosbio.com

Scientific contact

VP, Corporate Affairs,, Kronos Bio, Inc., +1 16507815200, media@kronosbio.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

09 Apr 2024

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

09 Apr 2024

Was the trial ended prematurely?

Yes

Main objective of the trial

For Phase 1b: To evaluate the safety of LANRA in combination with the FMS-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib, in participants with relapsed/refractory (R/R) FLT3-mutated AML. For Phase 2: To further evaluate the safety of LANRA at its recommended Phase 2 dose (RP2D) in combination with gilteritinib in participants with FLT3-mutated AML.

Protection of trial subjects

The investigator ensured that this study was conducted in accordance with the principles of the Declaration of Helsinki, International Council for Harmonisation (ICH) Good Clinical Practice (GCP), and other country-specific requirements, as applicable.

Background therapy

Evidence for comparator

Actual start date of recruitment

05 Aug 2022

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Spain: 12

Country: Number of subjects enrolled

United States: 12

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

A total of 24 participants were enrolled at sites in the United States and Europe.

Screening details

A total of 35 participants were screened, of which 24 participants were enrolled and received study treatment.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

LANRA 20 mg QD + Gilteritinib 120 mg QD

Arm description

Participants received LANRA 20 mg once daily (QD) as oral tablets in consecutive 28-day cycles starting from Cycle 1 Day 1. Participants also received gilteritinib 120 mg QD as oral tablets in consecutive 28-day cycles starting from Cycle 1 Day 2. Participants received treatment until progression/relapse or lack of at least a partial remission (PR) after 6 months of study treatment, intolerance, or withdrawal from treatment by the participant or study investigator.

Arm type

Experimental

Investigational medicinal product name

LANRA

Investigational medicinal product code

Other name

Lanraplenib

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

20 mg QD oral tablets.

Investigational medicinal product name

Gilteritinib

Investigational medicinal product code

Other name

Xospata

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

120 mg QD oral tablets.

LANRA 40 mg QD + Gilteritinib 120 mg QD

Arm description

Participants received LANRA 40 mg QD as oral tablets in consecutive 28-day cycles starting from Cycle 1 Day 1. Participants also received gilteritinib 120 mg QD as oral tablets in consecutive 28-day cycles starting from Cycle 1 Day 2. Participants received treatment until progression/relapse or lack of at least a PR after 6 months of study treatment, intolerance, or withdrawal from treatment by the participant or study investigator.

Arm type

Experimental

Investigational medicinal product name

LANRA

Investigational medicinal product code

Other name

Lanraplenib

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

40 mg QD oral tablets.

Investigational medicinal product name

Gilteritinib

Investigational medicinal product code

Other name

Xospata

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

120 mg QD oral tablets.

LANRA 60 mg QD + Gilteritinib 120 mg QD

Arm description

Participants received LANRA 60 mg QD as oral tablets in consecutive 28-day cycles starting from Cycle 1 Day 1. Participants also received gilteritinib 120 mg QD as oral tablets in consecutive 28-day cycles starting from Cycle 1 Day 2. Participants received treatment until progression/relapse or lack of at least a PR after 6 months of study treatment, intolerance, or withdrawal from treatment by the participant or study investigator.

Arm type

Experimental

Investigational medicinal product name

LANRA

Investigational medicinal product code

Other name

Lanraplenib

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

60 mg QD oral tablets.

Investigational medicinal product name

Gilteritinib

Investigational medicinal product code

Other name

Xospata

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

120 mg QD oral tablets.

LANRA 90 mg QD + Gilteritinib 120 mg QD

Arm description

Participants received LANRA 90 mg QD as oral tablets in consecutive 28-day cycles starting from Cycle 1 Day 1. Participants also received gilteritinib 120 mg QD as oral tablets in consecutive 28-day cycles starting from Cycle 1 Day 2. Participants received treatment until progression/relapse or lack of at least a PR after 6 months of study treatment, intolerance, or withdrawal from treatment by the participant or study investigator.

Arm type

Experimental

Investigational medicinal product name

LANRA

Investigational medicinal product code

Other name

Lanraplenib

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

90 mg QD oral tablets.

Investigational medicinal product name

Gilteritinib

Investigational medicinal product code

Other name

Xospata

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

120 mg QD oral tablets.

Number of subjects in period 1	LANRA 20 mg QD + Gilteritinib 120 mg QD	LANRA 40 mg QD + Gilteritinib 120 mg QD	LANRA 60 mg QD + Gilteritinib 120 mg QD	LANRA 90 mg QD + Gilteritinib 120 mg QD
Started	14	3	3	4
Completed	0	0	0	0
Not completed	14	3	3	4
Consent withdrawn by subject	-	-	1	-
Death	9	3	2	4
Miscellaneous	2	-	-	-
Study terminated by sponsor	3	-	-	-

