Clinical trial NCT05028751
Conditions: Acute Myeloid Leukemia Relapsed Acute Myeloid Leukemia Refractory Acute Myeloid Leukemia
Keywords: Acute Myeloid Leukemia Lanraplenib LANRA Relapsed Acute Myeloid Leukemia Refractory Acute Myeloid Leukemia
Sponsor: Kronos Bio
Start date: 2022-08-05; Completion date: 2024-04-09
Enrollment: 24 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The primary objective of this study is to evaluate the safety of lanraplenib (LANRA) in combination with the FMS-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib, in participants with relapsed or refractory (R/R) FLT3-mutated acute myeloid leukemia (AML).

Detailed description:

Arms: arm 1: 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 2: 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 3: 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 4: 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.
Interventions: intervention 1: Lanraplenib intervention 2: Gilteritinib
Intervention descriptions: intervention 1: Orally via tablets intervention 2: Orally via tablets

Protocol documents:
Prot_000.pdf: 
Protocol Number: KB-LANRA-1001 
 
Official Title: 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 
 
NCT Number: NCT05028751 
 
Document Date: 30 May 2023 


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Protocol KB-LANRA-1001 v7.0 Global 
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TITLE PAGE
Protocol Title:
 
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
Short Title:
A Study to Evaluate Lanraplenib (LANRA) in Combination With Gilteritinib in Participants 
with FLT3-mutated Relapsed or Refractory Acute Myeloid Leukemia (AML)
Protocol Number: KB-LANRA-1001
Version Number: 7.0 Global (Amendment 6.0 Global)
Compound: Lanraplenib (LANRA)
Brief Title: Lanraplenib plus gilteritinib therapy in patients with FLT3 mutated, R/R AML
Study Phase: 1b/2
Sponsor Name: Kronos Bio, Inc.
Legal Registered Address: 1300 So. El Camino Real
Suite 400
San Mateo, CA 94402
Regulatory Agency Identifier Number(s):
IND: 
156759
EudraCT:
2022-001279-15
Approval Date: 30 May 2023




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Protocol KB-LANRA-1001 v7.0 Global 
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SIGNATURE OF INVESTIGATOR
Protocol title: 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
Protocol identifier:  
KB-LANRA-1001
This protocol is a confidential communication of Kronos Bio, Inc. (Kronos Bio). I confirm that 
I have read this protocol, understand it, and will execute the trial according to all of its 
specifications. I will also adhere consistently to the ethical principles originating in the 
Declaration of Helsinki and that are consistent with good clinical practices and applicable laws 
and regulations. Acceptance of this document constitutes my agreement that no unpublished 
information contained herein will be published or disclosed without prior written approval of 
Kronos Bio.
I have read this protocol in its entirety and agree to conduct the study accordingly.
Signature of investigator and Date:
________________________________________________
Printed name of investigator:
________________________________________________
Investigator title:
________________________________________________
Name and address of study site:
________________________________________________
________________________________________________
________________________________________________
________________________________________________


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Protocol KB-LANRA-1001 v7.0 Global 
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Table of Contents
1.0
Synopsis .....................................................................................................................9
2.0
Introduction.............................................................................................................15
2.1
FLT3-mutated Acute Myeloid Leukemia – Biology, Incidence, Prognosis.............15
2.2
Treatment of FLT3-mutated AML: ..........................................................................16
2.2.1
Gilteritinib:................................................................................................................16
2.3
SYK Inhibition as a Therapeutic Strategy in FLT3-mutated AML..........................17
2.4
Preclinical and Clinical Rationale for the Evaluation of Lanraplenib in 
Combination with Gilteritinib in FLT3-mutated AML.............................................18
2.4.1
Preclinical Rationale.................................................................................................18
2.4.2
Clinical Rationale – Results from a Phase 1b/2 Study of ENTO in Newly 
Diagnosed AML (including patients with FLT3-ITD AML) ...................................21
2.5
Risk Benefit Assessment ..........................................................................................21
2.5.1
Gilteritinib-associated Toxicities:.............................................................................21
2.5.2
Lanraplenib-associated Toxicities ............................................................................22
2.5.3
Potential for Overlapping Toxicities Resulting from the Combination of 
LANRA and Gilteritinib ...........................................................................................24
2.5.4
COVID-19 Considerations........................................................................................25
2.6
Rationale for Starting Dose of LANRA and Selection of Recommended 
Phase 2 Dose (RP2D) ...............................................................................................25
2.7
Study Conduct...........................................................................................................26
3.0
Objectives & Endpoints: ........................................................................................27
3.1
Phase 1b....................................................................................................................27
3.2
Phase 2......................................................................................................................28
4.0
Summary of Study Design......................................................................................30
4.1
Phase 1b....................................................................................................................30
4.2
Phase 2......................................................................................................................32
5.0
Patient Population...................................................................................................33
5.1
Inclusion Criteria ......................................................................................................33
5.2
Exclusion Criteria .....................................................................................................34
6.0
Organizational Framework ...................................................................................37
6.1
Screening and Enrollment.........................................................................................37
6.2
Treatment Phase........................................................................................................37
6.3
End of Treatment ......................................................................................................37
6.4
Post-treatment Follow-up .........................................................................................37
6.5
End of Study .............................................................................................................37
7.0
Test product, dose, mode of administration.........................................................38
7.1
Gilteritinib:................................................................................................................38
7.2
LANRA:....................................................................................................................38
8.0
Treatment Modifications........................................................................................40
8.1
Non-hematologic toxicities.......................................................................................40
8.1.1
Gilteritinib.................................................................................................................40


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8.1.2
LANRA.....................................................................................................................42
8.2
Hematologic toxicities..............................................................................................43
9.0
Treatment of Overdose...........................................................................................46
10.0
Concomitant Medications and Supportive Care Measures................................47
10.1
Permitted Medications..............................................................................................47
10.2
Prohibited Medications.............................................................................................47
10.3
Potential Drug Interactions.......................................................................................48
10.3.1
Gilteritinib.................................................................................................................48
10.3.2
LANRA.....................................................................................................................48
11.0
Study Assessments & Procedures..........................................................................49
11.1
Informed Consent .....................................................................................................55
11.2
Confirmation of Eligibility .......................................................................................55
11.3
Medical and Leukemia History.................................................................................55
11.4
Study Drug Dispensation..........................................................................................56
11.5
Pharmacokinetics......................................................................................................56
11.6
Pharmacodynamic (Biomarker) Assessments ..........................................................56
11.7
Safety Assessments...................................................................................................57
11.7.1 
Physical examination, vital signs, pulse oximetry....................................................57
11.7.2 
Laboratory assessments (hematology, clinical chemistries, coagulation, 
urinalysis, pregnancy testing) ...................................................................................57
11.7.3 
Cardiac function and ECG........................................................................................58
11.7.4 
ECOG performance status ........................................................................................59
11.7.5 
Prior and concomitant medications and procedures .................................................59
11.7.6 
Adverse events..........................................................................................................59
12.0
Efficacy Assessments ..............................................................................................60
12.1
Bone Marrow Examination.......................................................................................60
12.1.1 
Measurable Residual Disease (MRD).......................................................................60
13.0
Criteria for Study Treatment Discontinuation ....................................................61
14.0
Criteria for Study Discontinuation .......................................................................62
15.0
Statistical Considerations.......................................................................................63
15.1
Study Endpoints........................................................................................................63
15.2
Statistical Analysis....................................................................................................63
15.2.1 
Analysis populations.................................................................................................63
15.2.2 
Patient Disposition....................................................................................................64
15.2.3 
Demographics ...........................................................................................................64
15.2.4 
Medical History ........................................................................................................64
15.2.5 
Leukemia History......................................................................................................64
15.2.6 
Prior and Concomitant Medications .........................................................................65
15.2.7 
Safety Analyses.........................................................................................................65
15.2.8 
Extent of Exposure....................................................................................................66
15.2.9 
Pharmacokinetic Analyses........................................................................................67
15.2.10 Efficacy Analyses .....................................................................................................67


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15.2.11 Pharmacodynamic Analyses.....................................................................................67
15.3
Sample Size Considerations......................................................................................68
15.4
Interim Analysis........................................................................................................68
15.5
Final Analysis ...........................................................................................................68
15.6
Other Statistical Issues (eg, Multiplicity Adjustment, If Applicable) ......................68
16.0
Safety Monitoring and Reporting .........................................................................69
16.1
Definitions ................................................................................................................69
16.2
Assessment of Severity.............................................................................................69
16.3
Assessment of Causality...........................................................................................70
16.4
Follow-up of Adverse Events ...................................................................................70
16.5
Abnormal Laboratory Results...................................................................................71
16.6
Adverse Event Reporting Period ..............................................................................71
16.7
Instructions for Reporting Adverse Events...............................................................71
16.7.1 
Leukemic progression...............................................................................................71
16.7.2 
Death.........................................................................................................................71
16.7.3 
Differentiation Syndrome (DS).................................................................................71
16.7.4 
Reporting Serious Adverse Events (SAEs)...............................................................72
16.7.5 
Pregnancy Reporting.................................................................................................72
17.0
Study Committees and Communication of Results .............................................73
17.1
Dose-escalation committee (DEC) ...........................................................................73
17.2
Provision of Study Results and Information to Investigators...................................74
18.0
Administrative Requirements of the Investigator and Sponsor.........................75
18.1
Regulatory Authority Approval................................................................................75
18.2
Investigator Responsibilities.....................................................................................75
18.2.1 
Good Clinical Practice..............................................................................................75
18.2.2 
Ethical Study Conduct and IRB/IEC Approval ........................................................75
18.2.3 
Informed Consent......................................................................................................75
18.2.4 
Investigator Reporting Requirements .......................................................................76
18.2.5 
Confidentiality ..........................................................................................................76
18.2.6
Data Collection .........................................................................................................76
18.2.7 
Data Management/Coding ........................................................................................77
18.2.8 
Drug Accountability..................................................................................................77
18.2.9 
Inspections ................................................................................................................77
18.2.10 Protocol Adherence...................................................................................................78
18.2.11 Financial Disclosure..................................................................................................78
18.3
Protocol Amendments...............................................................................................78
18.4
Study Report and Publications..................................................................................78
18.5
Study/Study Center Closure......................................................................................79
18.6
Record Retention and Study Files ............................................................................80
18.7
Information Disclosures............................................................................................81
18.8
Joint Investigator/Sponsor Responsibilities..............................................................81
18.8.1 
Access to Information for Monitoring/Source Data Verification.............................81
18.8.2 
Access to Information for Auditing or Inspections...................................................81
19.0
References................................................................................................................82


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Appendix 1: Definition of DLT.............................................................................................85
Appendix 2: Response Criteria.............................................................................................86
Appendix 3: ECOG Performance Status Scale...................................................................89
Appendix 4: Potential for Drug-Drug Interactions ............................................................90
Appendix 5: Guidance on the Management of Clinical Trials During COVID-19
Pandemic..................................................................................................................92
Appendix 6:  Contraceptive and Barrier Guidance............................................................93
Definitions................................................................................................................................93
Contraception Guidance...........................................................................................................93
Pregnancy Testing....................................................................................................................94
Appendix 7: Recommended Adjustments to Anti-Platelet and Anti-Coagulant 
Therapy in AML.....................................................................................................96
Appendix 8:  List of Abbreviations and Terms...................................................................97
List of Tables
Table 1: 
Dose-escalation Scheme (Provisional) ........................................................... 30
Table 2: 
Treatment Modifications for Gilteritinib-Associated Toxicities .................... 40
Table 3: 
Dose Reductions for LANRA-Associated Toxicities..................................... 42
Table 4: 
Treatment Modifications for LANRA-Associated Toxicities ........................ 42
Table 5: 
Treatment Modifications for Hematologic Toxicities Attributed to Study 
Treatment........................................................................................................ 44
Table 6: 
Schedule of Assessments – Screening Through Cycle 2................................ 50
Table 7: 
Schedule of Assessments – Cycle 3+, End-of-Treatment, Post-treatment 
Follow-up........................................................................................................ 51
Table 8: 
Schedule of PK and PD Assessments – Phase 1b, Cycle 1, Day 1 (C1D1) 
to Cycle 1, Day 8 (C1D8) ............................................................................... 54
Table 9: 
Schedule of PK and PD Assessments – Phase 1b, Cycle 1, Day 15 (C1D15) 
to Cycle 2, Day 1 (C2D1) ............................................................................... 54
Table 10: 
Schedule of PK and PD Assessments – Phase 2, Cycle 1, Day 1 (C1D1) 
to Cycle 2, Day 1 (C2D1) ............................................................................... 54
Table 11: 
Safety Stopping Rules for Part 2..................................................................... 66


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List of Figures 
Figure 1: 
Ex vivo Evaluation of the Dose-Response Relationship for LANRA and 
ENTO in Leukapheresis-derived Primary AML Isolates ............................... 18
Figure 2: 
LANRA and ENTO Show Comparable Activity Across a Panel of AML 
and Lymphoma Cell Lines.............................................................................. 19
Figure 3: 
Synergistic Effects of LANRA in Combination with the FLT3 Inhibitor, 
Gilteritinib or the BCL2 Inhibitor Venetoclax in NPM1m, FLT3-ITD 
AML Models................................................................................................... 20
Figure 4: 
LANRA in Combination with Gilteritinib Shows Improved Clearance of 
Leukemic Cells and Extends Overall Survival in a FLT3-ITD AML 
Patient derived Xenograft Model.................................................................... 21








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Phase 1b: Eligible patients will enroll sequentially into one of the following dose cohorts for
PK/PD evaluations and determination of the MTD/RP2D of LANRA in combination with 
standard dose gilteritinib:
Cohort 1, LANRA 20 mg QD + gilteritinib 120 mg QD
Cohort 2, LANRA 40 mg QD + gilteritinib 120 mg QD
Cohort 3, LANRA 60 mg QD + gilteritinib 120 mg QD
Cohort 4, LANRA 90 mg QD + gilteritinib 120 mg QD
A “3 + 3” dose escalation scheme will be employed in which 1 DLT reported among the first 
3 evaluable patients in a dose cohort will prompt enrollment of 3 additional evaluable 
patients. More than 1 DLT attributed to LANRA among 6 patients evaluable for DLT would 
indicate an intolerable dose, thus rendering the most proximate lower dose with either 0 of 3 
or 1 of 6 patients with LANRA-related DLTs the MTD. The starting dose of LANRA is 
20 mg once daily (QD).
Phase 2: Following completion of Phase 1b, an expansion cohort consisting of patients who 
meet all eligibility criteria will enroll in order to further assess the safety, PK, PD, and 
anti-leukemic activity of the combination at the LANRA MTD/RP2D. For both Phase 1b and 
Phase 2, response assessments will be based on bone marrow and physical examinations and 
peripheral blood counts. Bone marrow aspirates will be performed on C2D1, C3D1 and 
every 3 cycles thereafter until the patient exhibits 2 consecutive bone marrow examinations 
indicating CR or CRh. Patients who have not achieved at least a partial response per ELN 
2017 criteria after 6 months of study treatment will permanently discontinue study treatment. 
Enrollment in Phase 2 will follow a two-stage design for assessment of the primary efficacy 
endpoint, composite CR (cCR) rate, including those patients who achieve a best response of
CR or CRh, as defined by ELN response criteria (Appendix 2).
Number of Participants:
Approximately 100 patients are estimated to enroll across both parts; patients will be enrolled 
from multiple trial sites worldwide for Phase 1b and Phase 2. In both Phase 1b and Phase 2,
patients will receive their assigned treatment regimen until progression/relapse or lack of 
response after 6 months of study treatment, intolerance, or withdrawal from study by the 
patient or study investigator.
Study Duration:
The study will be completed after all enrolled patients either relapse or die, or 5 years after 
the last patient enrolls (whichever is earlier) or the Sponsor terminates the trial.
Statistical Analysis: 
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a Statistical Analysis Plan (SAP). 


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Summary statistics and listings will be used to analyze the study data. Continuous variables 
will be summarized by means, standard deviations, medians, interquartile ranges, minimal 
and maximal values. Categorical variables will be summarized by number and percent.
Unless otherwise specified, data summaries and analyses described below will be reported by 
dose group and overall in Phase 1b and overall in Phase 2 using all available data. Missing 
data will not be imputed unless otherwise described in the SAP.
DLTs will be summarized by dose group. Descriptive summaries will be generated for all 
safety data including treatment-emergent adverse events (TEAEs) as well as changes from 
baseline in selected laboratory assessments, vital signs, physical findings and 
electrocardiograms (ECGs). All AEs will be graded for severity using National Cancer 
Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) v5.0 (Common 
Terminology Criteria for Adverse Events (CTCAE) (cancer.gov)).
Plasma concentrations of LANRA and gilteritinib will be tabulated and summarized by dose 
level, study day, and time in Phase 1b. The PK parameters for gilteritinib and LANRA (and 
if possible, LANRA major metabolites, if any) will be derived from plasma concentrations 
using standard non-compartmental methods and actual sample times. Minimally, the 
following PK parameters will be calculated: Cmax, Tmax, AUC0-last, accumulation ratio (Racc)
and if data permit, half-life (t½), area under the concentration time curve from time 0 
extrapolated to infinity (AUC0-inf), apparent clearance (CL/F), and apparent volume of 
distribution at steady state (Vss/F). PK parameters such as trough plasma concentration
(Ctrough) will be summarized in conjunction with sparse sampling in Phase 2. PK parameters 
will be summarized using descriptive statistics (N, arithmetic means, standard deviations,
minimal, median and maximal values, geometric means and percent coefficient of variation). 
The relationship between changes from baseline in QTc at specified time points post-dose 
and plasma concentrations of LANRA may be assessed. A separate plan for such analyses 
will be generated in accordance with principles outlined in International Council for
Harmonisation (ICH) Directive E14 with results reported separately from the main clinical 
study report for this trial. Other exposure-response relationships (efficacy, safety and 
biomarkers) may be conducted, if supported by sufficient data.
Best response (CR, CRh, complete remission with incomplete blood count recovery [CRi],
partial response [PR], stable disease [SD], and progressive disease [PD]) will be summarized 
for the efficacy-evaluable population by frequency distributions and percentages in 
accordance with ELN 2017 criteria (Appendix 2). Patients with no post-baseline response 
assessments will be considered non-responders. The 80% confidence intervals (CIs) for 
estimates of the proportion of patients with CR/CRh will be constructed with exact methods 
for the binomial distribution (eg, Clopper-Pearson intervals). Additionally, 80% CIs for 
estimates of the proportion of patients with any CR (CR, CRh, CRi) will be constructed in a 
similar manner.
EFS is defined as the time from C1D1 until treatment failure (ie, failure to achieve CR or 
CRh), relapse from CR/CRh or death from any cause. DOR is defined as the time from the 
first documented CR/CRh until relapse or death. Kaplan-Meier (KM) methodology will be 
used to estimate the medians for EFS and duration of response and at specified landmark 


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timepoints. The 80% CIs for estimates of the medians and landmark rates for EFS and 
duration of response will be calculated using log-log transformation. Duration of follow-up
will be estimated using the reverse KM method. Patients who do not experience the event of 
interest will be censored at the last assessment of response at which they were both alive and
relapse-free. All summaries of EFS and those for duration of response will employ the safety 
and efficacy evaluable populations, respectively. OS will be estimated using KM 
methodology. Patients alive at last follow-up will be censored at the date of last contact.


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2.0
Introduction
2.1
FLT3-mutated Acute Myeloid Leukemia – Biology, Incidence, 
Prognosis 
FMS-like tyrosine kinase 3 (FLT3) is a transmembrane ligand-activated receptor tyrosine
kinase that is normally expressed by lineage-restricted hematopoietic stem or progenitor cells 
and plays an important role in the early stages of both myeloid and lymphoid lineage 
development (Pratz and Levis, 2017). FLT ligand binds and activates FLT3, promoting cell 
survival, proliferation, and differentiation through various signaling pathways, including
PI3K, RAS, and STAT5 (Daver et al, 2019). Mutations of the FLT3 gene are found in 
approximately 30% of newly diagnosed patients with acute myeloid leukemia (AML) and 
occur as either in-frame, internal tandem duplications (ITDs) of between 3 and >100 amino 
acids in the juxtamembrane domain (in approximately 25% of cases) or point mutations in 
the tyrosine kinase domain (TKD), most commonly at the aspartate residue at position 835
(D835) (in 7–10% of cases) (O’Donnell et al, 2017; Nagel et al, 2017; Stone et al, 2017).
Both FLT3-ITD and FLT3-TKD mutations lead to constitutive activation of FLT3 kinase 
activity, resulting in proliferation and survival of AML. FLT3-ITD is a common driver 
mutation that typically presents with a high leukemic burden and is associated with a poor 
prognosis: a meta-analysis demonstrated that the presence of FLT3-ITD in newly diagnosed 
AML patients is associated with shorter overall survival (OS) and relapse-free survival (RFS) 
compared with those without the mutation (hazard ratios [HRs] for death and relapse, 
1.86 and 1.75, respectively) (Port et al, 2014). In a large, randomized study of newly 
diagnosed AML patients with FLT3 mutations, the median event-free survival (EFS) was a 
mere 3.0 months (95% CIs: 1.9, 5.9) and the 4-year OS rate was 44.3% among patients 
treated with standard cytarabine/daunorubicin induction and high-dose cytarabine 
consolidation; 53.5% of patients (95% CIs: 48.2, 58.8) achieved a complete remission (CR)
(Stone et al, 2017). Other factors that may influence the prognostic utility of FLT3-ITD 
include mutant-to-wild-type allelic ratio, insertion site, ITD length, karyotype, and the 
presence of a concurrent mutation in the nucleophosmin-1 (NPM1) gene (Daver et al, 2019). 
One potentially important aspect of FLT3 biology is that the ITD-mutated receptors are 
highly responsive to FLT ligand (FL) (Sato et al, 2011). Autophosphorylation of FLT3-ITD 
receptors, as well as their ability to stimulate growth, are both significantly augmented by the 
addition of FL (Zheng et al, 2011). FL is expressed by leukemia cells as well as a broad array 
of cell types throughout the body, and levels in plasma, normally present at barely detectable 
levels, rise by a fold of two- to three-logs during chemotherapy-induced aplasia (Pratz & 
Levis, 2017). This may help explain why allelic burden is often significantly higher among 
the approximately 75% of patients with newly diagnosed, FLT3-ITD–mutated AML who 
harbor the mutation at relapse (Shih et al, 2002; Krönke et al, 2013; Pratz & Levis, 2017). In 
contrast to the poor prognosis associated with FLT3-ITD-mutated AML, the prognostic 
impact of FLT3-TKD mutations is less well defined (Daver et al, 2019).


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2.2
Treatment of FLT3-mutated AML:
Agents that target FLT3 are broadly classified as first-generation, multitargeted kinase 
inhibitors (eg, sunitinib, sorafenib, midostaurin) and next-generation potent and selective 
inhibitors, of which there are several currently in clinical development (quizartinib, 
crenolanib, gilteritinib) and one that is Food and Drug Administration (FDA)- and European 
Medicines Agency (EMA)-approved in the relapsed or refractory (R/R) setting (gilteritinib,
marketed as XOSPATA®) (Daver et al, 2019).
Both sorafenib and midostaurin exhibited relatively modest single-agent activity in patients 
with R/R disease (Stone et al, 2005; Borthakur et al, 2011). A randomized, 
placebo-controlled Phase 2 trial in newly diagnosed AML patients
60 years found that the 
addition of sorafenib to intensive induction and consolidation chemotherapy significantly 
prolonged EFS but not OS and was associated with increased toxicity (Röllig et al, 2015). In
an exploratory subgroup analysis, no EFS benefit was observed in the small group of patients 
with FLT3-ITD mutations whereas patients with non-FLT3 mutations had significantly 
improved EFS and RFS (Daver et al, 2019). In a Phase 1b study, midostaurin was
administered to newly diagnosed AML patients as part of an intensive induction and 
consolidation chemotherapy regimen beginning on Days 8 through Day 21 of each 
chemotherapy cycle and was found to have an acceptable safety profile at a dose of 50 mg 
twice daily (BID) (Stone et al, 2012). In response to the encouraging activity observed in
patients with FLT3 mutations in the Phase 1b study, the Cancer and Leukemia Group B 
(CALGB) in collaboration with Novartis (Basel, Switzerland) conducted a multicenter, 
international, Phase 3 trial comparing outcomes among 717 patients with newly diagnosed 
FLT3-mutated AML randomly assigned to treatment with midostaurin or placebo in 
combination with intensive induction and consolidation chemotherapy (the RATIFY study);
the primary endpoint was OS. Both EFS and OS were significantly longer among patients 
treated with midostaurin (HR for both EFS and OS, 0.78; p=0.002 and 0.009 [1-sided],
respectively). Subgroup analysis of patients with ITD (with high and low allelic ratio) and 
TKD mutations demonstrated clinical benefit from the addition of midostaurin and in an 
exploratory analysis of OS with censoring at the time of allogeneic stem cell transplantation, 
the OS benefit was maintained. Results from the RATIFY trial were the basis for FDA and 
EMA approval of midostaurin for treatment of FLT3-mutated AML in the front-line setting.
Next-generation FLT3 inhibitors have greater specificity for FLT3 and significantly higher 
potency than 1st generation multikinase inhibitors. Gilteritinib and crenolanib are type I 
inhibitors that target both the inactive and active conformational states of the FLT3 kinase 
domain, whereas quizartinib is a type II inhibitor that is specific for the inactive 
conformation. Unlike the 1st generation compounds, these have shown promising 
single-agent activity in the R/R setting (Daver et al, 2019).
2.2.1
Gilteritinib:
Gilteritinib is a small-molecule, oral FLT3 inhibitor with highly specific and potent 
inhibition of FLT3 receptors with both ITD and D835 mutations (either alone or in 
combination) (Mori et al, 2017; Lee et al, 2017). In vivo, gilteritinib inhibited tumor growth 
and induced tumor regressions in mice xenografted with MV4-11 AML cells (Mori et al, 


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2017). A Phase 1/2 dose-escalation/expansion study (the CHRYSALIS study) evaluated the 
safety/tolerability, pharmacokinetic (PK), and antileukemic activity of once-daily gilteritinib 
as a single agent at doses of 20–450 mg in patients with R/R, FLT3-wild type (n=58) or 
FLT3-mutated AML (n=194) (James et al, 2020; Perl et al, 2017). Gilteritinib was well 
tolerated with a maximally tolerated dose (MTD) of 300 mg QD. Potent FLT3 inhibition and 
dose-proportional PK were
with > 90% FLT3 inhibition and an overall response rate of 52% (including 41% with CR, 
CRi [CR with incomplete blood count recovery] or CRp [CR with partial platelet count 
recovery]) among patients with FLT3-mutated disease (Perl et al, 2017) and a median OS of 
31 weeks. The Phase 3 ADMIRAL trial compared the efficacy and safety of gilteritinib as a
QD dose of 120 mg with standard, either high or low intensity, salvage chemotherapy in 
patients with FLT3-mutated, R/R AML. The median OS in the gilteritinib treated group was 
9.3 months vs. 5.6 months for the chemotherapy-treated group (HR, 0.64; 95% CI, 0.49 to 
0.83; P<0.001) (Perl et al, 2019). Thirty-four percent of patients achieved CR with full or 
partial hematologic recovery in the gilteritinib group compared with 15.3% in the 
chemotherapy group; the percentages of patients achieving CR were 21.1% and 10.5%, 
(AEs) and serious adverse events (SAEs) occurred less 
frequently in the gilteritinib group than in the chemotherapy groups when adjusted for 
AEs in the gilteritinib group were febrile 
neutropenia (45.9%), anemia (40.7%), and thrombocytopenia (22.8%) (Perl et al, 2019).
Results from the CHRYSALIS and ADMIRAL studies were the basis for the recent FDA and 
EMA approval of gilteritinib in patients with R/R, FLT3-mutated AML.
2.3
SYK Inhibition as a Therapeutic Strategy in FLT3-mutated AML
Spleen tyrosine kinase (SYK) is a non-receptor tyrosine kinase involved in cellular 
proliferation, differentiation and survival that is broadly expressed in most hematopoietic 
cells. The loss of SYK expression in AML cell lines is associated with morphologic evidence 
of differentiation and expression of mature myeloid cell surface markers, suggesting that 
SYK plays a role in counteracting differentiation in leukemic cells (Hahn 2009). SYK protein 
expression and activity appear to be modulated by HOXA9 and MEIS1,
homeodomain-containing transcription factors that are overexpressed in approximately 
30-40% of AML patients and correlate with a poor prognosis (Drabkin 2002; Gao et al, 2016;
Heuser 2009; Zangenberg et al, 2009). Recent data have shown that overexpression of
HOXA9 and MEIS1 leads to an upregulation of SYK protein and increased SYK activity. 
Furthermore, transformation of myeloid progenitors with HOXA9 and MEIS1 in preclinical
models induced addiction to SYK signaling. Accordingly, pharmacologic inhibition or 
knock-down of SYK significantly reduced tumor burden and prolonged survival in AML 
mouse models (Mohr et al, 2017). In AML, SYK signaling occurs via stimulation of 
ß-integrin and Fc- receptors resulting in activation of STAT3 and STAT5 and promotion of 
leukemic cell proliferation (Oellerich 2015).
Importantly, activation and direct phosphorylation of the FLT3 receptor by SYK has also 
been reported. SYK has been shown to cooperate with FLT3 ITD to drive leukemogenesis. 
Combined pharmacologic inhibition of SYK and FLT3 results in robust anti-leukemic effects 
in murine models of FLT3 ITD-driven AML (Puissant et al, 2014).


