Randomized Trial of Gilteritinib vs Midostaurin in FLT3 Mutated Acute Myeloid Leukemia (AML)
Phase: PHASE2
Conditions: Acute Myeloid Leukemia
Sponsor: PrECOG, LLC.

PrECOG Protocol Number: PrE0905 
Date: 10/5/2022 
 
1 
 
 
PrECOG Protocol Number: PrE0905 
Randomized Trial of Gilteritinib vs Midostaurin in FLT3 Mutated 
Acute Myeloid Leukemia (AML) 
 
NCT#: 
NCT03836209 
IND #: 
143257 
Protocol Version Number: 
3.0 
Version Date: 
10/5/2022 
 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
.
 
 
PrECOG Protocol Number: PrE0905 
Randomized Trial of Gilteritinib vs Midostaurin in FLT3 Mutated 
Acute Myeloid Leukemia (AML) 
STUDY CHAIR: 
Selina Luger, MD 
STUDY CO-CHAIR: 
 
HEMATOPATHOLOGIST CO-CHAIR: 
 
ECOG-ACRIN COMMITTEE CHAIR: 
 
STATISTICIAN: 
 
PRECOG STUDY SITE CONTACT: 
 
MEDICAL MONITOR: 
 
(Internal Use Only) Astellas Pharma US, Inc. 
 
 
IND #: 
143257 
Version Number: 
3.0 
Version Date: 
October 5, 2022 
 
 
Release/Revision History 
Version 1.0: 4/1/2019 
Released to Sites 
Version 2.0: 1/21/2021 
Released to Sites 
Version 3.0: 10/5/2022 
Released to Sites 
 
This protocol contains information that is confidential and proprietary 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
2 
Table of Contents 
List of Abbreviations ..........................................................................................................................6 
1. 
Introduction- Background and Rationale .................................................................................. 11 
1.1 
Acute Myeloid Leukemia (AML) – Disease Overview ........................................................... 11 
1.2 
Background/Rationale ....................................................................................................... 11 
1.3 
Gilteritinib ......................................................................................................................... 12 
1.4 
Summary of Rationale for Proposed Study .......................................................................... 16 
2. 
Study Objectives ....................................................................................................................... 17 
2.1 
Primary Objective .............................................................................................................. 17 
2.2 
Secondary Objectives ........................................................................................................ 17 
2.3 
Exploratory Objectives ....................................................................................................... 17 
3. 
Selection of Patients ................................................................................................................. 18 
4. 
Registration Procedures ........................................................................................................... 22 
4.1 
Ethics ............................................................................................................................... 22 
4.2 
Regulatory Requirements .................................................................................................. 22 
4.3 
Patient Registration ........................................................................................................... 22 
4.4 
Patient Randomization ....................................................................................................... 23 
4.5 
Research Bone Marrow and Blood Samples ....................................................................... 23 
5. 
Treatment Plan .......................................................................................................................... 24 
5.1 
Overview .......................................................................................................................... 24 
5.2 
Treatment and Administration Schedule .............................................................................. 24 
6. 
Dose Modifications ................................................................................................................... 29 
6.1 
Dose Interruptions & Reductions ........................................................................................ 29 
6.2 
Concurrent Therapies ........................................................................................................ 31 
7. 
Study Duration and Discontinuation of Therapy ....................................................................... 33 
7.1 
Treatment Duration............................................................................................................ 33 
7.2 
Duration of Follow-Up ........................................................................................................ 33 
7.3 
Criteria for Removal from Study Treatment ......................................................................... 33 
8 
Adverse Event Reporting .......................................................................................................... 35 
8.1 
Collection of Safety Information .......................................................................................... 35 
8.2 
Serious Adverse Events (SAEs) ......................................................................................... 36 
8.3 
Drug-Induced Liver Injury Adverse Events........................................................................... 36 
8.4 
SAE Reporting Requirements............................................................................................. 37 
8.5 
Reporting of Other Second Primary Cancers ....................................................................... 38 
8.6 
Procedures in Case of Pregnancy ...................................................................................... 38 
8.7 
Reporting Guidelines in the Case of Overdose .................................................................... 39 
9 
Measurement of Effect36 ............................................................................................................ 40 
9.1 
Complete Remission (CR).................................................................................................. 40 
9.2 
Complete Remission with incomplete hematologic recovery (CRi) ........................................ 40 
9.3 
Morphologic Leukemia-Free State (MLFS) .......................................................................... 40 
9.4 
Partial Remission (PR)....................................................................................................... 40 
9.5 
Stable Disease .................................................................................................................. 41 
9.6 
Treatment Failure .............................................................................................................. 41 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
3 
9.7 
Progressive Disease (PD) .................................................................................................. 41 
9.8 
Relapse ............................................................................................................................ 41 
10. Study Parameters...................................................................................................................... 42 
11 
Drug Formulation and Procurement.......................................................................................... 48 
11.1 Gilteritinib27 ....................................................................................................................... 48 
11.2 Midostaurin21..................................................................................................................... 50 
11.3 Daunorubicin40,41,42 ............................................................................................................ 51 
11.4 Cytarabine43,44 ................................................................................................................... 52 
12 
Statistical Considerations ......................................................................................................... 54 
12.1 Study Design & Sample Size Considerations ...................................................................... 54 
12.2 Statistical Analysis............................................................................................................. 54 
12.3 Planned Interim Futility Analyses ........................................................................................ 56 
13. Laboratory and Pathology Correlative Studies ......................................................................... 58 
13.1 Correlative Studies: Mandatory Bone Marrow Samples ........................................................ 58 
14 
Administrative ........................................................................................................................... 63 
14.1 Protocol Compliance ......................................................................................................... 63 
14.2 Institutional Review Board (IRB) ......................................................................................... 63 
14.3 Informed Consent Procedures ............................................................................................ 63 
14.4 Safety Communication ....................................................................................................... 64 
14.5 Monitoring ......................................................................................................................... 64 
14.6 Study Records .................................................................................................................. 64 
14.7 Electronic Case Report Form (eCRF) Information ................................................................ 65 
14.8 Records Retention............................................................................................................. 65 
15 
References ................................................................................................................................ 66 
Appendix I: 
ECOG Performance Status ................................................................................. 69 
Appendix II: 
Calculation of Creatinine Clearance Using the Cockcroft-Gault Formula........... 70 
Appendix III: 
Contraceptive Requirements .............................................................................. 71 
Appendix IV: 
NYHA Classification ........................................................................................... 73 
Appendix V: 
Additional Excluded and Cautionary Medications.............................................. 74 
Appendix VI: 
Investigator’s Statement .................................................................................... 78 
 
 
 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
4 
PrECOG STUDY SITE CONTACT 
MEDICAL MONITOR 
 
Project Manager 
PrECOG, LLC 
1818 Market Street 
Suite 3000 
Philadelphia, PA 19103 
Phone: 215-789-7001 
Email: PrE0905@precogllc.org 
 
985 Old Eagle School Road 
Suite 510 
Wayne, PA 19087 
During normal business hours 
(8:30 am-5:00 pm EST): 
Phone: 610-354-0404 
After normal business hours: 
Phone: 484-574-2367 
Email: 
 
SAE Email: 
 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
5 
CR or CRi6 
CR or CRi6 
Brief Protocol Synopsis 
See Protocol Document Sections for complete details 
Study Schema 
 
 
 
 
 
 
 
INDUCTION3,4,5 
CONSOLIDATION4,5 
 
 
 
 
 
 
 
 
 
 
 