Baseline characteristics

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Reporting group title

LANRA 20 mg QD + Gilteritinib 120 mg QD

Reporting group description

Reporting group title

LANRA 40 mg QD + Gilteritinib 120 mg QD

Reporting group description

Reporting group title

LANRA 60 mg QD + Gilteritinib 120 mg QD

Reporting group description

Reporting group title

LANRA 90 mg QD + Gilteritinib 120 mg QD

Reporting group description

Reporting group values	LANRA 20 mg QD + Gilteritinib 120 mg QD	LANRA 40 mg QD + Gilteritinib 120 mg QD	LANRA 60 mg QD + Gilteritinib 120 mg QD	LANRA 90 mg QD + Gilteritinib 120 mg QD	Total
Number of subjects	14	3	3	4	24
Age categorical
Units: Subjects
Adults (18-64 years)	3	2	1	0	6
From 65-84 years	11	1	2	4	18
Age continuous
Units: years
arithmetic mean (standard deviation)	67.9 ( 19.00 )	54.0 ( 16.82 )	70.0 ( 13.45 )	74.3 ( 3.69 )	-
Gender categorical
Units: Subjects
Female	5	1	1	2	9
Male	9	2	2	2	15
Race/Ethnicity
Units: Subjects
White	13	2	3	4	22
Not Reported	1	0	0	0	1
Other	0	1	0	0	1
Ethnicity
Units: Subjects
Hispanic or Latino	3	2	0	1	6
Not Hispanic or Latino	8	1	3	3	15
Unknown or Not Reported	3	0	0	0	3

End points

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Reporting group title

LANRA 20 mg QD + Gilteritinib 120 mg QD

Reporting group description

Reporting group title

LANRA 40 mg QD + Gilteritinib 120 mg QD

Reporting group description

Reporting group title

LANRA 60 mg QD + Gilteritinib 120 mg QD

Reporting group description

Reporting group title

LANRA 90 mg QD + Gilteritinib 120 mg QD

Reporting group description

Subject analysis set title

LANRA QD + Gilteritinib 120 mg QD

Subject analysis set type

Full analysis

Subject analysis set description

Participants received LANRA QD as oral tablets in consecutive 28-day cycles starting from Cycle 1 Day 1. Participants also received gilteritinib 120 mg QD as oral tablets in consecutive 28-day cycles starting from Cycle 1 Day 2. Participants received treatment until progression/relapse or lack of at least a PR after 6 months of study treatment, intolerance, or withdrawal from treatment by the participant or study investigator.

Primary: Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE)

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End point title

Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) ^[1]

End point description

A TEAE was any unfavorable or unintended sign, symptom, laboratory abnormality or disease (new or exacerbated) temporally associated with the use of a study drug, whether considered causally related to the study drug or not that started after the first dose of the earliest study drug through the lesser of non-protocol anti-leukemic therapy initiation or end of treatment visit. A serious TEAE was defined as any TEAE that: • Resulted in death. • Was life-threatening. • Required or prolonged a pre-existing hospitalization. • Resulted in disability/incapacity. • Was a congenital anomaly/birth defect. • Was considered a significant medical event by the investigator. Safety Population: Consisted of all participants who received ≥ 1 dose of either study drug and had at least 1 on-treatment safety-related observation.

End point type

Primary

End point timeframe

Cycle 1 Day 1 (each cycle was 28 days) to 30 days after last dose of either LANRA or gilteritinib or initiation of non-protocol antileukemic therapy, whichever was earlier (maximum duration of treatment was 183 days)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No comparative statistical analyses were planned.

End point values	LANRA 20 mg QD + Gilteritinib 120 mg QD	LANRA 40 mg QD + Gilteritinib 120 mg QD	LANRA 60 mg QD + Gilteritinib 120 mg QD	LANRA 90 mg QD + Gilteritinib 120 mg QD
Number of subjects analysed	14	3	3	4
Units: participants
TEAEs	14	3	3	4
TESAEs	11	3	3	4
Grade 3 or Grade 4 TEAEs	12	3	2	3
AEs Leading to Death (Grade 5)	2	0	1	4
TEAEs Related to LANRA	5	0	1	0
TEAEs Related to Gilteritinib	8	0	1	0
TEAEs Leading to Dose Reduction of LANRA	0	0	0	0
TEAEs Leading to Dose Reduction of Gilteritinib	0	0	0	0
TEAEs Leading to LANRA Interruption	9	0	0	2
TEAEs Leading to Gilteritinib Interruption	9	0	0	2
TEAEs Leading to LANRA Discontinuation	1	0	1	2
TEAEs Leading to Gilteritinib Discontinuation	1	0	1	2

No statistical analyses for this end point

Primary: Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) for LANRA

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End point title

Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) for LANRA ^[2]

End point description

A DLT was defined as any of the following occurring within the DLT assessment period: • A nonhematologic toxicity of Grade ≥ 3 that was at least possibly related to LANRA (with noted exceptions). • Any toxicity that resulted in administration of < 80% of the cumulative, Cycle 1 dose for either LANRA or gilteritinib. • Grade 4 neutropenia or thrombocytopenia lasting > 28 days after treatment onset that was not attributed to AML and was at least possibly related to LANRA. • Any toxicity that resulted in reduction in the dose of LANRA in Cycle 1. TEAEs were graded for severity based on the NCI-CTCAE version 5.0 as follows: • Grade 3 - Severe. • Grade 4 - Life-threatening. Safety Population: Consisted of all participants who received ≥ 1 dose of either study drug and had at least 1 on-treatment safety-related observation.

End point type

Primary

End point timeframe

Cycle 1 Day 1 to pre-dose Cycle 2 Day 1 (each cycle was 28 days)

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No comparative statistical analyses were planned.