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2.4
Preclinical and Clinical Rationale for the Evaluation of Lanraplenib in 
Combination with Gilteritinib in FLT3-mutated AML
2.4.1
Preclinical Rationale 
Lanraplenib (LANRA; formerly GS-9876) is a 3rd generation ATP-competitive inhibitor of 
SYK with a half-maximal inhibitory concentration (IC50) of 9.5 nM against the purified SYK 
enzyme and is > 15-fold more selective for SYK compared with a panel of > 359 non-mutant 
kinases, except for ZAP70 (7-fold), JAK2 (13-fold), and SRC (15-fold more selective). 
The activities of LANRA and its predecessor, entospletinib (ENTO), were evaluated for
effects on the viability of AML patient samples in ex vivo cultures (Figure 1). Both
LANRA and ENTO exhibited dose-dependent reductions in viability of leukapheresis-
derived AML cells from 15 patients and in 11, the calculated IC50 values were within 2-fold
of each other.
Figure 1: Ex vivo Evaluation of the Dose-Response Relationship for LANRA and 
ENTO in Leukapheresis-derived Primary AML Isolates 
Fig 1:  Primary leukapheresis-derived AML cells were cultured for 6 days in the presence of vehicle (0.1% 
dimethyl sulfoxide [DMSO]) and either LANRA or ENTO across a range of dilutions. Five micromolar 
cytarabine was used as a positive control in the assay. On day 6, cell viability was measured by addition of 
CellTiter Glo reagent and relative luminescence units (RLUs) were recorded on a plate reader. Cell viability 
(Y-axis) was plotted against drug concentrations (X-axis); IC50 and coefficient of determination (R2) values 
were calculated and included in the table. A) A representative example of the comparable, 
concentration-dependent effects of ENTO and LANRA on viability of NPM1m leukemic cell a specific patient 
(CTC-2232) B) Average half-maximal effective concentration (EC50) values for LANRA in NPM1 mutated, 
NPM1/FTL3-ITD co-mutated and mutation negative samples.  
LANRA and ENTO also demonstrated comparable reductions in viability in a panel of AML 
and lymphoma cell lines. The inhibitory activities of LANRA and ENTO were evident in cell 
line cultures with differing mutational backgrounds, including those with FLT3 mutations 
(MOLM-13, MV-4-11) (Figure 2).  


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Figure 2: LANRA and ENTO Show Comparable Activity Across a Panel of AML and 
Lymphoma Cell Lines
Fig. 2: ENTO and LANRA show comparable, concentration-dependent effects on cell viability in a panel of AML cell lines, 
as assessed with CellTiter Glo® (left). A subset of AML (red) and lymphoma (black) cell lines showed low M to nM 
sensitivity to both agents (right).
The ability of LANRA and ENTO to induce additive or synergistic effects when combined 
with other active agents used in the treatment of AML was assessed (Figure 3). Two of the 
most potent combinations were with the selective FLT3 inhibitor, gilteritinib, and the BCL-2
inhibitor, venetoclax. LANRA showed a broad and robust synergistic effect in combination 
with both gilteritinib or venetoclax exceeding a Loewe synergy score of 10 at multiple doses.


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Figure 3: Synergistic Effects of LANRA in Combination with the FLT3 Inhibitor, 
Gilteritinib or the BCL2 Inhibitor Venetoclax in NPM1m, FLT3-ITD AML 
Models
Fig 3: An NPM1m/FLT3-ITD AML patient isolate was grown under semisolid colony forming conditions for 5 days with 
LANRA and either gilteritinib or venetoclax to assess effects of these combinations on cell viability. The antileukemic 
effects of the combination were assessed using CellTiterGlo® as readout for cell viability. 
This ex vivo study was followed by a patient derived xenograft study of the same AML 
isolate in which animals were treated with the combination of LANRA and gilteritinib for 
28 days (Figure 4). Leukemic burden was assessed as a percent of human CD45 positive cells 
in peripheral blood by flow cytometry. The combination of LANRA and gilteritinib showed 
meaningful improvements in tumor burden reduction and overall survival compared with 
either single agent alone.


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Figure 4: LANRA in Combination with Gilteritinib Shows Improved Clearance of 
Leukemic Cells and Extends Overall Survival in a FLT3-ITD AML Patient 
derived Xenograft Model
Fig 4. LANRA was studied alone and in combination with gilteritinib in an FLT3-ITD/NPM1m patient-derived xenograft 
model (PDX). Mice were treated with 60 mg/kg LANRA via sub-cutaneous injection, twice daily, or with 2 mg/kg 
gilteritinib via oral gavage, once daily, as single agents, or in combination. (A) Leukemic burden was assessed by flow 
cytometry measuring human CD45 in peripheral blood (PB) obtained from serial bleeds over time.
(B) Kaplan-Meier survival curve showing the probability of survival following treatment with each single agent or the 
combination.
2.4.2
Clinical Rationale – Results from a Phase 1b/2 Study of ENTO in Newly
Diagnosed AML (including patients with FLT3-ITD AML)
In a Phase 1b/2 study of 53 previously untreated AML patients, ENTO was evaluated at 
doses of 200 or 400 mg BID plus 1-2 cycles of intensive induction therapy (continuous 
infusion cytarabine x 7 days, bolus daunorubicin x 3 days; “7+3”) followed by high-dose 
cytarabine consolidation. In this study, 70% of patients achieved a CR or CRi including
5 (83%) of 6 patients with FLT3-ITD AML. The combination of ENTO with 7+3 induction 
and high dose cytarabine consolidation was generally well-tolerated with skin rash,
transaminase elevations and indirect hyperbilirubinemia being the mostly commonly 
reported, treatment-related toxicities (Walker et al, 2020).
Unlike ENTO, LANRA can be administered QD in either the fed or fasted state and with 
concurrent administration of gastric acid-reducing agents, specifically, proton pump 
inhibitors.
This study will evaluate the safety, PK, PD, and preliminary efficacy of LANRA in 
combination with the selective FLT3 inhibitor gilteritinib, in previously treated, 
FLT3-mutated AML patients.
2.5
Risk Benefit Assessment
2.5.1
Gilteritinib-associated Toxicities:
The safety profile for gilteritinib is based on data from 319 patients with R/R AML treated 
with gilteritinib 120 mg daily, who were enrolled to three clinical trials. The median duration 


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of exposure was 3.6 months (range 0.1 to 43.4 months). The most frequent adverse reactions 
following treatment with gilteritinib were increased alanine aminotransferase (ALT) (82%), 
increased aspartate aminotransferase (AST) (81%), increased blood alkaline phosphatase 
(69%), increased blood creatine phosphokinase (54%), diarrhea (35%), fatigue (30%), nausea 
(30%), constipation (28%), cough (28%), peripheral oedema (24%), dyspnea (24%), 
dizziness (20%), hypotension (17%), pain in extremity (15%), asthenia (14%), arthralgia 
(13%), and myalgia (13%). The most frequent serious adverse reactions were acute kidney 
injury (7%), diarrhea (5%), increased ALT (4%), dyspnea (3%), increased AST (3%) and 
hypotension (3%) (XOSPATA [gilteritinib] Summary of Product Characteristics 2021). 
Twenty-two (7%) patients permanently discontinued gilteritinib due to an adverse reaction,
most commonly increased AST (2%) and ALT (2%) (XOSPATA [gilteritinib] U.S. 
Prescribing Information, 2022).
Potentially fatal or life-threatening toxicities associated with gilteritinib included
Differentiation Syndrome (DS; a syndrome associated with rapid proliferation and 
differentiation of myeloid progenitors/precursors), reported in 2% of patients; Posterior 
Reversible Encephalopathy Syndrome (PRES) presenting with symptoms including seizures 
and altered mental status, reported in <1% of patients; pancreatitis reported in 4% of patients; 
and treatment-emergent QT interval prolongation in 9% of patients (XOSPATA [gilteritinib] 
U.S. Prescribing Information, 2022; XOSPATA [gilteritinib] Summary of Product 
Characteristics 2021). Guidelines for the management of these uncommon but potentially 
serious adverse reactions are provided in Section 8.1. In order to monitor for the occurrence 
of QT interval prolongation, electrocardiograms (ECGs) will be assessed at Screening, in 
Cycle 1 on Days 8 and 15, on Day 1 of Cycles 2 and 3, and thereafter, as clinically indicated
in accordance with the gilteritinib prescribing information (XOSPATA [gilteritinib] U.S. 
Prescribing Information, 2022; XOSPATA [gilteritinib] Summary of Product Characteristics 
2021).
2.5.2
Lanraplenib-associated Toxicities
2.5.2.1
Non-clinical data:
Findings associated with administration of LANRA to Sprague-Dawley rats at daily doses up 
to 100 mg/kg for up to 26 weeks consisted primarily of lymphodepletion in primary and 
secondary lymphoid organs (thymus, spleen, lymph nodes, bone marrow) accompanied by
multifocal bacterial infections, consistent with LANRA’s immunomodulatory mechanism of 
action. Additionally, findings indicative of low-grade hemolysis of uncertain origin in 
animals treated at the 100 mg/kg dose level were observed.
In addition to lymphodepletion, notable observations associated with administration of 
LANRA to cynomolgus monkeys
/kg for 2 weeks or up to 
20 mg/kg for 4 weeks included clinical and histopathologic findings consistent with a 
coagulopathy (ie, ecchymoses, visceral hemorrhage/ulceration and associated inflammatory 
cell infiltrates). These findings were not replicated in a study of LANRA administered to 
monkeys for up to 39 weeks at daily doses up to 15 mg/kg and have not been observed in 
human patients treated with total daily doses up to 50 mg for 7 days or 30 mg for up to 


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49.4 weeks (see below). Consult the LANRA Investigator’s Brochure (IB; Section 3.3) for 
additional details on non-clinical safety and PK findings associated with LANRA.
In light of the above-described coagulopathy observed in the 2- and 4-week monkey studies,
this study will monitor coagulation parameters including fibrinogen and D-dimer levels, on
Days 1 and 15 of Cycle 1, Day 1 of Cycle 2 and Cycle 3 and as clinically indicated 
thereafter. 
2.5.2.2
Clinical data:
Clinical data are derived from 233 patients enrolled to 7 studies of LANRA, including the 
following:
a Phase 1, ascending single dose, PK and safety study in which healthy volunteers 
received LANRA doses up to 50 mg (n=60);
a Phase 1, ascending multiple dose PK and safety study in healthy volunteers treated 
with LANRA for 7 days at doses up to 50 mg/day (n=24);
a Phase 1, single-dose (20 mg) PK and safety study in patients with moderate (n=10) 
or severe (n=9) renal functional impairment, including 16 healthy volunteers;
a Phase 2, safety and efficacy study in patients with rheumatoid arthritis (RA) treated 
at doses of 10 (n=20) or 30 mg/day (n=20) for 12 weeks;
a Phase 2, safety and efficacy study in patients with moderately to severely active 
cutaneous lupus erythematosus (CLE; n=23) treated at daily doses of 30 mg for up to 
48 weeks; 
a Phase 2, safety and efficacy study in patients with lupus membranous nephritis 
(LMN; n=4) treated at daily doses of 30 mg for up to 16 weeks; and 
a Phase 2, safety and efficacy study in patients with active Sjögren’s Syndrome
(n=47) treated at daily doses of 30 mg for up to 49.4 weeks.
In clinical studies of LANRA in healthy volunteers, no safety signals were identified and no 
Grade 3 or 4 AEs were reported. There were no clinically significant changes in vital signs,
physical findings, laboratory parameters, or ECGs.
The mean (SD) duration of exposure to LANRA in the RA study was 12.0 (0.67) weeks and 
the maximal exposure duration was 12.3 weeks. LANRA was generally well-tolerated; all 
patients in the 30-mg QD cohort completed protocol-specified treatment and 19 of 
20 patients completed study treatment in the 10 mg QD cohort (1 patient discontinued due to 
investigator discretion). Seven (30%) and 8 (40%) patients in the 30- and 10-mg LANRA 
cohorts, respectively, reported at least 1 non-serious AE. AEs reported in more than 1 patient 
in the 30 mg LANRA cohort were hypothyroidism (n=2), and in the 10 mg LANRA cohort, 
“condition aggravated” (n=2). One patient in the 30
increased blood pressure assessed by the investigator as not related to study treatment. No
SAEs or deaths were reported. In the CLE study, 2 patients experienced SAEs (coronary 
artery occlusion; drug hypersensitivity); there were no deaths. Twenty (87%) 
LANRA-treated patients reported at least 1 AE. AEs reported in >1 patient included: upper 


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respiratory tract infection (URI; n=4), urinary tract infection (UTI; n=3), diarrhea, nausea, 
bronchitis, nasopharyngitis, extremity pain and headache (each n=2). The Sponsor (Gilead 
Sciences) terminated the study of LANRA in LMN prematurely due to very low enrollment 
over a period of 16 months and in the absence of safety concerns. One patient reported
2 SAEs (systemic lupus erythematosus [SLE], acute kidney injury); there were no deaths. All 
patients reported at least 1 non-serious AE: bronchitis (n=2), amaurosis fugax, vitreous 
floaters, peripheral edema, sinusitis, URI, decreased lymphocyte count, hypoalbuminemia, 
SLE and anxiety (n=1 each). In the Sjögren’s Syndrome study, 3 patients reported SAEs 
(acute coronary syndrome, acute pancreatitis, and suicidal ideation). Forty (85.1%) patients 
reported at least 1 non-serious AE. Non-serious AEs reported in > 1 patient were fatigue 
(n=6), viral gastroenteritis (n=5), URI, nasopharyngitis, ALT increased, AST increased 
(n=4 each), diarrhea, pyrexia, sinusitis, UTI (n=3 each), lymphadenopathy, neutropenia, 
dental caries, nausea, vomiting, bronchitis, laryngitis, lower respiratory tract infection, and 
oral herpes (n=2 each).
Consult the LANRA IB (Section 4.0) for additional safety and PK findings from LANRA 
clinical studies collected to date. 
2.5.3
Potential for Overlapping Toxicities Resulting from the Combination of LANRA 
and Gilteritinib
In the reference safety information for LANRA, liver transaminase elevations are listed as 
potential adverse drug reactions, based on clinical trial experience to date. Transaminase 
elevations were infrequent and reversible upon discontinuation of LANRA. A review of the 
respective toxicity profiles for LANRA and gilteritinib reveals that the most likely 
overlapping and potentially treatment-limiting toxicity resulting from the combination is liver 
toxicity (ie, transaminase elevations). Other potential overlapping toxicities include (but are 
not limited to) rash, constitutional symptoms (fatigue/malaise, myalgia/arthralgia, fever,
headache) and gastrointestinal signs/symptoms (nausea, vomiting, diarrhea, abdominal pain, 
constipation). These can be monitored by close surveillance and conventional safety 
assessments as described in Section 11; all are potentially manageable with supportive care 
interventions and study treatment modifications (Section 8).
Co-administration with gilteritinib is not expected to impact LANRA plasma exposures. An 
evaluation of PK parameters for LANRA alone and in combination with gilteritinib will be 
conducted in this study to investigate the potential for meaningful PK interaction between the 
two.
In consideration of the above, the Sponsor has concluded that the potential benefits of the 
proposed study outweigh the risks for the following reasons:
the prognosis for patients with R/R FLT3-mutated AML is dismal,
there are limited effective treatment options available for this subgroup of patients,
there is significant room for improvement when considering outcomes for patients 
treated with gilteritinib monotherapy in this clinical setting (Section 2.2.1),


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there is compelling evidence from non-clinical pharmacologic studies (Puissant 
2014), as well as ex vivo pharmacodynamic studies of leukemic isolates from AML 
patients to suggest that incremental clinical benefit could be achieved from 
concurrent inhibition of SYK and FLT3,
there is preliminary clinical evidence that the SYK inhibitor ENTO (the predecessor 
to LANRA) may improve CR rates when combined with standard “7 + 3” induction 
chemotherapy in newly diagnosed patients with FLT3-mutatated AML (Walker 2020)
and,
the safety profile for LANRA based on clinical studies conducted to date along with 
the ability to closely monitor patients with frequent safety assessments as well as the
use of appropriate guidelines for treatment modification suggest that the combination 
can be tested with an adequate margin of safety.
2.5.4
COVID-19 Considerations
Patients undergoing systemic chemotherapy for cancer and leukemia have an increased risk 
of severe complications, some leading to death, following coronavirus disease 2019 
(COVID-19). This includes patients who have been fully vaccinated against the virus. The 
extent to which LANRA may increase the magnitude of risk when administered concurrently 
with gilteritinib (if any) is currently unknown. Prospective trial participants, including those 
who have been vaccinated against COVID-19, should be counseled to employ social 
distancing measures including the regular use of face coverings and avoidance of indoor 
congregant environments, especially those that include others for whom the vaccination 
and/or COVID-19 infection status are unknown. 
Consult Appendix 5 for additional risk mitigation procedures potentially associated with 
clinical trial conduct in the COVID-19 pandemic era.
2.6
Rationale for Starting Dose of LANRA and Selection of Recommended 
Phase 2 Dose (RP2D)
To date, 233 patients have received LANRA monotherapy. As noted, doses of LANRA up to 
50 mg/day for 7 days in healthy volunteers and up to 30 mg/day for up to 49.4 weeks in 
patients with autoimmune diseases have been safe and adequately tolerated. In light of the 
potential for overlapping toxicities with the combination of LANRA plus gilteritinib
(Section 2.5.3), the proposed starting dose for LANRA in the Phase 1b (dose escalation) 
component of this study will be 20 mg QD, which should allow for an acceptable safety 
margin when combined with the standard dose of gilteritinib (120 mg QD). Consistent with 
global regulatory guidance and the need to identify a safe dose that can induce durable 
responses, the dose will be escalated following a “3 + 3” dose escalation scheme to a 
maximal dose of 90 mg in combination with the standard dose gilteritinib, or until a 
MTD/RP2D (recommended Phase 2 dose) is defined.
To better understand the safety, tolerability, PK, PD, and anti-tumor activity of the study 
regimen, additional patients (up to a total of 20 per dose cohort) may be allocated to a dose 


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cohort previously cleared for safety and tolerability by the Dose Escalation Committee 
(DEC), if there are no available patient slots in the dose cohort currently being evaluated.
The decision to enroll additional patients at a dose level previously cleared by the DEC 
(ie, enrollment of a “backfill” cohort) will be based on agreement by the DEC coincident 
with each scheduled DEC convocation. Furthermore, additional patients may be added to a 
previously cleared dose cohort only if at least 1 of the 3 to 6 patients initially enrolled to that 
cohort have achieved one of the following European LeukemiaNet (ELN) 2017-defined 
response categories (Appendix 2): CR, CR with partial hematologic recovery (CRh), CRi, 
partial response (PR), morphologic leukemia-free state (MLFS). The 3+3 dose escalation rule 
will continue to be followed for each successively higher dose cohort however, should dose-
limiting toxicities (DLT[s]) occur in 1 or more patients enrolled to a backfill cohort(s), these
will be taken into account for purposes of future dose escalation decisions. Specifically, if a 
DLT occurs in a patient allocated to a backfill cohort, the DLT rate will be re-calculated for 
that cohort. If the updated DLT rate exceeds 20% with 80% probability, the updated DLT 
rate will be taken into consideration by the DEC when deciding whether to stop or continue 
dose escalation to the next higher dose level.
The dose of LANRA that will be selected as the RP2D will be the dose that most closely 
approximates the magnitude and duration of SYK inhibition achieved by the active dose of 
ENTO while maintaining a manageable safety profile. Specifically, the 400 mg BID dose of 
ENTO achieves responses in AML patients both as monotherapy and in combination with 
cytarabine/daunorubicin (7+3) induction (Walker et al, 2020). Plasma exposures at this dose 
of ENTO led to sustained, > 50% inhibition of SYK (as measured in ex vivo assays) 
(Ramanathan et al, 2017). We hypothesize that LANRA will need to achieve or exceed this 
threshold of SYK inhibition for efficacy. In addition to PK, safety and efficacy data,
reductions in pSYK in peripheral blood mononuclear cells (PBMCs), and/or changes in a 
SYK dependent gene expression signature will be assessed in patients at each dose level to 
identify a dose of LANRA at or below the MTD that consistently achieves sustained, >50% 
SYK inhibition.
2.7
Study Conduct
This study will be conducted in compliance with the protocol approved by the Institutional 
Review Board (IRB) or Independent Ethics Committee (IEC) and in accordance with Good 
Clinical Practice (GCP) standards, EU Regulation 536/2014, and other country-specific 
requirements, as applicable.






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To further characterize pharmacodynamic properties 
(including the extent of target engagement) of 
LANRA alone and in combination with gilteritinib.
peripheral blood and bone marrow aspirate using 
standard expression profiling platforms 
(eg, Nanostring® or NGS) for correlations with 
response and progression.
Baseline and longitudinal targeted 
protein/phosphoprotein profiling 
(eg, pSYK expression)/expression of other relevant 
genes in leukemic cells for correlations with response 
and progression.
To further assess the PK of LANRA in combination 
with gilteritinib.
Sparse PK sampling for LANRA and gilteritinib
plasma concentration.


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4.0
Summary of Study Design 
This multicenter, Phase 1b/2 study will investigate the safety, PK, PD and make a 
preliminary assessment of the anti-leukemic activity of the selective, 3rd generation SYK 
inhibitor, LANRA, in combination with the selective FLT3 inhibitor, gilteritinib, in patients 
with FLT3-mutated AML, who have recurrence of leukemia or are refractory after at 
least 1 prior regimen. This study will be conducted in 2 parts: dose escalation (Phase 1b) and 
cohort expansion (Phase 2). The study will consist of a Screening Phase lasting up to 21 days 
during which patients will be assessed for eligibility; a Treatment Phase beginning on 
Cycle 1, Day 1 (C1D1) consisting of consecutive 28-day cycles; an End-of-Treatment 
evaluation; and a Post-Treatment Follow-up Phase. During the Treatment Phase, patients will 
undergo study visits on Days 1, 2, 4, 8, 11, 15, 16 and 22 in Cycle 1, Days 1, 8, 15 and 22 in 
Cycle 2, and Days 1 and 15 in Cycle 3 and beyond. Approximately 100 patients are estimated
to enroll across both Phase 1b and Phase 2; patients will be enrolled from multiple trial sites 
worldwide. In both Phase 1b and Phase 2, patients will receive their assigned treatment
regimen until progression/relapse or lack of at least a PR after 6 months of study treatment, 
intolerance, or withdrawal from study treatment by the patient or study investigator. All 
patients will be followed for survival. 
4.1
Phase 1b
Eligible patients will be enrolled sequentially into dose cohorts listed in Table 1 for PK/
PD evaluations and determination of the MTD/RP2D of LANRA in combination with 
gilteritinib. 
Table 1: 
Dose-escalation Scheme (Provisional) 
Dose Cohort (n): 
LANRA Dose:
Gilteritinib Dose:
Cohort 1 
20 mg QD
120 mg QD
Cohort 2 
40 mg QD
120 mg QD
Cohort 3 
60 mg QD
120 mg QD 
Cohort 4 
90 mg QD
120 mg QD 
A “3 + 3” dose escalation scheme will be employed in which 1 DLT reported from among 
the first 3 evaluable patients in a dose cohort will prompt enrollment of 3 additional 
evaluable patients. More than 1 DLT attributed to LANRA among 6 patients evaluable for 
DLT would indicate an intolerable dose, thus rendering the most proximate lower dose with 
either 0 of 3 or 1 of 6 patients with LANRA-related DLTs the MTD. Dose-limiting toxicities 
are defined in Appendix 1. The starting dose of LANRA is 20 mg QD (Cohort 1, Table 1).
Enrollment will be staggered such that the first patient to enroll in a dose cohort will begin 
combination therapy on C1D2 (see below) and at least 24 hours before subsequent patients 
are enrolled to that cohort. All patients within a cohort (except those who discontinue in 
Cycle 1 due to DLT) must complete the DLT assessment period before a decision to begin 
testing the next higher dose. Enrollment of the next higher dose cohort will not proceed until 
a safety review has been completed for the preceding cohort(s) by a DEC consisting of 


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investigators with enrolled patients and sponsor representatives including (but not limited to) 
the medical monitor, safety officer, PK, and translational science leads. All decisions 
regarding dose escalation including declaration of the MTD/RP2D will be made by the DEC. 
The determination of whether or not to enroll the next higher dose cohort, enroll a lower dose 
cohort/add additional patients to a cohort previously cleared for safety/tolerability by the 
DEC or declare the MTD/RP2D will be based on available safety, PK, and PD data from all 
dose cohorts. If no protocol-defined MTD is identified for LANRA, the lowest dose that 
shows consistent evidence of adequate SYK inhibition based on PD assays will be deemed 
the RP2D (Section 2.6).  
Patients will be evaluated for DLTs beginning on C1D1 up to and including safety 
assessments collected on Cycle 2, Day 1 for determination of LANRA MTD in combination 
with standard-dose gilteritinib. Patients will be evaluable for DLT in Phase 1b if one of the 
following occurs: 
They experience a DLT after recei
LANRA during the DLT 
assessment period. 
They receive at least 80% of the intended cumulative dose of LANRA and gilteritinib 
during the DLT assessment period without the occurrence of a DLT.  
Should patients discontinue study treatment prior to completing the DLT assessment period 
for reasons other than a DLT, additional patients will be enrolled to ensure the required 
number of DLT-evaluable patients is achieved. To better understand the safety, tolerability, 
PK, PD, and anti-tumor activity of the study regimen, additional patients (up to a total of 
20 per dose cohort) may be allocated to previously cleared dose cohort(s) that are considered 
safe and adequately tolerated, if there are no available patient slots in the dose level currently 
being evaluated. The decision to enroll additional patients at a dose level previously cleared 
by the DEC (ie, enrollment of a “backfill” cohort) will be based on recommendations 
provided by the DEC coincident with each scheduled DEC convocation. Furthermore, 
additional patients may be added to a previously cleared dose cohort only if at least 1 of the 
3 to 6 patients initially enrolled to that cohort have achieved one of the following ELN 
2017-defined response categories (Appendix 2): CR, CRh, CRi, PR, MLFS. The 3+3 dose 
escalation rule will continue to be followed for each successively higher dose cohorts 
however, DLTs occurring in patients enrolled to backfill cohorts will be taken into account 
by the DEC for purposes of future dose escalation-making decisions, per guidelines outlined 
in Section 2.6.
PK and PD evaluations of LANRA monotherapy will begin at Hour 0 (predose) on C1D1
through Hour 24 (C1D2) after which, all patients will initiate combination therapy on C1D2.
PK evaluations for concurrently administered LANRA and gilteritinib will begin at Hour 0
(predose), C1D15 through Hour 24 (C1D16) (see Table 8 and Table 9).  
Patients who discontinue LANRA for intolerance may continue gilteritinib at the 
investigator’s discretion (in which case, no additional sampling for LANRA PK assessments
will be required). Patients who discontinue gilteritinib for intolerance may continue LANRA
at the investigator’s discretion for as long as they are deriving clinical benefit. An 


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End-of-Treatment evaluation will take place 30 (± 7) days after permanent discontinuation of 
both study drugs or prior to initiation of new anti-leukemic therapy, if sooner. Patients who 
discontinue study treatment for reasons other than progression/relapse may be followed until 
progression in the absence of intervening antileukemic therapy, at the discretion of the 
investigator.
4.2
Phase 2
Following completion of Phase 1b, an expansion cohort consisting of patients who meet all 
eligibility criteria will enroll in order to further assess the safety, PK, PD (Table 10), and 
anti-leukemic activity of the combination at the LANRA MTD/RP2D. Patients enrolled to 
Phase 2 will begin combination therapy with LANRA and gilteritinib on C1D1. 
For both Phase 1b and Phase 2, response assessments will be based on bone marrow,
physical examinations, as well as peripheral blood counts. Bone marrow aspirates will be 
performed on C2D1, C3D1 and every 3 cycles thereafter until the patient exhibits 2 
consecutive assessments indicating CR or CRh. Patients who have not achieved at least a 
partial response per ELN 2017 criteria after 6 months of study treatment will permanently 
discontinue study treatment. 
Enrollment in Phase 2 will follow a two-stage design for assessment of the primary efficacy 
endpoint, composite CR (cCR) rate, including those patients who achieve a best response of 
CR or CRh, as defined by ELN 2017 response criteria (Appendix 2). Section 15.0 [Statistical 
Considerations] describes the specifications for enrollment in Stage 1 and Stage 2 based upon 
the hypothesized improvement in cCR rate resulting from the addition of LANRA to 
gilteritinib.
As in Phase 1b, the frequency of DLTs will be assessed coincident with the first cycle of 
treatment during Phase 2, initially after the first 6 patients and every patient thereafter, until 
enrollment completion. If the probability that the true, first cycle DLT rate exceeds 20% with 
80% posterior probability given the accumulated data at these time points, further enrollment 
will be interrupted, and the DEC will be convened to assess the risk-benefit profile of the 
study regimen and provide recommendations regarding modifying or stopping the study (see 
Section 15.2.7.1 for safety stopping rules). Additionally, the occurrence of one Grade 5 event 
or two Grade 4 events that is considered at least possibly related to LANRA or gilteritinib 
will prompt an interruption of new patient accrual followed by a thorough safety analysis that 
will be submitted to health authorities in the countries where the study is being conducted 
for review prior to resuming enrollment.