Accrual Goal: 179 
1 
Any patient undergoing bone marrow biopsy with suspicion of or known diagnosis of AML will be asked to sign a Prescreening Consent in order to confirm diagnosis 
and determination/confirmation of FLT3 status at central laboratory and obtain research samples for the study prior to randomization. 
2 
Daunorubicin 90 mg/m2/day will be administered IV per package insert or institutional guidelines or over 30-60 minutes Days 1,2,3 (45 mg/m2/day if receives 
second cycle of induction). 
3 
Standard of care induction 7+3 chemotherapy may start prior to randomization using same regimen and doses as noted above while awaiting prescreening test 
results. 
4 
Patients may proceed to allogeneic TRANSPLANT after induction or after 0-4 cycles of consolidation. 
5 
Patients will go off treatment at the time of transplant or any non-protocol leukemia directed therapy. 
6 
If Complete Response (CR) or CR with incomplete hematologic recovery (CRi) is not achieved, a second induction cycle of therapy may be administered. 
7 
For patients age ≥ 55 or patients with decreased creatinine clearance recommend reducing consolidation cytarabine dose to 1.5 g/m2.
R 
A 
N 
D 
O 
M 
I 
Z 
A 
T 
I 
O 
N 
Arm A (7+3) + Gilteritinib 
Cytarabine 
100 
mg/m2/day 
continuous 
infusion x 7 days starting Day 1 
Daunorubicin 90 mg/m2/day IV Days 1,2,32 
Gilteritinib 120 mg QD x 14 days start Day 8 
Arm B (7+3) + Midostaurin 
Cytarabine 
100 
mg/m2/day 
continuous 
infusion x 7 days starting Day 1 
Daunorubicin 90 mg/m2/day IV Days 1,2,32 
Midostaurin 50 mg BID x 14 days start Day 8 
Arm A 
Cytarabine 3 g/m2 over approximately 1-
3 hours every 12 hours (+/- 2 hour 
window) IV Days 1,3,5 or Days 1-3 for 6 
doses for up to 4 cycles7 
Gilteritinib 120 mg QD x 14 days start 
Day 8 of each cycle (up to 4 cycles) 
Arm B 
Cytarabine 3 g/m2 over approximately 1-
3 hours every 12 hours (+/- 2 hour 
window) IV Days 1,3,5 or Days 1-3 for 6 
doses for up to 4 cycles7 
Midostaurin 50 mg BID x 14 days start 
Day 8 of each cycle (up to 4 cycles) 
Stratification 
TKD vs. ITD FLT3 Mutation 
○ If FLT3 ITD Mutation- NPM1 Mutation Status 
○ If FLT3 ITD Mutation-Signal Ratio (high vs. low) 
Pre-Screening1 
Screening Consent 
with Central Testing 
• FLT3 Mutation 
• NPM1 Mutation 
• Signal Ratio 
• Flow Cytometry 
Eligible 
1:1 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
6 
List of Abbreviations 
Abbreviation 
Term 
5HT2BR 
5-Hydroxytryptamine Receptor 2B. 
AE 
Adverse Event 
AESI 
Adverse Events Special Interest 
ALK 
Anaplastic Lymphoma Kinase 
ALT 
Alanine Aminotransferase 
AML 
Acute Myeloid Leukemia 
AML-MRC 
AML-Myelodysplasia-Related Changes 
ANC 
Absolute Neutrophil Count 
APL 
Acute Promyelocytic Leukemia 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Concentration-Time Curve 
BCRP 
Breast Cancer Resistance Protein 
BID 
Twice a Day 
bp 
Base Pair 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
C 
Celsius 
CBC 
Complete Blood Count 
CBPF 
Central Biorepository Pathology Facility 
CFR 
Code of Federal Regulations 
CHF 
Congestive Heart Failure 
CI 
Confidence Interval 
CK 
Creatine Kinase 
Cmax 
Maximum (Peak) Drug Concentration 
CNS 
Central Nervous System 
CPK 
Creatine Phosphokinase 
CR 
Complete Response 
CRc 
Composite Complete Remission 
CRh 
CR with Partial Hematologic Recovery 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
7 
Abbreviation 
Term 
CRi 
CR with Incomplete Hematologic Recovery 
CRp 
Complete Remission with Incomplete Platelet Recovery 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
Ctrough 
Trough Concentration 
CYP 
Cytochrome P450 
DFS 
Disease Free Survival 
dL 
Deciliter 
DLT 
Dose-Limiting Toxicity 
DNA 
Deoxyribonucleic Acid 
DNMT3A 
DNA Methyltransferase 3 Alpha 
DNR 
Daunorubicin 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ECOG-ACRIN 
Eastern Cooperative Oncology Group-American College of Radiology 
Imagine Network 
eCRF 
Electronic Case Report Form 
eDC 
Electronic Data Capture 
EDTA 
Ethylenediamine Tetraacetic Acid 
EFS 
Event Free Survival 
ELN 
European LeukemiaNet 
F 
Fahrenheit 
FDA 
Food and Drug Administration 
FISH 
Fluorescence In Situ Hybridization 
FLT3 
FMS-Like Tyrosine Kinase 3 
FSH 
Follicle-Stimulating Hormone 
g 
Gram 
GCP 
Good Clinical Practice 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
8 
Abbreviation 
Term 
GFR 
Glomerular Filtration Rate 
GI 
Gastrointestinal 
HiDAC 
High Dose Cytarabine 
HIPAA 
Health Information Portability and Accountability Act 
hr 
Hour 
HRT 
Hormone Replacement Therapy 
HSCT 
Hematopoietic Stem Cell Transplant 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IDR 
Idarubicin 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ITD 
Internal Tandem Duplication 
IUD 
Intrauterine Device 
IUS 
Intrauterine Hormone-Releasing System 
IV 
Intravenous; Intravenously 
LDH 
Lactate Dehydrogenase 
LTK 
Leukocyte Receptor Tyrosine Kinase 
LVEF 
Left Ventricular Ejection Fraction 
m2 
Square Meter 
mm3 
Cubic Millimeter 
MDS 
Myelodysplastic Syndrome 
mg 
Milligrams 
min 
Minute 
mL 
Milliliter 
MLFS 
Morphologic Leukemia-Free State 
MPN 
Myeloproliferative Neoplasms 
MRD 
Minimal Residual Disease 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
9 
Abbreviation 
Term 
msec 
Millisecond 
MTD 
Maximum Tolerated Dose 
MUGA 
Multigated Acquisition Scan 
Mut+ 
Mutation Positive 
n 
Number 
NCI 
National Cancer Institute 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NE 
Not Evaluable 
ng 
Nanogram 
ng·h/mL 
Hours Times Nanograms per Milliliter 
NGS 
Next Generation Sequencing 
NPM1 
Nucleophosmin 1-Mutated 
NR 
No Response 
NSCLC 
Non-Small Cell Lung Cancer 
NYHA 
New York Heart Association 
OCT1 
Organic Cation Transporter 1 
OS 
Overall Survival 
PCR 
Polymerase Chain Reaction 
PD 
Progressive Disease 
PDGF 
Platelet-Derived Growth Factor 
P-gp 
P-glycoprotein 
PIA 
Plasma Inhibitory Activity 
PO 
per os; By Mouth (orally) 
PK 
Pharmacokinetics 
PR 
Partial Remission/Response 
PRES 
Posterior Reversible Encephalopathy 
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
QD 
Daily 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
10 
Abbreviation 
Term 
QTc 
Corrected QT Interval 
QTcF 
Fridericia-Corrected QT Interval 
ΔQTcF 
Change from baseline in Fridericia-Corrected QT Interval 
Rac 
Accumulation Index 
SAE 
Serious Adverse Event 
T4 
Thyroxine 
t-AML 
Therapy-Related Acute Myeloid Leukemia 
TEAE 
Treatment-Emergent Adverse Event 
TK 
Tyrosine Kinase 
TKD 
Tyrosine Kinase Domain 
TKI 
Tyrosine Kinase Inhibitor 
tmax 
Time to Reach Maximum (Peak) Plasma Concentration Following Drug 
Administration 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of the Normal Range 
US 
United States 
vs 
Versus 
WBC 
White Blood Cell 
WOCBP 
Women of Childbearing Potential 
wt 
Weight 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
11 
1. 
Introduction- Background and Rationale 
1.1 
Acute Myeloid Leukemia (AML) – Disease Overview 
The American Cancer Society estimates about 60,300 new cases of leukemia (all kinds) 
and 24,370 deaths from leukemia (all kinds) will occur in 2018.1 The median age at 
diagnosis is 67 years of age, with 54% of patients diagnosed at 65 years or older.2 It is 
estimated that 19,520 people will be diagnosed with Acute Myeloid Leukemia (AML), and 
10,670 will die from the disease in 2018 in the United States.1 While 60% to 80% of younger 
patients achieve a complete remission (CR) with standard therapy, only about 30% to 40% 
of the overall patient population has long-term disease-free survival.3 
While patients under the age of 70 with AML are likely to achieve a remission with standard 
therapy, the majority will relapse and die of their disease. Cytogenetic and molecular factors 
have been found to be critical in prognosis. Currently, there is no effective cure for the 
disease. 
1.1.1 
Standard Chemotherapy for Induction and Consolidation 
Induction therapy for previously untreated patients with AML has been fairly 
standardized over the past two decades with an anthracycline and cytarabine, 
followed by consolidation usually with high-dose cytarabine (HiDAC). 
Based on the RATIFY trial (C10603) midostaurin was approved in 2017 for the 
treatment of patients with FLT3 mutated AML in combination with standard 
induction and consolidation.4 
1.2 
Background/Rationale 
An overall CR rate of 50% to 80% can be expected with standard induction chemotherapy. 
Consolidation therapy is given with the goal of decreasing the risk of relapse and improving 
survival. However, presence of a FLT3 mutation in AML patients of any age is a poor 
prognostic factor.5,6,7 In these patients, although the CR rate with standard chemotherapy 
regimens is generally equivalent, the relapse rate, disease free survival (DFS), event free 
survival (EFS), and overall survival (OS) at 5 years are significantly worse.8 The addition 
of a targeted agent against FLT3 offers the possibility for significant therapeutic advantage 
in AML patients expressing FLT3,9 through both an additive effect on leukemia cell kill, as 
well as through potentiation of chemotherapy-induced cell death. 
1.2.1 
FMS-Like Tyrosine Kinase (FLT3) 
FMS-like tyrosine kinase (FLT3) is a member of the class III receptor tyrosine 
kinase (TK) family that is normally expressed on the surface of hematopoietic 
progenitor cells. FLT3 and its ligand play an important role in proliferation, survival 
and differentiation of multipotent stem cells. FLT3 is overexpressed in the majority 
of AML cases. In addition, activated FLT3 with internal tandem duplication (ITD) 
in and around the juxtamembrane domain and tyrosine kinase domain mutations 
at around D835 in the activation loop are present in 28% to 34% and 11% to 14% 
of AML cases, respectively.10 These activated mutations in FLT3 are oncogenic 
and show transforming activity in cells.11 Patients with FLT3-ITD mutation show 
poor prognosis in clinical studies, with a higher relapse rate, a shorter duration of 
remission from initial therapy (6 months versus 11.5 months for those without 
FLT3-ITD mutations) as well as reduced disease-free survival (16% to 27% 
versus 41% at 5 years) and OS (15% to 31% versus 42% at 5 years).12,13,14,15,16 
The incidence of relapse after hematopoietic stem cell transplant (HSCT) is also 
higher for patients with FLT3-ITD (30% versus 16% at 2 years for those without 
FLT3-ITD mutations).17 Similar to their prognosis for first-line therapy, patients 
with relapsed/refractory FLT3 mutated AML have lower remission rates with 
salvage chemotherapy; shorter durations of remission to second relapse and 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
12 
decreased OS relative to FLT3 mutation negative patients.18,19,20 As such, efforts 
have been made to decrease the risk of relapse with allogeneic transplant in first 
remission and with the incorporation of novel agents in therapy. 
Midostaurin is a small molecule that inhibits multiple receptor tyrosine kinases.21 
Midostaurin demonstrated the ability to inhibit FLT3 receptor signaling and cell 
proliferation, and it induced apoptosis in leukemic cells expressing ITD and TKD 
mutant FLT3 receptors or overexpressing wild type FLT3 and PDGF receptors.21 
Midostaurin also demonstrated the ability to inhibit KIT signaling, cell proliferation 
and histamine release and induce apoptosis in mast cells.21 C10603 (Ratify) 
added midostaurin, a multikinase inhibitor, to induction and consolidation therapy 
and used midostaurin as maintenance therapy in patients with FLT3 mutated 
AML. Initial reports demonstrated a 5-year overall survival benefit (50.9% vs 
43.9%, P=0.0078) with fewer patients experiencing events (lack of CR by day 28, 
relapse in 19.3% vs 27.5%).4 Benefit was seen in patients with both FLT3-ITD 
and FLT3-TKD mutations. Based on the Ratify trial, midostaurin 50 mg orally 
twice a day (BID) has received Food and Drug Administration (FDA) approval for 
newly diagnosed AML that is FLT3 mutation-positive as detected by an FDA-
approved test, in combination with standard cytarabine and daunorubicin 
induction and high-dose cytarabine consolidation. 
1.3 
Gilteritinib 
Gilteritinib is a new chemical entity discovered by Astellas Pharma Inc. in collaboration with 
Kotobuki Pharmaceutical Co., Ltd. Gilteritinib has an inhibitory effect on TKs, mainly FLT3, 
tyrosine kinase receptor AXL (AXL), leukocyte receptor tyrosine kinase (LTK) and 
anaplastic lymphoma kinase (ALK). 
AXL tyrosine kinase (AXL) is a member of TAM family (Tyro-3, AXL and Mer) receptor TKs 
and is normally expressed in cells of mesenchymal origin, such as osteoblasts, fibroblasts 
and blood cells. AXL has been reported to be overexpressed or activated in many cancers, 
including AML.22 AXL overexpression in AML confers drug resistance23 and is associated 
with adverse prognosis.24,25 AXL inhibition suppresses the growth of human FLT3-positive 
AML in vivo.26 In addition, AXL inhibition is also effective against FLT3-negative AML 
expressing AXL in vivo.24 
Refer to the current Gilteritinib Investigator’s Brochure (IB) for information on non-clinical 
data, in vitro, in vivo pharmacology, etc. 
1.3.1 
Clinical Pharmacokinetics (PK) and Pharmacodynamics27 
Single and multiple dose gilteritinib PKs were characterized in subjects with 
relapse or refractory AML enrolled in Study 2215-CL-0101. Results indicated 
gilteritinib exhibits linear, dose-proportional PKs from 20 mg to 450 mg. 
Assessment of Ctrough at various time points indicated steady state is achieved by 
day 15 after multiple dose administrations of gilteritinib from 20 to 450 mg once 
daily. An ex vivo Plasma Inhibitory Activity (PIA) assay was used to assess target 
inhibition in subjects treated with gilteritinib. Samples collected pre-dose and 
post-dose on days 1, 8, 15 and 29 demonstrated marked and sustained inhibition 
of phospho-FLT3 at doses 80 mg and higher. 
The effect of strong and moderate cytochrome P450 (CYP)3A inhibitors on 
gilteritinib exposure was assessed in relapsed or refractory AML subjects (Study 
2215-CL-0101) and healthy subjects (Study 2215-CL-0108). In relapsed or 
refractory AML subjects, there was a less than 2-fold increase in gilteritinib 
exposure when gilteritinib was co-administered with moderate or strong CYP3A4 
inhibitors. In healthy subjects, gilteritinib exposure increased approximately 
2.2-fold when gilteritinib was co-administered with itraconazole, a strong CYP3A4 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
13 
and P-glycoprotein (P-gp) inhibitor. The effect of rifampin, a strong CYP3A and 
P-gp inducer, on gilteritinib PKs was evaluated in healthy adult subjects (Study 
2215-CL-0108). Co-administration of gilteritinib with rifampin, resulted in an 
approximate 70% decrease in gilteritinib exposure. Collectively, these data 
support monitoring subjects who require concomitant medications that are strong 
CYP3A4 inhibitors and restricting use of concomitant medications that are strong 
CYP3A4 inducers. 
A subset of relapsed or refractory AML subjects (2215-CL-0101) were co-
administered gilteritinib and cephalexin a MATE 1 substrate to evaluate a 
potential drug-drug interaction. Cephalexin exposure and urinary excretion were 
comparable after single dose administration of cephalexin alone and in 
combination with gilteritinib (administered once daily). These results suggest co-
administration of MATE1 substrates and gilteritinib is not expected to result in a 
clinically-relevant drug-drug interaction. 
A preliminary analysis of the relationship between ASP2215 plasma 
concentration and Fridericia-corrected QT interval (QTcF) change from baseline 
(ΔQTcF) was performed on data from the 2215-CL-0101 study (data cutoff 06 Jun 
2018). This assessment included 1885 observations from 251 patients. A model-
averaging approach was used to develop a robust model to describe and predict 
the ASP2215 concentration-ΔQTcF relationship. A concentration-related 
increase in ΔQTcF was observed and the mean ΔQTcF at the mean steady-state 
Cmax at 120 mg was predicted to be less than the 10 msec-threshold considered 
clinically significant. Additionally, 4.4% of relapse/refractory subjects had a 
maximum post-baseline QTcF interval >500 msec and 8.8% of patients had a >60 
sec change in their maximum corrected QT interval (QTc) relative to baseline. 
These data indicate clinically-relevant corrected QT interval (QTc) prolongation is 
not anticipated. 
With increasing dose of gilteritinib, increasing plasma concentrations of creatine 
kinase (CK) were observed. Comparison of day matched CK corrected relative to 
baseline with Ctrough ASP2215 values showed a correlation with a positive slope. 
Similarly, comparison of the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) grade for CK elevations with 
gilteritinib Ctrough values showed increasing incidence of higher CTCAE grades 
with increasing drug exposure. However, almost all of the elevations were grade 
1 and grade 2, and the incidence of grade 3 AEs reported in the study population 
was low (4.8%). Overall, increasing CK plasma concentrations from baseline 
appeared to correlate with increasing ASP2215 plasma concentrations; the 
mechanism for this effect is unknown. 
Gilteritinib clinical pharmacokinetics and pharmacology are summarized in the 
XOSPATA package insert. Additional details are described in the Gilteritinib IB. 
1.3.2 
Clinical Experience27 
As of the data cutoff date of 06 Jun 2018, 1 study in AML patients, 3 studies in 
healthy subjects, 1 study in healthy subjects and hepatic impairment subjects and 
1 study in patients with solid tumors were complete. A phase 1b/2 study in 
combination with erlotinib in NSCLC patients was terminated. Ongoing studies 
include, 8 studies in AML patients, a phase 1/2 rollover study, a taste profile study 
in healthy subjects and 2 expanded access studies. Overall, 170 healthy subjects, 
16 subjects with hepatic impairment and 931 patients have received at least 
1 dose of gilteritinib. 
 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
14 
In Study 2215-CL-0101, a Phase 1/2 study in patients with relapsed and refractory 
AML, gilteritinib generally exhibited linear, approximately dose-proportional 
pharmacokinetics after once daily administration over the dose range evaluated 
(20 to 450 mg). Median tmax was observed between 2 and 6 hours following single 
and repeat dosing of gilteritinib. At a dose of 120 mg once daily, the median Cmax 
at day 15 was approximately 282 ng/mL (n=3) and the median AUC24 at day 15 
was approximately 6180 ng·h/mL (n=3). After multiple dose administration, 
gilteritinib exhibited a long half-life, ranging from 45 to 159 hours and up to 10-
fold accumulation based on the accumulation index, Rac. 
Results from Study 2215-CL-0101 indicate that of the 252 patients who received 
at least 1 dose of gilteritinib, the majority of composite complete remission (CRc) 
and partial remission (PR) events were observed in FLT3 mutation-positive AML 
patients in dose groups of 80 mg and greater. The derived response rate (CRc + 
PR) at the end of treatment in the 191 FLT3 mutation-positive patients was 48.7% 
overall and 66.7%, 53.6%, 48.3%, 60.0% and 50.0% in the 80 mg, 120 mg, 200 
mg, 300 mg and 450 mg dose groups, respectively. 
Refer to the Gilteritinib IB for more details. 
1.3.3 
Clinical Safety27 
Of the 252 patients in Study 2215-CL-0101 who received at least 1 dose of 
gilteritinib, the majority (249 [98.8%]) experienced at least 1 treatment-emergent 
adverse event (TEAE), and most (189 [75.0%]) patients experienced at least 1 
TEAE considered by the investigator to be possibly or probably related to study 
drug. Common TEAEs (occurring in at least 10% of patients) included febrile 
neutropenia, anemia, thrombocytopenia, constipation, diarrhea, nausea, 
stomatitis, vomiting, abdominal pain, asthenia, fatigue, edema peripheral, 
pyrexia, pneumonia, sepsis, fall, alanine aminotransferase (ALT) increased, 
aspartate aminotransferase (AST) increased, blood alkaline phosphatase 
increased, blood creatinine increased, blood creatine phosphokinase increased, 
neutrophil count decreased, platelet count decreased, appetite decreased, 
hypoalbuminemia, 
hypocalcemia, 
hypokalemia, 
hypomagnesemia, 
hyponatremia, arthralgia, AML disease progression, dizziness, dysgeusia, 
headache, insomnia, acute kidney injury, cough, dyspnea, epistaxis, hypoxia, 
hypotension, pain in extremity and hypertension. No clear dose-dependent 
patterns were observed for overall TEAEs, TEAEs of grade 3 or higher, drug-
related TEAEs, serious TEAEs or drug-related serious TEAEs. Overall, 105 
patients experienced TEAEs leading to death. The incidence of deaths in the 20 
mg, 40 mg, 80 mg, 120 mg, 200 mg, 300 mg and 450 mg dose groups was 29.4%, 
37.5%, 45.8%, 34.8%, 48.5%, 40.0% and 33.3%, respectively. The majority of 
the deaths were attributed to disease progression. Thirty-one patients 
experienced dose-limiting toxicities (DLTs). None of the doses below 450 mg met 
the criteria for pausing enrollment. Thus, the maximum tolerated dose (MTD) in 
Study 2215-CL-0101 is considered to be 300 mg. 
Refer to the Gilteritinib IB for more details. 
1.3.4 
Dose Rationale 
A Phase I/II trial in AML patients with relapsed and refractory disease treated with 
gilteritinib has recently been completed.28 Gilteritinib was well tolerated in heavily 
pretreated patients. Grade 3 diarrhea and hepatic enzyme elevation were dose 
limiting at doses over 300 mg/day. At doses ≥ 80 mg/day, the derived response 
rate (CRc + PR) at the end of treatment in the 191 FLT3 mutation-positive patients 
was 48.7% overall and 66.7%, 53.6%, 48.3%, 60.0% and 50.0% in the 80 mg, 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
15 
120 mg, 200 mg, 300 mg and 450 mg dose groups, respectively. The median 
duration of response in FLT3 mutation positive patients in ≥ 80 mg dose levels 
was 147.0 days (95% CI: 97.0, 307.0). In FLT3 mutation positive patients with a 
response of CR/CRh, the median duration of response was 383.0 days (95% CI: 
136.0, Not Evaluable [NE]). The median overall survival (OS) from Kaplan-Meier 
estimates in FLT3 mutation positive patients in ≥ 80 mg dose levels was 218.0 
days, with survival probabilities of 56.2% at 26 weeks and 24.9% at 1 year. This 
is in contrast to similar studies with midostaurin in which single agent therapy 
rarely resulted in a decrease in the bone marrow blast percentage and response 
was brief. The response rate to gilteritinib was furthermore not impacted by the 
presence of concurrent FLT3 D835 mutations. Based on this study a dose of 120 
mg/day was chosen for future studies. A Phase 1 trial of gilteritinib + 
chemotherapy in newly diagnosed AML 2215-CL-0103 and a randomized trial of 
azacitidine +/- gilteritinib are ongoing. 
Data provided from the manufacturer, Astellas (1 Apr 2019): A Phase 1 trial of 
gilteritinib 
+ 
chemotherapy 
in 
newly 
diagnosed 
AML 
2215-CL-0103 
(NCT02236013) is ongoing with most recent results presented at American 
Society of Hematology in 2018.29 At the time of the presentation, 62 subjects were 
enrolled at gilteritinib dose levels ranging from 40 mg to 200 mg/day. Two 
subjects in the 200 mg/day cohort experienced DLTs (neutropenia, neutropenic 
enterocolitis). The maximum tolerated dose and the recommended expansion 
dose were established at 120 mg/day. 
The end-of-treatment investigator-reported rate of composite complete remission 
(CRc) for response evaluable FLT3mut+ subjects receiving gilteritinib 120 mg on 
Schedule 1 (n=17) was 100%. The CRc rate in FLT3mut+ subjects receiving 
Schedule 2 induction with daunorubicin was also 100%. Among subjects who 
received ≥ 80 mg/day gilteritinib (n=51), CRc rates for FLT3mut+ subjects were 
90.3% (n=28/31). 
Response by dose level is outlined below: 
Table 1-1: 
Antileukemic Response: FLT3+ Patients 
Response* 
S1 
40 mg 
(N=3) 
S1 
80 mg 
(N=1) 
S1 
120 mg 
(N=17) 
S1 
200 mg 
(N=2) 
S1 Total 
(N=23) 
S2 IDR 
(N=5) 
S2 DNR 
(N=6) 
CR      n (%) 
2 (67%) 
1 (100%) 
12 (71%) 
1 (50%) 
16 (70%) 
4 (80%) 
2 (33%) 
CRp    n (%) 
 