End point values	LANRA 20 mg QD + Gilteritinib 120 mg QD	LANRA 40 mg QD + Gilteritinib 120 mg QD	LANRA 60 mg QD + Gilteritinib 120 mg QD	LANRA 90 mg QD + Gilteritinib 120 mg QD
Number of subjects analysed	14	3	3	4
Units: participants	0	0	0	0

No statistical analyses for this end point

Primary: Maximally Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) of LANRA in Combination With Standard Doses of Gilteritinib

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End point title

Maximally Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) of LANRA in Combination With Standard Doses of Gilteritinib ^[3]

End point description

The MTD/RP2D was defined as the highest dose with either 0 of 3 or no more than 1 of 6 patients with LANRA-related DLTs. All decisions regarding dose escalation including declaration of the MTD/RP2D were made by the dose-escalation committee (DEC).

End point type

Primary

End point timeframe

Cycle 1 Day 1 to pre-dose Cycle 2 Day 1 (each cycle was 28 days)

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No comparative statistical analyses were planned.

End point values	LANRA QD + Gilteritinib 120 mg QD
Number of subjects analysed	0 ^[4]
Units: mg
number (not applicable)

Notes
[4] - The study was terminated before MTD/RP2D could be determined.

No statistical analyses for this end point

Secondary: Maximal Plasma Concentration (Cmax) of LANRA

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End point title

Maximal Plasma Concentration (Cmax) of LANRA

End point description

Cmax was derived from plasma concentrations of LANRA using standard non-compartmental methods and actual sample times. Pharmacokinetic (PK) Population: Consisted of all participants with at least 1 post-dose LANRA plasma concentration with available data at each PK assessment time point.

End point type

Secondary

End point timeframe

Cycle 1 Day 1 and Cycle 1 Day 15: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours post-dose.

End point values	LANRA 20 mg QD + Gilteritinib 120 mg QD	LANRA 40 mg QD + Gilteritinib 120 mg QD	LANRA 60 mg QD + Gilteritinib 120 mg QD	LANRA 90 mg QD + Gilteritinib 120 mg QD
Number of subjects analysed	5	3	3	4 ^[5]
Units: ng/mL
arithmetic mean (standard deviation)
Cycle 1 Day 1	148 ( 59.7 )	340 ( 277 )	441 ( 146 )	694 ( 242 )
Cycle 1 Day 15	181 ( 41.3 )	298 ( 111 )	591 ( 112 )	597 ( 65.1 )

Notes
[5] - Cycle 1 Day 15 N = 2

No statistical analyses for this end point

Secondary: Time to Cmax (Tmax) of LANRA

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End point title

Time to Cmax (Tmax) of LANRA

End point description

Tmax was derived from plasma concentrations of LANRA using standard non-compartmental methods and actual sample times. PK Population: Consisted of all participants with at least 1 post-dose LANRA plasma concentration with available data at each PK assessment time point.

End point type

Secondary

End point timeframe

Cycle 1 Day 1 and Cycle 1 Day 15: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours post-dose.

End point values	LANRA 20 mg QD + Gilteritinib 120 mg QD	LANRA 40 mg QD + Gilteritinib 120 mg QD	LANRA 60 mg QD + Gilteritinib 120 mg QD	LANRA 90 mg QD + Gilteritinib 120 mg QD
Number of subjects analysed	5	3	3	4 ^[6]
Units: hours
arithmetic mean (standard deviation)
Cycle 1 Day 1	2.2 ( 1.3 )	3.5 ( 2.78 )	3.33 ( 2.31 )	2.5 ( 1.29 )
Cycle 1 Day 15	2.8 ( 0.837 )	2.0 ( 0.0 )	2.0 ( 1.0 )	3.0 ( 1.4 )

Notes
[6] - Cycle 1 Day 15 N = 2

No statistical analyses for this end point

Secondary: Area of the Plasma Concentration x Time Curve From Hour 0 to the Last Measurable Time Point (AUC0-last) of LANRA

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End point title

Area of the Plasma Concentration x Time Curve From Hour 0 to the Last Measurable Time Point (AUC0-last) of LANRA

End point description

AUC0-last was derived from plasma concentrations of LANRA using standard non-compartmental methods and actual sample times. PK Population: Consisted of all participants with at least 1 post-dose LANRA plasma concentration with available data at each PK assessment time point.

End point type

Secondary

End point timeframe

Cycle 1 Day 1 and Cycle 1 Day 15: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours post-dose.

End point values	LANRA 20 mg QD + Gilteritinib 120 mg QD	LANRA 40 mg QD + Gilteritinib 120 mg QD	LANRA 60 mg QD + Gilteritinib 120 mg QD	LANRA 90 mg QD + Gilteritinib 120 mg QD
Number of subjects analysed	5	3	3	4 ^[7]
Units: h*ng/mL
arithmetic mean (standard deviation)
Cycle 1 Day 1	1600 ( 462 )	3100 ( 1920 )	5240 ( 1550 )	7700 ( 1520 )
Cycle 1 Day 15	2510 ( 557 )	3320 ( 1100 )	8430 ( 1860 )	8490 ( 1360 )

Notes
[7] - Cycle 1 Day 15 N = 2

No statistical analyses for this end point

Secondary: Cmax of Gilteritinib

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End point title

Cmax of Gilteritinib

End point description

Cmax was derived from plasma concentrations of gilteritinib using standard non-compartmental methods and actual sample times. PK Population: Consisted of all participants with at least 1 post-dose gilteritinib plasma concentration with available data at each PK assessment time point.

End point type

Secondary

End point timeframe

Cycle 1 Day 15: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours post-dose.