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5.0
Patient Population
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all the following criteria apply:
1.
and at least 1 prior line of therapy.
Note:  Patients must meet the criteria for a partial response, stable disease or
progressive disease as best response after the last prior line of therapy; primary 
refractory disease after 1st line induction; or recurrence of leukemia after CR, as 
defined by ELN 2017 response criteria (Appendix 2).
2. FLT3-mutated disease documented in a local reference laboratory at the time of 
consideration for enrollment in the study.
Note: Eligible patients may have either ITD or TKD mutations or both as detected in 
either peripheral blood or bone marrow.
Note: Patients with a history of exposure to midostaurin, other multikinase inhibitor 
(eg, sorafenib), or 2nd generation FLT3 inhibitors (including gilteritinib, quizartinib, 
or crenolanib) for the treatment of AML are eligible but must have discontinued 
treatment with these agents at least 7 days prior to Cycle 1, Day 1.
3. Have the ability to understand the requirements and procedures of the study and sign 
a written informed consent form (ICF).
4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1 or 2.
5. Adequate hepatic and renal function defined as:
a)
serum AST and ALT < 2.5 times the upper limit of normal (ULN); total 
bilirubin < 1.5 times ULN unless elevated due to Gilbert’s Disease or 
hemolysis 
b)
calculated creatinine clearance >30 ml/min 
6. Prothrombin time (PT), activated partial thromboplastin time (aPTT) and 
international normalized ratio (INR)
anticoagulation.
Note: Transition from a Vitamin K or Factor Xa antagonist to a low-molecular weight 
heparin preparation is recommended prior to the start of study treatment (see
Appendix 7 for guidelines on anticoagulation management).
7. Negative serum ß-HCG test in women of child-bearing potential (WOCBP).
8.
50% confirmed by echocardiogram (ECHO) or 
multi-gated acquisition (MUGA) scan.
9. For WOCBP, willingness to abstain from heterosexual intercourse OR use a 
protocol-recommended method of contraception from 7 days prior to C1D1
throughout the study treatment period and for 6 months following the last dose of 
study treatment (Appendix 6).


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10. For male patients with female sexual partners of childbearing potential, willingness to 
abstain from heterosexual intercourse OR use a protocol recommended method of 
contraception beginning 7 days prior to C1D1 throughout the study treatment period 
and for 4 months following the last dose of study treatment AND to refrain from 
sperm donation from the start of study treatment throughout the study treatment 
period and for 4 months following the last dose of study treatment (Appendix 6).
11. Willingness to comply with scheduled study visits, procedures, and treatment plan.
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
1. Known central nervous system (CNS) involvement with leukemia.
2. Clinical signs/symptoms of leukostasis that have failed therapy including 
hydroxyurea and/or leukapheresis of at least 3 days duration (see Exclusion Criterion 
#14 below).
3. Pregnant or breastfeeding women.
4. Active infection with hepatitis B, C or human immunodeficiency virus (HIV)
infection.
Note: Patients who are hepatitis B surface antigen (HBsAg) or anti-HIV positive at 
baseline are ineligible. Patients with a history of hepatitis B virus (HBV) infection
(hepatitis B antibody [anti-HBc] seropositivity) must agree to receive HBV 
prophylaxis during the study treatment period and undergo regular surveillance for 
HBV reactivation with serial HBV DNA measurements in plasma. Patients with a 
history of hepatitis C virus (HCV) infection who completed curative therapy may 
enroll but must undergo regular surveillance monitoring for HCV reactivation.
5. Disseminated intravascular coagulation with active bleeding or signs of thrombosis.
6. Known active COVID-19 either symptomatic or asymptomatic, as determined by 
nasopharyngeal swab for severe acute respiratory syndrome (SARS) coronavirus 2 
(SARS CoV-2) RNA or antigen.
Note: In the absence of signs, symptoms or physical findings suggestive of 
COVID-19, testing for SARS CoV-2 infection is not required for eligibility. Patients
with a history of SARS-CoV-2 nasopharyngeal carriage (either with or without 
symptoms), who have subsequently tested negative on follow-up nasopharyngeal 
swab and are without signs or symptoms of COVID-19 may enroll. Patients who have 
been vaccinated against SARS-CoV-2 at least 2 weeks prior to the start of study 
treatment may enroll. Patients without contraindications, may be vaccinated against 
COVID-19 while on study, preferably upon completion of the DLT assessment period
(Cycle 1).
7. Administration of a live attenuated virus vaccine within 35 days before C1D1.
8. History of non-myeloid malignancy except for the following: adequately treated 
localized basal cell, or squamous cell carcinoma of the skin, or localized melanoma 


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(with TNM stage either Tis [melanoma in-situ] or T1aN0M0) with complete 
resection; cervical carcinoma in situ; superficial bladder cancer; asymptomatic 
prostate cancer without known metastatic disease, with no requirement for therapy or 
requiring only hormonal therapy and with normal prostate specific antigen for 
> 1 year prior to start of study therapy; or any other cancer that has been in complete 
Note: Patients who are
3 years from definitive 
therapy for their primary tumor are eligible to enroll.
9. Clinically significant heart disease defined as:
a)
New York Heart Association Class 3 or 4 congestive heart failure,
b)
enrollment,
c)
Symptom
enrollment,
d)
History of clinically significant arrhythmias (eg, ventricular tachycardia or 
fibrillation; Torsades de Pointes) including Mobitz type II 2nd degree or 3rd
degree heart block without a permanent pacemaker in place.
10. Patients with a corrected QT interval (using the Fridericia formula, QTcF) >480 msec 
or Long QT Syndrome.
11. Evidence of ongoing uncontrolled systemic bacterial, fungal, or viral infection at the 
time of study treatment initiation.
Note: “Uncontrolled” infection would include (but is not limited to) persistence of 
fever or positive cultures in the setting of appropriate antimicrobial coverage.
12. Current (within 30 days of study enrollment) drug-induced liver injury, chronic active 
hepatitis, alcoholic liver disease, nonalcoholic steatohepatitis, primary biliary 
cholangitis with inadequate response to ursodeoxycholic acid or other health authority 
approved therapy, extrahepatic obstruction caused by cholelithiasis, cirrhosis of the 
liver, or portal hypertension.
13. Ongoing (within 6 weeks of study enrollment) hepatic encephalopathy.
14. Alcohol or drug addiction as determined by investigator.
15. Ongoing immunosuppressive therapy, including systemic chemotherapy for treatment 
of leukemia.
Note: Patients may receive hydroxyurea or leukapheresis for treatment of 
hyperleukocytosis until signs/symptoms and/or the risk of complications from 
leukostasis have abated, in the judgement of the investigator.
Note: Patients with a history of hematopoietic stem cell transplantation (HSCT) are 
eligible as long as they are receiving no more than 10 mg prednisone QD (or 
equivalent) for graft vs. host disease.
16. Concurrent (within 14 days of study enrollment) participation in an investigational 
drug study with therapeutic intent.


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17. Patient requiring chronic treatment with strong cytochrome P450 (CYP) 3A4 
inhibitors or inducers beginning 7 days prior to initiating study treatment until study 
treatment completion (see Appendix 4 for a list of strong CYP3A inducers or 
inhibitors; see Section 10.2 for LANRA treatment modification guidelines for 
patients requiring the use of strong CYP3A4 inhibitors during the Treatment Phase).
18. Unable to swallow capsules or concurrent disease affecting gastrointestinal function 
such as malabsorption syndrome, gastric or small bowel resection, bariatric surgery, 
inflammatory bowel disease or bowel obstruction.
19. Any prior or ongoing condition that, in the opinion of the investigator, could 
adversely affect the safety of the patient or impair the assessment of study results.
20. Known hypersensitivity to LANRA, gilteritinib, their metabolites or formulation 
excipient.


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6.0
Organizational Framework
6.1
Screening and Enrollment
After signing the ICF, all screening assessments and procedures must be completed within 
21 days before the start of study treatment. The study site is responsible for maintaining a 
record of all screened and enrolled patients. Patients who have failed 1 or more screening 
assessment may be re-tested for that assessment(s) within the designated time frame for final 
eligibility determination.
6.2
Treatment Phase
The treatment period starts with the first day of study treatment (C1D1) and continues until 
the End-of-Treatment Evaluation (see below). All treatment cycles are 28 days. Patients may 
discontinue study treatment at any time for reasons summarized in Section 13.0.
6.3
End of Treatment
All patients will undergo an End-of-Treatment Evaluation 30 ± 7 days after the last dose of 
either LANRA or gilteritinib (whichever is later) or prior to initiation of new antileukemic
therapy, if sooner. Patients must discontinue study treatment and complete the 
End-of-Treatment Evaluation prior to HSCT.
6.4
Post-treatment Follow-up
Patients who discontinue study treatment for reasons other than progression/relapse will be 
followed monthly until progression/relapse at the discretion of the investigator and in the 
absence of intervening new anti-leukemic therapy. Following progression/relapse or 
initiation of new anti-leukemic therapy, patients will be followed for survival every 
3 months.
6.5
End of Study
The study will end after all enrolled patients either relapse or die or 5 years after the last 
patient enrolls (whichever is earlier) or if the Sponsor decides to terminate the trial.


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7.0
Test product, dose, mode of administration
7.1
Gilteritinib:
Gilteritinib (XOSPATA®) is supplied as light yellow, round-shaped, film-coated tablets 
debossed with the Astellas logo and ‘235’ on the same side. Gilteritinib is provided in either
bottles of 90 tablets with child resistant closure or a carton containing 4 blister strips of 
21 tablets each for a total of 84 tablets. Each tablet contains 40 mg gilteritinib as well as the 
following commonly used excipients: ferric oxide, hydroxypropyl cellulose, hypromellose, 
low-substituted hydroxypropyl cellulose, mannitol, magnesium stearate, talc, polyethylene 
glycol and titanium dioxide. Store gilteritinib tablets at 20ºC to 25ºC (68°F to 77°F); 
excursions between 15ºC to 30ºC (59°F to 86°F) are permitted. Keep in the original container 
until dispensed and protect from light, moisture and humidity.
Do not break or crush gilteritinib tablets. Administer gilteritinib orally about the same time 
each day. If a dose of gilteritinib is missed or not taken at the usual time, administer the dose 
as soon as possible on the same day, and at least 12 hours prior to the next scheduled dose. 
Return to the normal schedule the following day. Do not administer 2 doses within 12 hours.
Gilteritinib may be taken in either the fed or fasted state either with or without gastric acid 
reducing agents, including proton pump inhibitors (PPIs).
7.2
LANRA:
LANRA is available as biconvex, blue film-coated tablets. Each tablet contains 10 mg or 
30 mg of LANRA free base as the succinate form. LANRA tablets contain commonly used 
excipients, including microcrystalline cellulose, mannitol, croscarmellose sodium, 
magnesium stearate, polyvinyl alcohol, polyethylene glycol, titanium dioxide, talc, and 
FD&C blue #2/indigo carmine aluminum lake. LANRA tablets are packaged in white, 
high-density, polyethylene bottles with silica gel desiccant and polyester packing material. 
Each bottle is enclosed with a white, continuous thread, child-resistant screw cap with an 
induction sealed liner. LANRA tablets should be stored at a controlled room temperature of 
15ºC to 30ºC (59°F to 86°F). Storage conditions are specified on the label. To ensure the 
stability of LANRA tablets, the drug product should not be dispensed into a container other 
than that in which it is supplied. Measures that minimize drug contact with the body should 
always be considered during handling, preparation, and disposal procedures. Appropriate 
precautions should be followed to avoid direct eye contact or exposure through inhalation
when handling LANRA. If eye contact does occur, affected areas should be washed with a 
large amount of water. 
In Phase 1b, administer LANRA without gilteritinib on Cycle 1, Day 1. Beginning on Day 2 
of Cycle 1, co-administer LANRA tablets with gilteritinib once daily at approximately the 
same time each day, with 8 ounces (240 mL) of water. In Phase 2, patients should initiate 
treatment with both LANRA and gilteritinib on Cycle 1, Day 1. 
Patients who have a delay of < 12 hours should take the planned dose as soon as possible 
after the intended time of administration. For patient
12 hours, the 
missed dose should not be taken. Return to the normal schedule the following day. Do not 


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administer 2 doses within 12 hours of each other. Vomited doses should not be repeated 
except if the tablets are clearly visible in the vomitus.
LANRA may be taken in either the fed or fasted state and with or without acid reducing 
agents, including PPIs.












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resume full dose gilteritinib followed 
by LANRA (
later), as 
tolerated.
For recurrence of Grade 4 
thrombocytopenia or Grade 3 
thrombocytopenia with clinically 
significant bleeding in the setting of 
reduced doses or lack of platelet 
2 after 
>28 days of treatment interruption,
discontinue study treatment.


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9.0 Treatment of Overdose
Any dose of LANRA or gilteritinib greater than the dose assigned is considered an overdose. 
AEs associated with an overdose will be recorded on the AE electronic case report form 
(eCRF) log. Events that meet the criteria for seriousness must be reported immediately, 
without undue delay, and within 24 hours of awareness via the SAE reporting process (see 
Section 16.7.4). In the event of an overdose, contact the medical monitor immediately. The 
patient must be monitored for evidence of toxicity and standard supportive treatment should 
be provided, as necessary. It is unknown whether LANRA or gilteritinib can be removed by 
dialysis. There is no known antidote for LANRA or gilteritinib. In the case of symptomatic 
overdose, the patient should receive standard treatment and supportive therapy based on the 
patient’s signs and symptoms.


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10.0
Concomitant Medications and Supportive Care Measures
All concomitant medications will be recorded beginning on C1D1 through 30 ± 7 days after 
treatment completion. The medical monitor should be contacted if there are any questions 
regarding the acceptability of concomitant or prior therapies.
10.1 Permitted Medications
Patients should receive full supportive care including transfusions of blood and blood 
products, antibiotics, anti-emetics, antifungal agents, tumor lysis syndrome treatment or 
prophylaxis, etc., when appropriate. Patients may receive prophylactic anti-microbial therapy 
in accordance with institutional standards of care. The use of myeloid growth factors is 
permitted in accordance with institutional standards of care. The use of intrathecal 
chemotherapy for prophylaxis against CNS leukemia is permitted in accordance with 
institutional care standards.
10.2 Prohibited Medications
Recombinant erythropoietin (rEPO) is not permitted at any time during the study. No other 
direct anti-leukemia therapy is permitted except for hydroxyurea in Cycle 1 to control or 
prevent signs/symptoms of leukostasis as required. Palliative radiation therapy may not be 
administered while the patient is on study except for management of localized leukemic 
infiltrates in the skin.
Patients must not receive medications that have a known risk to prolong the QT interval or 
induce Torsades de Pointes in light of the ability for gilteritinib to cause QT interval 
prolongation and the unknown potential for LANRA to do so (see Appendix 4).
In vitro data indicate that LANRA is predominantly metabolized by CYP3A4 in humans. As 
such, concurrent administration of strong CYP3A4 inducers is prohibited as these would be 
expected to cause reduced exposures to LANRA (see Section 6, LANRA Investigator 
Brochure; Appendix 4). Concurrent administration of strong CYP3A4 inhibitors should be 
avoided. If the use of a strong CYP3A4 inhibitor for patient management cannot be avoided,
patients should interrupt treatment with LANRA for the time period that the strong CYP3A4
inhibitor is required*. Administration of LANRA can resume at its previous dose 24 hours 
after discontinuation of the strong CYP3A4 inhibitor. Since grapefruit is known to be a 
strong inhibitor of CYP3A4, and Saint John’s wort is known to be a strong inducer of 
CYP3A4, patients must be instructed to refrain from consumption of grapefruit, its juice, or 
Saint John’s wort. 
*Most azole antifungal agents are strong CYP3A4 inhibitors (see Appendix 4), however, neither fluconazole 
nor isavuconazole are strong CYP3A inhibitors and can be concurrently administered with LANRA.


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10.3 Potential Drug Interactions
10.3.1 Gilteritinib
Concomitant use of gilteritinib with rifampin (a combined P-glycoprotein [P-gp] and strong 
CYP3A inducer) decreases gilteritinib exposure which may decrease its efficacy. Avoid 
concomitant use of gilteritinib with combined P-gp and other strong CYP3A inducers. 
Concomitant use of gilteritinib with itraconazole (a strong CYP3A inhibitor) increased
gilteritinib Cmax and AUC by approximately 20% and 120%, respectively. Consider 
alternative therapies that are not strong CYP3A inhibitors. If the concomitant use of these 
inhibitors is considered essential for care of the patient, monitor the patient more frequently 
for gilteritinib-mediated adverse reactions and/or consider dose reduction. See Appendix 4
for a list of commonly prescribed P-gp and strong CYP3A inducers and strong CYP3A 
inhibitors. Concomitant use of gilteritinib may reduce the effects of drugs that target the 
5HT2B receptor or the sigma nonspecific receptor (eg, escitalopram, fluoxetine, sertraline). 
Avoid concomitant use of these drugs with gilteritinib unless their use is considered essential 
for the care of the patient.
See the local prescribing information for gilteritinib for further information on potential drug 
interactions.
10.3.2 LANRA
In vitro, LANRA is an inhibitor of the drug transporter P-gp, which could potentially result 
in inhibition of P-gp mediated intestinal efflux of co-administered drugs. As such, orally 
administered P-gp substrates (eg, digoxin, dabigatran, etexilate) that have narrow therapeutic 
indices should be avoided (Appendix 4). In vitro, LANRA is a weak inducer of CYP3A4, 
thus caution should be taken if co-administered with oral drugs that are sensitive substrates of 
CYP3A4.


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11.0
Study Assessments & Procedures
Required study visits and corresponding assessments (except PK and PD assessments in 
Cycle 1 and Cycle 2) are outlined in Table 6 and Table 7 for the Screening evaluation 
through completion of Cycle 2 and for Cycle 3 through Post-treatment Follow-up,
respectively. All study visits should be scheduled relative to the C1D1 date regardless of any 
treatment interruptions. There are no windows for study visits from C1D1 through C1D16.
Acceptable windows for study visits beginning on Cycle 1, Day 22 are ± 1 day. Acceptable 
windows for post-treatment follow-up visits are ± 1 week. Unscheduled study visits may be 
required as clinically indicated for evaluation of AEs or suspected leukemic progression. 
Results of diagnostic evaluations performed as part of an unscheduled study visit must be 
entered into the Unscheduled Visit eCRF. Consistent with guidances from the FDA and other 
health authorities regarding the on-going COVID-19 pandemic (Appendix 5), certain safety 
assessments may be performed in a licensed facility other than the designated trial site, up to 
1 day prior to a scheduled study visit during the treatment phase beginning on Cycle 1, 
Day 22. These include hematology (complete blood count [CBC], differential, platelet 
count), clinical chemistries, urinalysis, coagulation studies and pregnancy testing (Table 6
and Table 7).
The schedule of PK and PD assessments on Cycle 1, Day 1 through Day 8 and Cycle 1,
Day 15 through Cycle 2, Day 1 in Phase 1b are outlined in Table 8 and Table 9, respectively. 
The schedule of PK and PD assessments in Cycle 1 and Cycle 2 in Phase 2, are outlined in 
Table 10.


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Table 6:
Schedule of Assessments – Screening Through Cycle 2
Assessment:
Screening
Cycle 1 †
Cycle 2 †
C1 
D1
C1 
D2
C1 
D4
C1 
D8
C1 
D11
C1
D15
C1
D16
C1 
D22
±1d 
**
C2 D1
±1d
C2 D8
±1d
C2 D15
±1d
C2 D22
±1d
Informed consent ††
X
Physical examination a
X
X
X
X
X
X
X
Vital signs/pulse 
oximetry b
X
X
X
X
X
X
X
X
X
X
X
X
Weight/height c
X
X
X
Medical history
X
Leukemia history d
X
ECOG PS
X
X
ECG e
X
X
X
X
X
ECHO/MUGAf
X
As clinically indicated
Hematology g, t
X
X*
X
X
X
X
X
X
X
X
X
Coagulation h, t
X
X*
X
X
Clinical chemistries i,t
X
X*
X
X
X
X
X
Urinalysis j, t
X
As clinically indicated
Viral serologies (HBsAg, 
anti-HBs, anti-HBc, 
anti-HCV, anti-HIV)
X
Serum pregnancy test 
(WOCBP) k
X
Urine pregnancy test 
(WOCBP) k, t
X
X
Bone marrow 
examination m
X
X
Study medication
dispensation n
X
X
Assessment of 
compliance
X
X
X
X
X
X
X
X
X
X
Adverse event review o
X
X
X
X
X
X
X
X
X
X
X
Prior medications p
X
Concomitant medication 
review q
X
X
X
X
X
X
X
X
X
X
X


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Pregnancy prevention 
counseling r
X
X
X
X
X
X
X
X
X
X
X
X
PK/PD Assessments 
X
X
See Table 8 and Table 9 for full descriptions of PK and PD sampling time points in Phase 1b. See
Table 10 for a full description of PK and PD sampling time points in Phase 2. After Cycle 2, additional 
blood samples for PD assessments are requested on Day 1 of Cycle 3 and every 3 cycles thereafter 
(ie, Cycle 6, Cycle 9, etc.) until 2 consecutive response assessments of CR/CRh are documented, and at 
End-of-Treatment in both Phase 1b and Phase 2 (see Table 7 below).
Bone marrow biopsy 
unstained slides 
(Optional)
Either archival samples or those obtained from patients at Screening or during the Treatment Phase are acceptable (see Section 11.6)
Table 7:
Schedule of Assessments – Cycle 3+, End-of-Treatment, Post-treatment Follow-up
Assessment
D1 ± 1 d
D15 ± 1 d
End of Treatment s
Post-treatment 
Follow-up
± 1 week
Physical examination a
X
X
X
Vital signs/pulse oximetry b
X
X
X
Weight/height c
X
X
ECOG PS
X
X
ECG e
X
X
ECHO/MUGAf
As clinically indicated
Hematology g, t
X
X
Coagulation h, t
X
Clinical chemistries, i, t
X
X
Urinalysis j, t
As clinically indicated
Serum pregnancy test (WOCBP) k
as clinically indicated (for confirmation of a positive urine 
pregnancy test)
Urine pregnancy test (WOCBP) k, t
X
X
Bone marrow examination m
X
Study drug dispensation n
X
Assessment of compliance
X
X
Adverse event review o
X
X
X
Concomitant medication review q
X
X
X
Pregnancy prevention counseling r
X
X
X
PD/biomarker assessments (peripheral blood) u
X
X


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Assessment
D1 ± 1 d
D15 ± 1 d
End of Treatment s
Post-treatment 
Follow-up
± 1 week
Bone marrow biopsy unstained slides (Optional)
Either archival samples or those obtained from patients at 
Screening or during the Treatment Phase are acceptable (see 
Section 11.6)
Progression/Relapse; Survival status v
X
Abbreviations:  AML, acute myeloid leukemia; ECG, electrocardiogram; ECHO, echocardiogram; FISH, fluorescence in situ hybridization; MUGA, multi-gated acquisition; 
WOCBP, women of child-bearing potential.
† All cycles are 28 days.
†† Study site personnel must obtain signed informed consent before any study-specific procedures are conducted unless these are part of the standard of care and must document the 
informed consent process in the patient’s medical record.
*These assessments need not be performed if obtained as part of the Screening evaluation within 48 hours of Cycle 1, Day 1 (C1D1) and are consistent with eligibility 
requirements.
**Beginning Cycle 1, Day 22, there is a study visit scheduling window of ± 1 day.
a Perform complete physical examination including neurological exam at Screening within 14 days of C1D1. At all other times, perform abbreviated, targeted examination. Report 
all treatment-emergent, clinically relevant abnormal physical findings on the adverse events eCRF.
b Includes resting heart rate, systolic/diastolic blood pressures, body temperature (°C); percent oxygen saturation is measured by pulse oximetry.
c Record both height and weight at Screening and thereafter only body weight.
d The following information minimally will be recorded: age and date of diagnosis; subtype of AML at diagnosis (de novo AML, AML with myelodysplastic features or 
therapy-related AML); best response to last prior regimen (partial response; stable or progressive disease; primary refractory disease after 1st line induction or recurrence of 
leukemia after CR) per ELN criteria (Appendix 2);
FLT3 mutation (ITD, TKD or both) and allelic frequency (high, low) at diagnosis (if 
applicable) and baseline; history of hematopoietic stem cell transplant including post-transplant best response; prior exposure to a FLT3 inhibitor (eg, midostaurin and/or selective
FLT3 inhibitor) and presence of other somatic mutations (eg, NPM1, IDH1, IDH2, DNMT3A, TP53) at diagnosis and baseline, if known.
e Obtain triplicate measurements, each separated by approximately 2 minutes with patient in semi-recumbent position at the following timepoints in Phase 1b: Screening, C1D1 
(pre-dose and paired with PK blood samples at 1, 2, 4, & 6 hours post-LANRA dose), C1D8 (pre- or post-dose), C1D15 (pre-dose and paired with PK blood samples at 1, 2, 4, & 
6 hours post LANRA and gilteritinib dosing), C2D1 and C3D1 (both pre- or post-dose), and as clinically indicated thereafter. NOTE: Pre-dose is considered 0-2 hours before 
LANRA dosing on C1D1 and LANRA/gilteritinib dosing on C1D15. See Table 8 below for C1D1 paired PK sampling timepoints and Table 9 for C1D15 paired PK sampling time 
points. In Phase 2, obtain triplicate ECG measurements at Screening, C1D8, C1D15, C2D1, and C3D1 (all pre- or post-dose).
f Record left ventricular ejection fraction and any other clinically relevant findings at Screening. Thereafter, repeat ECHO/MUGA as clinically indicated.
g Includes hemoglobin, hematocrit, white blood cell (WBC) count, platelet count and WBC differential (neutrophils, bands, lymphocytes, monocytes, eosinophils, basophils,
blasts).
h Includes prothrombin time (PT), activated partial thromboplastin time, international normalized ratio (INR), fibrinogen and D-dimer levels. After Screening, monitor coagulation 
parameters on Days 1 and 15 of Cycle 1, Day 1 of Cycles 2 and 3 and as clinically indicated thereafter.
i Includes electrolytes (sodium, potassium, chloride, total CO2 and/or bicarbonate, calcium, phosphate, magnesium), liver function studies (aspartate aminotransferase [AST], 
alanine aminotransferase [ALT], total and direct bilirubin), albumin, lactate dehydrogenase (LDH), alkaline phosphatase, blood urea nitrogen or serum/plasma urea, creatinine, uric 
acid, glucose, creatine phosphokinase (CPK), amylase and lipase. Monitor electrolytes, liver function tests (LFTs), blood urea nitrogen (BUN), creatinine, uric acid, and 