 
1 (6%) 
 
1 (4%) 
 
 
CRi     n (%) 
1 (33%) 
 
4 (23%) 
 
5 (22%) 
1 (20%) 
2 (33%) 
CRc‡   n (%) 
3 (100%) 
1 (100%) 
17 (100%) 
1 (50%) 
22 (96%) 
5 (100%) 
4 (67%) 
NR/NE n (%) 
 
 
 
1 (50%) 
1 (4%) 
 
2 (33%) 
*Response parameters were defined according to the International Working Group Criteria for AML 
(Cheson B, et al. J Clin Oncol. 2003; 12 (24):4642–4649). 
‡CRc included patients who achieved CR, CRp, and CRi. 
Abbreviations: CR, complete remission; CRc, composite complete remission; CRi, complete 
remission with incomplete hematologic recovery; CRp, complete remission with incomplete platelet 
recovery; FLT3, fms-like tyrosine kinase 3; mut+, mutation positive; NR, no response; NE, not 
evaluable; IDR, Idarubicin; DNR, Daunorubicin. 
Grade ≥ 3 AEs in ≥ 10% of patients were febrile neutropenia (63.3%), thrombocytopenia 
(18.3%), decreased platelet count (16.7%), neutropenia (15.0%), bacteremia (10.0%), sepsis 
(10.0%), and decreased white blood cell count (10.0%). Serious drug-related AEs in >1 
subject were febrile neutropenia (n=9), small intestinal obstruction, lung infection, sepsis, and 
decreased ejection fraction (all n=2). 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
16 
1.3.4.1 
Gilteritinib Pharmacokinetics and Pharmacodynamics 
In an ongoing Phase 1/2 study (Study 2215-CL-0103), gilteritinib is 
administered in combination with combination 7+3 chemotherapy 
regimens to newly diagnosed patients with AML.29 The maximum 
tolerated dose was determined to be 120 mg. Preliminary analysis of 
gilteritinib pharmacokinetics was performed and found to be 
comparable to that observed in the monotherapy setting.30 Gilteritinib 
concentrations after once-daily 120 mg gilteritinib in combination with 
7+3 chemotherapy generally exceed 100 ng/mL, a threshold level 
associated with improved clinical response in subjects with relapsed 
or refractory AML administered 120 mg gilteritinib as monotherapy. 
These data coupled with the safety, efficacy and tolerability result 
described above, support the proposed dose of 120 mg gilteritinib in 
combination with 7+3 chemotherapy. 
Refer to Gilteritinib IB for more details. 
1.4 
Summary of Rationale for Proposed Study 
Activating mutations of the receptor tyrosine kinase FLT3 are one of the most common 
molecular abnormalities in AML and are present in about 30% of newly diagnosed 
patients.31 The presence of a FLT3-ITD mutation in an AML patient implies a poor prognosis 
with only 22% of patients maintaining a remission for two years in a Phase III national 
study.32 The prognostic impact of the FLT3-ITD mutation does appear to be lessened in 
those with a lower allelic burden (signal ratio) who are also Nucleophosmin 1- Mutated 
(NPM1) mutated. 
FLT3-ITD AML is rarely cured with chemotherapy alone. Current approaches often 
incorporate allogeneic bone marrow transplant in first remission (CR1) for those patients 
who have a matched donor and are medically qualified for transplantation. The first hurdle 
to achieve on the road to potential curative therapy is achievement of remission with 
induction therapy. Intensification of anthracycline (daunorubicin) dose has been shown to 
improve survival in newly diagnosed AML when compared to standard dose.32 In subgroup 
analysis of this Phase III study, FLT3-ITD patients demonstrated a prolonged median 
survival (15.2 months vs 10.2 months, P=0.09) with high dose daunorubicin which was 
demonstrated to be statistically significant on longer follow-up.33 Hematopoietic stem cell 
transplant (HSCT) holds the most potential of cure for patients with high risk leukemias. In 
a single institution retrospective study of FLT3 -ITD patients who underwent early HSCT in 
CR1, 75% remained disease free at 3 years post transplantation.34 However, patients who 
do not achieve remission or relapse early on do not have the opportunity to proceed to 
allogeneic transplant. 
Midostaurin is known to be a nonselective inhibitor with low FLT3 inhibitory potency 
compared to newer agents. Gilteritinib has been designed as a FLT3 inhibitor that is both 
selective and potent. In a recently reported Phase I/II trial, 252 patients with relapsed and 
refractory AML were treated with this agent. It was well tolerated and at dose levels ≥ 80 
mg/day, FLT3 inhibition was consistently seen with overall response rates >50% in this 
heavily pretreated population. We are hoping gilteritinib, a more potent FLT3 inhibitor than 
midostaurin, will have further improvement in both FLT3-ITD and FLT3-TKD mutations. 
Despite advances in AML therapy, the majority of patients die of their disease. The first 
hurdle to achieve on the road to potential curative therapy in AML is achievement of 
remission with induction therapy. Pharmacologic targeting of FLT3 (both ITD and TKD) 
represents an important potential approach for improving these outcomes. While C10603 
demonstrated an improvement in CR and in survival in FLT3 mutated AML patients, 
gilteritinib as a more potent FLT3 inhibitor has in Phase I/II studies in induction had 
promising CR rate and will hopefully allow for more Minimal Residual Disease (MRD) 
negative CRs and decreased risk of relapse after CR. 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
17 
2. 
Study Objectives 
2.1 
Primary Objective 
To improve the FLT3 mutation negative (evaluated by polymerase chain reaction [PCR] at 
the end of induction) Composite Complete Response (CRc) [includes Complete Response 
(CR) or CR with incomplete hematologic recovery (CRi)] rate of patients with FLT3 mutated 
AML who receive gilteritinib compared to those who receive midostaurin in addition to 
standard therapy with cytarabine and daunorubicin during induction. 
2.2 
Secondary Objectives 
• 
To improve the FLT3 mutation negative Complete Response (CR) rate of patients with 
FLT3 mutated AML who receive gilteritinib compared to those who receive midostaurin 
in addition to standard therapy with cytarabine and daunorubicin during induction. 
• 
To improve the MRD- CRc (evaluated by flow cytometry) rate of patients with FLT3 
mutated AML who receive gilteritinib compared to those who receive midostaurin in 
addition to standard therapy with cytarabine and daunorubicin during induction. 
• 
To improve CRc (CR or CRi) rate of patients with FLT3 mutated AML who receive 
gilteritinib compared to those who receive midostaurin in addition to standard therapy 
with cytarabine and daunorubicin during induction. 
• 
To improve the Event Free Survival (EFS) of patients with FLT3 mutated AML who 
receive gilteritinib to those who receive midostaurin in addition to cytarabine and 
daunorubicin during induction and high-dose cytarabine during consolidation. 
• 
To improve the overall survival (OS) of patients with FLT3 mutated AML who receive 
gilteritinib to those who receive midostaurin in addition to cytarabine and daunorubicin 
during induction and high-dose cytarabine during consolidation. 
• 
To assess the toxicities of gilteritinib plus standard therapy during induction and 
consolidation in this patient population. 
• 
To assess the toxicities of midostaurin plus standard therapy during induction and 
consolidation in this patient population. 
2.3 
Exploratory Objectives 
• 
To evaluate the effect of gilteritinib on CRc rate, EFS and OS in patients with de novo 
AML, t-AML and AML-MRC separately. 
• 
To evaluate the effect of gilteritinib on CRc rate, EFS and OS in patients with favorable, 
intermediate, and adverse risk separately, determined by 2017 ELN risk classification. 
• 
To determine the predictive value of Minimal Residual Disease (MRD) positivity and 
negativity post induction therapy. 
• 
To assess the MRD status of patients with AML by flow cytometry after induction therapy 
with a Tyrosine Kinase Inhibitor (TKI) and compare flow MRD to molecular studies in 
patients in CRc. 
• 
To evaluate the FLT3 mutation negative CRc rate after first cycle of consolidation by 
treatment arm for those patients who are FLT3 mutation positive after induction and 
administered consolidation. 
• 
To assess the feasibility of immediate transplant as post-remission therapy. 
• 
Correlation of characteristics of FLT3 mutation and outcome. 
 
 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
18 
3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be considered 
eligible for this study. Use the checklist to confirm a patient’s eligibility. For each patient, this 
checklist may be photocopied, completed and maintained in the patient’s chart. 
In calculating days of tests and measurements, the day a test or measurement is done is 
considered Day 0. Therefore, if a test is done on a Monday, the Monday four weeks later 
would be considered Day 28. 
PrECOG Patient No. 
 
 
Patient’s Initials ( F, M, L) 
 
 
Physician Signature and Date 
 
NOTE: PrECOG does not allow waivers to any protocol specified criteria. All eligibility criteria listed 
in Section 3 must be met, without exception. All questions regarding clarification of eligibility 
criteria must be directed to the Medical Monitor or PrECOG Study Contact. 
NOTE: Institutions may use the eligibility checklist as source documentation if it has been reviewed, 
signed, and dated prior to registration by the treating physician; however source must be 
the first documentation. In some cases the checklist will therefore only serve as confirmation 
of the information in the patient records. 
REGISTRATION ELIGIBILITY: Patients age ≥ 18 years to ≤ 70 years. 
Any patient undergoing bone marrow biopsy with suspicion of or known diagnosis of acute myeloid 
leukemia (AML) will be asked to sign a Prescreening Consent to allow for centralized testing of bone 
marrow/peripheral blood samples and for ongoing storage of research samples for future 
evaluations. Patients will be asked to consent to collect minimal demographic information for 
screening and for future optional evaluation of samples. 
The following will be performed at a Central Laboratory: 
• 
Flow cytometry to confirm blasts are myeloid 
• 
FLT3 mutation status (includes signal ratio) 
• 
NPM1 mutation status 
Patients negative for FLT3 mutated AML will not be eligible for further evaluation for study entry (will 
be counted as a screen failure). 
A diagnosis of acute myeloid leukemia will be documented by the study investigator from site 
evaluation. 
RANDOMIZATION ELIGIBILITY CRITERIA: 
3.1 
Patient must have previously untreated FLT3 mutated Non M3 AML (FLT3-TKD or FLT3-
ITD allowed). 
Date of Diagnosis (i.e., date of diagnostic bone marrow biopsy): _____________ 
FLT3 Mutation Status (Invivoscribe Report): _____________________ 
ITD vs TKD Status (Invivoscribe Report):  ITD 
 
 TKD 
If ITD, Signal Ratio (Invivoscribe Report): _____________ 
 High (≥ 0.5) 
 Low (<0.5) 
NOTE: 
Standard of care induction 7+3 chemotherapy may start prior to randomization 
using same regimen and doses as defined in Section 5.2.1 while awaiting 
prescreening test results. 
_____ 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
19 
3.2 
Patient must have had no prior systemic therapy for AML, except as noted below: 
• 
Hydroxyurea and emergent leukapheresis or preemptive treatment with retinoic acid 
prior to exclusion of Acute Promyelocytic Leukemia (APL) allowed. 
• 
Prior therapy for myelodysplastic syndrome (MDS) or myeloproliferative neoplasms 
(MPN) (e.g., thalidomide or lenalidomide, interferon, jakafi, cytokines, 5-azacytidine or 
decitabine, histone deacetylase inhibitors). 
• 
Initiation of standard of care 7+3 induction chemotherapy using same regimen and 
doses as defined in protocol (Section 5.2.1) while awaiting prescreening test results. 
3.3 
Patients may not have received hypomethylating agent within 21 days. 
Date of Last Hypomethylating Agent Treatment (if applicable): __________ 
3.4 
The patient may not have M3 AML. 
3.5 
The patient may not have AML with known Core Binding Factor –t(8;21), inv(16), t(16;16) 
(if tested prior to registration [testing not required]). 
If available: FISH:  
 