End point values	LANRA 20 mg QD + Gilteritinib 120 mg QD	LANRA 40 mg QD + Gilteritinib 120 mg QD	LANRA 60 mg QD + Gilteritinib 120 mg QD	LANRA 90 mg QD + Gilteritinib 120 mg QD
Number of subjects analysed	5	3	3	2
Units: ng/mL
arithmetic mean (standard deviation)	434 ( 130 )	621 ( 392 )	352 ( 198 )	326 ( 168 )

No statistical analyses for this end point

Secondary: Tmax of Gilteritinib

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End point title

Tmax of Gilteritinib

End point description

Tmax was derived from plasma concentrations of gilteritinib using standard non-compartmental methods and actual sample times. PK Population: Consisted of all participants with at least 1 post-dose gilteritinib plasma concentration with available data at each PK assessment time point.

End point type

Secondary

End point timeframe

Cycle 1 Day 15: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours post-dose.

End point values	LANRA 20 mg QD + Gilteritinib 120 mg QD	LANRA 40 mg QD + Gilteritinib 120 mg QD	LANRA 60 mg QD + Gilteritinib 120 mg QD	LANRA 90 mg QD + Gilteritinib 120 mg QD
Number of subjects analysed	5	3	3	2
Units: hours
arithmetic mean (standard deviation)	5.8 ( 2.28 )	3 ( 2.65 )	5 ( 2.65 )	5.5 ( 3.54 )

No statistical analyses for this end point

Secondary: AUC0-last of Gilteritinib

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End point title

AUC0-last of Gilteritinib

End point description

AUC0-last was derived from plasma concentrations of gilteritinib using standard non-compartmental methods and actual sample times. PK Population: Consisted of all participants with at least 1 post-dose gilteritinib plasma concentration with available data at each PK assessment time point.

End point type

Secondary

End point timeframe

Cycle 1 Day 15: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours post-dose.

End point values	LANRA 20 mg QD + Gilteritinib 120 mg QD	LANRA 40 mg QD + Gilteritinib 120 mg QD	LANRA 60 mg QD + Gilteritinib 120 mg QD	LANRA 90 mg QD + Gilteritinib 120 mg QD
Number of subjects analysed	5	3	3	2
Units: h*ng/mL
arithmetic mean (standard deviation)	8610 ( 2630 )	12100 ( 8200 )	7460 ( 4870 )	6390 ( 3060 )

No statistical analyses for this end point

Secondary: Composite Complete Remission (cCR) Rate Per European LeukemiaNet (ELN) 2017 Criteria

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End point title

Composite Complete Remission (cCR) Rate Per European LeukemiaNet (ELN) 2017 Criteria

End point description

Percentage of participants with cCR included CR and CR with partial hematologic recovery (CRh). CR required all of the following, per ELN 2017 criteria: • Bone marrow blasts < 5 %. • Absence of circulating blasts and blasts with Auer rods. • Absence of extramedullary disease (ie, leukemia outside of bone marrow confirmed by biopsy). • Absolute neutrophil count > 1.0 x 10^9/L (1,000/μL). • Platelet count >100 x 10^9/L (100,000/μL). CRh required all aforementioned CR criteria except for the below: • Absolute neutrophil count > 0.5 x 10^9/L (500/μL) and/or; • Platelet count > 50 x 10^9/L (50,000/μL). Efficacy Evaluable Population: Consisted of all participants who received ≥1 dose of either study drug and completed the first protocol-specified response assessment or discontinued study treatment for toxicity or died prior to the first response assessment. Participants with no post-baseline response assessments were considered non-responders.

End point type

Secondary

End point timeframe

Cycle 1 Day 1 until occurrence of documented CR or CRh (maximum duration of follow-up was 16.1 months).

End point values	LANRA 20 mg QD + Gilteritinib 120 mg QD	LANRA 40 mg QD + Gilteritinib 120 mg QD	LANRA 60 mg QD + Gilteritinib 120 mg QD	LANRA 90 mg QD + Gilteritinib 120 mg QD
Number of subjects analysed	13	3	3	4
Units: percentage of participants
number (confidence interval 95%)	0 (0 to 24.7)	0 (0 to 70.8)	0 (0 to 70.8)	0 (0 to 60.2)

No statistical analyses for this end point

Secondary: Duration of Response (DOR)

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End point title

Duration of Response (DOR)

End point description

DOR was defined as the time from first qualifying response (CR/CRh) until relapse or death from any cause, as assessed by study investigators. CR required all of the following, per ELN 2017 criteria: • Bone marrow blasts < 5 %. • Absence of circulating blasts and blasts with Auer rods. • Absence of extramedullary disease (ie, leukemia outside of bone marrow confirmed by biopsy). • Absolute neutrophil count > 1.0 x 10^9/L (1,000/μL). • Platelet count >100 x 10^9/L (100,000/μL). CRh required all aforementioned CR criteria except for the below: • Absolute neutrophil count > 0.5 x 10^9/L (500/μL) and/or; • Platelet count > 50 x 10^9/L (50,000/μL). Relapse was defined as the reappearance of circulating blasts or ≥ 5% blasts in the bone marrow not attributable to any other cause or reappearance of cytologically or biopsy documented extramedullary disease. Efficacy Evaluable Population including only participants who had a CR/CRh.

End point type

Secondary

End point timeframe

From first qualifying response (CR/CRh) until relapse or death from any cause (maximum duration of follow-up was 16.1 months).