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phosphate in accordance with institutional care standards until the risk of tumor lysis syndrome has abated. For patients receiving nephrotoxic antimicrobial agents, closer 
monitoring of renal function is recommended, consistent with institutional standards of care.
j Includes dipstick evaluation for pH, glucose, protein, blood, and leukocyte esterase; conduct microscopic evaluation for red and white blood cells only if dipstick is abnormal.
Perform urinalysis at Screening, and as clinically indicated thereafter if urine dipstick is abnormal.
k Perform serum pregnancy test in WOCBP during Screening within 7 days of C1D1. Thereafter, perform urine ß-hCG test at the beginning of each new cycle of study treatment 
and at End-of-Treatment. Perform serum pregnancy test for confirmation of a positive urine ß-hCG test result.
m Perform bone marrow aspiration at Screening for morphology, karyotyping/FISH and biomarker assessments. A trephine bone marrow biopsy is required for patients in whom a
satisfactory aspirate cannot be obtained (eg, due to dry tap, hypocellular or hemodiluted sample). Perform bone marrow aspiration (or biopsy) for response and biomarker
assessments on Day 1 of Cycle 2 and Cycle 3 and every 3 cycles thereafter (ie, Cycle 6, Cycle 9, etc.) until CR/CRh is documented on 2 consecutive bone marrow examinations.
At other times, perform bone marrow examination for confirmation of suspected progression/relapse. MRD will be assessed retrospectively in bone marrow aspirate (and 
peripheral blood concurrently) as an exploratory efficacy endpoint in patients who achieve CR or CRh. MRD assessments will be performed in a central testing facility designated 
by the Sponsor beginning with the 1st documented CR or CRh. 
n LANRA will be dispensed by study center personnel at the beginning of each 28-day cycle to ensure adequate drug supply for home administration throughout the treatment 
phase in accordance with details outlined in the Pharmacy Manual. Instructions will be provided to patients for dosing, storage and disposition of unused study drug. In Phase 1b,
patients will receive LANRA only on C1D1 under medical supervision after predose PK/PD blood samples are obtained. Beginning on C1D2, patients will begin combination 
therapy with LANRA and gilteritinib, after the C1D2 (Hour 24) PK/PD blood samples are obtained (see Table 8). In Phase 2, patients will begin combination therapy with 
LANRA and gilteritinib on C1D1.
o Record all treatment-emergent adverse events (TEAEs) including clinically relevant laboratory abnormalities on the adverse event eCRF. TEAEs are those that either begin or 
increase in intensity on C1D1 through the End-of-Treatment Evaluation. Record only serious adverse events that occur during the Screening evaluation. Events that meet the 
criteria for seriousness must be reported immediately, without undue delay, and within 24 hours to Kronos Bio Drug Safety (or designee). All adverse events are graded for 
severity using NCI-CTCAE, v. 5.0. See Section 16.0 for further details on AE reporting.
p Record all medications (including over-the-counter medications) patient is taking from the time of informed consent until C1D1.
q Record all new or continuing medications patient is taking from C1D1 until the End-of-Treatment Visit.
r All male patients capable of fathering a child and WOCBP should be counseled regarding the need for pregnancy prevention in accordance with guidelines outlined in 
Appendix 6. After the Screening period, counseling will consist of reminding enrolled patients of the need to continue pregnancy prevention measures including the consistent use 
of effective contraception at time points stipulated in Table 6 and Table 7 and for 4 months (males) or 6 months (females) after the last dose of study drug.
s The End-of -Treatment Study Visit must occur 30 ± 7 days after the last dose of either gilteritinib or LANRA (whichever is later) or prior to initiation of new anticancer therapy.
t During the treatment phase, these assessments may be performed at a licensed facility other than the trial site up to 1 day prior to a scheduled study visit.
u After Cycle 2, additional blood samples for PD assessments are requested on Day 1 of Cycle 3 and every 3 cycles thereafter (ie, Cycle 6, Cycle 9, etc.) until 2 consecutive 
response assessments of CR/CRh are documented, and at End-of-Treatment. Blood samples for PD assessments on Day 1 of Cycle 3 and every 3 cycles thereafter should be 
collected pre-dose.
v Patients who discontinue study treatment for reasons other than progression/relapse will be followed monthly until progression/relapse at the discretion of the investigator and in 
the absence of intervening anti-leukemic therapy. Following progression/relapse, patients will be followed for survival every 3 months. Acceptable windows for post-treatment 
follow-up visits are ± 1 week.


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Table 8:
Schedule of PK and PD Assessments – Phase 1b, Cycle 1, Day 1 (C1D1) to Cycle 1, Day 8 (C1D8)
Cycle, Day
C1D1
C1D2
C1D8
Hour
-2 to 0
(predose)
0.5 ± 5 min 
(postdose)
1.0 
± 5 min
2.0 
± 10 min
3.0 
± 10 min
4.0 
± 30 min
6.0 
± 30 min
8.0 
± 30 min
24 ± 2 
(predose)
24 ± 2 
(predose)
PK (plasma)
X
X
X
X
X
X
X
X
X
X
PD (whole 
blood)
X
X
X
X
X
X
Table 9:
Schedule of PK and PD Assessments – Phase 1b, Cycle 1, Day 15 (C1D15) to Cycle 2, Day 1 (C2D1)
Cycle, Day
C1D15
C1D16
C1D22
C2D1
Hour
-2 to 0 
(predose)
0.5 ± 5 min 
(postdose)
1.0 
± 5 min
2.0 
± 10 min
3.0 
± 10 min
4.0 
± 30 min
6.0 
± 30 min
8.0 
± 30 min
24 ± 2 
(predose)
24 ± 2 
(predose)
24 ± 2 
(predose)
PK 
(plasma)
X
X
X
X
X
X
X
X
X
X
PD (whole 
blood)
X
X
X
X
X
X
X
Table 10:
Schedule of PK and PD Assessments – Phase 2, Cycle 1, Day 1 (C1D1) to Cycle 2, Day 1 (C2D1)
Cycle, Day
C1D1
C1D15
C1D22
C2D1
Hour
-2 to 0
(predose)
2.0 
± 10 min
4.0 
± 30 min
0 to -2
(predose)
2.0 
± 10 min
4.0 
± 30 min
0 to -2
(predose)
24 ± 2 
(predose)
PK (plasma)
X
X
X
X
X
X
X
PD (whole blood)
X
X
X
X
X
X
X
X
Abbreviations:  PD, pharmacodynamic(s); PK, pharmacokinetic(s).


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In both Phase 1b and Phase 2, plasma samples for LANRA and gilteritinib concentrations should 
be obtained at the following additional unscheduled time points:
1. As part of the diagnostic evaluation of AEs attributed to LANRA and/or gilteritinib (if 
possible).
2. Coincident with an increase in ECG QTc interval of >500 msec or >60 msec above 
baseline, based on 2 consecutive measurements (see Section 11.7.3).
11.1 Informed Consent
Study site personnel must obtain signed informed consent before any study-specific procedures 
are conducted unless these are part of the standard of care and must document the informed 
consent process in the patient’s medical record. Consent must be obtained using the most current 
version of the ICF approved by the study site’s IRB/IEC. Once the patient signs the ICF, that 
will signal the beginning of the 21-day Screening Period. Patients who provide informed consent 
and subsequently do not meet eligibility criteria (or withdraw consent prior to enrollment) should 
be documented as screening failures, with the reason(s) for not meeting eligibility or not 
enrolling recorded.
11.2 Confirmation of Eligibility
All screening assessments and relevant medical history must be available and reviewed by the 
investigator before eligibility can be confirmed. Eligibility waivers will not be granted. After the 
investigator determines that a patient is eligible, study site personnel will complete an enrollment 
authorization form to be sent to the medical monitor for review/approval. Written authorization 
by the medical monitor is required before a patient can be officially enrolled and begin study 
treatment.
11.3 Medical and Leukemia History
Clinically significant medical history not pertaining to the underlying malignancy under study,
which started prior to informed consent, will be captured on the eCRF. “Clinically significant” is 
generally regarded as any diagnosis requiring on-going treatment intervention and follow-up.
Signs and symptoms of concurrent medical conditions must be adequately documented at 
Screening in order to establish baseline severities.
The following information regarding the history of AML will be collected and recorded on the 
eCRF: age and date of diagnosis; subtype of AML at diagnosis (de novo AML; AML with 
myelodysplastic features or therapy-related AML); best response to last prior regimen (partial 
response, stable or progressive disease; primary refractory disease after 1st line induction or 
recurrence of leukemia after CR) per ELN 2017 criteria (Appendix 2); number of relapses (0, 1, 
FLT3 mutation (ITD, TKD or both) and allelic frequency (high, low) at diagnosis (if 
applicable) and at baseline; history of hematopoietic stem cell transplant including 
post-transplant best response; prior exposure to a FLT3 inhibitor (eg, midostaurin and/or 
selective FLT3 inhibitor) and presence of other somatic mutations (eg, NPM1, IDH1, IDH2,
DNMT3A, TP53) at diagnosis and baseline, if known.


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11.4 Study Drug Dispensation
LANRA will be dispensed by study center personnel at the beginning of each 28-day cycle to 
ensure adequate drug supply for home administration throughout the Treatment Phase in 
accordance with details outlined in the Pharmacy Manual. Instructions will be provided to 
patients for dosing, storage and disposition of unused study drug. In Phase 1b, patients will 
receive LANRA only on C1D1 while under medical supervision after predose PK/PD blood 
samples are obtained. Beginning on C1D2, patients will begin combination therapy with 
LANRA and gilteritinib, after the C1D2 (Hour 24) PK/PD blood samples are obtained (see
Table 8). In Phase 2, patients will begin combination therapy with LANRA and gilteritinib
on C1D1.
Patients will be provided a dosing diary to record dosing information when at home. Patients will 
be instructed to record the date and time of study treatment administration along with any 
pertinent notes (eg, nausea, vomiting after ingestion of the dose) in the dosing diary. Deviation(s) 
from the prescribed treatment regimen should be recorded by the patient in the dosing diary. The 
dosing diary will be evaluated by study site personnel at study visits.
Patient compliance with the study treatment will be by direct questioning, counting returned 
tablets, and reviewing patient’s dosing diaries. Treatment start and stop dates, including dates 
and reasons for treatment interruption and/or dose reductions will also be recorded in the eCRF. 
11.5 Pharmacokinetics
Blood will be collected at specified intervals in order to measure the plasma concentrations of 
LANRA both alone and in combination with gilteritinib, and plasma concentrations of 
gilteritinib administered in combination. Plasma samples collected for PK analysis may also be 
used for an exploratory assessment of the LANRA metabolite profile. The schedule for PK blood 
sampling in Phase 1b, Cycle 1 is provided in Table 8 and Table 9 and for Phase 2, Cycle 1 in 
Table 10. On PK sample collection days, administration of study drug must occur under the 
supervision of study site personnel after the predose PK sample is collected. The time of study 
drug administration must be recorded on the eCRF and include the last administration of study 
medication (both LANRA and gilteritinib) prior to the predose sample collection as well as in 
other situations where dosing occurred outside of the clinic (eg, in conjunction with evaluation of 
AEs or QTc prolongation, see Section 11.7.3). For each blood sample collected, the actual time 
of collection (to the nearest minute) will be captured in the eCRF. Plasma concentrations 
of LANRA, gilteritinib, and their metabolite(s), if applicable, will be quantified by liquid 
chromatography with tandem mass spectrometry (LC-MS/MS) using validated assays.
Details concerning the processing and handling of PK samples, including labeling and shipping 
instructions, will be provided in the Laboratory Manual.
11.6 Pharmacodynamic (Biomarker) Assessments
Peripheral blood will be collected at Screening and specified intervals during Phase 1b and 
Phase 2 in order to characterize the pharmacodynamic activity of LANRA and to support 
selection of the RP2D. The schedules of blood sampling for biomarker assessments on Cycle 1 
Day 1 through Day 8 and Cycle 1 Day 15 through Cycle 2 Day 1 in Phase 1b are outlined in 


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Table 8 and Table 9, respectively. The schedule of blood sampling for Cycle 1 and 2 biomarker 
assessments in Phase 2 is provided in Table 10. After Cycle 2, additional blood samples for 
biomarker assessments are requested on Day 1 of Cycle 3 and every 3 cycles thereafter until 
2 consecutive response assessments of CR/CRh are documented, and at the End-of-Treatment
Evaluation (Table 7).
Bone marrow aspirate for biomarker assessments will be collected at Screening, Day 1 of 
Cycle 2 and Cycle 3 and every 3 cycles thereafter (ie, coinciding with response assessments)
until 2 consecutive response assessments indicate CR or CRh.
Biomarker assessments will include (but are not limited to) an evaluation of somatic mutations 
other than FLT3 in baseline blood and bone marrow samples as well as pre- vs on-treatment 
changes in phosphorylated (p)SYK and gene expression in whole blood and/or bone marrow 
aspirate samples using standard proteomic, transcriptomic, and genomic tools such as 
immunohistochemistry (IHC), Nanostring®, and next-generation sequencing (NGS). Levels of 
circulating proteins (such as, but not limited to IL-1b, TNF-
-6) in plasma may also be 
assessed and quantified throughout the Treatment Phase using technologies such as 
enzyme-linked immunosorbent assay (ELISA) or Luminex® (Austin, TX), for example. 
Optional unstained slides (n=3-5) from bone marrow biopsies are requested to explore the 
immunologic profile in the bone marrow microenvironment of study patients. Results from 
preclinical studies suggest that a.) SYK inhibition may activate T-cell responses, and b.) integrin 
signaling via SYK plays a role in creating a permissive microenvironment for survival and 
propagation of leukemic cells in the bone marrows of AML patients. Immunologic profiling of 
biopsies from study patients may help us understand whether/if specific immune cell profiles
correlate with response to the study regimen. Slides from archival bone marrow biopsies or those 
obtained from study patients either at Screening or during the Treatment Phase are acceptable for 
study.
11.7 Safety Assessments
Unless otherwise stated, all safety assessments will be conducted locally in accordance with 
institutional standards of care.
11.7.1 Physical examination, vital signs, pulse oximetry
Perform a complete physical examination including neurological exam at Screening within 
14 days of C1D1. At all other times, perform abbreviated, targeted examinations. Physical 
examination always includes body weight; height is obtained only at Screening. Report all 
treatment-emergent, clinically relevant abnormal physical findings on the AEs eCRF. Vital signs 
include resting heart rate, seated systolic/diastolic blood pressures and body temperature (°C);
percent oxygen saturation is measured by pulse oximetry.
11.7.2 Laboratory assessments (hematology, clinical chemistries, coagulation, urinalysis,
pregnancy testing)
CBCs are required at time points specified in Table 6 and Table 7 and includes hemoglobin 
concentration, hematocrit, platelet count, white blood cell (WBC) count with differential 


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including neutrophils (including bands), lymphocytes, monocytes, eosinophils, basophils and 
blasts. Coagulation screening studies (PT, aPTT and INR, fibrinogen, D-dimer levels) are 
required at Screening, on Days 1 and 15 of Cycle 1, Day 1 of Cycles 2 and 3 and as clinically 
indicated thereafter.
Chemistries include electrolytes (sodium, potassium, chloride, total CO2 and/or bicarbonate, 
calcium, phosphate, magnesium), liver function studies (AST, ALT, total and direct bilirubin), 
albumin, lactate dehydrogenase (LDH), alkaline phosphatase, blood urea nitrogen or 
serum/plasma urea, creatinine, uric acid, glucose, creatine phosphokinase (CPK), amylase and 
lipase. Monitor electrolytes, LFTs, BUN, creatinine, uric acid, and phosphate in accordance with 
institutional care standards until the risk of tumor lysis syndrome has abated. For patients
receiving nephrotoxic antimicrobial agents, closer monitoring of renal function is recommended, 
consistent with institutional standards of care.
Urinalysis includes dipstick evaluation for pH, glucose, protein, blood, and leukocyte esterase;
conduct microscopic evaluation for red and white blood cells only if the dipstick result is
abnormal. Perform urinalysis at Screening and as clinically indicated thereafter if urine dipstick 
is abnormal.
Perform a serum pregnancy test in WOCBP during Screening within 7 days of C1D1.
Thereafter, perform urine ß-hCG test at the beginning of each new cycle of study treatment and 
at End-of-Treatment. Perform a serum pregnancy test for confirmation of a positive urine ß-hCG 
test result.
11.7.3 Cardiac function and ECG
Obtain triplicate ECG measurements, each separated by approximately 2 minutes with the 
patient in semi-recumbent position at the following time points in Phase 1b: Screening, on 
Days 1 (predose), 8 (pre- or post-dose) and 15 (predose) of Cycle 1, Day 1 of Cycle 2 and 
Cycle 3 (both pre- or postdose). On Cycle 1, Day 1 and Cycle 1, Day 15, additional triplicate 
ECGs paired with PK blood samples are required at Hours 1, 2, 4 and 6 post-dose (see 
Table 8 and Table 9). In Phase 2, obtain triplicate ECG measurements at Screening, Cycle 1 
Day 8, Cycle 1 Day 15, Cycle 2 Day 1, and Cycle 3 Day 1 (all pre- or post-dose). 
All ECG recordings will be performed using a high-quality, high-fidelity digital 
electrocardiograph and centrally reviewed and interpreted. To minimize postural variability, 
ECG recordings must be obtained after the patient has been resting in a semi-recumbent position 
for at least 10 minutes. When coinciding with blood draws or other procedures (eg, vital sign 
measurements), ECG assessments should precede these. Environmental factors that may induce 
changes in heart rate (eg, television, radio, etc.) should be avoided as much as possible. 
For safety monitoring purposes, the investigator or his/her designee should review, sign and date 
all ECG tracings with paper copies kept as part of the patient’s permanent study file at the site. 
Digital recordings of ECGs sent to the central reading facility will be stored in a repository under 
the supervision of the reading facility or with the sponsor/designee. If QTc interval prolongation 
is observed (mean QTcF > 500 msec and/or >60 msec longer than baseline) during study 
treatment, another triplicate ECG must be obtained within the next 5 minutes. If confirmed on 
repeat triplicate ECG, an unscheduled PK sample should be collected (Section 11.5) and 
follow-up ECGs recorded at least hourly, until the prolongation is reversed or stabilized, or the 


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investigator determines that there is no significant arrhythmic risk. Other possible causes for QTc 
prolongation should be investigated including electrolyte abnormalities, concurrent medication 
use known to prolong QT interval, etc. The medical monitor should be notified, and a decision 
made whether to discontinue study treatment. See Table 2 for gilteritinib treatment 
modification in the setting of QTcF interval prolongation to > 500 msec at any time and/or 
a >30 msec increment on Cycle 1, Day 8 compared to baseline.
The sponsor will evaluate the relationship between LANRA PK parameters and ECG intervals 
on an on-going basis and may modify the schedule of Cycle 1, Day 1 PK/ECG paired
assessments based on updated information during the study. 
An assessment of left ventricular ejection fraction will be performed at Screening and as 
clinically indicated during the treatment phase. An ECHO or MUGA scan is acceptable. 
11.7.4 ECOG performance status
ECOG PS will be assessed at time points indicated in Table 6 and Table 7 and in accordance 
with criteria outlined in Appendix 3.
11.7.5 Prior and concomitant medications and procedures
Record all medications (including over-the-counter medications) patient is taking from the time 
of informed consent until Cycle 1, Day 1 (C1D1). All new or continuing medications including 
dose, frequency, route of administration and start and stop dates, which are administered between 
C1D1 and the End-of-Treatment Visit must be recorded in the eCRF concomitant medication 
log. Record all surgical and diagnostic procedures (eg, X-rays, scans) on the designated eCRFs.
11.7.6 Adverse events
During the Screening period, record only serious AEs. Beginning on C1D1 until the 
End-of-Treatment Evaluation, record all new AEs as well as any that predate C1D1 but that 
worsen in intensity or recur during the Treatment Phase. After the End-of-Treatment Evaluation, 
only serious AEs that are assessed as causally related to LANRA must be reported. Guidelines 
for the reporting of AEs and serious AEs are provided in Section 16.0.


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12.0
Efficacy Assessments
Assessments that define the quality of response to study treatment will include physical
examination, peripheral blood counts, and bone marrow examination. All assessments of 
response will be made by the investigator in accordance with ELN 2017 criteria (Döhner 2017). 
See Appendix 2 for criteria that define each response category.
12.1 Bone Marrow Examination
Perform bone marrow aspiration at Screening for morphology, karyotyping/fluorescence in situ 
hybridization (FISH) and biomarker assessments. A trephine bone marrow biopsy is required for 
patients in whom a satisfactory aspirate cannot be obtained (eg, due to dry tap, hypocellular or 
hemodiluted sample). Perform bone marrow aspirate (or biopsy) for response assessments and 
biomarker assessments (Section 11.6) on Day 1 of Cycle 2 and Cycle 3 and every 3 cycles 
thereafter (Cycle 6, Cycle 9, etc.) until CR/CRh is documented on 2 consecutive bone marrow 
examinations. At other times, perform bone marrow examination for confirmation of suspected 
progression/relapse.
12.1.1 Measurable Residual Disease (MRD)
MRD will be assessed retrospectively in peripheral blood and bone marrow aspirate concurrently 
as an exploratory efficacy endpoint. MRD assessments will be performed in a central testing 
facility designated by the Sponsor beginning with the 1st documented CR or CRh.


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13.0
Criteria for Study Treatment Discontinuation
Study treatment will be discontinued for the following reasons:
Unequivocal leukemic progression or recurrence of leukemia after a response
Failure to achieve at least a PR after completion of 6 cycles of study treatment
Pregnancy
Death
Withdrawal of consent
A TEAE that:
o
is Grade 3 and unresponsive to treatment modification guidelines outlined in 
Table 2 and Table 4 (for gilteritinib and LANRA non-hematologic toxicities,
respectively) and Table 5 (for hematologic toxicities associated with either or 
both drugs) OR,
o
chronic, Grade 1 or 2 toxicities that may not be tolerable when experienced for 
long periods of time either with or without treatment modification, thereby 
prompting the decision by the investigator, patient, or both to discontinue study 
treatment
Need for, or use of a prohibited concomitant medication
Hematopoietic stem cell transplantation
Non-compliance with the study regimen
Trial is discontinued by the study sponsor
Patients who discontinue study treatment must complete the End-of-Study Visit 30 ± 7 days 
after the last dose of either gilteritinib or LANRA (whichever is later) or prior to initiation of 
new anticancer therapy.
During Part 1 (dose escalation), any dosing interruption resulting in administration of <80%
of the cumulative, Cycle 1 dose for either LANRA or gilteritinib in the absence of DLT will 
require the patient to be replaced.


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14.0
Criteria for Study Discontinuation
Study participation will be discontinued for the following reasons:
Death
Withdrawal of consent
Trial is discontinued by the study sponsor


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15.0
Statistical Considerations
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in a Statistical Analysis Plan (SAP), which will be maintained by the sponsor. 
This document may modify the plans outlined in the protocol, however, any major modifications 
of the primary endpoint definition and/or its analysis will also be reflected in a protocol 
amendment. 
Summary statistics and listings will be used to analyze the study data. Continuous variables will 
be summarized by means, standard deviations, medians, interquartile ranges, minimal and 
maximal values. Categorical variables will be summarized by number and percent.
Unless otherwise specified, data summaries and analyses described below will be reported by 
dose group and overall in Phase 1b and overall in Phase 2 using all available data. Missing data 
will not be imputed unless otherwise described in the SAP.
15.1 Study Endpoints
See Section 3.0 for a description of study endpoints for Phase 1b and Phase 2.
15.2 Statistical Analysis
15.2.1 Analysis populations
Patients will be evaluable for DLT in Part 1 if one of the following occurs:
They experience a DLT (as defined in Appendix 1
LANRA
during the DLT assessment period (Cycle 1, Day 1 until Cycle 2, Day 1).
They receive at least 80% of the intended cumulative doses of LANRA and gilteritinib 
during the DLT assessment period without the occurrence of a DLT.
Note: If there are patients within a dose cohort who receive less than the intended 
cumulative dose of either study medication, due to reasons other than a DLT, additional 
patients will be enrolled to ensure the desired number of evaluable patients.
Note: To better understand the safety, tolerability, PK, PD, and anti-tumor activity of the study 
regimen, additional patients (up to a total of 20 per dose cohort) may be allocated to previously 
cleared dose cohort(s) that are considered to be safe and adequately tolerated by the DEC, if 
there are no available patient slots in the dose cohort currently under evaluation. The decision to 
enroll additional patients at a dose level previously cleared by the DEC (ie, enrollment of a
“backfill” cohort) will be based on agreement by the DEC coincident with each scheduled DEC 
convocation. Furthermore, additional patients may be added to a previously cleared dose cohort 
only if at least 1 of the 3 to 6 patients initially enrolled to that cohort have achieved one of the 
following ELN 2017-defined response categories (Appendix 2): CR, CRh, CRi, PR, MLFS. The 
3+3 dose escalation rule will continue to be followed for each successively higher dose cohort
however, should DLT(s) occur in 1 or more patients enrolled to backfill cohorts, these will be 
taken into account for purposes of future dose escalation decisions. Specifically, if a DLT occurs 
in a patient allocated to a backfill cohort, the DLT rate will be re-calculated for that cohort. If the 


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updated DLT rate exceeds 20% with 80% probability, the updated DLT rate will be taken into 
consideration by the DEC when deciding whether to stop or continue dose escalation to the next 
higher dose level.
gilteritinib or LANRA and have at least 1 on-treatment safety -related observation (ie, report of 
an AE or post-dose assessment of vital signs, ECGs, or safety laboratory assessments).
The PK analysis population will include all patients with at least 1 post-dose LANRA plasma 
concentration. 
The PD analysis population will include all patients with a baseline and at least 1 post-dose 
pharmacodynamic assessment.
The efficacy evaluable population will include all patients 
tinib or 
LANRA and complete the first protocol-specified response assessment or have discontinued 
study treatment for toxicity or die prior to the first response assessment.
15.2.2 Patient Disposition
The number of patients screened, enrolled, treated, and discontinued from study treatment and 
follow-up will be summarized. The primary reason for study treatment discontinuation and study 
discontinuation will be summarized separately for Phase 1b and Phase 2 in accordance with the 
reasons specified in Section 13.0 and Section 14.0, respectively.
15.2.3 Demographics
Demographics (age, sex, race) and ECOG PS will be summarized for the safety populations in 
Phase 1b and Phase 2 separately, using descriptive statistics.
15.2.4 Medical History
All clinically relevant prior or concurrent medical conditions will be mapped to a system organ 
class (SOC) and preferred term (PT) using the version of the Medical Dictionary for Regulatory 
Activities (MedDRA) in effect at the time of database lock. The number and percent of patients 
in the safety populations in Phase 1b and Phase 2 reporting medical conditions will be 
summarized separately.
15.2.5 Leukemia History
The following baseline characteristics will be summarized using descriptive statistics for patients 
in Phase 1b and Phase 2 separately: age and years since initial diagnosis; subtype of AML at 
diagnosis (de novo AML, AML with myelodysplastic features or therapy-related AML); best 
response to last prior regimen (partial response, stable or progressive disease, primary refractory 
disease after 1st line induction or recurrence of leukemia after CR) per ELN criteria
(Appendix 2); number of 
; type of FLT3 mutation (ITD, TKD or both) and 
allelic frequency (high, low); history of hematopoietic stem cell transplant including 
post-transplant best response (if known); prior exposure to a FLT3 inhibitor (eg, midostaurin
and/or selective FLT3 inhibitor) and presence of other somatic mutations (eg, NPM1, IDH1,
IDH2, DNMT3A, TP53) at diagnosis and baseline, if known.