 
Date of Test: ___________ AND/OR 
Cytogenetics:  
 
 
 
Date of Test: ___________ 
NOTE: 
If results return with known Core Binding Factor –t(8;21), inv(16), t(16;16) after 
patient is registered, patient may be allowed to remain on-study per investigator’s 
discretion after discussion with PrECOG. 
3.6 
The patient may not have known active Central Nervous System (CNS) leukemia. 
NOTE: 
- Prophylaxis with intrathecal chemotherapy is allowed prior to or during 
induction/consolidation. 
- If prophylactic lumbar puncture is performed, recommend scheduling so results 
are available prior to Day 8 or wait until Day 21 to perform. 
3.7 
Patient must have an ECOG performance status of 0-3 (Appendix I). 
3.8 
Patient must be age ≥ 18 years to ≤ 70 years. 
3.9 
Patient must be able to understand and willing to sign IRB-approved informed consent. 
3.10 
Patient must be willing to provide mandatory bone marrow and blood samples for research 
(Section 13.0). 
3.11 
Patient must have adequate organ function as measured by the following criteria, obtained 
≤ 48 hours prior to randomization except ECG and left ventricular ejection fraction (LVEF) 
which can be done ≤ 2 weeks prior to randomization: 
• 
Serum creatinine ≤ 1.5x institutional upper limit of normal (ULN), or if serum creatinine 
outside normal range, then glomerular filtration rate (GFR) >40 mL/min as measured by 
Cockcroft-Gault formula (Appendix II). 
Creatinine: ________ 
Institution ULN: ______ 
Date of Test: __________ 
GFR (if applicable): ______ 
 
 
 
Date of Test: __________ 
• 
ALT and AST ≤ 3x ULN, unless secondary to leukemia. 
ALT: _____________ 
Institution ULN: ______ 
Date of Test: __________ 
AST: _____________ 
Institution ULN: ______ 
Date of Test: __________ 
• 
Serum total or direct bilirubin <2 mg/dL, unless due to Gilbert’s, hemolysis or leukemic 
infiltration. 
Total Bilirubin: ______________ 
 
 
Date of Test: __________ OR 
Direct Bilirubin: _____________  
 
 
Date of Test: __________ 
_____
_____ 
_____
_____
_____ 
_____
_____ 
_____ 
_____ 
_____ 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
20 
• 
QTcF interval ≤ 500 msec (using Fridericia’s correction). 
QTcF: ____________________ 
 
 
Date of Test: __________ 
• 
Left Ventricular Ejection Fraction >45%. 
Multigated Acquisition Scan (MUGA):  
 
Date of Test: __________ OR 
Echocardiogram (ECHO):  
 
 
 