End point values	LANRA 20 mg QD + Gilteritinib 120 mg QD	LANRA 40 mg QD + Gilteritinib 120 mg QD	LANRA 60 mg QD + Gilteritinib 120 mg QD	LANRA 90 mg QD + Gilteritinib 120 mg QD
Number of subjects analysed	0 ^[8]	0 ^[9]	0 ^[10]	0 ^[11]
Units: months
arithmetic mean (standard deviation)	( )	( )	( )	( )

Notes
[8] - No participants had a CR/CRh so DOR was not estimable.
[9] - No participants had a CR/CRh so DOR was not estimable.
[10] - No participants had a CR/CRh so DOR was not estimable.
[11] - No participants had a CR/CRh so DOR was not estimable.

No statistical analyses for this end point

Secondary: Event-free Survival (EFS)

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End point title

Event-free Survival (EFS)

End point description

EFS was defined as the time from treatment onset until treatment failure (ie, failure to achieve CR/CRh), relapse from CR/CRh, or death from any cause. CR required all of the following: • Bone marrow blasts < 5 %. • Absence of circulating blasts and blasts with Auer rods. • Absence of extramedullary disease (ie, leukemia outside of bone marrow confirmed by biopsy). • Absolute neutrophil count > 1.0 x 10^9/L (1,000/μL). • Platelet count >100 x 10^9/L (100,000/μL). CRh required all aforementioned CR criteria except for the below: • Absolute neutrophil count > 0.5 x 10^9/L (500/μL) and/or; • Platelet count > 50 x 10^9/L (50,000/μL). Relapse was defined as the reappearance of circulating blasts or ≥ 5% blasts in the bone marrow not attributable to any other cause or reappearance of cytologically or biopsy documented extramedullary disease. Efficacy Evaluable Population.

End point type

Secondary

End point timeframe

Cycle 1 Day 1 to treatment failure (ie, failure to achieve CR or CRh), relapse from CR/CRh or death from any cause (maximum duration of follow-up was 16.1 months).

End point values	LANRA 20 mg QD + Gilteritinib 120 mg QD	LANRA 40 mg QD + Gilteritinib 120 mg QD	LANRA 60 mg QD + Gilteritinib 120 mg QD	LANRA 90 mg QD + Gilteritinib 120 mg QD
Number of subjects analysed	0 ^[12]	0 ^[13]	0 ^[14]	0 ^[15]
Units: months
number (confidence interval 95%)	( to )	( to )	( to )	( to )

Notes
[12] - No data was evaluable as no participants had a CR or CRh.
[13] - No data was evaluable as no participants had a CR or CRh.
[14] - No data was evaluable as no participants had a CR or CRh.
[15] - No data was evaluable as no participants had a CR or CRh.

No statistical analyses for this end point

Secondary: Overall Survival

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End point title

Overall Survival

End point description

Overall survival was defined as the time from enrollment until death from any cause. Overall survival was estimated using Kaplan-Meier methodology. 9999.9 = Upper limit was not reached due to low number of events. Safety Population: Consisted of all participants who received ≥ 1 dose of either study drug and had at least 1 on-treatment safety-related observation. Participants alive at last follow-up were censored at the date of last contact.

End point type

Secondary

End point timeframe

Enrollment until death from any cause (maximum duration of follow-up was 16.1 months).

End point values	LANRA 20 mg QD + Gilteritinib 120 mg QD	LANRA 40 mg QD + Gilteritinib 120 mg QD	LANRA 60 mg QD + Gilteritinib 120 mg QD	LANRA 90 mg QD + Gilteritinib 120 mg QD
Number of subjects analysed	14	3	3	4
Units: months
median (confidence interval 95%)	4.0 (0.9 to 10.9)	2.6 (2.2 to 9999.9)	3.7 (1.5 to 9999.9)	0.5 (0.3 to 9999.9)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Cycle 1 Day 1 to 30 days after last dose of either LANRA or gilteritinib or initiation of new, non-protocol, anti-leukemic therapy, if sooner. All-cause mortality: Enrollment to end of study.

Adverse event reporting additional description

Safety Population: Consisted of all participants who received ≥ 1 dose of either study drug and had at least 1 on-treatment safety-related observation.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