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The median, minimal and maximal number of prior systemic antileukemic regimens will be 
summarized. By-patient listings of systemic leukemia treatment regimens, including start and 
stop dates for each regimen component, will be generated for Phase 1b and Phase 2 patients 
separately. Anti-neoplastic agents will be classified using 11-digit, World Health Organization 
(WHO) Drug Dictionary codes preferred name and the Anatomic Therapeutic Chemical (ATC) 
Classification for pharmacologic properties and summarized by frequency distributions for 
Phase 1b and Phase 2 patients separately. 
15.2.6 Prior and Concomitant Medications
Prior medications (defined as all medications administered from signing of informed consent 
until C1D1) will be summarized by frequency distributions and percentages for Phase 1b and 
Phase 2 patients separately. Concomitant medications (defined as all new or on-going 
medications administered from C1D1 until the End-of-Treatment Evaluation) will be 
summarized by frequency distributions for Phase 1b and Phase 2 patients separately. Both prior 
and concomitant medications will be classified using WHO Drug Dictionary codes preferred 
name and ATC Classification for therapeutic indication.
15.2.7 Safety Analyses
Dose-limiting toxicities will be summarized for Phase 1b and Phase 2 patients separately. 
Descriptive summaries will be generated for all safety data including TEAEs as well as changes 
from baseline in selected laboratory assessments, vital signs, physical findings and ECGs. All 
AEs will be graded for severity using NCI-CTCAE v5.0 (Common Terminology Criteria for 
Adverse Events (CTCAE) (cancer.gov)).
15.2.7.1 Safety Stopping Rules
For Part 2, evaluation of DLTs will be assessed coincident with the first cycle of treatment, 
initially after the first 6 patients and each additional patient thereafter. If the true incidence of 
DLTs exceeds 20% with 80% posterior probability given the accumulated data at these time 
points, further enrollment will be interrupted. Using the Bayesian stopping rules with the defined 
parameters, the stopping rule is given in Table 11.




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15.2.9 Pharmacokinetic Analyses
Plasma concentrations of LANRA and gilteritinib will be tabulated and summarized by dose 
level, study day, and time in Phase 1b. The PK parameters for gilteritinib and LANRA (and if 
possible, LANRA major metabolites, if any) will be derived from plasma concentrations using 
standard non-compartmental methods and actual sample times. Minimally, the following PK 
parameters will be calculated: Cmax, Tmax, AUC0-last, accumulation ratio (Racc) and if data permit, 
half-life (t½), AUC0-inf, CL/F, and apparent volume of distribution at steady state (Vss/F). PK 
parameters such as Ctrough will be calculated in conjunction with sparse sampling in Phase 2. PK 
parameters will be summarized using descriptive statistics (N, arithmetic means, standard 
deviations, minimal, median and maximal values, geometric means and percent coefficient of 
variation). 
The relationship between changes from baseline in QTc at specified time points post-dose and 
plasma concentrations of LANRA may be assessed. A separate analysis plan for such analyses 
will be generated in accordance with principles outlined in ICH E14 (Clinical Evaluation of 
QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs) with 
results reported separately from the main clinical study report for this trial. Other 
exposure-response relationships (efficacy, safety and biomarkers) may be conducted, if 
supported by sufficient data.  
15.2.10 Efficacy Analyses
Best response (CR, CRh, CRi, partial response [PR], stable disease [SD], and progressive disease 
[PD]) will be summarized for the efficacy-evaluable population by frequency distributions and 
percentages in accordance with ELN criteria (Appendix 2). Patients with no post-baseline 
response assessments will be considered non-responders. The 80% CIs for estimates of the 
proportion of patients with CR/CRh will be constructed with exact methods for the binomial 
distribution (eg, Clopper-Pearson intervals). Additionally, 80% CIs for the estimates of the 
proportion of patients with any CR (CR, CRh or CRi) will be constructed in a similar manner.
EFS is defined as the time from C1D1 until treatment failure (ie, failure to achieve CR or CRh), 
relapse from CR/CRh or death from any cause. DOR is defined as the time from the first 
documented CR/CRh until relapse or death. Kaplan-Meier (KM) methodology will be used to 
estimate the medians for EFS and duration of response and at specified landmark timepoints. The 
80% CIs for estimates of the medians and landmark rates for EFS and duration of response will 
be calculated using the log-log transformation (Kalbfleisch and Prentice, 1980). Duration of 
follow-up will be estimated using the reverse KM method. Patients who do not experience the 
event of interest will be censored at the last assessment at which they are deemed relapse-free.
All summaries of EFS and duration of response will employ the safety and efficacy evaluable 
populations, respectively. OS will be estimated using KM methodology. Patients alive at last 
follow-up will be censored at the date of last contact.
15.2.11 Pharmacodynamic Analyses
Descriptive summaries for results of individual biomarkers of interest will be generated. A 
separate analysis plan for evaluating changes in pre- vs. on-treatment biomarkers of interest will 
be generated with results reported separately from the main clinical study report for this trial. 


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15.3 Sample Size Considerations
Approximately 100 patients in total are planned for enrollment in the study.
Up to 69 patients will be enrolled to Phase 1b with the actual number determined by the number 
of dose cohorts and number of patients in each cohort (including those patients enrolled to 
backfill cohorts) for determination of LANRA MTD/RP2D. Approximately 31 patients are 
planned for enrollment in Phase 2. The optimal two-stage design to test the null hypothesis that 
the composite CR rate (CR/CRh) is
23% (XOSPATA [gilteritinib] US Prescribing Information, 
2022) versus the alternative hypothesis, that CR/CRh is > 23% has an expected (average) sample 
size of 19.26 and a probability of early termination of 0.710. If the study regimen is not effective, 
there is a 0.025 probability of concluding that it is (the target for this value was 0.025 one-sided). 
If the study regimen is effective, as defined by CR/CRh = 46%, there is a 0.806 probability of 
concluding that it is (the target for this value was 0.800). After testing the treatment regimen on
12 patients in the first stage (including those treated at the MTD/RP2D in Phase 1b), the trial will 
be terminated if 3 or fewer patients respond. If the trial enrolls the second stage, additional 
patients will be enrolled to obtain at least 37 patients treated on the RP2D dose (including at least 
6 patients enrolled to Phase 1b and treated at the RP2D). If the total number of patients enrolled 
to Stage 1 and Stage 2 who achieve a CR/CRh is 13, the study regimen is rejected (Calculations 
made using PASS 2020).
15.4 Interim Analysis
There will be no interim analyses in Phase 1b other than those associated with decisions 
pertaining to dose escalation and final determination of the MTD/RP2D. 
In Phase 2, a review of the first stage composite CR rate will be evaluated after 12 patients are 
enrolled at the RP2D and evaluated for response.
15.5 Final Analysis
The final analysis will occur at the End of Study, as defined in Section 6.5.
15.6 Other Statistical Issues (eg, Multiplicity Adjustment, If Applicable)
Not applicable.


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16.0
Safety Monitoring and Reporting
16.1 Definitions
An AE is defined as 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.
When an AE occurs, it is the responsibility of the investigator to review all documentation 
(eg, progress notes, laboratory results, diagnostic reports) relevant to the event. The investigator
or his/her designee will record all relevant information regarding the event in the eCRF. There 
may be instances when copies of medical records are requested by the study sponsor. In these 
instances, all patient identifiers will be redacted on copies of medical records prior to submission 
to the sponsor.
A serious AE (SAE) is any untoward medical occurrence that:
Results in death
Is life-threatening
Note: Life-threatening implies that the patient was at risk of imminent death at the time of the 
event; it does not refer to an event that hypothetically might have caused death, were it more 
severe.
Requires or prolongs a pre-existing hospitalization.
Note: Hospitalization signifies that the patient was admitted to a hospital or emergency ward for 
an overnight stay (at least) for observation and/or treatment.
Results in disability/incapacity.
Note: Disability refers to a substantial disruption of person’s ability to conduct daily functions.
Is a congenital anomaly/birth defect.
Is considered a significant medical event by the investigator that may jeopardize the 
patient or require medical or surgical intervention to prevent one of the outcomes listed 
above.
A suspected, unexpected serious adverse reaction (SUSAR) is an AE that is both unexpected 
(ie, not listed in the Reference Safety Information for the investigational agent) and meets the 
definition of a serious adverse drug reaction, the specificity or severity of which is not consistent 
with those noted in the Reference Safety Information (ie, the Investigator’s Brochure for an 
investigational agent).
16.2 Assessment of Severity
The investigator will make an assessment of severity for each AE reported during the study. AEs
should be assessed and graded for severity based on the NCI-CTCAE v. 5.0 (Common 
Terminology Criteria for Adverse Events (CTCAE) (cancer.gov).


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Toxicities that are not specified in the NCI-CTCAE will be graded for severity as follows:
Grade 1 (Mild): asymptomatic or mild symptoms; clinical or diagnostic observation only; 
intervention not indicated
Grade 2 (Moderate): minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL)
Grade 3 (Severe): Medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL
Grade 4 (Life-threatening): Urgent intervention indicated required to remove or abrogate 
risk of death
Grade 5: Death related to AE
Note: The terms “severe” and “serious” are not synonymous. Severity is a measure of intensity 
(as characterized above) whereas seriousness as defined above, defines the requirements for 
reporting obligations from the sponsor to applicable regulatory authorities.
16.3 Assessment of Causality
The investigator will assess the causal relationship between and the occurrence of all AEs using 
best clinical judgement and taking into consideration the natural history of the underlying 
disease, concomitant therapies, biological plausibility, the mechanism of action of the study drug
and the temporal relationship between the event and the administration of study drug. The 
investigator should consult relevant safety information and “Guidance for the Investigator” in the 
IB in formulating his/her assessment of causality.
Each AE should be assessed as either “related” or “not related” to, based on all available 
information at the time of reporting. Causality assessments may be modified in the context of 
additional information or details pertaining to the event, after the initial causality assessment is 
made. An event should be considered related if any of the following criteria are met:
There is clear evidence to suggest a causal relationship and other possible causal factors 
can be ruled out.
There is evidence to suggest a causal relationship and the influence of other factors is 
unlikely.
There is evidence to suggest a causal relationship, however, other factors (eg, the 
patient’s underlying condition or other concurrent AEs) may have contributed to the 
occurrence of the event.
16.4 Follow-up of Adverse Events
After an initial AE or serious AE is reported, those that are designated as ongoing from a 
previous visit/contact must be reviewed at subsequent visits. All AEs will be followed until 
resolution, stabilized, or considered chronic, or the study participant is either lost to follow-up or 
withdraws consent. The investigator will ensure that follow-up reporting includes any 
supplemental investigations that were obtained to further elucidate the nature and/or causality of 
the event, including additional laboratory or radiographic evaluations, histopathologic 
examination, or consultation with other health care professionals.


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The sponsor may request that the investigator perform or arrange for the conduct of supplemental 
evaluations to elucidate as fully as possible the nature and/or causality of any event. If a study 
participant dies while on study or during a pre-specified follow-up period, the sponsor will be 
provided with a redacted copy of any postmortem findings, including histopathologic findings. 
16.5 Abnormal Laboratory Results
Abnormal laboratory test results (eg, chemistries, blood counts, coagulation studies or urinalysis) 
or other abnormal assessments (eg, ECGs, X-rays) that are judged by the investigator as 
clinically significant will be recorded as AEs or serious AEs, as appropriate. This includes 
clinically significant blood, urine or other abnormalities that are present at baseline and 
significantly worsen during the study. In general, clinically significant laboratory test 
abnormalities are those associated with signs or symptoms, require active medical intervention, 
lead to study treatment interruption or dose reduction and/or require more frequent follow-up or 
further diagnostic investigation.
16.6 Adverse Event Reporting Period
Report only SAEs after signing of the ICF, but before administration of study drug. Beginning 
on C1D1 until the End-of-Treatment Evaluation (or until initiation of new anticancer therapy,
whichever is sooner), report all AEs regardless of the relationship to study treatment. Thereafter, 
only SAEs assessed as related to LANRA must be reported. 
16.7 Instructions for Reporting Adverse Events
16.7.1 Leukemic progression
Leukemic progression should not be reported as an AE. Signs, symptoms, or clinical sequelae of 
leukemic progression should be reported (eg, worsening cytopenias, fatigue, infection as
manifestations of recurrence or worsening of AML should be reported as such on the AE eCRF).
16.7.2 Death
Death is an outcome and not usually considered an event. For example, in the case of 
overwhelming sepsis leading to death, “overwhelming sepsis (Grade 5)” would be recorded as 
the event with death as the outcome. If the cause of death is unknown, the death is then reported 
as an event (ie, “death due to unknown cause” or “death unexplained”).
16.7.3 Differentiation Syndrome (DS)
Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid 
cells and may be life-threatening or fatal if not treated. Symptoms of differentiation syndrome 
include fever, dyspnea, pleural effusion, pericardial effusion, pulmonary edema, hypotension, 
rapid weight gain, peripheral edema, rash, and renal dysfunction. Some cases may present with 
concomitant acute febrile neutrophilic dermatosis. Differentiation syndrome may occur as early 
as 2 days and up to 75 days after gilteritinib initiation and has been observed with or without 
concomitant leukocytosis (Fathi 2021). In this study, DS is considered an adverse event of 
special interest (AESI) for reporting purposes. AESIs are collected from the time of informed 


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consent until the End-of-Treatment evaluation or until initiation of new anticancer therapy, 
whichever is sooner.
Presumptive DS events, whether serious or non-serious, must be promptly entered into the 
electronic data capture (EDC) system by the investigator within 24 hours of knowledge of the 
event. For DS events that meet the criteria for seriousness, sites must follow the reporting 
procedures outlined in Section 16.7.4 below.
16.7.4 Reporting Serious Adverse Events (SAEs)
Once an investigator becomes aware that a SAE has occurred, a SAE report must be completed 
as thoroughly as possible with all available details relevant to the event and forwarded to the 
sponsor or designee immediately, without undue delay, and within 24 hours. If the investigator 
does not have access to all relevant details related to an event, he/she is not to wait to receive 
additional information before notifying the sponsor or designee of the SAE. Additional details of 
the event as they become available will be forwarded to the sponsor or designee in a follow-up
report. The investigator must always provide an assessment of causality at the time of the initial 
SAE report. The sponsor will provide contact information to the investigator for SAE report 
submission. The investigator, or responsible individual (in accordance with local standard 
operating procedures) will comply with all applicable requirements related to reporting of SAEs 
to regulatory authorities and their IRB/IEC.
The sponsor will promptly assess all SAEs against cumulative safety experience to identify and 
communicate new safety findings to regulatory authorities, investigators and IRBs/IECs based on 
applicable regulations. To define the reporting requirement for individual SAEs, the sponsor will 
assess “expectedness” using the IB as the reference safety document. All SUSARs will be 
submitted to all applicable regulatory authorities and investigators.
16.7.5 Pregnancy Reporting
If a female patient becomes pregnant while receiving or within 6 months of discontinuing study 
treatment, OR the female partner of a male patient becomes pregnant while he is receiving or 
within 4 months of discontinuing study treatment, a pregnancy report form must be completed 
and submitted to the sponsor to facilitate outcomes follow-up. While pregnancy itself is not 
considered an AE, any pregnancy complication or elective termination of a pregnancy for 
medical reasons will be recorded as an AE. An abortion whether therapeutic or spontaneous must 
be reported as a SAE. 
For pregnancies taken to term, details on the status of the mother and child will be forwarded to 
the sponsor, with follow-up generally no longer than 6-8 weeks after the delivery date. Any 
congenital anomaly in a child born to a patient exposed to study treatment must be reported as a 
SAE.


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17.0
Study Committees and Communication of Results
17.1 Dose-escalation committee (DEC)
As noted in Section 4.0, this study will utilize a DEC consisting of all study investigators with 
enrolled patients and sponsor representatives including (but not limited to) the sponsor’s medical 
monitor, safety officer, and PK and translational science leads. The DEC will convene by 
conference call or videoconference as promptly as possible upon completion of the DLT 
assessment period for all patients within a dose cohort in Phase 1b. Representation by at least 
1 medically qualified member (ie, an MD) from each trial site with at least 1 patient enrolled to 
any cohort will be required for all DEC convocations. Ad hoc meetings of the DEC may be 
conducted for adjudication of individual safety-related events, if requested by an individual 
investigator. All decisions regarding dose escalation including declaration of the MTD/RP2D
will require unanimous consent of the participating investigators. These will be documented 
within the study’s trial master file along with the minutes of each DEC meeting. 
To better understand the safety, tolerability, PK, PD, and anti-tumor activity of the study 
regimen, additional patients (up to a total of 20 per dose cohort) may be allocated to previously 
cleared dose cohort(s) that are considered safe and adequately tolerated, if there are no available 
patient slots in the most recently enrolled dose cohort. The decision to enroll additional patients
at a dose level previously cleared by the DEC (ie, enrollment of a “backfill” cohort) will be 
based on agreement by the DEC coincident with each scheduled DEC convocation. Furthermore, 
additional patients may be added to a previously cleared dose cohort only if at least 1 of the 3 to 
6 patients initially enrolled to that cohort have achieved one of the following ELN 2017-defined 
response categories (Appendix 2): CR, CRh, CRi, PR, MLFS. The 3+3 dose escalation rule will 
continue to be followed for each successively higher dose cohort however, should DLT(s) occur
in 1 or more patients enrolled to backfill cohorts, these will be taken into account for purposes of 
future dose escalation-making decisions. Specifically, if a DLT occurs in a patient allocated to a 
backfill cohort, the DLT rate will be re-calculated for that cohort. If the updated DLT rate
exceeds 20% with 80% probability, the updated DLT rate will be taken into consideration by the 
DEC when deciding whether to stop or continue dose escalation to the next higher dose level 
(Section 2.6; Section 15.2.1). 
The frequency of DLTs as defined in Appendix 1 will be assessed coincident with the first cycle 
of treatment during Part 2, initially after the first 6 patients and each subsequent patient
thereafter. If the true incidence of DLTs exceeds 20% with 80% posterior probability given the 
accumulated data at these time points (see Section 15.2.7.1 for additional detail), further 
enrollment will be interrupted, and the DEC will be convened to assess the risk-benefit profile of 
the study treatment and provide recommendations regarding modifying or stopping the study. 
Additionally, the DEC will be convened for discussions and recommendations in the setting of
one Grade 5 event or two Grade 4 events that are considered at least possibly related to LANRA 
or gilteritinib coincident with the interruption of new patient accrual. Recommendations 
proffered by the DEC in this setting will not preempt a final decision on the resumption of 
enrollment by FDA, which will be based on a thorough safety analysis that will be submitted to 


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FDA and any other applicable authority per local requirement for review prior to resuming 
enrollment.
17.2 Provision of Study Results and Information to Investigators
When a clinical study report is completed for this study, the sponsor will provide the major 
findings of the study to the investigators. The sponsor will not routinely inform the investigator 
or patient of individual test results because the information generated from this study will be 
preliminary in nature and the significance and scientific validity of the results may be 
undermined at such an early stage of research.


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18.0
Administrative Requirements of the Investigator and Sponsor
18.1 Regulatory Authority Approval
The sponsor will submit the study protocol and obtain approval to conduct the study from the 
appropriate regulatory agency in accordance with any applicable country-specific regulatory 
requirements before the study is initiated within that country. 
18.2 Investigator Responsibilities
18.2.1 Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki, ICH GCP, and other country-specific requirements, as applicable.
18.2.2 Ethical Study Conduct and IRB/IEC Approval
The investigator is responsible for ensuring that this protocol, the study site’s ICF and any other 
information that will be presented to potential study participants (eg, advertisements or 
information that supports or supplements the ICF) are reviewed and approved by the appropriate 
IRB/IEC. The IRB/IEC must be constituted in accordance with applicable regulatory 
requirements. The sponsor will provide the investigator with relevant documents that are needed 
for IRB/IEC review and approval of the study. Before study drug can be dispatched to the study 
site, the sponsor (or its designee) must receive copies of the IRB/IEC approval letter, the ICF that 
the study site will use, and any other information that the IRB/IEC has approved for presentation 
to prospective study participants. If the protocol, ICF or any other information presented to 
prospective study participants as approved by the IRB/IEC is amended, the investigator is
responsible for ensuring that the IRB/IEC reviews and approves amended study documents, 
where applicable. The investigator must adhere to applicable regulatory requirements pertaining 
to the use of an amended ICF before new study participants can consent to take part in the study. 
Copies of all IRB/IEC correspondence including those related to approval of an amended ICF, 
protocol or other information as well as copies of said amended documents must be forwarded to 
the study sponsor or its designee promptly.
18.2.3 Informed Consent
The investigator is responsible for obtaining written, informed consent from each prospective 
study participant using the IRB/IEC-approved consent form, after adequately explaining the 
objectives, methods, and potential hazards of study participation and before conducting 
study-related procedures or assessments. Each ICF will be signed and dated by the patient or the 
patient’s legally authorized representative and the person obtaining consent. The process of 
obtaining informed consent and contents of the ICF will be in accordance with all applicable 
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18.2.4 Investigator Reporting Requirements
The investigator (or sponsor, where applicable) is responsible for reporting SAEs to their 
IRB/IEC in accordance with all applicable regulations (see Section 16.7.4). The investigator may 
be required to provide periodic safety updates during the conduct of the study and notification of 
study closure to their IRB/IEC. Such periodic safety updates and notifications are the 
responsibility of the investigator and not the sponsor.
18.2.5 Confidentiality
Information on steps to maintain patient confidentiality in accordance with local and national 
patient privacy regulations must be provided to each study participant as part of the informed 
consent process, either as part of the ICF or as a separate signed document (eg, a site-specific 
Health Insurance Portability and Accountability Act [HIPAA] consent form in the US). The 
investigator must assure that the anonymity of study participants will be strictly maintained and 
that their identities are protected from unauthorized parties. Only the date and an identification 
code (not names) should be recorded on any form or biological sample submitted to the sponsor, 
IRB/IEC or the sponsor’s designated central laboratories. The investigator will maintain a 
screening log including patient codes, names and contact details or local medical record 
identifiers for all prospective study participants screened and for patients subsequently enrolled 
into the study.
The investigator and sponsor will maintain confidentiality by following applicable data privacy 
laws covering the collection, storage, transmission, and processing of personal and medical 
information of study participants. Medical information on study participants obtained during the 
study may only be disclosed to third parties as permitted by the signed ICFs or a separate 
authorization for the use and disclosure of personal health information that has been signed by 
the study participant, unless permitted or required by law. Medical information may be given to a 
study participant’s personal physician or other appropriate medical personnel responsible for the 
study participant’s health and welfare, for treatment purposes. Data generated by this study must 
be available for inspection upon request by representatives of the FDA and all other national and 
local health authorities, the sponsor’s study monitors, representatives and collaborators as well as 
the IRB/IEC for each study site, as appropriate.
In the event of a breach of confidentiality, the investigator and sponsor, as appropriate, shall 
undertake all remediation efforts and obligations to report said breach under applicable data 
privacy laws.
18.2.6 Data Collection
Data required by the study protocol will be entered into eCRFs in an EDC system that is 
compliant with all regulatory requirements. All study-related data collected or received by the 
investigator or study team shall be promptly entered into the eCRFs after the data is collected or 
received by the investigator or study team in a time frame consistent with what is stipulated in 
the study site contract. 
Data recording onto eCRFs must follow the data entry instructions provided in the eCRF 
completion guidelines. The investigator has ultimate responsibility for the collection and 


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reporting of all clinical data. The investigator or his/her designee in the “Statement of 
Investigator Form” at the front of this protocol must sign the completed casebooks to attest to its 
accuracy, authenticity, and completeness.
18.2.7 Data Management/Coding
All final patient data recorded onto eCRFs as well as external data (eg, central laboratory 
assessments) collected in accordance with this protocol will be stored at Kronos Bio or a 
designated off-site facility at the end of the study. Data will be reviewed for the presence of 
potential outliers or inconsistencies as well as for logic and completeness. Standard procedures 
including data review guidelines, computerized validation for query generation and maintenance 
of an audit file that includes database modifications will be followed to ensure accurate data 
collection.
During the course of the study, a study monitor will make regular visits to the study site or 
engage with the study site via videoconference or through other digital media to review protocol 
compliance, compare data entered onto eCRFs with individual study participants’ medical 
records (ie, source data verification) and ensure that the study is being conducted in accordance 
with pertinent regulatory requirements. The source data verification process will be conducted in 
a manner to ensure that the confidentiality of study participants is maintained. Direct access to 
source data will also be required for inspections and audits and be carried out with due 
consideration to data protection and confidentiality.
18.2.8 Drug Accountability
The investigator or his/her designee (ie, pharmacist) is responsible for ensuring adequate 
accountability of all used and unused study drug. This includes acknowledgement of receipt of 
each shipment of study product (including quantity and condition), patient drug dispensation 
records, and returned or destroyed study product. Dispensing records will document quantities 
received from Kronos Bio, and quantities dispensed to study participant, including lot number, 
date dispensed, patient identifier and the initials of the person dispensing the medication. All 
drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor during the conduct of the study.
At study initiation, the sponsor’s study monitor will evaluate each site’s standard operating 
procedures for study drug disposal/destruction to ensure it complies with Kronos Bio’s 
requirements. During and at the end of the study, the study site will dispose of and/or destroy all 
unused study drug supplies and study drug returned by study participants (including empty 
containers) according to standard operating procedures after drug inventory reconciliation by the 
study monitor. If the site cannot meet Kronos Bio’s requirements for disposal, arrangements will 
be made for off-site destruction or return of unused study drug and study drug supplies.
18.2.9 Inspections
Investigators should understand that source documents for this study must be made available to 
appropriately qualified personnel from Kronos Bio or its representatives, IRBs/IECs, or 
regulatory authority inspectors.


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18.2.10 Protocol Adherence
Investigators are responsible for ensuring that the study is conducted in accordance with the 
procedures and evaluations outlined in this protocol and assert that they will apply due diligence 
to avoid protocol deviations. Investigators must document and explain to the sponsor any 
deviations from the IRB/IEC-approved protocol and must report any major deviations that might 
impact patient safety and/or the integrity of study data to the sponsor and the IRB/IEC, in 
accordance with established IRB/IEC policies and procedures.
18.2.11 Financial Disclosure
Investigators are required to provide the sponsor with complete and accurate financial 
information in accordance with regulations to allow the sponsor to submit disclosure or 
certification of the absence of certain financial interest or to disclose those financial interests as 
required, to the appropriate health authorities. This is to ensure that financial interests and 
arrangements between clinical investigators and Kronos Bio, which could affect the reliability of 
data submitted to health authorities, are identified and disclosed. Investigators are responsible for 
providing information about their financial interests before their participation in the study, and to 
update this information if any relevant changes occur during the study, and for 1 year after 
completion of the study. 
18.3 Protocol Amendments
Except for those intended to reduce immediate risk to study patients, protocol amendments may 
be initiated only by Kronos Bio. All protocol amendments must be submitted to regulatory 
authorities according to local requirements as well as to the IRB/IEC together with, if applicable, 
a revised model ICF. Written documentation indicating approval of the amendments from 
regulatory authorities (if applicable) and from the study site’s IRB/IEC must be obtained by the 
sponsor before changes to study conduct can be implemented.
New or updated information that indicate a change in risk and/or study scope must be provided 
to study participants already actively participating in the study in an amended ICF and they must 
read, understand, and sign each revised ICF confirming their willingness to remain in the study.
18.4 Study Report and Publications
A clinical study report will be prepared detailing the outcomes of this study and provided to 
regulatory bodies including the US FDA and others, as applicable. Kronos Bio will ensure that 
this report meets the standards set out in the ICH Guideline for Structure and Content of Clinical 
Study Reports (ICH E3). The final clinical study report will be signed by the coordinating 
(principal) investigator, if applicable. Note that an abbreviated report may be prepared in certain 
cases.
Results from this study will be published or presented at scientific meetings in a timely and 
objective manner, regardless of the outcome of the study, consistent with good science, industry,
and regulatory guidance, and in accordance with the terms of the applicable clinical study 
agreement. Data generated in this clinical study are the exclusive property of the sponsor and 
will remain confidential until such time as they are publicly disclosed. As this is a multicenter 


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study, the first publication or disclosure of study results shall be a joint, multicenter publication 
or disclosure coordinated by the sponsor or its designee. Thereafter, any secondary publications 
will reference the first (original) publication. Authorship shall be determined by mutual 
agreement and all authors must meet the criteria for authorship established by the International 
Committee of Medical Journal Editors Uniform Requirements for manuscripts or alternatively, 
stricter local criteria (International Committee of Medical Journal Editors, 2013).
No communication, presentation or publication will include Kronos Bio’s confidential 
information.
Each investigator agrees to submit all manuscripts, abstracts, posters, publications, and 
presentations (both oral and written) to the sponsor prior to submission for peer-review or 
presentation in accordance with the terms outlined in the clinical study agreement. This will 
allow the sponsor to protect proprietary information, provide comments based on information 
from other studies that may not yet be available to the investigator, and ensure scientific and 
clinical accuracy. The procedure for reviewing manuscripts and presentations that are based on 
results from this study is detailed in the investigator’s clinical study agreement. Each investigator 
acknowledges and agrees that in accordance with the clinical study agreement, a delay in 
publication/presentation may be requested by the sponsor to allow for patent filings in advance 
of the latter or deletion of sponsor’s confidential information.
18.5 Study/Study Center Closure
Upon completion of the study, the study monitor will conduct the following close-out activities 
in collaboration with the investigator or other study center personnel, as appropriate:
Retrieval of all outstanding study data
Resolution and closure of all outstanding data queries
Accountability, reconciliation and arrangement for disposal/destruction of unused study 
drug
Review of study records for completeness
Return of treatment codes to the sponsor
Shipment of final PK or PD samples to central laboratories
The sponsor reserves the right to suspend or prematurely discontinue this study either at a single 
or multiple study sites, or in its entirety, at any time for reasons including but not limited to 
safety or ethical issues or severe noncompliance. If it is determined that such action is warranted, 
the sponsor will discuss this with the investigator (including the reasons for taking such action) 
at that time. When feasible, the sponsor will provide advanced notification to the investigator of 
the impending action prior to it taking effect.
The sponsor will promptly inform all investigators and/or institutions conducting the study if it is 
to be suspended or terminated for safety reasons and will also inform regulatory authorities of 
the suspension or termination and the reason for the action. If required by applicable regulations, 
the investigator must inform the IRB/IEC promptly and provide the reason for the suspension or 
termination.