Date of Test: __________ 
3.12 
The patient may not be known to have hypokalemia and/or hypomagnesemia that does not 
respond to supplementation. 
3.13 
A female patient is eligible to participate if she is not pregnant and at least one of the 
following conditions apply: 
• 
Not a woman of childbearing potential (WOCBP) as defined in Appendix III OR 
• 
WOCBP who agrees to follow the contraceptive guidance as defined in Appendix III 
throughout the treatment period and for at least 180 days after the final study drug 
administration. 
A blood test to rule out pregnancy ≤ 2 weeks prior to randomization. 
Is the patient a woman of childbearing potential? _____________________ (yes/no) 
If yes, Date of Test: _______________ Results: _____________________________ 
3.14 
Female patient must agree not to breastfeed or donate ova starting at treatment and 
throughout the study period, and for at least 180 days after the final study drug 
administration. 
3.15 
A male patient must agree not to donate sperm starting at treatment and throughout the 
study period, and for at least 120 days after the final study drug administration. 
3.16 
A male patient with female partner(s) of child-bearing potential must agree to use 
contraception as detailed in Appendix III during the treatment period, and for at least 120 
days after the final study drug administration. 
3.17 
Male patient with a pregnant or breastfeeding partner(s) must agree to remain abstinent or 
use a condom for the duration of the pregnancy or time partner is breastfeeding throughout 
the treatment period, and for at least 120 days after the final study drug administration. 
3.18 
Patients may not have another malignancy that could interfere with the evaluation of safety 
or efficacy of this combination. Patients with a prior malignancy will be allowed in the 
following circumstances: 
1) Not currently active and diagnosed at least 3 years prior to the date of enrollment. 
2) Non-invasive diseases such as low risk cervical cancer or any cancer in situ. 
3.19 
The patient may not have a history of Long QT Syndrome. 
3.20 
The patient may not have evidence of uncontrolled angina, severe uncontrolled ventricular 
arrhythmias, electrocardiographic evidence of acute ischemia, or congestive heart failure 
(CHF) New York Heart Association (NYHA) Class 3 or 4 (Appendix IV). Patient may also 
not have a history of CHF NYHA Class 3 or 4 in the past, unless a prescreening 
echocardiogram (ECHO) or multigated acquisition scan (MUGA) performed within 2 weeks 
prior to study entry with results of left ventricular ejection fraction >45%. 
3.21 
The patient may not have had major surgery or radiation therapy within 4 weeks of 
registration. 
3.22 
The patient may not require treatment with concomitant drugs that are strong inducers of 
CYP3A and P-gp (Appendix V). 
_____ 
_____ 
_____ 
_____ 
_____ 
_____ 
_____ 
_____ 
_____ 
_____ 
_____ 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
21 
3.23 
Patients with a known allergy to any of the study medications, their analogues, or excipients 
in the various formulations of any agent are not eligible. 
3.24 
Patients with known gastrointestinal (GI) disease or prior GI procedure that could interfere 
with the oral absorption or tolerance of gilteritinib or midostaurin including difficulty 
swallowing are not eligible. 
3.25 
Patients with any serious medical or psychiatric illness that could, in the investigator’s 
opinion, potentially interfere with the completion of the treatment according to the protocol 
are not eligible. 
3.26 
Patients may not participate in any other therapeutic clinical trials, including those with other 
investigational agents not included in this trial during treatment on this study without prior 
approval from PrECOG. 
_____ 
_____ 
_____ 
_____ 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
22 
4. 
Registration Procedures 
4.1 
Ethics 
This study will be conducted in accordance with the ethical principles that have their origin 
in the current Declaration of Helsinki and will be consistent with applicable US regulatory 
requirements and International Conference on Harmonization/Good Clinical Practice 
(ICH/GCP). 
The study will be conducted in compliance with the protocol. The protocol and any 
amendments and the patient informed consent will receive Institutional Review Board (IRB) 
approval prior to initiation of the study. 
Freely given written informed consent must be obtained from every patient or their legally 
acceptable representative prior to clinical trial participation, including informed consent for 
any screening procedures conducted to establish patient eligibility for the trial. 
Study personnel involved in conducting this trial will be qualified by education, training, and 
experience to perform their respective task(s). This trial will not use the services of 
investigators or study personnel where sanctions have been invoked or where there has 
been scientific misconduct or fraud (e.g., loss of medical licensure, debarment). 
Investigators are responsible for the conduct of the study at their study site. 
4.2 
Regulatory Requirements 
Before a site may enroll patients, protocol-specific regulatory and other documents must be 
submitted to PrECOG as noted in study materials. Detailed information regarding document 
submission and control is provided to each site in separate study materials. 
Once required documents are received, reviewed, and approved by PrECOG or their 
representative, study materials will be forwarded to the site. Any changes to site regulatory 
documents must be submitted by the investigator to the responsible party in a timely 
manner. Initial study drug shipment will not occur until PrECOG approval. Once PrECOG 
activates a site, enrollment make occur. No patients will begin protocol therapy without 
formal registration as per the process below. 
4.3 
Patient Registration 
Patients may not undergo any study-required procedures that are not part of standard of 
care, until signed informed consent is obtained (prescreening and main consent). 
Prescreening 
Any patient undergoing bone marrow biopsy with suspicion of or known diagnosis of AML 
will be asked to sign a Prescreening Consent form. Patients must provide written consent 
to submission of bone marrow and/or peripheral blood samples for centralized testing for 
immunophenotyping at baseline for later MRD assessment, FLT3, NPM1 and DNMT3 
mutation status. Patients will also confirm if they agree to the future use of optional research 
samples. 
After prescreening consent, the patient will be registered in the study by site personnel via 
an electronic data capture (eDC) system. Demographic and diagnostic information will be 
collected on registered patients and recorded on electronic Case Report Forms (eCRFs) 
regardless of their FLT3 mutation status or final diagnosis. 
Standard of care induction 7+3 chemotherapy may start prior to randomization using same 
regimen and doses as defined in Section 5.2.1 while awaiting prescreening test results. 
Patients that are negative for FLT3 mutated AML by Central Laboratory testing, will be 
considered screen failures. 
 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
23 
Screening Eligibility 
Once patient results are positive for FLT3 mutation by Central Laboratory testing and are 
Non M3 AML, the study site will have the patient sign the main consent and proceed to 
confirmation of eligibility and randomization. 
Eligibility requirements per Section 3 will be confirmed by the investigator site during the 
registration process. This includes receipt and review of the central laboratory assessments 
as well as institutional diagnosis of acute myeloid leukemia. 
4.4 
Patient Randomization 
Patients who then meet eligibility requirements may be randomized for study participation. 
Patients will be stratified prior to randomization by criteria noted below based on central 
laboratory assessment of prescreening samples. 
Patients will be assigned in 1:1 randomization to Arm A or Arm B (treatment assignments 
are not blinded): 
● 
TKD vs. ITD FLT3 Mutation 
○ 
If FLT3-ITD Mutation: NPM1 Mutation Status (positive vs. negative) 
○ 
If FLT3-ITD Mutation: Signal Ratio (high [≥ 0.5] vs. low [<0.5] of FLT3 Wild Type) 
Treatment will begin no later than 3 days after randomization. 
Full information regarding registration/randomization procedures can be found in the 
materials provided to study sites. Documentation from the web randomization system 
including the treatment assignment will be placed in the patient record. Correspondence 
regarding patient registration/randomization must be kept in the study records. 
4.5 
Research Bone Marrow and Blood Samples 
Mandatory bone marrow and blood samples are required during the study. 
Time points for bone marrow and blood samples are outlined in the study parameters 
(Section 10) and specific preparation and shipment requirements are outlined in the 
correlative section of this protocol (Section 13) and the lab manuals. 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
24 
5. 
Treatment Plan 
5.1 
Overview 
Eligible AML patients with FLT3 mutation by central laboratory testing prior to randomization 
will be stratified according to TKD vs. ITD FLT3 mutation. Patients with FLT3-ITD mutation 
will undergo further stratification with NPM1 mutation status (positive vs. negative) and 
signal ratio (high [≥ 0.5] vs. low [<0.5] of FLT3 Wild Type). 
All patients will receive standard induction chemotherapy with cytarabine and daunorubicin 
and standard consolidation with high-dose cytarabine. 
NOTE: 
Standard of care induction 7+3 chemotherapy may start prior to randomization 
using same regimen and doses as defined in Section 5.2.1 while awaiting 
prescreening test results. 
Patients will be randomized to receive either open label gilteritinib or midostaurin and will 
receive the assigned study drug during induction and consolidation therapy. 
5.2 
Treatment and Administration Schedule 
End of Cycle = Count Recovery 
5.2.1 
Induction 
Day 1 of treatment will begin no later than 3 days after randomization with the first 
dose of induction chemotherapy, and each day is 24 hours in length. Therefore, if 
chemotherapy were to have begun in the evening, then it is possible that the 
scheduled gilteritinib or midostaurin administration on day 8 may occur on calendar 
day 9. 
Prophylaxis with intrathecal chemotherapy is allowed prior to or during 
induction/consolidation. 
If prophylactic lumbar puncture is performed, recommend scheduling so results 
are available prior to Day 8 or wait until Day 21 to perform. 
Arm A (7+3) + Gilteritinib 
• 
Cytarabine 100 mg/m2/day will be administered by continuous IV infusion for 
a total of 7 days beginning Day 1 
• 
Daunorubicin 90 mg/m2/day will be administered IV per package insert or 
per institutional guidelines or over 30-60 minutes Days 1,2,3. 
• 
Gilteritinib 120 mg orally QD (daily) x 14 days starting on day 8 
ARM B (7+3) + Midostaurin 
• 
Cytarabine 100 mg/m2/day will be administered by continuous IV infusion for 
a total of 7 days beginning Day 1 
• 
Daunorubicin 90 mg/m2/day will be administered IV per package insert or 
per institutional guidelines or over 30-60 minutes Days 1,2,3. 
• 
Midostaurin 50 mg orally BID x 14 days beginning on day 8 
If there is a delay in starting FLT3 inhibitors in Arm A or Arm B (due to obtaining 
drug, i.e. insurance, formulary, etc.), the FLT3 inhibitor will need to stop after Day 
21 dose (i.e., Day 21 or Day 22 [if FLT3 inhibitor started on Day 9]). No missed 
doses will be made up. 
NOTE: 
If second cycle of induction is needed, daunorubicin dose will be 
decreased to 45 mg/m2/day IV Days 1,2,3. 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
25 
A bone marrow aspirate/biopsy will be performed on all patients on Day 21 (+/-1 
day window; delays due to holidays, weekends, or other unforeseen 
circumstances will be permitted) to determine the need for a second induction 
cycle. If the marrow aspirate/biopsy is inadequate to make a determination, 
consider repeating the bone marrow assessment in 5-7 days. 
Arm A + Gilteritinib: If second cycle of induction is planned, treatment will begin 
after Day 28 (i.e., ≥ 7 days after completing gilteritinib) but no later than Day 45. 
Arm B + Midostaurin: If second cycle of induction is planned, treatment will begin 
after Day 24 (i.e., ≥ 3 days after completing midostaurin) but no later than Day 45. 
A repeat bone marrow aspirate/biopsy should be done to assess for response and 
MRD status upon peripheral blood count recovery (Absolute Neutrophil Count 
(ANC) ≥ 1000/mm3, platelets ≥ 100,000/mm3) but no later than Day 60 after 
initiation of the first cycle of induction therapy for patients who receive 1 cycle of 
induction or no later than Day 60 after initiation of the second cycle of induction 
therapy (i.e., Day 84-105) for patients who receive 2 cycles of induction (MRD 
sample will be obtained by Day 60 on all patients even if counts have not 
recovered. The only exception is a patient who has been declared a relapse 
based on blood counts). 
Patients who do not achieve a CR or CR with incomplete hematologic recovery 
(CRi) by Day 60 if one cycle and Day 84-105 if 2 cycles of induction therapy will 
be removed from study. 
Patients who achieve CR or CRi can proceed to post remission consolidation 
therapy on study (if otherwise eligible) or may proceed to allogeneic transplant if 
desired. Patients who do not achieve CR/CRi are removed from study. 
Patients who go to transplant or any other non-protocol leukemia directed therapy 
will complete an end of treatment visit, and will be followed for relapse and 
survival only. 
5.2.2 
Consolidation 
Patients deemed suitable by the treating investigator may proceed to allogeneic 
TRANSPLANT at any time after induction or after 0-4 cycles of chemotherapy 
consolidation. 
Patients will continue to receive the same study drug (gilteritinib or midostaurin) 
assigned during induction for consolidation. 
NOTE: Patients are not eligible to proceed to consolidation on study unless bone 
marrow samples are obtained for Minimal Residual Disease (MRD) at the 
time of CR/CRi. 
Consolidation Cycle 1 
Patients who achieve a CR or CRi and have no residual significant toxicities from 
the induction course are eligible for further protocol therapy. In general, 
consolidation therapy should start within 1 month of documentation of CR/CRi, 
after the resolution of any non-hematologic toxicity of previous chemotherapy 
(≤ Grade 1 or baseline). Patients must have maintained peripheral blood 
evidence of a remission as defined in Section 9 and must have an ANC 
≥ 1000/mm3. For patients who have not recovered from the toxicities of 
chemotherapy within 30 days of documentation of remission, and thus require 
additional time, a repeat marrow should be obtained to confirm remission and 
PrECOG must be contacted for approval to continue on study. 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
26 
NOTE: Patients who achieve a CRi post remission therapy are eligible to proceed 
to consolidation once their ANC recovers to 1000/mm3 even if that 
happens more than 60 days after the initiation of their last induction cycle. 
ARM A 
• 
Cytarabine 3 g/m2* over approximately 1-3 hours every 12 hours (+/- 2 hour 
window) on days 1,3,5 or days 1-3 for a total of 6 doses for up to 4 cycles 
• 
Gilteritinib 120 mg orally QD x 14 days beginning on day 8 of each cycle (up 
to 4 cycles) 
ARM B 
• 
Cytarabine 3 g/m2* over approximately 1-3 hours every12 hours (+/- 2 hour 
window) on days 1,3,5 or days 1-3 for a total of 6 doses for up to 4 cycles 
• 
Midostaurin 50 mg orally BID x 14 days beginning on day 8 of each cycle 
(up to 4 cycles) 
* For patients age ≥ 55 or patients with decreased creatinine clearance 
recommend reducing consolidation cytarabine dose to 1.5 g/m2. 
A repeat bone marrow aspirate/biopsy is required at the end of the first 
consolidation cycle for repeat response assessment and MRD testing. 
Consolidation Cycle 2-4 
Patients must have maintained peripheral blood evidence of a remission as 
defined in Section 9. Consolidation Cycle 2-4 should commence within 2 weeks 
following recovery of peripheral blood counts after previous consolidation. 
Patients who do not begin consolidation Cycle 2-4 within 30 days of recovery from 
previous cycle are ineligible for further protocol therapy. 
ARM A 
• 
Cytarabine 3 g/m2* over approximately 1-3 hours every 12 hours (+/- 2 hour 
window) on days 1,3,5 or days 1-3 for a total of 6 doses for up to 4 cycles 
• 
Gilteritinib 120 mg orally QD x 14 days beginning on day 8 of each cycle (up 
to 4 cycles) 
ARM B 
• 
Cytarabine 3 g/m2* over approximately 1-3 hours every12 hours (+/- 2 hour 
window) on days 1,3,5 or days 1-3 for a total of 6 doses for up to 4 cycles 
• 
Midostaurin 50 mg orally BID x 14 days beginning on day 8 of each cycle 
(up to 4 cycles) 
* 
For patients age ≥ 55 or patients with decreased creatinine clearance 
recommend reducing consolidation cytarabine dose to 1.5 g/m2. 
If there is a delay in starting FLT3 inhibitors in Arm A or Arm B (due to obtaining 
drug, i.e. insurance, formulary, etc.), the FLT3 inhibitor will need to stop after Day 
21 dose. No missed doses will be made up. 
Patients will go off treatment at the time of transplant or any non-protocol 
leukemia directed therapy after completion of the end of treatment visit, and will 
be followed for relapse and survival only. 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
27 
5.2.3 
Arm A: Gilteritinib Administration 
Gilteritinib 120 mg tablets (three 40 mg tablets) are taken once daily by mouth on 
days 8-21 (if chemotherapy were to have begun in the evening, then it is possible 
that the scheduled gilteritinib administration on day 8 may occur on calendar day 
9). Patients will be instructed to take the daily gilteritinib with water as close to the 
same time each morning as possible. Tablets should not be chewed, crushed or 
broken. 
Gilteritinib will be self-administered at home when patients are not hospitalized. If a 
patient forgets to take a dose in the morning and are within 6 hours of the planned 
dosing time, they should be instructed to take their dose. If the patient forgets to 
take their daily dose and are more than 6 hours has passed the planned dosing 
time, they should be instructed to wait for the next morning to dose. If vomiting 
occurs after dosing, the patient should not receive another dose, but wait until the 
next morning to dose. 
When patients are hospitalized for treatment (i.e. induction, aplasia or events), 
gilteritinib will be administered per site procedures for inpatient study management. 
Instructions to patients and study staff regarding the above recommendations for 
administration should be included in orders or related patient record 
documentation, including drug handling and disposal. 
Patient compliance for gilteritinib administration will be assessed by pill counts and 
IRB reviewed medication diary provided to sites. Bottles containing gilteritinib 
tablets will be given to patients for self-administration, when not hospitalized, and 
at scheduled visits. Previously distributed bottles will be returned to the study site 
and tablets counted by the study staff. Investigational product accountability will be 
maintained on the drug accountability record as per regulatory requirements. 
Any discrepancy will be reviewed with the patient during the visit and documented 
as needed. The medication diary will be maintained in the patient records and 
available for review at site monitoring visits. 
Dose reductions are permitted (Section 6). Missed doses are not made up. 
Assigned treatment should continue through induction and consolidation cycles 
until unacceptable toxicity occurs, or the patient meets a treatment 
discontinuation criterion as provided in Section 6 and/or Section 7.3. 
5.2.4 
Arm B: Midostaurin Administration 
Midostaurin 50 mg (two 25 mg capsules) twice a day by mouth on days 8-21 (if 
chemotherapy were to have begun in the evening, then it is possible that the 
scheduled midostaurin administration on day 8 may occur on calendar day 9). 
Patients should take their doses at approximately the same time each day, and 
approximately 12 hours should elapse between the morning and evening doses. 
Each daily dose should be given with food and a glass of water (~240 mL). 
Patients should be instructed to swallow capsules whole and not open, break or 
chew capsules. If vomiting occurs, no re-dosing is allowed prior to the next 
scheduled dose. 
When patients are hospitalized for treatment (i.e. induction, aplasia or events), 
midostaurin will be administered per site procedures for inpatient study 
management. Instructions to patients and study staff regarding the above 
recommendations for administration should be included in orders or related 
patient record documentation, including drug handling and disposal. 
 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
28 
Compliance in taking assigned dose of midostaurin (commercial stock) when the 
patient is not hospitalized, will be assessed by a medication diary. Patients should 
be instructed to bring medication diaries to the site at each visit, for staff review. 
Patients may be counseled by the study staff regarding adherence concerns. 
Dose interruptions are permitted (Section 6). Missed doses are not made up. 
Assigned treatment should continue through induction and consolidation cycles 
until unacceptable toxicity occurs, or the patient meets a treatment 
discontinuation criterion as provided in Section 6 and/or Section 7.3. 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
29 
6. 
Dose Modifications 
6.1 
Dose Interruptions & Reductions 
All toxicities should be graded according to the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE V5.0). A copy 
of 
the 
CTCAE 
V5.0 
can 
be 
downloaded 
from 
the 
CTEP 
website 
(http://www.ctep.cancer.gov). 
Delays due to holidays, weekends, or other unforeseen circumstances will be permitted. 
6.1.1 
Arm A and Arm B: Daunorubicin 
Initial and subsequent daunorubicin doses should be reduced as follows for 
hepatotoxicity (Table 6-1): 
Table 6-1: Daunorubicin Hepatotoxicity Dose Reduction 
Direct Bilirubin 
Dose Reduction 
<2 
None 
2-3 
25% 
>3 
50% 
For patients with evidence of hepatic dysfunction, reassess regularly per 
institutional standards during induction treatment. 
6.1.2 
Arm A: Gilteritinib 
The dose levels include the following (Table 6-2): 
Table 6-2 Gilteritinib Dose Levels 
Dose Level (DL) 
Gilteritinib Dose 
DL 1 (starting dose) 
120 mg 
DL -1 
80 mg 
DL -2 
40 mg 
The gilteritinib dose may be initially reduced by 1 dose level for a described 
instance meeting criteria for dose reduction. The study drug dose can be further 
reduced by a second dose level. Note that dose reductions should occur in a step-
wise manner. Only 2 dose level reductions are permitted. Dose re-escalation is 
not allowed following dose reduction unless there is a specific reason not related 
to gilteritinib for temporarily holding or reducing gilteritinib. 
Gilteritinib will be interrupted per Table 6-3. When the grade of the adverse event 
(AE) decreases to ≤ 1, study drug may be resumed at the next lower dose level, 
unless the investigator deems the AE was, in retrospect, unlikely to be or not 
related to the study drug, at which point the original dose may be resumed. 
Additionally, if the investigator deems it necessary to ensure subject safety, 
dosing may be interrupted or reduced for reasons other than those provided in 
Table 6-3. In the unusual circumstance that dosing is interrupted or reduced for 
reasons not specified in the table, the investigator should promptly inform 
PrECOG. 
Missed doses of gilteritinib will not be made up. 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
30 
Table 6-3 Guidelines for Gilteritinib Dose Interruption or Reduction Event 
Event 
Action 
First occurrence: 
Grade 
≥ 
3 
nonhematological 
AE 
possibly, probably or definitely related to 
the study drug (excluding pancreatitis, 
see below) 
Dosing will be interrupted. If the AE resolves to ≤ grade 1 
within 14 days, the patient may resume dosing at the 
reduced dose during this or subsequent cycles. If the AE 
does not resolve to ≤ grade 1 within 14 days, the subject 
will be discontinued from treatment and an end of 
treatment visit will be performed. 
Second occurrence: 
Recurrence 
of 
the 
same 
nonhematological AE or appearance of 
other new nonhematological AE Grade 
≥ 3 probably, possibly or definitely due 
to 
the 
study 
drug 
(excluding 
pancreatitis, see below) 
Dosing will be interrupted. If the AE resolves to ≤ grade 1 
within 14 days, the patient may resume dosing at the 
reduced dose during this or subsequent cycles. If the AE 
does not resolve to ≤ grade 1 within 14 days, the subject 
will be discontinued from treatment and an end of 
treatment visit will be performed. 
Third occurrence: 
Recurrence of a prior nonhematological 
AE or appearance of other new 
nonhematological 
AE 
Grade 
≥ 
3 
probably, possibly or definitely due to 
the study drug (excluding pancreatitis, 
see below) 
The study drug will be discontinued. 
At any point, in retrospect, if the 
investigator 
determines 
prior 
non-
hematological Grade ≥ 3 AE which was 
initially attributed as possibly, probably 
or definitely related to study drug is now 
deemed unrelated 
The study drug will be re-escalated to dose that the 
participant was on at the time of the AE. 
Pancreatitis 
Dosing will be interrupted until pancreatitis is resolved, 
then resume gilteritinib at 80 mg during this or 
subsequent cycles. 
QTcF >500 ms 
If the QTcF is >500 ms at any time point, the ECG will be 
repeated (within 2 hours or as soon as possible). Confirm 
that potassium and magnesium abnormalities are 
corrected. A cardiology consult will be obtained as 
medically indicated. If the repeat ECG confirms a QTcF 
>500 ms, dosing of study treatment will be interrupted. If 
QTcF resolves to ≤ 480 ms within 14 days from study 
drug interruption, subsequent dosing will be reduced to 
80 mg (or if currently at 80 mg, reduction to 40 mg). 
QTc interval increased by >30 msec 
over screening on ECG on Day 15 of 
Cycle 1 
Confirm with ECG on Day 16. If confirmed, consider dose 
reduction to 80 mg. If currently at 80 mg, dose reduction 
to 40 mg. 
Posterior Reversible Encephalopathy 
Syndrome (PRES) 
Contact PrECOG, discontinue gilteritinib. 
6.1.3 
Arm B: Midostaurin 
Interrupt midostaurin for Grade 3/4 non-hematologic toxicity thought to be 
possibly related to midostaurin and restart at same dose when toxicity resolves 
to ≤ Grade 1. If the toxicity resolves prior to day 21, then restart at same dose to 
complete current cycle. Missed doses will not be made up. 
For QTcF >500, confirmed on repeat study, check potassium and magnesium 
and correct any abnormalities. If at that time QTcF is >480, restart at 50 mg daily, 
until QTcF is ≤ 480. Once QTcF ≤ 480 restart at 50 mg BID. 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
31 
6.1.4 
Arm A and Arm B: Cytarabine Consolidation 
For patients age ≥ 55 or patients with decreased creatinine clearance recommend 
reducing consolidation cytarabine dose to 1.5 g/m2. 
* Cytarabine may be interrupted for 72 hours. Gilteritinib/Midostaurin cannot be 
started until at least 48 hours after last dose of Cytarabine. If Cytarabine is not 
completed by Day 6, contact PrECOG to discuss schedule. 
6.2 
Concurrent Therapies 
6.2.1 
Permitted 
Patients should receive full supportive care, including transfusions of blood and 
blood products, antibiotics, antiemetics, allopurinol, growth factors, etc., when 
appropriate. 
NOTE: Prophylaxis with intrathecal chemotherapy is allowed prior to or during 
induction/consolidation. 
6.2.2 
Not Permitted 
• 
Treatment with concomitant drugs that are strong inducers of CYP3A and P-gp 
are prohibited unless essential for the care of the patient. 
6.2.3 
Cautionary Use 
Caution is advised when considering the following: 
• 
Treatment with concomitant drugs that are strong inhibitors of P-gp and 
concomitant drugs that target serotonin 5HT2BR or sigma nonspecific receptor 
are to be avoided with the exception of drugs that are considered absolutely 
essential for the care of the subject. 
• 
Treatment with concomitant drugs that are strong inhibitors of CYP3A should 
be avoided with the exception of antibiotics, antifungals and antivirals that are 
used as standard of care to prevent or treat infections. Grapefruit juice should 
not be ingested during study treatment. If strong CYP3A inhibitors are used 
concomitantly, patients should be closely monitored for AEs. 
• 
Precaution should be used in use of gilteritinib with concomitant drugs that 
are known to prolong QT intervals or QTc. A cardiology consult should be 
obtained as medically indicated. 
• 
Precaution should be used in use of gilteritinib with concomitant drugs that 
are substrates of P-gp, BCRP and OCT1, since these transporters have been 
shown to be inhibited by gilteritinib in in vitro studies. 
• 
The investigator should consult individual labels for all drugs that the subject 
is taking to evaluate if they fall into any of the above named categories. 
(Appendix V: Additional Excluded and Cautionary Medications). 
Table 6-4 Guidelines 
for 
Cytarabine 
Dose 
Interruption 
or 
Discontinuation 
Dose Interruption or Discontinuation 
Induction 
Consolidation 
Cerebellar Toxicity (any grade) 
Discontinue 
Discontinue 
Direct Bilirubin ≥ 2 mg/dL 
NA 
Interrupt* 
Creatinine >2 mg/dL 
NA 
Interrupt* 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
32 
• 
Any other treatments of AML (including but not limited to chemotherapy, 
radiotherapy, surgery, HSCT, immunotherapy or cellular therapy) are 
prohibited during therapy. 
 