25.1

Reporting group title

LANRA 20 mg QD + Gilteritinib 120 mg QD

Reporting group description

Reporting group title

LANRA 40 mg QD + Gilteritinib 120 mg QD

Reporting group description

Reporting group title

LANRA 60 mg QD + Gilteritinib 120 mg QD

Reporting group description

Reporting group title

LANRA 90 mg QD + Gilteritinib 120 mg QD

Reporting group description

Serious adverse events	LANRA 20 mg QD + Gilteritinib 120 mg QD	LANRA 40 mg QD + Gilteritinib 120 mg QD	LANRA 60 mg QD + Gilteritinib 120 mg QD	LANRA 90 mg QD + Gilteritinib 120 mg QD
Total subjects affected by serious adverse events
subjects affected / exposed	11 / 14 (78.57%)	3 / 3 (100.00%)	3 / 3 (100.00%)	4 / 4 (100.00%)
number of deaths (all causes)	9	3	2	4
number of deaths resulting from adverse events	2	0	1	4
Injury, poisoning and procedural complications
Craniofacial fracture
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subdural haemorrhage
subjects affected / exposed	0 / 14 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypotension
subjects affected / exposed	0 / 14 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Superficial vein thrombosis
subjects affected / exposed	0 / 14 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardiac arrest
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Sinus tachycardia
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebral haemorrhage
subjects affected / exposed	0 / 14 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Intracranial mass
subjects affected / exposed	0 / 14 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Ischaemic stroke
subjects affected / exposed	0 / 14 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subarachnoid haemorrhage
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	5 / 14 (35.71%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 4 (25.00%)
occurrences causally related to treatment / all	1 / 8	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Hyperleukocytosis
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Leukocytosis
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	2 / 14 (14.29%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Neutropenic colitis
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	2 / 14 (14.29%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Acute febrile neutrophilic dermatosis
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rash maculo-papular
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Bacteraemia
subjects affected / exposed	2 / 14 (14.29%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchopulmonary aspergillosis
subjects affected / exposed	0 / 14 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
COVID-19
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Enterococcal bacteraemia
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Enterococcal infection
subjects affected / exposed	0 / 14 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Enterocolitis infectious
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia infection
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Klebsiella bacteraemia
subjects affected / exposed	0 / 14 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	2 / 14 (14.29%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Pneumonia fungal
subjects affected / exposed	0 / 14 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Pneumonia staphylococcal
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal bacteraemia
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Streptococcal bacteraemia
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	LANRA 20 mg QD + Gilteritinib 120 mg QD	LANRA 40 mg QD + Gilteritinib 120 mg QD	LANRA 60 mg QD + Gilteritinib 120 mg QD	LANRA 90 mg QD + Gilteritinib 120 mg QD
Total subjects affected by non serious adverse events
subjects affected / exposed	14 / 14 (100.00%)	3 / 3 (100.00%)	3 / 3 (100.00%)	3 / 4 (75.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Differentiation syndrome
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Haematoma
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Hypertension
subjects affected / exposed	0 / 14 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0
Orthostatic hypotension
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Hypotension
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	1	0	1	0
Catheter site pain
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Chest discomfort
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Chills
subjects affected / exposed	4 / 14 (28.57%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	4	0	1	0
Facial pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0
Fatigue
subjects affected / exposed	3 / 14 (21.43%)	0 / 3 (0.00%)	2 / 3 (66.67%)	0 / 4 (0.00%)
occurrences all number	3	0	4	0
Generalised oedema
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Localised oedema
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Malaise
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Mucosal inflammation
subjects affected / exposed	0 / 14 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0
Oedema peripheral
subjects affected / exposed	3 / 14 (21.43%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	3	1	0	0
Pain
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	1	0	0	1
Pyrexia
subjects affected / exposed	2 / 14 (14.29%)	1 / 3 (33.33%)	2 / 3 (66.67%)	0 / 4 (0.00%)
occurrences all number	4	2	2	0
Immune system disorders
Acute graft versus host disease
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Cough
subjects affected / exposed	3 / 14 (21.43%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	4	0	1	0
Dyspnoea
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Dyspnoea exertional
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Epistaxis
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	1	0	1	0
Haemoptysis
subjects affected / exposed	2 / 14 (14.29%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	2	0	0	0
Hypoxia
subjects affected / exposed	2 / 14 (14.29%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	3	0	0	0
Pulmonary alveolar haemorrhage
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Pulmonary oedema
subjects affected / exposed	0 / 14 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0
Tachypnoea
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Psychiatric disorders
Confusional state
subjects affected / exposed	2 / 14 (14.29%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	2	0	1	0
Depression
subjects affected / exposed	0 / 14 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	1
Dysphoria
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	4 / 14 (28.57%)	0 / 3 (0.00%)	2 / 3 (66.67%)	0 / 4 (0.00%)
occurrences all number	5	0	3	0
Amylase increased
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	2	0	0	0
Aspartate aminotransferase increased
subjects affected / exposed	3 / 14 (21.43%)	0 / 3 (0.00%)	2 / 3 (66.67%)	0 / 4 (0.00%)
occurrences all number	3	0	3	0
Bilirubin conjugated increased
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Blood alkaline phosphatase increased
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	1	0	1	0
Blood bilirubin increased
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	1	0	0	1
Blood creatinine increased
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Blood lactate dehydrogenase increased
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Clostridium test positive
subjects affected / exposed	0 / 14 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0
International normalised ratio increased
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Lipase increased
subjects affected / exposed	2 / 14 (14.29%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	3	0	2	0
Lymphocyte count decreased
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Neutrophil count decreased
subjects affected / exposed	3 / 14 (21.43%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	4	0	0	0
Pantoea agglomerans test positive
subjects affected / exposed	0 / 14 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	1