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If the study is prematurely discontinued, all study data must be returned to the sponsor. 
Arrangements for the disposal or destruction of all unused study drug will be made in accordance 
with the applicable sponsor procedures. Financial compensation to investigators and/or 
institutions will be in accordance with the agreement established between the investigator and 
the sponsor.
18.6 Record Retention and Study Files
The investigator must maintain accurate and up-to-date records to enable an assessment of study 
conduct (ie, investigator’s study files) as well as the veracity and completeness of the study data 
(ie, patient source documents). 
The investigator’s study file will contain the protocol/protocol amendments, eCRF and query 
forms, IRB/IEC and regulatory agency approval (if applicable) along with correspondence, 
informed consent, drug records, staff curriculum vitae and authorization forms as well as other 
appropriate documents and correspondence. Patient source documents would generally include 
but are not limited to, patient hospital/clinic records, physician/nurse’s notes, original laboratory 
reports, ECG, X-ray and pathology reports, consultant notes/letters, special assessment reports, 
screening, and enrollment log, etc.
Following closure of the study, the investigator must maintain all study records in a safe and 
secure location. The records must be maintained in a manner that will allow for easy and timely 
retrieval when needed (eg, for audit or inspections) and whenever feasible, to allow for 
subsequent review of data in conjunction with assessment of the facility, supporting systems and 
personnel. Where permitted by local laws/regulations or institutional policy, some or all of these 
records may be maintained in a format other than hard copy (eg, scanned, electronic); however, 
the investigator must assure that all reproductions are legible, a true and accurate copy of the 
original and meet accessibility and retrieval standards, including re-generating a hard copy, if 
required.
The sponsor will inform the investigator of the time period for retaining these records. The 
minimal retention time will meet the strictest standard applicable to that study center as dictated 
by any institutional requirements, local laws or regulations or the sponsor’s 
standards/procedures. In the absence of any of these, the retention period will default to 15 years. 
The investigator must notify the sponsor of any changes in the archival arrangements including 
but not limited to the following: archiving at an off-site facility and transfer of ownership of the 
records in the event the investigator leaves the study site.
The sponsor may conduct genomics, transcriptomic, and/or proteomic studies in the future 
utilizing residual biospecimens that may be left over after completion of the planned biomarker 
studies described herein. The focus of such future research would be limited to oncology 
indications. Biospecimen retention for such future research will be optional for patients enrolled 
into the current study, with the ability to withdraw consent. If the patient withdraws consent for 
use of retained biospecimens, he/she must notify the study investigator in writing. The 
investigator will notify Kronos Bio forthwith, after which any retained samples will be destroyed 
as soon as is feasible. Retained biospecimens will be de-identified and stored in a central 
repository for the shorter of a period of up to 10 years or as allowed by the site’s IRB/IEC. Data
generated as a consequence of future testing may be used indefinitely. Specimens and data 


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generated will be accessible by only Kronos Bio, and/or contracted third parties for any future 
research involving retained biospecimens. Data and results generated will not be shared with 
patients and investigators but may be included anonymously in clinical study reports, scientific 
presentations, or publications. Any data generated from the analysis of retained biospecimens 
will be de-identified and patient confidentiality will be maintained. 
18.7 Information Disclosures
All information provided by the sponsor including but not limited to the investigator’s brochure, 
this protocol, eCRFs, the investigational drug and any other study information, as well as all data 
generated as part of the study, is the sole and exclusive property of the sponsor. Study data may 
be included in patient medical records, but the sponsor makes no claim of ownership with respect 
to such patient medical records. This information will not be used by the investigator or other 
study personnel for any purpose other than conducting the study and will not be disclosed to any 
third party (except employees or agents directly involved in the conduct of the study or as 
required by law) without prior written consent from the sponsor. The investigator agrees to take 
all reasonable precautions to prevent the disclosure by any employee or agent of the study site to 
any third party or into the public domain. 
Any inventions or discoveries arising from the study will be handled in accordance with the 
applicable clinical study agreement.
18.8 Joint Investigator/Sponsor Responsibilities
18.8.1 Access to Information for Monitoring/Source Data Verification
In accordance with ICH GCP guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to corroborate the veracity of data entered into the 
eCRFs. The monitor will review the eCRFs at regular intervals throughout the study to verify
adherence to the study protocol and the completeness, consistency and accuracy of data being 
entered onto them. The monitor must have access to any and all patient records needed to verify 
eCRF entries. The investigator agrees to cooperate with the monitor to ensure that 
issues/problems detected in the course of his/her monitoring activities are addressed.
18.8.2 Access to Information for Auditing or Inspections
Regulatory authorities or representatives of Kronos Bio may conduct inspections or audits any 
time during or after completion of this clinical study. If the investigator is notified of an 
inspection by representatives from a regulatory authority, he/she agrees to notify the sponsor or 
its designee immediately. The investigator agrees to provide regulatory authority inspectors or 
those retained by Kronos Bio access to records, facilities, and study site personnel for the 
effective conduct of any inspection or audit.


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19.0
References
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current knowledge and evidence. Leukemia. 2019; 33:299–312.
Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN 
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Drabkin HA, Parsy C, Ferguson K, et al. Quantitative HOX expression in chromosomally 
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Mori M, Kaneko N, Ueno Y, et al. Gilteritinib, a FLT3/AXL inhibitor, shows antileukemic 
activity in mouse models of FLT3 mutated acute myeloid leukemia. Invest New Drugs. 
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Appendix 1: Definition of DLT
During Part 1 (dose escalation), the DLT assessment period is defined as Cycle 1, Day 1 through 
Cycle 1, Day 28 and includes the pre-dose assessments for Day 1 of Cycle 2.
NCI-CTCAE Version 5.0 (Common Terminology Criteria for Adverse Events (CTCAE) 
(cancer.gov) will be used to grade the severity of all AEs. A DLT is defined as any of the 
following toxicities occurring within the DLT assessment period:
A nonhematologic toxicity of Grade 
that is at least possibly related to LANRA with 
the exception of:
o
nausea, and vomiting controlled with antiemetic therapy, 
(Note: Grade 3 nausea or vomiting that requires tube feeding, total parenteral 
nutrition and/or initial or prolonged hospitalization for management will 
constitute a DLT. Grade 4 nausea or vomiting will always constitute a DLT 
regardless of management.)
o
infection or infection-related toxicities such as fever/sepsis, febrile neutropenia*,
o
fatigue,
o
alopecia,
o
isolated electrolyte abnormalities (ie, those without clinical consequences) 
correctable 
within 72 hours with or without supplementation,
o
Grade 3 or 4 Differentiation Syndrome (Section 8.1) successfully managed with 
high-dose steroids plus supportive care interventions with resolution within 7 days 
and without resulting end-organ damage. 
Any toxicity resulting in administration of <80% of the cumulative, Cycle 1 dose for 
either LANRA or gilteritinib.
o
Note:  Administration of <80% of the cumulative Cycle 1 dose for LANRA or 
gilteritinib for reasons other than toxicity (eg, non-compliance or administrative 
reasons) will not be considered a DLT but will make the patient unevaluable for 
purposes of MTD determination and require the patient to be replaced.
Grade 4 neutropenia or thrombocytopenia lasting >28 days after treatment onset that is 
not attributed to active AML and at least possibly related to LANRA.
Any toxicity resulting in reduction in the dose of LANRA in Cycle 1.
*In general, infection will not constitute a DLT unless it is assessed as having resulted from 
unexpectedly prolonged myelosuppression in the setting of < 5% blasts in the bone marrow, 
absence of myelodysplastic changes, and/or absence of AML by flow cytometry in the bone 
marrow.
 


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Appendix 2: Response Criteria
Assessments of response will be made according to the European LeukemiaNet 2017 criteria 
(Döhner 2017) with minor modifications. The major criteria for judging response will include 
physical examination and examination of peripheral blood and bone marrow. All laboratory 
studies that are abnormal prior to study will be repeated to document the degree of maximal 
response.
Complete Remission (CR):
CR requires 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 109
Platelet count >100 x 109
Complete Remission with partial hematologic recovery (CRh):
CRh requires all aforementioned CR criteria except for residual thrombocytopenia and/or 
neutropenia and is defined as:
Bone marrow blasts <5%
Absence of circulating blasts and blasts with Auer rods
Absence of extramedullary disease 
Absolute neutrophil count > 0.5 x 109
Platelet count > 50 x 109
Complete Remission with incomplete blood count recovery (CRi)*:
CRi requires all aforementioned CR criteria except for residual neutropenia or thrombocytopenia 
and is defined as:
Bone marrow blasts <5%
Absence of circulating blasts and blasts with Auer rod
Absence of extramedullary disease
Absolute neutrophil count <1.0 x 109
9/L (100
*If patients meet criteria for both CRh and CRi, they should be classified as CRh


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Morphologic leukemia free state (MLFS)**
Bone marrow blasts <5%
Absence of blasts with Auer rods.
Absence of extramedullary disease
No hematologic recovery required
** Marrow should not be merely “aplastic”; at least 200 cells should be enumerated or cellularity 
on bone marrow biopsy should be at least 10% of normal
Partial Remission (PR):
PR meets all hematologic criteria of CR:
Absolute 
9
9
and
Residual bone marrow blast percentage of 5% to 25%
Stable Disease (SD):
Absence of CR, CRh, CRi, PR, MLFS and criteria for PD not met.
Progressive Disease (PD):
Evidence for an increase in bone marrow blast percentage and/or circulating blast counts as 
defined by at least one of the following:
>50% increase in bone marrow blasts over baseline (a minimal absolute 15% increase is 
required in cases with <30% blasts at baseline) or
100% 
improvement in absolute neutrophil counts (ANC) to an absolute level >0.5 x 109
and/or platelet count to >50 x 109
or
>50% increase in circulating blasts to >25 x 109
Differentiation Syndrome*** or
New extramedullary disease
*** Certain targeted therapies, for example, those inhibiting mutant IDH proteins, other kinase 
or targets may cause a Differentiation Syndrome, ie, a transient increase in the percentage of 
bone marrow blasts accompanied by an increase in circulating blasts. In the setting of therapy 
with such compounds, an increase in blasts may not necessarily indicate progressive disease. 
Such instances should be discussed with the study medical monitor on a case-by-case basis.


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Treatment Failure
Treatment failure will be classified as one of the following:
Primary refractory disease: failure to achieve CR or CRh after induction excluding patients 
with death in the setting of bone marrow aplasia or death due to indeterminate cause
Death in the setti
initial treatment while cytopenic with an aplastic or hypoplastic bone marrow documented within 
7 days of death and without evidence of persistent leukemia
Death from indeterminate cause: deaths occurring either before completion of initial therapy or 
therapy without circulating blasts but no bone marrow examination is available
Recurrence
Recurrence for patients with prior CRh, CRi or MLFS is defined as:
bone marrow not attributable to any other cause. Note: In the setting of recent treatment, if there 
are no circulating blasts and the bone marrow contains 5-20% blasts, a bone marrow 
aspirate/biopsy should be repeated within 1 week to distinguish relapse from bone marrow 
regeneration.
Reappearance of cytologically or biopsy documented extramedullary disease, including new 
CNS disease or other new sites of extramedullary involvement. Note: The reappearance of a 
cytogenetic or molecular abnormality would be considered a cytogenetic or molecular relapse. In 
the absence of morphologic relapse, this would not be considered a recurrence.


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Appendix 3: ECOG Performance Status Scale
Source: Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am 
J Clin Oncol. 1982;5:649-655.


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Appendix 4: Potential for Drug-Drug Interactions
Concomitant administration of study treatment with medications listed below could result in 
drug-drug interactions that potentially lead to reduced activity or enhanced toxicity of the 
concomitant medication, gilteritinib and/or LANRA.   
5HT2B receptor inhibitors 
Escitalopram, fluoxetine, sertraline
Strong CYP3A inducers* 
Rifampin, mitotane, avasimibe, rifapentine, apalutamide, 
ivosidenib, phenytoin, carbamazepine, enzalutamide, 
St John’s wort, lumacaftor, phenobarbital 
Strong CYP3A inhibitors** 
Boceprevir, clarithromycin, cobicistat, conivaptan, 
grapefruit juice, indinavir, itraconazole, ketoconazole, 
mibefradil, mifepristone, nefazodone, nelfinavir, 
posaconazole, ritonavir, saquinavir, telaprevir, 
telithromycin, troleandomycin, voriconazole 
P-gp substrates with narrow 
therapeutic index
Digoxin, dabigatran 
*P-gp inducers already listed as CYP3A inducers.
** See Section 10.2 for instructions on the interruption and subsequent resumption of LANRA in 
patients who require treatment with a strong CYP3A inhibitor. Note that neither fluconazole nor
isavuconazole are strong CYP3A inhibitors and can be administered concurrently with LANRA. 
A more comprehensive listing of strong CYP3A inducers and inhibitors can be found at: 
Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table, Indiana
University School of Medicine (2007). https://drug-interactions.medicine.iu.edu 
QT interval prolongation: 
Gilteritinib has been reported to be associated with QT interval prolongation in 9% of patients 
(see Section 2.5.1, XOSPATA [gilteritinib] U.S. Prescribing Information, 2022; XOSPATA 
[gilteritinib] Summary of Product Characteristics 2021); the potential for LANRA to induce QT 
interval prolongation is not currently known.  
Thus, patients must not receive medications that have a known risk to prolong the QT interval or 
induce Torsades de Pointes in light of the ability for gilteritinib to cause QT interval 
prolongation and the unknown potential for LANRA to do so.  


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Commonly Prescribed Drugs with Potential for QT Interval Prolongation*:
Indication
Drug With Known QT/Torsades de Pointe Effect
Antiarrhythmics
amiodarone, disopyramide, dofetilide, ibutilide, procainamide, quinidine, sotalol 
Antibiotics
clarithromycin, erythromycin, gatifloxacin, moxifloxacin, sparfloxacin 
Antipsychotics
chlorpromazine, haloperidol, mesoridazine, pimozide, risperidone, thioridazine, 
ziprasidone
Antidepressants
amitriptyline, desipramine, doxepin, imipramine, maprotiline, venlafaxine 
Antifungals (azoles)
ketoconazole, itraconazole
Antimalarials
chloroquine, halofantrine
Antiemetics
dolasetron, domperidone, droperidol, ondansetron, tropisetron 
Miscellaneous
arsenic trioxide, bepridil, methadone, pentamidine, cisapride, tacrolimus
*A more comprehensive listing of drugs can be found at: https://crediblemeds.org/druglist.
Accessed 25 May 2021 


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Appendix 5: Guidance on the Management of Clinical Trials During 
COVID-19 Pandemic
FDA Guidance on the Conduct of Clinical Trials of Medical Products During the COVID-19
Public Health Emergency 
EU Guidance on the Management of Clinical Trials During COVID-19 Pandemic 
In other jurisdictions (eg, South Korea) that have published similar guidances referring to 
precautionary measures to be taken during clinical trial execution in the COVID-19 pandemic era, 
these may be followed in deference to those cited above for the US and EU.


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Appendix 6: Contraceptive and Barrier Guidance
Definitions
Women in the following categories are not considered Women of Childbearing potential 
(WOCBP)
1. Premenopausal female with one of the following:
Documented hysterectomy.
Documented bilateral salpingectomy.
Documented bilateral oophorectomy.
Documentation can come from a review of the patient’s medical records, medical 
examination, or medical history interview.
2. Postmenopausal female
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle-stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient.
Females on HRT and whose menopausal status is in doubt will be required to use one of 
the nonhormonal highly effective contraception methods if they wish to continue their 
HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment.
Contraception Guidance
Male patients
Male patients with female partners of child-bearing potential are eligible to participate if they 
agree to the following during the study: 
Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinence on a long term and persistent basis) and agree to remain abstinent for the 
duration of study and for at least 4 months after the last dose of study medication.
Female partner is using a highly effective contraceptive method, including one of the 
highly effective contraceptives listed in the table below.
Agree to use a male condom.
Men with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a condom during the study. 
Refrain from donating sperm for the duration of study and for at least 4 months after the 
last dose of study medication.




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Collection of Pregnancy Information 
Male patients with partners of reproductive potential who become pregnant 
The investigator will attempt to collect pregnancy information on any female partner of a 
male study patient who becomes pregnant while participating in this study. This applies only 
to patients who receive study treatment.
After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the investigator will record pregnancy information on the appropriate form and 
submit it to the sponsor or designee within 24 hours of learning of the partner’s pregnancy.
The partner will also be followed to determine the outcome of the pregnancy. Information 
on the status of the mother and child will be forwarded to the sponsor or designee.
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery 
date. Any termination of the pregnancy will be reported regardless of fetal status (presence 
or absence of anomalies) or indication for procedure.
Female Patients who become pregnant 
The investigator will collect pregnancy information on any female patient, who becomes 
pregnant while participating in this study.
Information will be recorded on the appropriate form and submitted to the sponsor or 
designee within 24 hours of learning of a patient’s pregnancy. 
The patient will be followed to determine the outcome of the pregnancy. The investigator 
will collect follow up information on the patient and the neonate, which will be forwarded to 
the sponsor or designee. Generally, follow-up will not be required for longer than 6 to 
8 weeks beyond the estimated delivery date.
Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
or elective termination of a pregnancy will be reported as an AE or SAE.
A spontaneous abortion is always considered to be an SAE and will be reported as such.
Any SAE occurring as a result of a post-study pregnancy that is considered reasonably 
related to the study treatment by the investigator, will be reported to the sponsor or designee. 
While the investigator is not obligated to actively seek this information in former study 
patients, he or she may learn of an SAE through spontaneous reporting.
Any female patient who becomes pregnant while participating will discontinue study treatment
but may continue to be followed for leukemic progression/relapse, first salvage therapy and 
survival. Further treatment options will be discussed.


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Appendix 7: Recommended Adjustments to Anti-Platelet and Anti-Coagulant 
Therapy in AML
1. If aspirin is administered for primary prevention of cerebrovascular events, discontinue. 
If given for secondary prevention of cerebrovascular events, interrupt when platelets 
.
2. Coronary artery stents (bare metal and drug eluting): Work closely with a consulting 
cardiologist to adjust anti-platelet therapy especially within first month of bare stent 
placement and first year of drug eluting stent placement. Consider holding aspirin and 
supported by cardiology consult recommendations, especially within first year of stent 
placement.
3. Atrial fibrillation: If patient is on aspirin only, hold when platelet count is < 50,000/µL 
-coagulant therapy 
(eg, anti-Factor Xa), treat with therapeutic doses of low molecular weight heparin 
counts between 20-
4. Mechanical heart valves: Work closely with a consulting cardiologist. Treat with 
therapeutic d
doses when platelet count is between 20-
of anti-coagulant therapy, based on a recommendation from cardiology consultation.
5. Acute events:
a.
Catheter thrombosis: Remove catheter, consider anticoagulation if symptomatic 
b. Distal thrombosis: Follow-up scans in 3 days and every week for 6 weeks to make 
sure thrombosis does not progress.
c.
Proximal thrombosis and pulmonary embolism: Treat with therapeutic doses of 
LMWH if platelet count is
/
, prophylactic doses if platelet count is 
20-
or vena filter if platelet count is < 20,000/
on a case-by-case basis after discussion with cardiology consult and the medical 
monitor.
6. Acute coronary syndrome: administer aspirin to all patients, regardless of platelet count. 
Individualize therapy based on cardiology consultation (patient may need to discontinue 
study participation after discussion with medical monitor).


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Appendix 8: List of Abbreviations and Terms
Abbreviation/Term
Definition
ADL
activities of daily living
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
AML
acute myeloid leukemia
ANC
absolute neutrophil count
anti-HBc
hepatitis B antibody
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
ATC
Anatomic Therapeutic Chemical
AUC
area under the concentration × time curve
AUC0-inf
area under the concentration × time curve from time 0 extrapolated to 
infinity
AUC0-last
area under the concentration × time curve from time 0 until the last 
measurable plasma concentration
BID
twice a day
BUN
blood urea nitrogen
C1D1
Cycle 1 Day 1
CALBG
Cancer and Leukemia Group B
CBC
complete blood count
cCR
composite complete remission
CFR
Code of Federal Regulations
CI
confidence interval
CL/F
apparent clearance
CLE
cutaneous lupus erythematosus
Cmax
maximal plasma concentration
CNS
central nervous system
COVID-19
coronavirus disease 2019
CPK
creatine phosphokinase


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Abbreviation/Term
Definition
CR
complete remission
CR/CRh
composite CR rate
CRh
complete remission with partial hematologic recovery
CRi
complete remission with incomplete blood count recovery 
Ctrough
trough plasma concentration
CYP
cytochrome P450
DEC
Dose Escalation Committee 
DLT
dose-limiting toxicity
DOR
duration of response
DS
Differentiation Syndrome
ECG
electrocardiogram
ECHO
echocardiogram
ECOG PS
Eastern Cooperative Oncology Group Performance Status
eCRF
electronic case report form
EDC
electronic data capture
EFS
Event free survival
ELN
European LeukemiaNet
ENTO
entospletinib
FDA
Food and Drug Administration
FISH
fluorescence in situ hybridization
FLT3
FMS-like tyrosine kinase 3
GCP
Good Clinical Practice
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HOXA9
homeobox protein 
HR
hazard ratio
HSCT
hematopoietic stem cell transplantation
IB
Investigator’s Brochure


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Abbreviation/Term
Definition
IC50
half-maximal inhibitory concentration 
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
INR
international normalized ratio
IRB
Institutional Review Board
ITD
internal tandem duplication
IV
intravenous 
LANRA
lanraplenib
LDH
lactate dehydrogenase
LFT
liver function test
LMN
lupus membranous nephritis
MedDRA
Medical Dictionary for Regulatory Activities 
MLFS
morphologic leukemia-free state
MRD
measurable residual disease
MRI
magnetic resonance imaging
MTD
maximally tolerated dose
MUGA
Multi-gated acquisition
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse 
Events
NCCN
National Comprehensive Cancer Network
MGS
next generation sequencing
NPM1
nucleophosmin-1
OS
overall survival
P-gp
P-glycoprotein
PD
pharmacodynamic(s)
or
progressive disease
PK
pharmacokinetic(s)
PPI
proton pump inhibitor


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Abbreviation/Term
Definition
PR
partial remission or partial response
PRES
Posterior Reversible Encephalopathy Syndrome
pSYK
phosphorylated spleen tyrosine kinase
PT
prothrombin time
or
preferred term
QD
once daily
RA
rheumatoid arthritis
Racc
accumulation ratio
rEPO
recombinant erythropoietin
RLS
relapse-free survival
RP2D
recommended Phase 2 dose
R/R
relapsed/refractory
RT-PCR
reverse transcriptase polymerase chain reaction
SAE
serious adverse event
SAP
Statistical Analysis Plan
SARS CoV-2
severe acute respiratory syndrome (SARS) coronavirus 2 (CoV-2)
SD
stable disease
or
standard deviation
SUSAR
suspected, unexpected serious adverse reaction
SLE
Systemic lupus erythematosus 
SOC
system organ class
SYK
spleen tyrosine kinase
TEAE
treatment-emergent adverse event
TKD
tyrosine kinase domain
t½
half-life
Tmax
time to maximal plasma concentration
ULN
upper limit of normal
URI
upper respiratory tract infection


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Abbreviation/Term
Definition
UTI
urinary tract infection
US
United States
Vss/F
apparent volume of distribution at steady state
WBC
white blood cell
WHO
World Health Organization
WOCBP
woman of child-bearing potential

SAP_001.pdf: 
Protocol Number: KB-LANRA-1001 
 
Official Title: 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 
 
NCT Number: NCT05028751 
 
Document Date: 15 March 2024 






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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN REVIEW AND APPROVAL ................................. 2 
1.1. 
Glossary of Abbreviations ................................................................................................................. 5 
2. 
INTRODUCTION ........................................................................................................ 9 
2.1. 
Study Overview .................................................................................................................................. 9 
2.2. 
Schedule of Assessments.................................................................................................................. 11 
3. 
OBJECTIVES AND ENDPOINTS ........................................................................... 18 
Part 1:  Dose Escalation .......................................................................................................................... 18 
Part 2: Cohort Expansion ....................................................................................................................... 19 
4. 
GENERAL STATISTICAL CONSIDERATIONS ................................................. 21 
4.1. 
Statistical Hypothesis ...................................................................................................................... 21 
4.2. 
Sample Size ....................................................................................................................................... 21 
4.3. 
Randomization and masking .......................................................................................................... 21 
4.4. 
Handling of Data .............................................................................................................................. 21 
4.4.1. 
Strata and Covariates ....................................................................................................................21 
4.4.2. 
Examination of PatientSubsets ..................................................................................................... 21 
4.4.3. 
Multiple Testing and Comparisons ............................................................................................... 21 
4.4.4. 
Definitions and Data Derivations .................................................................................................. 22 
4.4.4.1.Presentations by Study Visits ..................................................................................................... 28 
4.4.4.2.Missing Data............................................................................................................................... 28 
4.4.4.3.Imputation for Alphanumeric Data ............................................................................................. 28 
4.4.4.4.Incomplete or Missing Dates ...................................................................................................... 28 
4.5. 
Timing of Analyses .......................................................................................................................... 29 
5. 
ANALYSIS POPULATIONS .................................................................................... 30 
5.1. 
DLT Evaluable Population ............................................................................................................. 30 
5.2. 
Safety Population ............................................................................................................................. 30 
5.3. 
Pharmacokinetic Population ........................................................................................................... 30 