Initiation of standard of care 7+3 induction chemotherapy using same 
regimen and dose as defined in protocol (Section 5.2.1) while awaiting 
prescreening test results is allowed. 
 
Prophylaxis with intrathecal chemotherapy is allowed prior to or during 
induction/consolidation. 
• 
Participation in another interventional study with an investigational agent 
while on treatment is prohibited. 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
33 
7. 
Study Duration and Discontinuation of Therapy 
7.1 
Treatment Duration 
Patients will receive protocol therapy as outlined unless: 
1. Disease progression per Section 9 guidelines or clinical progression. 
2. Toxicities considered unacceptable by either the patient or the investigator, despite 
optimal supportive care and dose modifications as per Section 6. 
3. Patient proceeds to bone marrow transplant or any non-protocol leukemia directed 
therapy. 
4. Development of an inter-current illness that prevents further administration of study 
treatment. 
5. Extraordinary Medical Circumstances: If at any time the constraints of this protocol are 
detrimental to the patient's health, protocol treatment should be discontinued. 
6. Patient withdraws consent or is unable to comply with study procedures. 
7.2 
Duration of Follow-Up 
Patients will be followed for adverse events for 30 days after their last dose of study 
medication. However, if a patient experiences an adverse event >30 days after their last 
dose of study medication that is felt to be, in the opinion of the investigator, possibly, 
probably or definitely related to study therapy, the adverse event should be reported. 
NOTE: Pregnancy within 180 days for WOCBP and for 120 days for a female partner of 
child-bearing potential after the final study drug administration will be reported and 
followed per Section 8.6. 
Patients should be followed every 3 months from end of treatment for 2 years, then every 4 
months for 1 year, then every 6 months for 1 year, then annually for progression and survival 
until death or study closure (+/- 1 month) whichever comes first. Patients should be seen up 
to the 2 year point at the treating institution. If the patient is unable to be seen at the treating 
institution, copies of office visit notes including labs with local oncologist should be obtained 
until year 5 per schedule above. Initiation of all anticancer therapy for current remission and 
first anticancer therapy for relapse will be documented. 
If a patient is removed from treatment for reason(s) other than progression or full consent 
withdrawal, follow for survival/relapse until death or study closure. 
For patients who are registered with tissue submitted for the study and are FLT3 negative 
or other condition, no further information will be collected after baseline demographics, 
sample submission, sample results and final diagnosis. For eligible patients randomized to 
the trial, but do not receive any protocol therapy, baseline, safety [as applicable] and end of 
treatment follow-up information per Section 10 will also be collected. 
7.3 
Criteria for Removal from Study Treatment 
A genuine effort will be made to determine the reason(s) why a patient fails to return for the 
necessary visits or is discontinued from the trial, should this occur. It will be documented 
whether or not each patient completed the clinical study. If for any patient study treatment 
or observations were discontinued, the reason will be recorded on the appropriate electronic 
case report form. Reasons that a patient may discontinue treatment in a clinical study are 
considered to constitute one of the following: 
1. If the patient has already initiated midostaurin or gilteritinib therapy and CNS 
involvement is detected, the patient may either come off protocol therapy immediately 
or complete therapy through Day 21 then will be removed from protocol treatment. 
2. Failure to achieve CR or CRi after 2 cycles of induction. 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
34 
3. Patient requires treatment with therapy not allowed per protocol, or patient goes on to 
receive HSCT. 
4. Recurrence of disease or documented progression of disease. 
5. Intercurrent illness that prevents further administration of treatment per investigator 
discretion. 
6. Unacceptable adverse events. 
7. Investigator and/or patient discontinue chemotherapy. 
8. Pregnancy. 
9. Develops a second malignancy (except for non-melanoma skin cancer or cervical 
carcinoma in-situ) that requires treatment, which would interfere with this study. 
10. The patient may choose to withdraw from the study at any time for any reason. 
11. General or specific changes in the patient's condition that render the patient 
unacceptable for further treatment in the judgment of the investigator. 
12. Severe non-compliance to protocol as judged by the investigator. 
13. Lost to follow-up. 
14. Death. 
15. Closure of study by PrECOG. 
Patients who discontinue study treatment early should be followed for response 
assessments and survival, if possible. Follow-up will continue per Section 10, as applicable. 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
35 
8 
Adverse Event Reporting 
8.1 
Collection of Safety Information 
Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of 
a pre-existing medical condition in a patient administered a medicinal product in a clinical 
investigation and which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (e.g., including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a product 
(investigational or marketed), whether or not considered related to the product 
(investigational or marketed). 
After either informed consent, but prior to initiation of induction, only AEs/SAEs caused by 
a protocol-mandated intervention not considered standard of care will be collected (e.g., 
SAEs related to invasive procedures such as biopsies). Please note, if induction is started 
prior to randomization, AE/SAE collection will start at time of randomization. After the 
initiation of treatment on-study, any changes from baseline which meet (CTCAE V 5.0) 
Grade ≥ 3 AEs and SAEs must be recorded on the appropriate page of the electronic Case 
Report Form (eCRF). In addition, AEs less than Grade 3 that meet dose interruption, 
reduction or discontinuation criteria per Section 6.1 must also be recorded, including: ≥ 
Grade 2 pancreatitis, QTc interval, PRES, cerebellar toxicity of any grade, creatinine >2 
mg/dL and direct or total bilirubin ≥ 2 mg/dL. All laboratory results required by protocol 
(Section 10) will be recorded directly on the laboratory eCRF pages. Per Sections 8.2 to 8.7 
additional events will be recorded as AEs and/or SAEs (meeting definitions) on the 
appropriate eCRF. 
If known, the diagnosis of the underlying illness or disorder should be recorded, rather than 
individual symptoms. The following information should be included for all documented AEs: 
date of onset and resolution, severity of the event; the investigator’s opinion of the 
relationship to study drug (see definitions below); intervention or treatment required for the 
AE; action taken with study drug; cause of the event (if known); and information regarding 
resolution/outcome. 
If the Grade ≥ 3 laboratory abnormality is a sign of a disease or syndrome (e.g., alkaline 
phosphatase and bilirubin 5x the ULN associated with cholecystitis), only the diagnosis 
(e.g., cholecystitis) needs to be recorded on the Adverse Event eCRF. 
If the Grade ≥ 3 laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded as an AE or SAE on the eCRF. If the laboratory 
abnormality can be characterized by a precise clinical term in CTCAE Version 5.0, the 
clinical term should be recorded as the AE or SAE. For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as “hyperkalemia”. 
Observations of the same Grade ≥ 3 laboratory abnormality from visit to visit should not be 
repeatedly recorded unless their severity, seriousness, or etiology changes. 
Severity 
The categories and definitions of severity used for clinical trials AEs are defined in the NCI’s 
Common Terminology Criteria (CTCAE) V5.0 (http://www.ctep.cancer.gov). 
Attribution 
The following categories and definitions of causal relationship or attribution to study drug 
should be used to assess Adverse Events: 
• Definite: There is a reasonable causal relationship between the study drug and the event. 
The event response to withdrawal of study drug (dechallenge) and recurs with 
rechallenge, if clinically feasible. 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
36 
• Probable: There is a reasonable causal relationship between the study drug and the 
event. The event responds to dechallenge. Rechallenge is not required. 
• Possible: There is a reasonable causal relationship between the study drug and the 
event. Dechallenge information is lacking or unclear. 
• Unlikely: There is doubtful causal relationship between the study drug and the event. 
• Unrelated: There is clearly not a causal relationship between the study drug and the 
event or there is a causal relationship between another drug, concurrent disease, or 
circumstances and the event. 
Categories ‘definite’, ‘probable’ and ‘possible’ are considered study drug related. Categories 
‘unlikely’ and ‘unrelated’ are considered not study drug-related. 
The development of a new cancer should be regarded as an AE. New cancers are those 
that are not the primary reason for administration of study treatment and have been 
identified after inclusion of the patient into the clinical study. 
AEs related to cytarabine, daunorubicin, gilteritinib or midostaurin should be 
followed for 30 days after last dose of study therapy until ≤ grade 1 or stabilization, 
and reported as SAEs if they become serious. Any AE’s (serious or not) that occur 
more than 30 days after the last dose of study therapy but that are deemed to be at 
least possibly related to study therapy shall be reported. 
NOTE: Pregnancy within 180 days for WOCBP and for 120 days for a female partner of 
child-bearing potential after the final study drug administration will be reported and 
followed per Section 8.6. 
8.2 
Serious Adverse Events (SAEs) 
A serious AE is any untoward medical occurrence occurring after initiation of study 
treatment or that at any dose: 
• 
results in death (i.e., the adverse event actually causes or leads to death) 
• 
is life-threatening (defined as an event in which the study patient was at risk of death at 
the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe) 
• 
requires inpatient hospitalization or causes prolongation of existing hospitalization 
• 
results in persistent or significant disability/incapacity 
• 
is a congenital anomaly/birth defect 
• 
is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the patient or may require 
intervention (e.g., medical, surgical) to prevent one of the other serious outcomes listed 
in the definition above). 
Examples of such events include, but are not limited to, intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalization. 
8.3 
Drug-Induced Liver Injury Adverse Events 
The following adverse events must be reported to PrECOG as Serious Adverse Events, 
irrespective of regulatory seriousness criteria. 
● 
Liver specific adverse events leading to study (study drug) discontinuation 
● 
Hepatic laboratory abnormalities meeting potential Drug-induced Liver Injury criteria 
including: 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
37 
○ 
Any potential Hy's Law case*, including those where review and adjudication 
concluded they did not meet the criteria 
○ 
All patients who died of hepatic illness 
○ 
All patients who discontinued trial drugs for hepatotoxicity, including patients 
with abnormalities consistent with protocol-specified stopping rules 
○ 
ALT and/or AST>3x ULN AND Total Bilirubin >2x ULN 
*Criteria for Hy’s Law35 
Hy’s law is defined as drug-induced jaundice caused by hepatocellular injury, without a 
significant obstructive component, has a high rate of bad outcomes, from 10% to 50% 
mortality (or transplant). The 2 “requirements” for Hy’s Law are: 
- 
Evidence that a drug can cause hepatocellular-type injury, generally shown by an 
increase in transaminase elevations higher than 3x ULN (2x ULN elevations are too 
common in treated and untreated patients to be discriminating). 
- 
Cases of increased bilirubin (at least 2x ULN) with concurrent transaminase elevations 
at least 3x ULN and no evidence of intrahepatic or extrahepatic bilirubin obstruction 
(elevated alkaline phosphatase) or Gilbert’s syndrome. 
8.4 
SAE Reporting Requirements 
Serious adverse events (SAE) are defined above. The investigator should inform PrECOG 
of any SAE within 24 hours of being aware of the event. The date of awareness should be 
noted on the report. This must be documented on the SAE form provided for this trial. This 
form must be completed and supplied to PrECOG within 24 hours or 1 business day at the 
latest on the following working day. The initial report must be as complete as possible, 
including details of the current illness and (serious) adverse event, and an assessment of 
the causal relationship between the event and the investigational product(s). Information 
not available at the time of the initial report (e.g., an end date for the adverse event or 
laboratory values received after the report) must be documented on a follow-up SAE report 
form. A final report to document resolution of the SAE is required. The investigator is 
responsible for following all SAEs until resolution, until the subject returns to baseline status, 
or until the condition has stabilized with the expectation that it will remain chronic, even if 
this extends beyond study participation. A copy of the transmission confirmation of the SAE 
report should be attached to the SAE and retained in the patient records. 
Collection of complete information concerning SAEs is extremely important. Full 
descriptions of each event will be followed. Thus, follow-up information which becomes 
available as the SAE evolves, as well as supporting documentation (e.g., hospital discharge 
summaries and autopsy reports), should be collected subsequently, if not available at the 
time of the initial report, and immediately sent using the same procedure as the initial SAE 
report. 
SAEs should be scanned and emailed to PrE0905SAE@qdservices.com as per the 
instructions found in study materials provided to the investigator site. 
 