Platelet count decreased
subjects affected / exposed	2 / 14 (14.29%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	13	0	0	0
Troponin I increased
subjects affected / exposed	0 / 14 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0
White blood cell count decreased
subjects affected / exposed	3 / 14 (21.43%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	8	0	2	0
White blood cell count increased
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	2 / 14 (14.29%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	2	0	1	0
Face injury
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Fall
subjects affected / exposed	0 / 14 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0
Subdural haematoma
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	2	0	0	0
Transfusion reaction
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Cardiac disorders
Sinus tachycardia
subjects affected / exposed	0 / 14 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	0	0
Supraventricular tachycardia
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Nervous system disorders
Aphasia
subjects affected / exposed	0 / 14 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	2	0
Brain injury
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Dizziness
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	2	0	1	0
Dysgeusia
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Headache
subjects affected / exposed	0 / 14 (0.00%)	0 / 3 (0.00%)	2 / 3 (66.67%)	1 / 4 (25.00%)
occurrences all number	0	0	2	1
Hemiparesis
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	1	0	1	0
Lethargy
subjects affected / exposed	0 / 14 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0
Paraesthesia
subjects affected / exposed	2 / 14 (14.29%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	2	0	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 14 (7.14%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	6	1	0	0
Disseminated intravascular coagulation
subjects affected / exposed	0 / 14 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	1
Febrile neutropenia
subjects affected / exposed	2 / 14 (14.29%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	2	0	0	0
Leukopenia
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	2	0	0	0
Lymphopenia
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Neutropenia
subjects affected / exposed	1 / 14 (7.14%)	2 / 3 (66.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	5	0	0
Splenic infarction
subjects affected / exposed	0 / 14 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	1
Thrombocytopenia
subjects affected / exposed	1 / 14 (7.14%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	4	0	0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	2 / 14 (14.29%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	2	0	0	0
Abdominal pain upper
subjects affected / exposed	0 / 14 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0
Constipation
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Diarrhoea
subjects affected / exposed	4 / 14 (28.57%)	0 / 3 (0.00%)	2 / 3 (66.67%)	0 / 4 (0.00%)
occurrences all number	4	0	2	0
Dry mouth
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	2	0	0	0
Gingival bleeding
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Hypoaesthesia oral
subjects affected / exposed	0 / 14 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0
Melaena
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Mouth ulceration
subjects affected / exposed	0 / 14 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	1
Nausea
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	1	0	0	1
Stomatitis
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	2	0	1	0
Vomiting
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Hepatobiliary disorders
Cholestasis
subjects affected / exposed	0 / 14 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0
Skin and subcutaneous tissue disorders
Acute febrile neutrophilic dermatosis
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Alopecia
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Blister
subjects affected / exposed	0 / 14 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0
Dermatitis
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Rash
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	1	0	1	0
Skin mass
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Umbilical haematoma
subjects affected / exposed	0 / 14 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	1
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	1	0	1	0
Chronic kidney disease
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Haematuria
subjects affected / exposed	0 / 14 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0
Pollakiuria
subjects affected / exposed	0 / 14 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0
Renal haemorrhage
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Urinary incontinence
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Musculoskeletal and connective tissue disorders
Bone pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	2	0
Neck pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0
Rhabdomyolysis
subjects affected / exposed	0 / 14 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0
Infections and infestations
Bacteraemia
subjects affected / exposed	0 / 14 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0
Catheter site infection
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Clostridium difficile colitis
subjects affected / exposed	2 / 14 (14.29%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	2	0	0	0
Enterobacter infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	1
Enterococcal bacteraemia
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	1	0	0	1
Enterococcal infection
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Enterovirus infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0
Fungal infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	1
Nasopharyngitis
subjects affected / exposed	0 / 14 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0
Perichondritis
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Pneumonia
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Pneumonia klebsiella
subjects affected / exposed	0 / 14 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	0	1	0	0
Respiratory syncytial virus infection
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Rhinovirus infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0
Sepsis
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Septic shock
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Vulvovaginal mycotic infection
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 14 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0
Hyperglycaemia
subjects affected / exposed	3 / 14 (21.43%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	3	0	0	0
Hyperkalaemia
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Hypernatraemia
subjects affected / exposed	0 / 14 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	0	0	0	2
Hyperphosphataemia
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	1	0	0	0
Hyperuricaemia
subjects affected / exposed	2 / 14 (14.29%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	2	0	0	0
Hypoalbuminaemia
subjects affected / exposed	2 / 14 (14.29%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)
occurrences all number	5	0	0	1
Hypocalcaemia
subjects affected / exposed	5 / 14 (35.71%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	8	0	0	0
Hypokalaemia
subjects affected / exposed	0 / 14 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)
occurrences all number	0	0	2	1
Hypomagnesaemia
subjects affected / exposed	1 / 14 (7.14%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	1	0	1	0
Hyponatraemia
subjects affected / exposed	3 / 14 (21.43%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)
occurrences all number	3	0	0	0
Hypophosphataemia
subjects affected / exposed	0 / 14 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)
occurrences all number	0	0	1	0