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5.4. 
Pharmacodynamic Population ....................................................................................................... 30 
5.5. 
Efficacy Evaluable Population ........................................................................................................ 31 
6. 
STATISTICAL METHODS ...................................................................................... 31 
6.1. 
Patient Disposition, Demographic, and Baseline Characteristics ................................................ 31 
6.2. 
Medical History................................................................................................................................ 31 
6.3. 
Leukemia History ............................................................................................................................ 31 
6.4. 
Exposure to Treatment ................................................................................................................... 32 
6.5. 
Efficacy Analysis .............................................................................................................................. 32 
6.6. 
Safety Analysis ................................................................................................................................. 32 
6.6.1. 
Adverse Events ............................................................................................................................. 33 
6.6.2. 
Dose Limiting Toxicities .............................................................................................................. 33 
6.6.3. 
Clinical Laboratory Assessments .................................................................................................. 33 
6.6.4. 
Prior and Concomitant Medications ............................................................................................. 33 
6.6.5. 
Vital Signs .................................................................................................................................... 34 
6.6.6. 
Electrocardiograms ....................................................................................................................... 34 
6.6.7. 
Physical Examinations .................................................................................................................. 34 
7. 
CHANGES IN THE PLANNED ANALYSES ......................................................... 34 
8. 
REVISION HISTORY ............................................................................................... 35 
9. 
REFERENCES ........................................................................................................... 35 
10. PROPOSED TABLES, LISTINGS, AND FIGURES ............................................. 35 
APPENDIX A: PROGRAMMING CONVENTIONS .................................................... 38 
APPENDIX B: PROGRAMMING MODIFIED NCI-CTCAE GRADING FOR 
LABORATORY ABNORMALITIES .............................................................................. 40 
 


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1.1. 
GLOSSARY OF ABBREVIATIONS 
Abbreviation/Term  
Definition  
ADL 
activities of daily living  
AE  
adverse event  
ALC 
absolute lymphocytes count  
ALT  
alanine aminotransferase  
AML  
acute myeloid leukemia  
ANC  
absolute neutrophil count  
anti-HBc  
hepatitis B antibody  
Anti-HBs 
hepatitis B antibody 
Anti-HCV 
hepatitis C antibody 
Anti-HIV 
HIV antibody 
aPTT  
activated partial thromboplastin time  
AST  
aspartate aminotransferase  
ATC 
Anatomic Therapeutic Chemical 
AUC  
area under the concentration × time curve  
AUC0-last  
area under the concentration × time curve from time 0 until the last 
measurable plasma concentration  
BUN 
blood urea nitrogen 
C1D1  
Cycle 1 Day 1  
cCR 
composite complete remission 
CI  
confidence interval  
Cmax 
maximal plasma concentration 


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CPK 
creatine phosphokinase 
CR  
complete remission  
CRh  
complete remission with partial hematologic recovery  
CRi  
complete remission with incomplete blood count recovery   
DEC 
Dose Escalation Committee 
DLT  
dose-limiting toxicity  
ECG  
electrocardiogram  
ECHO  
echocardiogram  
ECOG PS  
Eastern Cooperative Oncology Group Performance Status  
eCRF  
electronic case report form  
EE 
Efficacy Evaluable  
EFS  
Event free survival  
ELN  
European LeukemiaNet  
FISH  
fluorescence in situ hybridization  
FLT3  
FMS-like tyrosine kinase 3  
HBsAg  
hepatitis B surface antigen  
HCV  
hepatitis C virus  
HOXA9  
homeobox protein   
HOXA9 
Homeobox A9 
INR  
international normalized ratio  
ITD  
internal tandem duplication   
K-M 
Kaplan-Meier 
LANRA  
lanraplenib  


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LDH 
Lactate dehydrogenase 
LLN 
lower limit of normal 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEIS1 
Meis Homeobox 1 
MRD  
measurable residual disease  
MTD  
maximally tolerated dose  
MUGA  
Multi-gated acquisition  
N 
number of patients 
NCI-CTCAE  
National Cancer Institute Common Terminology Criteria for Adverse 
Events  
NGS 
next-generation sequencing 
NPM1  
nucleophosmin-1  
NPM1-m  
nucleophosmin-1 mutated  
PD  
pharmacodynamic(s) 
or progressive disease  
PK  
pharmacokinetic(s)  
PR  
partial remission  
pSYK  
phosphorylated spleen tyrosine kinase  
PT  
prothrombin time or preferred term 
QD 
once a day 
QTcF 
Fridericia corrected QT interval 
R/R  
relapse/refractory 
RP2D  
recommended Phase 2 dose  
RT-PCR 
Reverse transcriptase polymerase chain reaction 


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SAE  
serious adverse event  
SAP  
Statistical Analysis Plan  
SD  
stable disease  
SOC 
system organ class 
SOC 
system organ class  
ß-hCG 
hormone found in blood and urine during pregnancy  
STD 
standard deviation 
SYK  
spleen tyrosine kinase   
TEAE  
treatment-emergent adverse event  
TELT 
treatment-emergent laboratory toxicity 
TESAE 
treatment-emergent serious adverse event 
TKD  
tyrosine kinase domain  
Tmax  
time to maximal plasma concentration  
ULN  
upper limit of normal  
US  
United States  
WBC  
white blood cell  
WHO  
World Health Organization  
WOCBP  
woman of child-bearing potential  
 


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2. 
INTRODUCTION 
This document (statistical analysis plan [SAP]) describes the statistical methods and data 
presentations to be used in the summary and planned analysis of demographic, baseline disease 
characteristics, medical and cancer treatment history, prior and concomitant medications, 
disposition, safety, exposure, and efficacy data obtained from Phase 1b of Study KB-LANRA-
1001. Background information is provided for the overall study design and objectives. The reader 
is referred to the study protocol and electronic case report forms (eCRFs) for details of study 
conduct and data collection, the pharmacokinetics (PK) analysis plan for analysis of PK data, the 
pharmacodynamic (PD) analysis plan for the analysis of PD data, and to the Dose Escalation 
Committee (DEC) charter for the roles and the responsibilities for that committee in safety 
monitoring and determination of the maximum tolerated dose (MTD)/recommended phase 2 dose 
(RP2D) for LANRA. 
2.1. 
STUDY OVERVIEW 
This multicenter, Phase 1b/2 study will investigate the safety, PK, PD and make a preliminary 
assessment of the anti-leukemic activity of the selective, 3rd generation SYK inhibitor, lanraplenib 
(LANRA), in combination with the selective FLT3 inhibitor, gilteritinib, in patients with FLT3-
mutated acute myeloid leukemia (AML), who have recurrence of leukemia or are refractory after 
at least 1 prior regimen. This study will be conducted in 2 parts: dose escalation (Phase 1b) and 
cohort expansion (Phase 2). The study will consist of a Screening Phase lasting up to 21 days 
during which patients will be assessed for eligibility; a Treatment Phase beginning on Cycle 1, Day 
1 (C1D1) consisting of consecutive 28-day cycles; an End-of-Treatment evaluation; and a Post-
Treatment Follow-up Phase. During the Treatment Phase, patients will undergo study visits on 
Days 1, 4, 8, 11, 15, 16 and 22 in Cycle 1, Days 1, 8, 15 and 22 in Cycle 2, and Days 1 and 15 in 
Cycle 3 and beyond. Approximately 100 patients are estimated to enroll across both Phase 1b and 
Phase 2; patients will be enrolled from multiple trial sites worldwide for Phase 1b and for Phase 2. 
In both Phase 1b and Phase 2, patients will receive their assigned treatment regimen 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 patient or study investigator. All patients will be 
followed for survival. 
In Phase 1b, eligible patients will be enrolled sequentially into dose cohorts listed in Table 1 for 
PK/PD evaluations and determination of the MTD/RP2D of LANRA in combination with 
gilteritinib. 
 
 


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Table 1:  
Dose-escalation Scheme (Provisional) 
 
Dose Cohort (n): 
LANRA Dose: 
Gilteritinib Dose: 
Cohort 1  
20 mg QD 
120 mg QD 
Cohort 2  
40 mg QD 
120 mg QD 
Cohort 3  
60 mg QD 
120 mg QD 
Cohort 4  
90 mg QD 
120 mg QD 
 
-limiting toxicity (DLT) 
reported from among the first 3 evaluable patients in a dose cohort will prompt enrollment of 3 
additional evaluable patients. More than 1 DLT attributed to LANRA among 6 patients evaluable 
for DLT would indicate an intolerable dose, thus rendering the most proximate lower dose with 
either 0 of 3 or 1 of 6 patients with LANRA-related DLTs the MTD in combination with 
gilteritinib. The starting dose of LANRA is 20 mg QD (Cohort 1, Table 1). To better understand 
the safety, tolerability, PK, PD, and anti-tumor activity of the study regimen, additional patients 
(up to a total of 20 per dose cohort) may be allocated to previously cleared dose cohort(s) that are 
considered safe and adequately tolerated, if there are no available patient slots in the dose level 
currently being evaluated. The decision to enroll additional patients at a dose level previously 
provided by the DEC coincident with each scheduled DEC convocation. Furthermore, additional 
patients may be added to a previously cleared dose cohort only if at least 1 of the 3 to 6 patients 
initially enrolled to that cohort have achieved one of the following ELN 2017-defined response 
categories: CR, CRh, CRi, PR, MLFS. 
Following completion of Phase 1b, an expansion cohort consisting of patients who meet all 
eligibility criteria will enroll in order to further assess the safety, PK, PD and anti-leukemic activity 
of the combination at the LANRA MTD/RP2D. Patients enrolled in phase 2 will begin combination 
therapy with LANRA and gilteritinib on C1D1. Enrollment in Phase 2 will follow a two-stage 
design for assessment of the primary efficacy endpoint, composite CR (cCR) rate, including those 
patients who achieve a best response of complete remission (CR) or complete remission with 
partial hematology recovery (CRh), as defined by European LeukemiaNet 2017 (ELN) response 
criteria. 
 






















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4. 
GENERAL STATISTICAL CONSIDERATIONS 
4.1. 
STATISTICAL HYPOTHESIS 
There is no formal statistical hypothesis to be evaluated in this study; all statistical testing will be 
descriptive in nature.  
 
4.2. 
SAMPLE SIZE  
 
Approximately 100 patients in total are planned for enrollment in the study. Up to 69 patients will 
be enrolled to phase 1b with the actual number determined by the number of dose cohorts and 
number of patients in each cohort evaluated for determination of LANRA MTD/RP2D. 
Approximately 31 patients are planned for enrollment in Phase 2. The optimal two-stage design to 
OSPATA® [gilteritinib] 
US Prescribing Information, 2022
23% has an 
expected (average) sample size of 19.26 and a probability of early termination of 0.710. If the study 
regimen is not effective, there is a 0.025 probability of concluding that it is (the target for this value 
was 0.025 one-sided). If the study regimen is effective, as defined by CR/CRh = 46%,  there is a 
0.806 probability of concluding that it is (the target for this value was 0.800). (Calculations made 
using PASS 2020). After testing the treatment regimen on 12 patients in the first stage (including 
those treated at the MTD/RP2D in Phase 1b), the trial will be terminated if 3 or fewer patients 
respond. If the trial enrolls the second stage, additional patients will be enrolled to obtain at least 37 
patients treated on the RP2D dose (including at least 6 patients enrolled to Phase 1b and treated at 
the RP2D). If the total number of patients enrolled to stage 1 and stage 2 who achieve a CR/CRh is 
 
4.3. 
RANDOMIZATION AND MASKING 
This is an open-label study. Patients who satisfy all inclusion and exclusion criteria will be enrolled 
into the next available patient slot.  
4.4. 
HANDLING OF DATA 
4.4.1. Strata and Covariates 
There are no planned adjustments for covariates. 
4.4.2. Examination of Patient Subsets 
There are no planned subsets.  
4.4.3. Multiple Testing and Comparisons  
All analyses will be conducted without adjustments for multiple testing or comparisons.  


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4.4.4. 
Definitions and Data Derivations  
Age 
The age of a patient is defined as (Date of Day Informed Consent Signed  Date of Birth + 
1)/365.25. 
 
Cycle 1 Day 1  
Cycle 1 Day 1 (C1D1) is defined as the earliest day that either study drug is administered.  
 
Baseline Value 
Baseline value is defined as the last observation of an assessment prior to the first dose of either 
study drug.  For ECG assessments, the baseline value is the average of the predose triplicate 
measures taken on C1D1.   
 
Study Day 
Defined as the day relative to the administration of the first dose of either study drug (i.e., Cycle 1 
Day 1). For events prior to C1D1, Study Day is calculated as: 
 
 
Study Day = event date  date of C1D1 
 
For events occurring on or after C1D1, Study Day is calculated as: 
 
 
Study Day = event date  date of C1D1 + 1 
 
Post-Baseline Value 
Any assessment occurring after the initiation of either study drug will be considered a post-baseline 
value. For assessments occurring on C1D1 where no time of assessment is captured, the value will 
be considered as post-baseline if the assessment was not planned as part of the set of 
predose/screening assessments (e.g., an assessment taken on C1D1 where no time was recorded but 
was not designated as a predose assessment will be considered a post-baseline assessment and an 
assessment on C1D1 without a time but designated as a predose assessment will be considered as 
such). 
  
Change from Baseline 
Change from baseline will be determined for post-baseline assessments (where applicable) as:  
 
Post-baseline value  baseline value 
 
Months since Initial Diagnosis 
Months since initial diagnosis will be calculated as the actual number of calendar months between 
the date of initial diagnosis and C1D1.   
 
Overall Duration of Exposure 


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The latest Date of either study drug  C1D1 + 1.  Dates of last dose are captured on the End of 
Treatment eCRFs.  
 
Duration of Exposure to LANRA 
Duration of exposure to LANRA will be defined as the Date of Last Dose of LANRA  Date of 
First Dose of LANRA + 1.  The date of last dose is captured on the End of Treatment eCRF.  
 
Duration of Exposure to Gilteritinib 
Duration of exposure to Gilteritinib will be defined as the Date of Last Dose of Gilteritinib  Date 
of First Dose of Gilteritinib + 1.  The date of last dose is captured on the End of Treatment eCRF.  
 
Last Study Drug 
The study drug with the latest date of exposure.  
 
Cumulative Dose of LANRA 
The sum of the LANRA doses administered to a patient measured in milligrams (mg) 
 
Cumulative Dose of Gilteritinib 
The sum of the gilteritinib doses administered to a patient measured in milligrams (mg) 
 
Actual Dose Intensity of LANRA (mg/cycle) 
Defined as the cumulative dose of LANRA / (duration of exposure / 28)  
 
Actual Dose Intensity of Gilteritinib (mg/cycle) 
Defined as the cumulative dose of gilteritinib / (duration of exposure / 28) 
 
Relative LANRA Dose Intensity 
Relative dose is set to 100*(Actual LANRA Dose Intensity/ Expected Cumulative Dose / 28)  
 
Relative Gilteritinib Dose Intensity 
Relative dose is set to 100*(Actual Gilteritinib Dose Intensity/ Expected Cumulative Dose / 28)  
 
Treatment Interruptions 
Treatment Interruptions will be defined as doses that are missed for any reason and will be 
calculated using the Dosing Log eCRF page by obtaining the number of missed doses over the 
duration of treatment.  
 
Dose Reductions 
Dose reductions will be defined as a planned reduction in dose level for AE management. These 
will be managed as noted in Table 2 (for gilteritinib) and Table 3 (for LANRA) of the protocol and 
identified by comparing the dose received as recorded in the Dosing Log eCRF page versus the 
dose assigned.  
 
Duration of Follow-up 


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Duration of follow-up will be defined as the End of Study date  C1D1 + 1. End of study date is 
collected on the End of Study eCRF.  Patients who are lost to follow-up will be censored at their 
date of last contact.  
 
Measurable Residual Disease (MRD) 
Presence of leukemia cells using a molecular characterization platform (eg. RT-PCR, NGS) 
 
MRD Negative 
A patient is considered MRD Negative if he/she has exhibits MRD negativity (<0.01%) in bone 
marrow as measured by a molecular assay for FLT3 mutation (e.g., by next generation sequencing) 
in a central laboratory in the setting of a CR or CRh . 
 
Overall Survival  
The time from enrolment until death from any cause. 
 
 
Complete Remission (CR) 
Complete remission requires 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 109/L (1,000/µL) 
 
Platelet count > 100 x 109/L (100,000/µL) 
 
Complete Remission with partial hematologic recovery (CRh) 
Complete remission with partial hematologic recovery requires all aforementioned CR criteria 
except for residual thrombocytopenia and/or neutropenia and is defined as: 
 
 
Bone marrow blasts <5% 
 
Absence of circulating blasts and blasts with Auer rods 
 
Absence of extramedullary disease 
 
Absolute neutrophil count > 0.5 x 109/L (500/µL) 
 
Platelet count > 50 x 109/L (50,000/µL) 
 
 
Complete Remission with incomplete blood count recovery (CRi)* 
Complete remission with incomplete blood count recovery requires all aforementioned CR criteria 
except for residual neutropenia or thrombocytopenia and is defined as 
 
 
Bone marrow blasts < 5% 
 
Absence of circulating blasts and blasts with Auer rods 


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Absence of extramedullary disease 
 
Absolute neutrophil count > 1.0 x 109/L (1,000/µL) or platelet count > 100 x 109/L 
(100,000/µL) 
 
*If patients meet criteria for both CRh and CRi, they should be classified as CRh  
 
Morphological Leukemia Free State (MLFS)** 
 
 
Bone marrow blasts < 5% 
 
Absence of blasts with Auer rods 
 
Absence of extramedullary disease 
 
No hematologic recovery required 
 
** 
on bone marrow biopsy should be at least 10% of normal 
 
Partial Remission (PR) 
PR meets all hematologic criteria of CR: 
 
 
9/L (1,000/µL) 
 
 100 x 109/L (100,000/µL) and 
 
Residual bone marrow blast percentage of 5% to 25% 
 
pre-treatment 
 
Stable Disease 
Absence of CR, CRh, CRi, PR, MLFS and criteria for PD not met. 
 
Progressive Disease (PD) 
Evidence for an increase in bone marrow blast percentage and/or circulating blast count as defined 
by at least one of the following: 
 
 
>50% increase in bone marrow blasts over baseline (a minimal absolute 15% increase is 
required in cases with < 30% blasts at baseline)  
 
improvement in absolute neutrophil counts (ANC) to an absolute level > 0.5 x 109/L 
(500/µL) and/or platelet count to > 50 x 109/L (50,000/µL) without transfusion  
 
> 50% increase in circulating blasts to > 25 x 109/L (>25,000/µL) in the absence of 
Differentiation Syndrome***  
 
New Extramedullary disease 
 
*** Certain targeted therapies, for example, those inhibiting mutant IDH proteins, other kinases or 
targets may cause a Differentiation Syndrome, i.e., a transient increase in the percentage of bone 
marrow blasts accompanied by an increase in circulating blasts. In the setting of therapy with such 


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compounds, an increase in blasts may not necessarily indicate progressive disease. Such instances 
should be discussed with the study medical monitor on a case-by-case basis. 
 
Composite Complete Remission (cCR) 
Achieving either complete remission or complete remission with partial hematologic recovery. 
 
Duration of Response 
Duration of response is defined as the time from first qualifying CR (CR or CRh) until relapse or 
death from any cause, as assessed by study investigators. 
 
 
Event-free survival (EFS) 
Event-free survival (EFS) is defined as the time from C1D1 until treatment failure (i.e., failure to 
achieve CR or CRh), relapse from CR/CRh or death from any cause. 
 
 
Dose Limiting Toxicity 
A DLT is defined as any of the following toxicities occurring within the DLT assessment period 
unless it can be unequivocally determined to be unrelated to LANRA: 
 
 
exception of:  
 nausea, and vomiting controlled with antiemetic therapy,  
(Note:  Grade 3 nausea or vomiting that requires tube feeding, total parenteral 
nutrition and/or initial or prolonged hospitalization for management will constitute 
a DLT. Grade 4 nausea or vomiting will always constitute a DLT regardless of 
management.) 
 infection or infection-related toxicities such as fever/sepsis, febrile neutropenia*, 
 fatigue, alopecia, 
 isolated electrolyte abnormalities (ie. those without clinical consequences) 
corr
 
 Grade 3 or 4 Differentiation Syndrome successfully managed with high-dose 
steroids plus supportive care interventions with resolution within 7 days and 
without resulting end-organ damage.  
 
Any toxicity resulting in administration of <80% of the cumulative, Cycle 1 dose for either 
LANRA or gilteritinib. 
 Note: Administration of <80% of the cumulative Cycle 1 dose for LANRA or 
gilteritinib for reasons other than toxicity (eg, non-compliance or administrative 
reasons) will not be considered a DLT but will make the subject unevaluable for 
purposes of MTD determination and require the subject to be replaced.  
 
Grade 4 neutropenia or thrombocytopenia lasting >28 days after treatment onset that is not 
attributed to active AML and at least possibly related to LANRA.  


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Any toxicity resulting in reduction in the dose of LANRA in Cycle 1. 
 
*In general, infection will not constitute a DLT unless it is assessed as having resulted from 
unexpectedly prolonged myelosuppression in the setting of < 5% blasts in the bone marrow, 
absence of myelodysplastic changes, and/or absence of AML by flow cytometry in the bone 
marrow. 
 
Adverse Event  
An AE is defined as 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. 
All AEs defined as reportable in Section 16.6 of the protocol will be recorded on the ADVERSE 
EVENTS CRF. 
 
Treatment-emergent Adverse Event (TEAE)  
Any adverse event that occurs on or after C1D1 and up to the End-of-Treatment visit following 
discontinuation of the last study drug is considered treatment-emergent.  
 
Events that occur after the initiation of non-protocol anti-leukemic therapy will be considered as 
non-treatment emergent even if they occur before the End-of-Treatment visit. 
 
Treatment-emergent Laboratory Toxicity (TELT) 
A TELT is identified based on the laboratory data recorded in the eCRF and is defined as a 
National Cancer Institute - Common Toxicity Criteria for Adverse Events (NCI-CTCAE) v5.0 
(NCI 2017) grade 1 or higher abnormality, which occurs on or after C1D1 and up to the End-of- 
Treatment visit and exhibits at least 1 grade shift from the baseline value. 
 
Events that occur after the initiation of non-protocol anti-leukemic therapy will be considered as 
non-treatment emergent even if they occur before the End-of-Treatment visit. 
 
Concomitant Medications 
Concomitant medications are those medications taken on or after C1D1. This includes medications 
started prior to C1D1 and continued after C1D1. These medications will be recorded in the 
PRIOR/CONCOMITANT MEDICATION eCRF.  
 
Prior Medications 
Prior medications are those medications taken from the time of informed consent until C1D1.  
These medications will be recorded in the PRIOR/CONCOMITANT MEDICATION eCRF.  
 
End of Study 
After all enrolled patients either relapse or die or 5 years after the last patient enrolls (whichever is 
earlier) or if the sponsor decides to terminate the trial. 


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4.4.4.1. 
Presentations by Study Visits 
All study visits should be scheduled relative to C1D1 regardless of any treatment interruptions. 
Visits will be presented according to the visit designation (eg, Cycle 1, Day 4) as recorded on the 
eCRF.  If the same assessment(s) are collected multiple times within a given visit, the last non-
missing value will be used for summary presentations. There are no windows for study visits from 
C1D1 through C1D16. Acceptable windows for study visits beginning on Cycle 1, Day 22 are ± 1 
day. Unscheduled visits will not be included in by-visit data presentations but will be included in 
all tables of treatment-emergent laboratory toxicities.  All data will be presented in data listings. 
4.4.4.2. 
Missing Data  
Every effort will be made to obtain required data at each scheduled evaluation from all enrolled 
patients.  See Section 4.4.4.4 for details of imputing missing dates. AEs with missing causal 
relationship will be assessed as related to study treatment. AEs with missing severity will be 
included in the denominator for all grade events of the same preferred term (PT) but will not be 
included in the numerator for any severity when reporting the frequency of events by severity.  
 
Unless otherwise specified, all other missing data will not be imputed. 
4.4.4.3. 
Imputation for Alphanumeric Data  
Should there be instances where a clinical laboratory parameter is reported with imbedded non-
summaries. The actual values as reported in the database will be presented in data listings.  
For incorporation in quantitative summaries, the following imputation rules will be employed: 
The limit of quantitation will be increased by one level of precision in the direction of the symbol 
 
4.4.4.4. 
Incomplete or Missing Dates 
An incomplete date occurs when the exact date an event started or ended cannot be obtained.  The 
database contains data fields for month, day, and year. A date is incomplete if at least one of these 
three fields is not known.   
For many of the planned analyses, a complete date is necessary to determine if the event should be 
included in the analysis (eg, if an adverse event is treatment-emergent) or to establish the duration 
of an event.  In such cases, incomplete or missing dates will be imputed. 


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For the purposes of handling partially reported start and stop dates for an event the following 
algorithm will be applied: 
 
Missing start day, but month and year present: 
If the event occurs in the same month and year as C1D1, then the start day of the event 
will be assigned to the date corresponding to C1D1. For example, if an AE occurred in 
December 2021, and C1D1 was on 8 December 2021, the date of AE onset would be 
set to 8 December 2021. 
Otherwise, the start day will be set to the first day of the month. 
 
Missing start day and month, but year present: 
If event occurs in the same year as C1D1, then the start date of the event will be 
assigned to the C1D1 date.  Following this rule, in the event a patient started treatment 
on 20 January 2022 and had an AE starting in 2022 with no Month and Day indicated, 
the AE date would be set to 20 January 2022. 
Otherwise, the start day and month will be set to 01 January. Thus, for AEs with a start 
date of 2023 and initiation of LANRA in 2021, the AE start date would be 01 January 
2023. 
 
Missing start day, month, and year will be set to C1D1. 
 
Missing end day, but month and year present: 
The day will be set to the last day of the month. 
 
Missing end day and month, but year present: 
The end day and month will be set to 31 December of that year or the study treatment 
completion date, if earlier. 
If any imputed date causes the end date to occur prior to the start date of the event, the start date of 
the event will be used for the imputation of the end date.  In data listings, start and stop dates of 
events will be displayed as reported on the eCRF (i.e., imputed values will not be listed). 
4.5. 
TIMING OF ANALYSES 
There will be no interim analyses in Phase 1b other than those associated with decisions pertaining 
to dose escalation and final determination of the MTD/RP2D.   
The final analysis will occur at the End of Study as defined in section 4.4.4, where the clinical 
database has been cleaned, quality checked, and the database has been locked. 


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5. 
ANALYSIS POPULATIONS 
The following analysis populations will be defined for this study: DLT Evaluable, Safety, 
Pharmacokinetic, Pharmacodynamic, and Efficacy Evaluable. 
5.1. 
DLT EVALUABLE POPULATION 
Patients will be evaluable for DLT in Part 1 if they meet the following criteria: 
 
They experience a DLT (as defined in Appendix 1 of the study protocol) 
dose of LANRA during the DLT assessment period (Cycle 1, Day 1 until Cycle 2, Day 1). 
 
They receive at least 80% of the intended cumulative doses of LANRA and gilteritinib 
during the DLT assessment period without the occurrence of a DLT. 
The DLT Evaluable Population will be used for all DLT data summaries. 
5.2. 
SAFETY POPULATION 
The Safety Population 
either study drug and have at 
least 1 on-treatment safety-related observation, where a safety-related observation is defined as a 
reported AE or post-baseline assessment of vital signs, ECGs or safety laboratory assessments. 
Patients will be analyzed according to their assigned dose level. The safety population will be used 
for all summaries of Safety data. 
5.3. 
PHARMACOKINETIC POPULATION 
The PK population consists of all patients with at least 1 post-dose LANRA plasma concentration. 
Patients will be analyzed according to the dose level received at time of assessment. The PK 
population will be used for all summaries of PK data. 
5.4. 
PHARMACODYNAMIC POPULATION 
The PD population consists of all patients with baseline, and at least 1 post-dose pharmacodynamic 
assessment.  
Patients will be analyzed according to the dose level received at the time of assessment. The PD 
population will be used for all summaries of PD data. 