Medical Monitor 
During normal business hours: 
(8:30 am-5:00 pm EST): 
Phone: 610-354-0404 
After normal business hours: 
Phone: 
 
 
Manager, Clinical Safety 
During normal business hours: 
(8:30 am-5:00 pm EST): 
Phone: 610-354-0404 
After normal business hours: 
Cell: 
 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
38 
PrECOG will have accountability for both initial and follow-up reporting of SAEs to the 
investigational product manufacturer and regulatory authorities within appropriate timelines. 
Investigators should also report event(s) to their IRB as required. 
All SAEs, regardless of causality, must be collected which occur within 30 days of last dose 
of study treatment. This includes all deaths within 30 days of last dose of cytarabine, 
daunorubicin, gilteritinib or midostaurin regardless of attribution. In addition, the Investigator 
should notify PrECOG or designee of any SAE that may occur after this time period which 
they believe to be definitely, probably or possibly related to investigational product. 
NOTE: After study closure, study-drug related SAEs should be reported voluntarily by the 
treating physician directly to the manufacturer. 
Serious adverse event reporting to regulatory authorities and all participating investigators 
will be conducted by PrECOG (or designee) in accordance with 21CFR312.32, local 
requirements and international regulations, as appropriate. FDA reporting requirement 
timelines will be followed. PrECOG will also concurrently forward any such reports to 
Astellas. 
8.5 
Reporting of Other Second Primary Cancers 
New cancers are those that are not the primary reason for administration of study treatment 
and have been identified after inclusion of the patient into the clinical study. 
All cases of new primary cancers that occur during or after protocol treatment must be 
reported to PrECOG on a Second Primary Cancer form within 30 days of diagnosis, 
regardless of relationship to protocol treatment. Secondary primary malignancies should 
also be reported as a SAE. The SAE form is not for use for reporting recurrence or 
development of metastatic disease. A copy of the pathology report, if applicable, should be 
sent, if available. 
NOTE: Once data regarding survival and remission status are no longer required by the 
protocol, no follow-up data should be submitted. 
8.6 
Procedures in Case of Pregnancy 
Prior to study enrollment, women of childbearing potential (WOCBP-not surgically sterilized 
and between menarche and 1 year post menopause) and male patients with a female 
partner of childbearing potential must be advised of the importance of avoiding pregnancy 
during trial participation and the potential risk factors for an unintentional pregnancy, 
documented in the informed consent. In addition, all WOCBP should be instructed to contact 
the Investigator immediately if they suspect they might be pregnant (e.g., missed or late 
menstrual period) at any time during study participation. 
Pregnancy of a female patient or the female partner of a male patient occurring while the 
patient is receiving study drug or within 180 days for female patient or 120 days for female 
partner after the patient’s last dose of study drug will be reported to PrECOG on a Pregnancy 
Form within 24 hours of the investigator’s knowledge of the pregnancy. 
All reports of congenital abnormalities/birth defects and spontaneous miscarriages should 
also be reported and handled as SAEs. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal 
birth including health of the newborn or congenital abnormality) must be followed and 
documented on the Pregnancy Form even if the subject was discontinued from the study 
treatment. Should pregnancy occur during a subject’s participation, the subject will 
immediately be discontinued from the treatment and followed per protocol. 
The study-specific Pregnancy Form can be found in the Study Reference Manual. 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
39 
8.7 
Reporting Guidelines in the Case of Overdose 
In the event of an overdose with any of the drugs on-study (cytarabine, daunorubicin, 
gilteritinib [defined as more than 300 mg for a single dose] or midostaurin), defined as any 
dose higher than the patient allocated dose in the study, unless otherwise noted, should be 
captured as an adverse event. Both symptomatic and non-symptomatic overdose must be 
reported. For any accidental or intentional overdose with the study treatment that is 
symptomatic, even if not fulfilling a seriousness criterion, a SAE form should also be 
completed and reported to PrECOG within 24 hours of the investigator’s knowledge of the 
overdose. 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
40 
9 
Measurement of Effect36 
Response assessments will require a bone marrow aspirate/biopsy to be performed. The 2017 
European LeukemiaNet (ELN) recommendations will be used to assess response.36 
End of Cycle = Count Recovery 
A bone marrow aspirate/biopsy is required on all patients on Day 21 (+/- 1 day window; delays due 
to holidays, weekends, or other unforeseen circumstances will be permitted) after initiating the first 
cycle of induction. Patients who have residual disease will be eligible to receive a second cycle of 
induction identical to the first (Section 10). 
A repeat bone marrow aspirate/biopsy should be done to assess for response and MRD upon count 
recovery (Absolute Neutrophil Count (ANC) ≥ 1000/mm3, platelets ≥ 100,000/mm3) but no later than 
Day 60 after initiation of the cycle of induction therapy (i.e., Day 60 or patients who receive one cycle 
of induction and Day 84-105 for patients that receive 2 cycles of induction. (MRD sample will be 
obtained by Day 60 on all patients even if counts have not recovered. The only exception is a patient 
who has been declared a relapse based on blood counts). 
Patients who do not achieve a CR or CRi by Day 60 after initiation of the last cycle of induction 
therapy will be removed from study. 
Patients are not eligible to proceed to Consolidation unless bone marrow samples are obtained for 
MRD at the time of CR/CRi. 
A bone marrow aspirate/biopsy is also required at the end of the first Consolidation cycle to assess 
disease and MRD status. 
9.1 
Complete Remission (CR) 
Complete remission is defined as the following: 
• 
Bone marrow blasts <5% 
• 
Absence of circulating blasts and blasts with Auer rods 
• 
Absence of extramedullary disease 
• 
ANC ≥ 1000/mm3 
• 
Platelet count ≥ 100,000/mm3 
9.2 
Complete Remission with incomplete hematologic recovery (CRi) 
Requires that all the same response criteria in peripheral blood and bone marrow as CR 
with the exception of the following: 
• 
Residual neutropenia (<1000/mm3) or 
• 
Residual thrombocytopenia ( <100,000/mm3 independent of platelet transfusions) 
9.3 
Morphologic Leukemia-Free State (MLFS) 
• 
Bone marrow blasts <5% 
• 
Absence of blast with Auer rods 
• 
Absence of extramedullary disease 
• 
No hematologic recovery required 
Marrow should not merely be “aplastic”. At least 200 cells should be enumerated or 
cellularity should be at least 10%. 
9.4 
Partial Remission (PR) 
• 
All hematologic criteria of CR 
• 
Decrease of bone marrow blast percentage to 5% to 25% 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
41 
• 
Decrease of pretreatment bone marrow blast percentage by at least 50% 
9.5 
Stable Disease 
Absence of CR, CRi, PR, MLFS; and criteria for PD not met. 
Period of stable disease should last at least 3 months. 
9.6 
Treatment Failure 
Primary Refractory Disease: No CR or CRi after 2 courses of intensive induction treatment 
or recovery with blasts/loss of CR/CRi within 28 days of documentation of initial CR/CRi. 
Exclude patients with death in aplasia or death due to indeterminate cause. 
Death in Aplasia: Deaths occurring ≥ 7days following completion of initial treatment while 
cytopenic; with an aplastic or hypoplastic bone marrow obtained within 7 days of death, 
without evidence of persistent leukemia. 
Death from Indeterminate Cause: Deaths occurring before completion of therapy, or <7 days 
following its completion; or deaths occurring ≥ 7 days following completion of initial therapy 
with no blasts in the blood, but no bone marrow examination available. 
9.7 
Progressive Disease (PD) 
Evidence for an increase in bone marrow blast percentage and/or increase of absolute blast 
counts in the blood: 
• 
>50% increase in marrow blasts over baseline (a minimum 15% point increase is 
required in cases with <30% blasts at baseline; or persistent marrow blast percentage 
of >70% over at least 3 months; without at least a 100% improvement in ANC to 
500/mm3 and/or platelet count to >50,000/mm3 non-transfused); or 
• 
>50% increase in peripheral blasts (White Blood Count (WBC) × % blasts) to 
>25 000/mm3 (in the absence of differentiation syndrome); or 
• 
New extramedullary disease 
“Progressive disease” is usually accompanied by a decline in ANC and platelets and 
increased transfusion requirement and decline in performance status or increase in 
symptoms. 
9.8 
Relapse 
Relapse following CR/CRi is defined as (only if this happens >28 days after CR/CRi): 
Bone marrow blasts ≥ 5%; or reappearance of blasts in the blood; or development of 
extramedullary disease. 
 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
42 
10. 
Study Parameters 
1. Pre-study assessments should be done ≤ 48 hours prior to randomization (except for bone marrow biopsy, thyroid function testing, 
pregnancy testing, ECG and left ventricular ejection fraction which can be done ≤ 2 weeks). 
Procedures 
Pre-
screen 
Screening/ 
Prior to 
Randomization 
Induction* 
Consolidation* 
End of 
Treatment24 
Follow-
Up25 
Daily 
Weekly 
Day 21 
from Start 
of Cycle 1 
Induction 
Prior to 2nd 
Induction, if 
applicable 
End of 
Induction 
Prior to Each 
Consolidation 
Cycle 
Weekly 
End of 
Consolidation 
Cycle 1 
Written Informed 
Consent 
X1 
X 
 
 
 
 
 
 
 
 
 
 
Disease 
Characteristics2 
 
X 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical 
History 
 
X 
 
 
 
 
 
 
 
 
 
 
Assessment of Baseline 
Signs & Symptoms 
 
X 
 
 
 
 
 
 
 
 
 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
 
X 
X3 
 
 
X 
 
X 
X3 
 
X 
 
Vital Signs 
(Temperature, Pulse, 
Blood Pressure) 
 
X 
X3 
 
 
X 
 
X 
 
 
X 
 
Weight4 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
BSA 
 
X 
 
 
 
X 
 
X 
 
 
 
 
Performance Status 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
CBC/Differential/ 
Platelets4,5 
 
X 
X6 
 
 
X 
 
X 
X6 
 
X 
 
Chemistry4,7 
 
X 
 
X8 
 
X 
 
X 
X8 
 
X 
 
Liver Functions4,9 
 
X 
 
X8 
 
X 
 
X 
X8 
 
X 
 
Thyroid Function Tests 
(T4 & TSH)10 
 
X 
 
 
 
 
 
 
 
 
X 
 
Serum Pregnancy 
Test11 
 
X 
 
 
 
 
 
 
 
 
 
 
Left Ventricular Ejection 
Fraction (MUGA or 
ECHO)12 
 
X 
 
 
 
X12 
 
 
 
 
 
 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
43 
Procedures 
Pre-
screen 
Screening/ 
Prior to 
Randomization 
Induction* 
Consolidation* 
End of 
Treatment24 
Follow-
Up25 
Daily 
Weekly 
Day 21 
from Start 
of Cycle 1 
Induction 
Prior to 2nd 
Induction, if 
applicable 
End of 
Induction 
Prior to Each 
Consolidation 
Cycle 
Weekly 
End of 
Consolidation 
Cycle 1 
12-Lead ECG 
(QTcF Interval)4 
 
X13 
 
X14 
X14 
X14 
 
 
X14 
 
X15 
 
Local Bone Marrow 
Aspirate/Biopsy 
(Mandatory) 
X2 
 
 
 
X16 
 
X17 
 
 
X 
X18 
Optional 
X19 
Research Bone Marrow 
Samples Submission 
(Mandatory)20 
X1 
 
 
 
 
 
X 
 
 
X 
 
X19 
Protocol Therapy 
Administration21 
 
 
X 
 
 
 
 
X 
 
 
 