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Were there any global substantial amendments to the protocol? Yes

27 Jul 2021

The following updates were made: • The starting dose of LANRA in Phase 1b was reduced from 30 mg QD to 20 mg QD. • A potential fourth dose cohort in Phase 1b was added. • The estimated study enrollment was increased to 55 participants (from 35 participants) to accommodate the potential fourth dose cohort and to allow greater statistical precision for the primary efficacy endpoint, composite CR (CR, CRh) rate. • A requirement was added that participants who had not achieved at least a PR after 6 months of study treatment must have permanently discontinued for lack of efficacy. • Criteria defining eligibility for renal function and left ventricular ejection fraction were modified. • Changes were made in the treatment modification guidelines for potential gilteritinib- or LANRA-related hematologic and non-hematologic toxicities. • Additional electrocardiograms (ECGs) timed to coincide with PK blood sampling were added. • Criteria for study treatment discontinuation were updated. • The requirement for cumulative treatment intensity of at least 80% for both study drugs in Cycle 1 as a condition of eligibility for DLT assessment in the absence of a DLT was added. Other changes to the DLT definition were made at the request of the Food and Drug Administration (FDA).

12 May 2022

The following updates were made: • The protocol was updated to reflect that the study is being conducted worldwide rather than only at US sites. • Eligibility was broadened to allow previous exposure to not only midostaurin or other multikinase inhibitors (eg, sorafenib) but also to gilteritinib or another selective FLT3 inhibitor, in order to expand the pool of eligible patients. • Updates were made to allow for interruption of treatment with LANRA in the event that treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor was required. • Contraceptive guidance was revised to require the use of a condom or other barrier method, in addition to other highly effective methods of contraception. • A new section was added to provide brief context regarding the added risks associated with COVID-19 resulting from compromised immunity due to cancer chemotherapy and to reference the latest US and European Union (EU) guidelines for clinical trial conduct in the setting of the COVID-19 pandemic. • Clarifications were added to indicate the difference between initial doses of study medications in Phase 1b (LANRA only on C1D1) and Phase 2 (combination therapy starting from C1D1).

14 Oct 2022

The following updates were made: • Differentiation Syndrome (DS) was designated as an adverse event of special interest (AESI). • The DLT criteria for nonhematologic toxicity of Grade ≥ 3 was modified to exclude “manifestations of DS that are responsive within 48 hours to treatment with systemic high-dose steroids plus supportive care interventions including but not limited to: hemodynamic support; use of diuretics for management of fluid retention; uricolytic agents in participants at risk for tumor lysis syndrome; and hydroxyurea in participants with hyperleukocytosis without evidence of infection, either with or without interruption of study treatment.” • The section on permitted medications was amended to allow intrathecal chemotherapy for prophylaxis against central nervous system (CNS) leukemia in accordance with institutional care standards.

17 Nov 2022

The following updates were made: • Revisions were made to clarify that both serious and non-serious DS events must be recorded promptly in the electronic data capture (EDC) system and reported promptly. • The DLT criteria for nonhematologic toxicity of Grade ≥ 3 was revised to exclude “Grade 3 or 4 DS … successfully managed with systemic high-dose steroids plus supportive care interventions with resolution within 7 days and without resulting end-organ damage.”

31 Mar 2023

The following updates were made: • Allocation of participants to backfill cohorts was allowed to better understand the safety, tolerability, PK, pharmacodynamics (PD), and antitumor activity of the study regimen across multiple dose levels. • The overall enrollment estimate was increased to 100 participants (from 55 participants) to accommodate enrollment to backfill cohorts. • The Screening Phase was extended to 21 days to allow greater flexibility for the scheduling of screening assessments. • Changes were made to allow for treatment interruptions of up to 28 days for specified toxicities and to provide additional clarity regarding treatment modifications for hematologic toxicities. • Additional detail was added regarding study treatment discontinuation in the setting of toxicity (and in particular, chronic, low-grade cumulative toxicities) or non-compliance with the study regimen. • The summary of gilteritinib safety data was updated to align with the Summary of Product Characteristics, which was the reference safety information for the study.

30 May 2023

The following updates were made: • A requirement was added to indicate that backfill participants may be added only to cohort(s) with at least 1 of the 3 to 6 participants initially enrolled to that cohort having achieved a response of CR, CRh, complete remission with incomplete blood count recovery (CRi), PR, or morphologic leukemia-free state (MLFS). • Treatment interruptions for nonhematologic toxicities were limited to a maximum of 14 days.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

In light of the Sponsor’s decision to terminate the trial at completion of Phase 1b, all analyses were restricted to results from Phase 1b participants only. Phase 2 was not enrolled.

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Clinical trials

Clinical Trial Results: A Phase 1b/2 Study of the Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of the Selective SYK Inhibitor Lanraplenib (LANRA) in Combination with the FLT3 Inhibitor Gilteritinib, in Patients with FLT3-mutated Relapsed or Refractory AML

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE)

Primary: Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE)

Primary: Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) for LANRA

Primary: Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) for LANRA

Primary: Maximally Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) of LANRA in Combination With Standard Doses of Gilteritinib

Primary: Maximally Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) of LANRA in Combination With Standard Doses of Gilteritinib

Secondary: Maximal Plasma Concentration (Cmax) of LANRA

Secondary: Maximal Plasma Concentration (Cmax) of LANRA

Secondary: Time to Cmax (Tmax) of LANRA

Secondary: Time to Cmax (Tmax) of LANRA

Secondary: Area of the Plasma Concentration x Time Curve From Hour 0 to the Last Measurable Time Point (AUC0-last) of LANRA

Secondary: Area of the Plasma Concentration x Time Curve From Hour 0 to the Last Measurable Time Point (AUC0-last) of LANRA

Secondary: Cmax of Gilteritinib

Secondary: Cmax of Gilteritinib

Secondary: Tmax of Gilteritinib

Secondary: Tmax of Gilteritinib

Secondary: AUC0-last of Gilteritinib

Secondary: AUC0-last of Gilteritinib

Secondary: Composite Complete Remission (cCR) Rate Per European LeukemiaNet (ELN) 2017 Criteria

Secondary: Composite Complete Remission (cCR) Rate Per European LeukemiaNet (ELN) 2017 Criteria

Secondary: Duration of Response (DOR)

Secondary: Duration of Response (DOR)

Secondary: Event-free Survival (EFS)

Secondary: Event-free Survival (EFS)

Secondary: Overall Survival

Secondary: Overall Survival

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase 1b/2 Study of the Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of the Selective SYK Inhibitor Lanraplenib (LANRA) in Combination with the FLT3 Inhibitor Gilteritinib, in Patients with FLT3-mutated Relapsed or Refractory AML