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5.5. 
EFFICACY EVALUABLE POPULATION 
The Efficacy Evaluable (EE) population will include all patients 
either 
study drug and complete the first protocol-specified response assessment or have discontinued 
study treatment for toxicity or die prior to the first response assessment. 
Patients in the EE population will be analyzed according to their assigned dose level. The EE 
population will be used for all summaries of efficacy data unless otherwise stated. 
6. 
STATISTICAL METHODS 
Descriptive statistical methods will be used to summarize the data from this study. Unless stated 
patients (n), mean, medians, 
interquartile ranges, standard deviation (STD), minimum, and maximum for continuous data and 
frequencies and percentages for categorical data.  The 
refers to the dose level of LANRA. Unless otherwise specified, data summaries and analyses 
described below will be reported by dose group and overall, in Phase 1b.  Select data collected 
during the study will be included in data listings.  Unless otherwise noted, the data will be sorted 
first by dose level/cohort, patient number, and then by date within each patient number.   
6.1. 
PATIENT DISPOSITION, DEMOGRAPHIC, AND BASELINE 
CHARACTERISTICS 
The number of patients screened, enrolled, treated, and discontinued from study treatment and 
follow-up will be summarized. The primary reason for study treatment discontinuation and follow-
up will be summarized  for Phase 1b.. The number of patients in each analysis population will be 
presented by treatment group.  
Demographic data including age (years), sex, race, and ECOG PS will be summarized for the 
safety population in Phase 1b  using descriptive statistics.  
6.2. 
MEDICAL HISTORY 
All clinically relevant prior or concurrent medical conditions will be mapped to a system organ 
class (SOC) and PT using the version of the Medical Dictionary for Regulatory Activities 
(MedDRA) in effect at the time of database lock. Medical history will be listed. 
6.3. 
LEUKEMIA HISTORY 
The following baseline characteristics will be summarized using descriptive statistics for patients in 
Phase 1b: age; months since initial diagnosis; subtype of AML at diagnosis (de novo AML, AML 
with myelodysplastic features or therapy-related AML); best response to last prior regimen (partial 
remission, stable or progressive disease, primary refractory disease after 1st line induction or 
recurrence of leukemia after CR) per ELN criteria; number of 
 type of FLT3 
mutation (ITD, TKD or both) and allelic frequency (high, low); history of hematopoietic stem cell 


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transplant including post-transplant best response (if known); prior exposure to a FLT3 inhibitor 
(e.g. midostaurin) and presence of other somatic mutations (e.g. NPM1, IDH1, IDH2, DNMT3A, 
TP53) at diagnosis and baseline, if known.  
The number of prior systemic antileukemic regimens will be summarized. By-patient listings of 
systemic leukemia treatment regimens, including start and stop dates for each regimen component, 
will be generated for Phase 1b. Anti-neoplastic agents will be classified using 11-digit, World 
Health Organization (WHO) Drug Dictionary codes preferred name and the Anatomic Therapeutic 
Chemical (ATC) Classification for pharmacologic properties and summarized by frequency 
distributions for Phase 1b.   
6.4. 
EXPOSURE TO TREATMENT  
Duration of exposure, cumulative dose, actual and relative dose intensities will be summarized for 
LANRA and gilteritinib. Treatment interruptions, dose reductions and reasons for discontinuation 
of gilteritinib/LANRA will be summarized by frequency distributions and percentages.   
6.5. 
EFFICACY ANALYSIS 
Best response (CR, CRh, CRi, PR, MFLS, stable disease [SD], and progressive disease [PD]) will 
be summarized for the efficacy-evaluable population by frequency distributions and percentages in 
accordance with ELN 2017 criteria. Patients with no post-baseline response assessments will be 
considered non-responders. The 95% confidence interval (CI) for estimates of the proportion of 
patients with CR/CRh will be constructed with exact methods for the binomial distribution (eg 
Clopper-Pearson intervals). Additionally, 95% CIs for the estimates of the proportion of patients 
with any CR (CR, CRh or CRi) will be constructed in a similar manner.  
Overall survival will be estimated using K-M methodology, including 95% CIs for quartiles 
Minimal and maximal survival times will be computed by dose level. Patients alive at last follow-
up will be censored at the date of last contact. 
6.6. 
SAFETY ANALYSIS 
Descriptive summaries will be generated for select safety data including treatment-emergent 
adverse events, changes from baseline in selected laboratory assessments,  and worst QTcF 
interval. All adverse events will be graded for severity using NCI-CTCAE v5.0. Toxicities that are 
not specified in the NCI-CTCAE will be graded for severity as follows: 
 
Grade 1 (Mild): asymptomatic or mild symptoms; clinical or diagnostic observation only; 
intervention not indicated 
 
Grade 2 (Moderate): minimal, local or non-invasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL) 
 
Grade 3 (Severe): Medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL 


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Grade 4 (Life-threatening): Urgent intervention indicated required to remove or abrogate risk 
of death 
 
Grade 5: Death related to AE 
6.6.1. Adverse Events 
Adverse events will be mapped to the MedDRA version in effect at the time of database lock. 
TEAEs will be reported by dose level and overall. . 
If a patient experiences multiple events that map to a single preferred term, the event of greatest 
severity will be assigned to the preferred term for the appropriate summaries.  Patients with events 
mapping to multiple preferred terms within the same system organ class will be counted once at the 
system organ class level.   
TEAEs will be summarized by treatment group using PT and SOC.  Separate summaries of Grade 
3 and 4 treatment-emergent adverse events, treatment-emergent serious adverse events (TESAEs), 
TEAEs related to LANRA, and events leading to treatment interruption, dose reduction, treatment 
discontinuation or death will be generated.  All adverse events reported will be listed for individual 
patients showing both verbatim and preferred terms.  
Missing onset dates will be imputed as previously outlined in Section 4.4.4.4.  
6.6.2. Dose Limiting Toxicities 
DLTs will be summarized for Phase 1b. DLTs will be summarized using descriptive statistics. 
Frequency counts for each unique DLT will also be presented. 
6.6.3. Clinical Laboratory Assessments 
Laboratory toxicities will be graded for severity using NCI-CTCAE Version 5.0 (see Appendix B 
for more details about laboratory grading). Frequencies and percentages of patients experiencing 
treatment-emergent grade 3 and 4 toxicities will be summarized.  
 
Descriptive summaries of select quantitative clinical laboratory results (hemoglobin, white blood 
cells [WBC], absolute neutrophil count [ANC], platelets, blasts count, AST, ALT, alkaline 
phosphatase, amylase, lipase, total bilirubin, direct bilirubin, serum creatinine, urea nitrogen) and 
their changes from baseline will be presented by study visit. 
6.6.4. Prior and Concomitant Medications 
Both prior and concomitant medications will be classified using WHO Drug Dictionary codes 
preferred name and ATC Classification for therapeutic indication. Prior medications (defined as all 
medications administered from signing of informed consent until C1D1) and concomitant 
medications (defined as all new or ongoing medications administered from C1D1 until the End-of-
Treatment Evaluation) will be listed.   


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6.6.5. Vital Signs, Oxygen Saturation 
Vital signs include resting heart rate, seated systolic and diastolic blood pressures and body 
temperature (ºC). Percent oxygen saturation as measured by pulse oximetry will be recorded. Vital 
signs/percent oxygen saturation will be listed. 
6.6.6. Electrocardiograms  
The number and proportion of patients having a worst post-baseline average Fridericia corrected 
QT interval (QTcF) value from > 450 msec to 480 msec, > 480 msec to 500 msec, and > 500 msec 
will be summarized. In addition, patients with an increase from baseline of > 30 msec to 60 msec 
and > 60 msec will be summarized.   
ECG results will be listed. 
6.6.7. Physical Examinations 
Physical examination will include body weight, height (at screening only), and a full neurological 
examination; results will be listed Clinically relevant abnormal physical findings that are treatment-
emergent will be reported as TEAEs. 
 
7. 
CHANGES IN THE PLANNED ANALYSES 
The estimated total number of patients was increased from 35 to 100 to accommodate a potential 
4th dose cohort in Phase 1b, to increase precision of the type 1 error to 0.025 (1-sided) in Phase 2 
for the composite CR endpoint, and to allow for backfill patient enrollment. Eighty percent (80%) 
CIs for proportions of patients with CR/CRh, those with any CR (CR, CRh or CRi), medians and 
landmark rates for EFS and duration of response were increased to 95% to reflect the increase in 
estimated total number of patients.  
e 1b, all analyses, data 
summaries and listings will be restricted to results from Phase 1b patients only.  Phase 2 was not be 
enrolled. 
Following the completion of the protocol specified analyses as specified in this SAP, the sponsor 
may choose to conduct additional exploratory analyses.  Such analyses will be detailed in a 
separate document.  
  


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8. 
REVISION HISTORY 
Date 
Revision 
Rationale 
15MAR2024 
Removed Phase 2 analysis 
Align with new protocol 
amendments and analysis 
reduction due to study 
termination 
 
9. 
REFERENCES 
Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 
2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424-
447.  
Kalbfleisch JD, Prentice RI. The Statistical Analysis of Failure Time Data. New York, NY: John 
Wiley & Sons, Inc; 1980. 
 
Lee JJ, Kuo Y-W, Liu D, Chen N. Bayesian Toxicity Monitoring. MD Anderson Cancer Center, 
Houston, TX. v2.2.3.0; last updated April 22, 2021.  
 
10. 
PROPOSED TABLES, LISTINGS, AND FIGURES 
Tables 
 
14.1.1 
Subject Disposition and Discontinuation Summary, All Patients Enrolled: Phase 1b 
14.1.2.1   
Demographics, Safety Population : Phase 1b 
14.1.2.2  
Baseline Disease Characteristics, Safety Population : Phase 1b  
14.1.4.1   
Summary of Exposure, Safety Population: Phase 1b  
14.1.4.2   
Summary of Prior Antileukemic Regimens, Safety Population: Phase 1b 
14.2.1
 
Summary of Best Response by ELN 2017 response criteria, Efficacy Evaluable     
Population: Phase 1b  
14.2.2 
Overall Survival, Safety Population: Phase 1b  
14.3.1.1   
Overview of Treatment Emergent Adverse Events, Safety Population: Phase 1b  
14.3.1.2 
Treatment-Emergent Adverse Events by System Organ Class, Preferred Term (All 
Cycles), Safety Population: Phase 1b  
14.3.1.3 
Treatment-Emergent Non-Serious Adverse Events by System Organ Class, Preferred 
Term (All Cycles), Safety Population: Phase 1b 
14.3.1.4 
Grade 3 or 4 Treatment-Emergent Adverse Events by System Organ Class, Preferred 
Term and Greatest Severity (All Cycles), Safety Population: Phase 1b  
14.3.1.5     Treatment-Emergent Serious Adverse Events by System Organ Class, Preferred 
Term (All Cycles), Safety Population: Phase 1b  
14.3.1.6   
Treatment Related Adverse Events by System Organ Class, Preferred Term (All 
Cycles), Safety Population: Phase 1b  


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Final Version 2 
 
 
 
 
CONFIDENTIAL  
Page 36 of 45 
15 March 2024 
 
 
14.3.1.7 
Treatment Emergent Adverse Events Leading to Dose Reduction by System Organ 
Class, Preferred Term (All Cycles), Safety Population: Phase 1b  
14.3.1.8 
Treatment Emergent Adverse Events Leading to Treatment Discontinuation by 
System Organ Class, Preferred Term (All Cycles), Safety Population: Phase 1b  
14.3.1.9   
Treatment Emergent Adverse Events Leading to Death by System Organ Class, 
Preferred Term (All Cycles), Safety Population: Phase 1b  
14.3.2 
Select Grade 3 or 4 Treatment-Emergent Laboratory Toxicities, All Cycles, Safety 
Population: Phase 1b  
14.3.3     
Electrocardiogram by Worst QTcF Results: Phase 1b  
Listings 
 
16.2.1 
Subject Disposition, All Patients Enrolled: Phase 1b  
16.2.2.1 
Informed Consent, All Patients Enrolled: Phase 1b  
16.2.2.2     Subject Eligibility, All Patients Enrolled: Phase 1b  
16.2.3 
Analysis Populations, All Patients Enrolled: Phase 1b  
16.2.4.1   
Demographics, All Patients Enrolled: Phase 1b  
16.2.4.2   
General Medical History, All Patients Enrolled: Phase 1b  
16.2.4.3     AML Diagnosis, All Patients Enrolled: Phase 1b  
16.2.4.4 
Additional AML Details, All Patients Enrolled: Phase 1b  
16.2.4.5 
Prior Systemic Anti-Leukemia Regimens, All Patients Enrolled: Phase 1b  
16.2.5.1 
Drug Accountability, All Patients Enrolled: Phase 1b  
16.2.5.2   
Exposure Dosing Log, All Patients Enrolled: Phase 1b  
16.2.5.3   Cycle Day 1 Dose, All Patients Enrolled: Phase 1b  
16.2.5.4   
Pharmacokinetic Sampling, All Patients Enrolled: Phase 1b  
16.2.5.5 
Prior and Concomitant Medications, All Patients Enrolled: Phase 1b  
16.2.5.6     Bone Marrow Transplant Post-Study Treatment, All Patients Enrolled: Phase 1b  
16.2.6.1 
Response Assessment, All Patients Enrolled: Phase 1b  
16.2.6.2 
Bone Marrow Examination, All Patients Enrolled: Phase 1b  
16.2.6.3 
Relapse/Progression Assessment, All Patients Enrolled: Phase 1b  
16.2.6.4 
Relapse Assessment Continued, All Patients Enrolled: Phase 1b  
16.2.6.5 
Survival Status, All Patients Enrolled: Phase 1b  
16.2.7.1   
Adverse Events, All Patients Enrolled: Phase 1b  
16.2.7.2   
Serious Adverse Events, All Patients Enrolled: Phase 1b  
16.2.7.3     Deaths, All Patients Enrolled: Phase 1b  
16.2.8.1  
Laboratory Toxicities  Select Hematology Analytes, All Patients Enrolled: Phase 
1b  
16.2.8.2 
Laboratory Toxicities  Select Serum Chemistry Analytes, All Patients Enrolled: 
Phase 1b  
16.2.8.3
 
 
Vital Signs, Height, and Weight, All Patients Enrolled: Phase 1b  
16.2.8.4
 
Physical Examinations  Abnormal Findings, All Patients Enrolled: Phase 1b  
16.2.8.5 
ECG Central Reading  Triplicate, All Patients Enrolled: Phase 1b  
16.2.8.6    Echocardiogram/MUGA, All Patients Enrolled: Phase 1b  


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Lanraplenib
Statistical Analysis Plan
KB-LANRA-1001 
 
Final Version 2 
 
 
 
 
CONFIDENTIAL  
Page 37 of 45 
15 March 2024 
 
 
16.2.8.7 
ECOG Performance Status, All Patients Enrolled: Phase 1b  


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Lanraplenib
Statistical Analysis Plan
KB-LANRA-1001 
 
Final Version 2 
 
CONFIDENTIAL  
Page 38 of 45 
15 March 2024
 
 
APPENDIX A: PROGRAMMING CONVENTIONS 
 
Statistical software: The statistical analyses will be conducted with the SAS® software package 
version 9.4 or higher.  
 
Verification procedures: All analyses will be subject to formal verification procedures.  
Specifically, results will be verified utilizing independent programming prior to issuance of the 
draft statistical report.  All documents will be verified by the lead statistician to ensure 
accuracy and consistency of analyses. 
 
Page orientation, margins, and fonts: Summary tables, listings, and figures will appear in 
Output should be 
printed in Courier New with a point size of 8.  Titles may be printed using a larger font (e.g., 
Arial point size 10). 
 
Identification of analysis population: Every summary table and figure should clearly specify 
the analysis population being summarized.  Listings will be prepared for all patients enrolled. 
 
Group headers: In the summary tables, the group headers will identify the treatment group and 
the within-
sample size does not necessarily equal the number of patients actually summarized within any 
given summary module; some patients in the analysis population may have missing values and 
thus may not be summarized. 
 
Suppression of percentages corresponding to null categories: When count data are presented as 
category frequencies and corresponding percentages, the percent should be suppressed when 
the count is zero in order to draw attention to the non-zero counts. 
 
Presentation of sample sizes: Summary modules should indicate, in one way or another, the 
number of patients actually contributing to the summary statistics presented in any given 
summary module.  As mentioned above, this may be less than the number of patients in the 
analysis population. 
 In the quantitative modules describing continuous variables (and thus presenting sample 
size, means, and standard deviations), the sample size should be the number of non-
missing observations. 
 For categorical variables that are presented in frequency tables, the module should present 
the total count in addition to the count in each category.  Percentages should be calculated 
using this total as the denominator, and the percentage corresponding to the sum itself (that 
is, 100%) should be presented so as to indicate clearly to a reviewer the method of 
calculation. 
 
Sorting: Listings will be sorted by treatment group, patient number and date, if applicable.  If a 
listing is sorted in a different manner, a footnote will indicate as such.  
 
 


Kronos Bio  
Lanraplenib
Statistical Analysis Plan
KB-LANRA-1001 
 
Final Version 2 
 
CONFIDENTIAL  
Page 39 of 45 
15 March 2024
 
 
 
General formatting rules: Rounding for all variables will occur only as the last step, 
immediately prior to presentation in listings, tables, and figures.  No intermediate rounding will 
be performed on derived variables.  The standard rounding practice of rounding numbers 
ending in 0-4 down and numbers ending in 5-9 up will be employed.   
 
The presentation of numerical values will adhere to the following guidelines:  
 Raw measurements will be reported to the number of significant digits as captured 
electronically or on the eCRFs. 
 Standard deviations will be reported to two decimal place beyond the number of decimal 
places the original parameter is presented. 
 Means, medians, first and third quartiles will be reported to one decimal place beyond the 
number of decimal places in the original parameter presented.  
 Calculated percentages will be reported with no decimals. 
 
Dates will be formatted as DDMMMYYYY.  Partial dates will be presented on data listings as 
recorded on CRFs. 
 
Time will be presented according to the 24-hour clock (HHMM). 
 


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Lanraplenib 
 
 
 
 
Statistical Analysis Plan 
KB-LANRA-1001 
 
 
 
 
 
Final Version 2 
CONFIDENTIAL 
Page 40 of 45 
 
15 March 2024 
 
 
 
 
APPENDIX B: PROGRAMMING MODIFIED NCI-CTCAE GRADING FOR LABORATORY ABNORMALITIES 
Category 
Analyte Name 
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Chemistry 
Albumin 
Hypoalbuminemia 
<lower limit of 
normal (LLN) - 3 
g/dL 
<3 - 2 g/dL 
<2 g/dL 
- 
Chemistry 
Amylase 
Serum amylase increased 
>upper limit of 
normal (ULN) - 1.5 x 
ULN 
>1.5 - 5.0 x ULN  
>5.0 x ULN 
- 
Chemistry 
Alanine 
Aminotransferase  Alanine aminotransferase 
increased 
>ULN - 3.0 x ULN if 
baseline was normal; 
1.5 - 3.0 x baseline if 
baseline was 
abnormal 
>3.0 - 5.0 x ULN if 
baseline was normal; 
>3.0 - 5.0 x baseline 
if baseline was 
abnormal 
>5.0 - 20.0 x ULN if 
baseline was normal; 
>5.0 - 20.0 x baseline 
if baseline was 
abnormal 
>20.0 x ULN if 
baseline was normal; 
>20.0 x baseline if 
baseline was 
abnormal 
Chemistry 
Alkaline 
Phosphatase 
Alkaline phosphatase 
increased 
>ULN - 2.5 x ULN if 
baseline was normal; 
2.0 - 2.5 x baseline if 
baseline was 
abnormal 
>2.5 - 5.0 x ULN if 
baseline was normal; 
>2.5 - 5.0 x baseline 
if baseline was 
abnormal 
>5.0 - 20.0 x ULN if 
baseline was normal; 
>5.0 - 20.0 x baseline 
if baseline was 
abnormal 
>20.0 x ULN if 
baseline was normal; 
>20.0 x baseline if 
baseline was 
abnormal 
Chemistry 
Aspartate 
Aminotransferase  
Aspartate 
aminotransferase 
increased 
>ULN - 3.0 x ULN if 
baseline was normal; 
1.5 - 3.0 x baseline if 
>3.0 - 5.0 x ULN if 
baseline was normal; 
>3.0 - 5.0 x baseline 
>5.0 - 20.0 x ULN if 
baseline was normal; 
>5.0 - 20.0 x baseline 
>20.0 x ULN if 
baseline was normal; 
>20.0 x baseline if 


Kronos Bio
Lanraplenib 
 
 
 
 
Statistical Analysis Plan 
KB-LANRA-1001 
 
 
 
 
 
Final Version 2 
CONFIDENTIAL 
Page 41 of 45 
 
15 March 2024 
 
 
 
 
Category 
Analyte Name 
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
baseline was 
abnormal 
if baseline was 
abnormal 
if baseline was 
abnormal 
baseline was 
abnormal 
Chemistry 
Bilirubin (Total 
or Direct) 
Blood bilirubin increased 
>ULN - 1.5 x ULN if 
baseline was normal; 
> 1.0 - 1.5 x baseline 
if baseline was 
abnormal 
>1.5 - 3.0 x ULN if 
baseline was normal; 
>1.5 - 3.0 x baseline 
if baseline was 
abnormal 
>3.0 - 10.0 x ULN if 
baseline was normal; 
>3.0 - 10.0 x baseline 
if baseline was 
abnormal 
>10.0 x ULN  
 
 
Chemistry 
Calcium 
Corrected for 
Albumin 
Hypocalcemia 
<LLN - 8.0 mg/dL  
<8.0 - 7.0 mg/dL  
<7.0 - 6.0 mg/dL  
<6.0 mg/dL 
 
 
Hypercalcemia 
 >ULN - 11.5 mg/dL >11.5 - 12.5 mg/dL 
>12.5 - 13.5 mg/dL >13.5 mg/dL  
Chemistry/ 
Lipid Profile 
Cholesterol  
 
Cholesterol high 
>ULN - 300 mg/dL 
>300 - 400 mg/dL 
>400 - 500 mg/dL; 
>500 mg/dL 
Chemistry 
Creatine Kinase 
CPK increased 
>ULN - 2.5 x ULN 
>2.5 x ULN - 5 x 
ULN 
>5 x ULN - 10 x 
ULN 
>10 x ULN 
Chemistry 
Creatinine 
Creatinine increased 
>ULN - 1.5 x ULN 
>1.5 - 3.0 x baseline 
or >1.5 - 3.0 x ULN 
>3.0 x baseline or 
>3.0 - 6.0 x ULN 
>6.0 x ULN 


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Lanraplenib 
 
 
 
 
Statistical Analysis Plan 
KB-LANRA-1001 
 
 
 
 
 
Final Version 2 
CONFIDENTIAL 
Page 42 of 45 
 
15 March 2024 
 
 
 
 
Category 
Analyte Name 
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Chemistry 
GGT 
GGT increased 
>ULN - 2.5 x ULN if 
baseline was normal; 
2.0 - 2.5 x baseline if 
baseline was 
abnormal 
>2.5 - 5.0 x ULN if 
baseline was normal; 
>2.5 - 5.0 x baseline 
if baseline was 
abnormal 
>5.0 - 20.0 x ULN if 
baseline was normal; 
>5.0 - 20.0 x baseline 
if baseline was 
abnormal 
>20.0 x ULN if 
baseline was normal; 
>20.0 x baseline if 
baseline was 
abnormal 
Chemistry 
eGFR or CrCL 
eGFR decreased/CrCL 
decreased 
 <LLN  60 
ml/min/1.73 m2 
<60  30 
ml/min/1.73 m2 
<30 - 15 
ml/min/1.73 m2 
<15 
ml/min/1.73 m2 
Chemistry 
Glucose 
Hypoglycemia 
<LLN - 55 mg/dL 
<55 - 40 mg/dL 
<40 - 30 mg/dL 
<30 mg/dL 
Chemistry 
Lipase 
Serum lipase increased 
>ULN - 1.5 x ULN 
>1.5 - 5.0 x ULN  
>5.0 x ULN  
- 
 
Chemistry 
Magnesium 
Hypermagnesemia 
>ULN - 3.0 mg/dL  
 - 
>3.0 - 8.0 mg/dL 
mmol/L 
>8.0 mg/dL 
Hypomagnesemia 
<LLN - 1.2 mg/dL 
<1.2 - 0.9 mg/dL 
<0.9 - 0.7 mg/dL 
<0.7 mg/dL  
 
Chemistry 
Potassium 
Hyperkalemia 
>ULN - 5.5 mmol/L >5.5 - 6.0 mmol/L 
>6.0 - 7.0 mmol/L 
>7.0 mmol/L 
Hypokalemia 
<LLN - 3.0 mmol/L - 
<3.0 - 2.5 mmol/L 
<2.5 mmol/L 
 
Sodium 
Hypernatremia 
>ULN - 150 mmol/L >150 - 155 mmol/L; >155 - 160 mmol/L >160 mmol/L  


Kronos Bio
Lanraplenib 
 
 
 
 
Statistical Analysis Plan 
KB-LANRA-1001 
 
 
 
 
 
Final Version 2 
CONFIDENTIAL 
Page 43 of 45 
 
15 March 2024 
 
 
 
 
Category 
Analyte Name 
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Chemistry 
Hyponatremia 
<LLN - 130 mmol/L 125-129 mmol/L  
120-124 mmol/L  
<120 mmol/L  
Chemistry/ 
Lipid Profile 
Triglycerides  
Hypertriglyceridemia 
150 mg/dL - 300 
mg/dL 
>300 mg/dL - 500 
mg/dL 
>500 mg/dL - 1000 
mg/dL 
>1000 mg/dL 
Chemistry 
 
Uric Acid  
Hyperuricemia 
> ULN 
- 
- 
- 
Chemistry 
Bicarbonate or 
CO2  
Blood bicarbonate 
decreased 
< LLN 
- 
- 
- 
 
Chemistry 
Serum pH 
Acidosis 
pH <normal, but 
>=7.3 
 - 
pH <7.3 
- 
Alkalosis 
pH >normal, but 
<=7.5 
 - 
pH >7.5 
- 
Hematology 
 
Hemoglobin 
Anemia 
<LLN - 10.0 g/dL; 
<LLN - 6.2 mmol/L; 
<LLN - 100 g/L 
Hgb <10.0 - 8.0 g/dL; 
<6.2 - 4.9 mmol/L; 
<100 - 80g/L 
Hgb <8.0 g/dL; <4.9 
mmol/L; <80 g/L; 
 
 
 
 
 
 


Kronos Bio
Lanraplenib 
 
 
 
 
Statistical Analysis Plan 
KB-LANRA-1001 
 
 
 
 
 
Final Version 2 
CONFIDENTIAL 
Page 44 of 45 
 
15 March 2024 
 
 
 
 
Category 
Analyte Name 
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
 
 
Hematology 
Lymphocytes  
Lymphocyte count 
decreased 
<LLN - 800/mm3 
<800 - 500/mm3 
<500 - 200/mm3 
<200/mm3 
 
 
Lymphocyte count 
increased 
 - 
>4000/mm3 - 
20,000/mm3 
>20,000/mm3 
 - 
 
Hematology 
Neutrophils 
Neutrophil count 
decreased 
<LLN - 1500/mm3 
<1500 - 1000/mm3  <1000 - 500/mm3 
<500/mm3 
 
Hematology 
Platelets  
 
Platelet count decreased 
 
<LLN - 75,000/mm3 
<75,000 - 
50,000/mm3 
<50,000 - 
25,000/mm3 
<25,000/mm3 
 
Hematology 
Leukocytes/Whit
e Blood Cells 
Leukocytosis 
- 
- 
>100,000/mm3 
- 
 
Hematology 
 
Urinalysis 
Leukocytes/Whit
e Blood Cells 
Urine Glucose 
White blood cell 
decreased 
<LLN - 3000/mm3 
<3000 - 2000/mm3 
<2000 - 1000/mm3 
<1000/mm3 
Glucosuria 
Present 
 - 
 - 
 
 - 
Urinalysis 
Urine Protein 
Proteinuria 
1+ proteinuria 
2+ and 3+ proteinuria 4+ proteinuria 
 - 


Kronos Bio
Lanraplenib 
 
 
 
 
Statistical Analysis Plan 
KB-LANRA-1001 
 
 
 
 
 
Final Version 2 
CONFIDENTIAL 
Page 45 of 45 
 
15 March 2024 
 
 
 
 
Category 
Analyte Name 
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
 
Coagulation 
Activated partial 
thromboplastin 
time 
Activated partial 
thromboplastin time 
prolonged 
>ULN - 1.5 x ULN 
>1.5 - 2.5 x ULN 
>2.5 x ULN 
- 
 
Coagulation 
Fibrinogen 
 
Fibrinogen decreased 
<1.0 - 0.75 x LLN; if 
abnormal, <25% 
decrease from 
baseline 
<0.75 - 0.5 x LLN; if 
abnormal, 25 - <50% 
decrease from 
baseline 
<0.5 - 0.25 x LLN; if 
abnormal, 50 - <75% 
decrease from 
baseline 
<0.25 x LLN; if 
abnormal, 75% 
decrease from 
baseline; absolute 
value <50 mg/dL 
 
Coagulation 
International 
Normalized Ratio INR increased 
>1.2 - 1.5 
>1.5 - 2.5 
>2.5 
-