 
Concomitant 
Medications22 
 
X 
X3 
 
 
X 
 
X 
 
 
X 
 
Adverse Events 
Assessment 
 
 
X3 
 
 
X 
 
X 
 
 
X23 
 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
X 
* 
Scheduled Visits: Delay due to holidays, weekends, bad weather or other unforeseen circumstances will be permitted. 
** 
If prophylactic lumbar puncture is performed, recommend scheduling so results are available prior to Day 8 or wait until Day 21 to perform. 
1 
Any patient undergoing bone marrow biopsy with suspicion of or known diagnosis of AML will be asked to sign a Prescreening Consent in order to obtain 
baseline immunophenotyping and determination/confirmation of FLT3 status and obtain research samples for the study prior to randomization. FLT3 (includes 
signal ratio), NPM1 and DNMT3 mutation status will be performed on all patients. These tests will be completed at Central Labs. See Section 13.1, Invivoscribe 
Lab Manual and PrE0905 Lab Manual for details. FLT3 and NPM1 mutation status results must be available on all patients. Patients must have known 
FLT3 mutation and will be stratified according to TKD vs. ITD FLT3 mutation. Patients with FLT3-ITD mutation will undergo further stratification with NPM1 
mutation status (positive vs. negative) and signal ratio (high [≥ 0.5] vs. low [<0.5] of FLT3 Wild Type). 
For patients who are registered with tissue submitted for the study and are FLT3 negative or other condition, no further information will be collected after baseline 
demographics, sample submission, sample results and final diagnosis. 
2. 
Record date of diagnosis (date of diagnostic bone marrow biopsy), primary tumor type, histology, cytogenetics and molecular markers. 
3 
Induction: Daily if admitted to hospital, otherwise weekly until count recovery. 
Consolidation: May be done locally after Day 8 visit per institutional guidelines. 
4. 
Per Study Parameters and as clinically indicated. 
5 
CBC with differential and platelet count which includes WBC, ANC, Platelets, Hemoglobin, and Hematocrit. Additionally, required within 24 hours prior to each 
cycle of chemotherapy. 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
44 
6 
Induction: Differential daily until disappearance of peripheral blasts, then twice weekly at nadir, after peripheral blasts gone and while WBC <500. If the patient 
is discharged prior to recovery of WBC (≥ 500), obtain differential twice weekly until end of induction, then per institutional guidelines until consolidation starts. 
Consolidation: Twice weekly or per institutional guidelines. 
7 
BUN/creatinine, uric acid, sodium, potassium, chloride, glucose, calcium, magnesium, and phosphorus. Additionally, required within 24 hours prior to each cycle 
of chemotherapy. 
8 
Induction: Twice weekly. 
Consolidation: Weekly or per institutional guidelines. 
9 
AST, ALT, and total bilirubin. If total bilirubin ≥ 2, obtain direct bilirubin (if direct bilirubin ≥ 2, refer to Section 6.1 for Dose Modifications/Interruptions). Additionally, 
required within 24 hours prior to each cycle of chemotherapy. 
10 Thyroid Function test results not required for randomization. 
11 Required for sexually active females of child-bearing potential. 
12 LVEF must be obtained before initiating second induction cycle (if applicable) and must use same method as initial assessment. 
13 Perform 12-lead ECG in triplicate (3 separate ECGs recorded at least 5 minutes apart) following a 10 minute resting period. Patient may not have QTcF interval 
>500 msec or Long QT Syndrome. 
Calculation of QTc interval using the Fridericia formula: 
https://qxmd.com/calculate/calculator_48/ecg-corrected-qt37,38,39 
14 Perform 12-lead ECG in triplicate (3 separate ECGs recorded at least 5 minutes apart) following a 10 minute resting period prior to gilteritinib or midostaurin 
administration (ECG within 1 hour of dosing preferred). The mean QTcF of the triplicate ECG tracings will be used for final treatment decisions and AE reporting. 
If the mean of the triplicate QTcF is >500 msec, then triplicate ECGs will be repeated (within 2 hours). If the repeat ECGs confirm a mean QTcF >500 msec, 
refer to Section 6.1.2 and Section 6.1.3 for further guidance on treatment decision. In addition, on Cycle 1, Day 15 if QTcF is increased >30 msec over screening, 
repeat ECG on Day 16 and refer to Section 6.1.2 for further guidance on treatment decision. 
Induction (First Induction) 
Day 8, Day 15 and Day 21 
Second Induction and Consolidation 
Day 8 of each cycle 
See footnote 13 for Calculation of QTc interval using the Fridericia formula. 
15 Perform 12-lead ECG in triplicate (3 separate ECGs recorded at least 5 minutes apart) following a 10 minute resting period. 
See footnote 13 for Calculation of QTc interval using the Fridericia formula. 
16 +/- 1 day window (Delays due to holidays, weekends, or other unforeseen circumstances will be permitted). 
17 For patients that receive 1 cycle of induction, no later than Day 60 after initiation of first cycle of induction therapy. For patients that receive 2 cycles of induction, 
no later than Day 60 after initiation of the second cycle of induction therapy (i.e., Day 84-105). [MRD sample will be obtained by Day 60 on all patients even if 
counts have not recovered. The only exception is a patient who has been declared a relapse based on blood counts.] 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
45 
18 Optional, after last cycle of consolidation per institutional guidelines. 
19 Optional, at time of relapse, bone marrow samples are requested to be sent for correlative studies (Section 13.1). 
20 Mandatory Research Bone Marrow Samples: See Section 13.1, Invivoscribe Lab Manual and PrE0905 Lab Manual for details. 
Prescreening 
Invivoscribe: One 4 mL sodium heparin green top tube 
- 
If bone marrow sample (preferred) is not available, then one 4 mL Sodium Heparin green top tube of peripheral blood will be allowed if patient 
has any circulating blasts. 
CBPF: 
Two 10 mL EDTA tubes 
- 
If diagnostic bone marrow was done prior to study enrollment or patient is inaspirable, then two 10 mL EDTA tubes of peripheral blood will be 
allowed if patient has any circulating blasts. 
End of Induction (First and Second Induction, as applicable) 
Invivoscribe: If FLT3 ITD+, one 4 mL EDTA tube (bone marrow) 
CBPF: 
All patients (ITD+ and/or TKD+), one 10 mL EDTA tube (bone marrow) 
If FLT3 TKD+, one additional 10 mL EDTA tube (bone marrow) 
NOTE: Patients are not eligible to proceed to consolidation unless bone marrow samples are obtained for MRD at time of CR/CRi. 
End of First Cycle of Consolidation 
Invivoscribe: If FLT3 ITD+, one 4 mL EDTA tube (bone marrow) 
CBPF: 
All patients (ITD+ and/or TKD+), one 10 mL EDTA tube (bone marrow) 
If FLT3 TKD+, one additional 10 mL EDTA tube (bone marrow) 
Relapse (OPTIONAL) 
CBPF: Two 10 mL EDTA tubes (bone marrow) 
Optional: Any leftover tissue banked for future research. 
21 INDUCTION: 
Standard of care induction 7+3 chemotherapy may start prior to randomization using same regimen and dose as defined in Section 5.2.1 while awaiting 
prescreening test results. 
Arm A (7+3 + Gilteritinib) 
• 
Cytarabine 100 mg/m2/day will be administered by continuous IV infusion for a total of 7 days beginning Day 1 
• 
Daunorubicin 90 mg/m2/day will be administered IV per package insert or institutional guidelines or over 30-60 minutes Days 1,2,3 (45 mg/m2/day if 
receives second cycle of induction) 
• 
Gilteritinib 120 mg orally QD x 14 days starting on day 8 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
46 
If second cycle of induction is needed, treatment will begin after Day 28 (i.e., ≥ 7 days after completing gilteritinib) but no later than Day 45. 
ARM B (7+3) + Midostaurin 
• 
Cytarabine 100 mg/m2/day will be administered by continuous IV infusion for a total of 7 days beginning Day 1 
• 
Daunorubicin 90 mg/m2/day will be administered IV per package insert or institutional guidelines or over 30-60 minutes Days 1,2,3 (45 mg/m2/day if 
receives second cycle of induction) 
• 
Midostaurin 50 mg orally BID x 14 days beginning on day 8 
If second cycle of induction is needed, treatment will begin after Day 24 (i.e., ≥ 3 days after completing midostaurin) but no later than Day 45. 
If there is a delay in starting FLT3 inhibitors in Arm A or Arm B (due to obtaining drug, i.e. insurance, formulary, etc.), the FLT3 inhibitor will need to stop after 
Day 21 dose (i.e., Day 21 or Day 22 [if FLT3 inhibitor started on Day 9]). No missed doses will be made up. 
Prophylaxis with intrathecal chemotherapy is allowed prior to or during induction. 
See Section 5 for dosing instructions and additional information for gilteritinib and midostaurin administration and Section 6 for dose delays/modifications. If CR 
or CRi is not achieved, a second induction cycle of therapy may be administered. 
NOTE: Patients are not eligible to proceed to consolidation unless bone marrow samples are obtained for MRD at time of CR/CRi. 
CONSOLIDATION: 
ARM A 
• 
Cytarabine 3 g/m2*  over approximately 1-3 hours every 12 hours (+/- 2 hour window)  on days 1,3,5 or days 1-3 for a total of 6 doses for up to 4 cycles 
• 
Gilteritinib 120 mg orally QD x 14 days beginning on day 8 of each cycle (up to 4 cycles) 
ARM B 
• 
Cytarabine 3 g/m2* over approximately 1-3 hours every12 hours (+/- 2 hour window)  on days 1,3,5 or days 1-3 for a total of 6 doses for up to 4 cycles 
• 
Midostaurin 50 mg orally BID x 14 days beginning on day 8 of each cycle (up to 4 cycles) 
* For patients age ≥ 55 or patients with decreased creatinine clearance recommend reducing consolidation cytarabine dose to 1.5 g/m2. 
If there is a delay in starting FLT3 inhibitors in Arm A or Arm B (due to obtaining drug, i.e. insurance, formulary, etc.), the FLT3 inhibitor will need to stop after 
Day 21 dose. No missed doses will be made up. 
Prophylaxis with intrathecal chemotherapy is allowed prior to or during consolidation. 
See Section 5 for dosing instructions and additional information for gilteritinib and midostaurin administration and Section 6 for dose delays/modifications. 
NOTE: Patients deemed suitable by the treating investigator may proceed to allogeneic TRANSPLANT after induction or after 0-4 cycles of consolidation. 
Patients will go off treatment at the time of transplant or any non-protocol leukemia directed therapy after completion of the end of treatment visit. 
22 Please review all concomitant medications. Section 6.2.2 for medications not permitted and Section 6.2.3 for medications to use with caution. Only record 
concomitant medications for SAE and/or AESI in eCRF. 
23 Patients will be followed for adverse events for 30 days after their last dose of study medication. However, an adverse event occurring at any time after 
discontinuation of study therapy that is felt to be at least possibly related to study therapy should be recorded. 
NOTE: Pregnancy within 180 days for WOCBP and for 120 days for a female partner of child-bearing potential after the final study drug administration will be 
reported and followed per Section 8.6. 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
47 
24 Upon count recovery after last cycle of chemotherapy and completion of gilteritinib or midostaurin. 
25 Every 3 months from end of treatment for 2 years, then every 4 months for 1 year, then every 6 months for 1 year, then annually for progression and survival 
until death or study closure (+/- 1 month) whichever comes first. Patients should be seen up to the 2 year point at the treating institution. If the patient is unable 
to be seen at the treating institution, copies of office visit notes including labs with local oncologist should be obtained until year 5 per schedule above. Initiation 
of all anticancer therapy for current remission and first anticancer therapy for relapse will be documented. If patient is removed from treatment for reason(s) 
other than progression or full consent withdrawal, follow for relapse/survival until death or study closure. 
NOTE: For patients who are registered with tissue submitted for the study and are FLT3 negative, no further information or other condition will be collected 
after baseline demographics, sample submission, sample results and final diagnosis. For eligible patients randomized to the trial, but do not receive 
any protocol therapy, baseline, safety [as applicable] and end of treatment follow-up information will also be collected. 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
48 
11 
Drug Formulation and Procurement 
11.1 
Gilteritinib27 
Please refer to the current Investigator’s Brochure for additional information. 
11.1.1 
Other Names 
 
11.1.2 
Classification 
Gilteritinib is a tyrosine kinase inhibitor under development for the treatment of AML. 
Gilteritinib has an inhibitory effect on FMS-like tyrosine kinase 3 (FLT3), AXL, 
leukocyte receptor tyrosine kinase (LTK) and anaplastic lymphoma kinase (ALK). 
11.1.3 
Storage and Stability 
Gilteritinib is an oral drug that is available in a 40 mg tablet. In addition to the active 
ingredient, gilteritinib 40 mg tablets contain well-characterized excipients. Gilteritinib 
tablets are round light-yellow, debossed, film-coated tablets. The tablets are 
contained within a high-density polyethylene bottle. Each bottle of gilteritinib 
contains 30 tablets. 
The storage conditions of gilteritinib tablets 40 mg packed into bottles is 20-25°C 
(68-77°F) with excursions permitted to 15°C and 30°C (59°F and 86°F). Do not 
freeze. Protect from light. 
11.1.4 
Dose Specifics 
Gilteritinib 120 mg tablets (three 40 mg tablets) are taken once daily by mouth on 
days 8-21. Patients will be instructed to take the daily gilteritinib with water as close 
to the same time each morning as possible. Tablets should not be chewed, crushed 
or broken. 
Gilteritinib will be self-administered at home when patients are not hospitalized, and 
when scheduled for clinic visits. If a subject forgets to take a dose in the morning 
and within 6 hours of the planned dosing time, they should be instructed to take their 
dose. If the subject forgets to take their daily dose and more than 6 hours has passed 
the planned dosing time, they should be instructed to wait for the next morning to 
dose. If vomiting occurs after dosing, the subject should not receive another dose, 
but just wait until the next morning to dose. 
Sites should review the medication diary instructions at each visit. 
Dose reductions are permitted (Section 6). 
11.1.5 
Drug Interactions 
Treatment with concomitant drugs that are strong inducers of CYP3A and P-gp (e.g., 
rifampin, phenytoin, St. John’s Wort) are prohibited as they can decrease the plasma 
exposure of gilteritinib. Treatment with concomitant drugs that are strong inhibitors 
of CYP3A and P-gp (e.g., voriconazole, itraconazole, posaconazole, clarithromycin, 
erythromycin, captopril, carvedilol, ritonavir, azithromycin) should be avoided with 
the exception of antibiotics, antifungals and antivirals that are used as standard of 
care to prevent or treat infections. If CYP3A inhibitors are used concomitantly, 
patients should be monitored closely for AEs. 
Treatment with concomitant drugs that target serotonin 5HT2BR or sigma nonspecific 
receptor should be avoided with the exception of drugs that are considered 
absolutely essential for the care of the patient. 
 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
49 
Precaution should be used in treatment of gilteritinib with concomitant drugs that are 
substrates of P-gp (e.g., digoxin, dabigatran etexilate), BCRP (e.g. mitoxantrone, 
rosuvastatin) and OCT1 (e.g., metformin), since these transporters have been 
shown to be inhibited by gilteritinib in vitro. 
Caution should be used when treating patients concomitantly with gilteritinib and 
drugs that are known to prolong QT or QTc intervals. 
Additionally, patients with moderate or severe hepatic dysfunction as measured by 
laboratory tests should be closely monitored. 
11.1.6 
Agent Availability 
Gilteritinib will be supplied by Astellas and provided to PrECOG’s designated depot. 
PrECOG designated depot will distribute to sites. 
The initial supply of gilteritinib will be sent directly to the site upon site activation. As 
needed, gilteritinib may be requested by the Principal Investigator (or their 
authorized designees) at each participating institution. The investigator, or a 
responsible party designated by the investigator, must maintain a careful record of 
the receipt, disposition, and return/destruction (site’s drug destruction policy must 
be reviewed and approved by PrECOG before any study drug can be destroyed at 
a site) of gilteritinib. 
11.1.7 
Agent Ordering 
PrECOG will be responsible for ordering drug for re-supply to the site. 
Requests for shipments of gilteritinib to the PrECOG designated depot will be 
coordinated between PrECOG and Astellas. 
11.1.8 
Agent Accountability 
Gilteritinib will be stored in a secure location. Only authorized pharmacy and study 
staff will have access to this agent. Drug accountability will be reviewed by PrECOG. 
11.1.9 
Important Identified Risks 
11.1.9.1 
Posterior Reversible Encephalopathy Syndrome 
Posterior Reversible Encephalopathy Syndrome (PRES) is an important 
identified risk for gilteritinib. During the 2215-CL-0101 study, 2 patients, 
1 in the 120 mg dose group and 1 in the 200 mg dose group, developed 
PRES. Both events were assessed by the investigator to be possibly 
related to gilteritinib. One patient (120 mg) also experienced seizure. 
This patient continued taking gilteritinib. At the time of reporting, the 
PRES was resolving and the seizure had resolved. The other patient 
(200 mg) experienced seizure and confusional state (both events 
started 1 day prior to the onset of PRES). This patient discontinued 
gilteritinib and the events of PRES, seizure and confusional state 
resolved. 
Study drug discontinuation should be considered if PRES is diagnosed 
in patients receiving gilteritinib. 
11.1.9.2 
QT Prolongation 
Arrhythmias due to QT prolongation is a potential risk for gilteritinib. 
4.4% of relapse/refractory patients had a maximum post baseline QTcF 
interval >500 msec and approximately 8.8% of patients had a >60 msec 
change in their maximum QTc relative to baseline. Although clinically 
relevant QTc prolongation is not anticipated, additional eligibility criteria 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
50 
for enrollment (exclusion of patients with QTcF >500 ms, long QT 
syndrome, hypokalemia or hypomagnesemia) and ECG assessments 
during induction and consolidation have been implemented. 
11.1.9.3 
Other Identified Risks 
Other identified risks of gilteritinib include peripheral edema, increased 
blood creatine phosphokinase, myopathy, increased liver transaminase 
and diarrhea. 
11.1.10 
Important Potential Risks 
11.1.10.1 
Cardiac Failure 
Cardiac Failure has been reported in oncology clinical studies. Although 
these patients had other potentially contributing factors including a 
medical history of cardiac failure, prior chemotherapy treatment 
(anthracyclines) and concurrent bacteremia/sepsis, the role of 
gilteritinib could not be completely excluded. Patients should be 
monitored for signs and symptoms of cardiac failure while being treated 
with gilteritinib. 
11.1.10.2 
Pericarditis and Pericardial Effusions 
Pericarditis and pericardial effusions has been reported in oncology 
clinical studies. Some of these patients had concurrent lung infection or 
sepsis, the role of gilteritinib could not be completely excluded. Patients 
should be monitored for signs and symptoms of pericarditis and 
pericardial effusion while being treated with gilteritinib. 
11.1.10.3 
Pancreatitis Acute 
Pancreatitis and pancreatitis acute have been reported in oncology 
clinical studies. Patients should be monitored for signs and symptoms 
of pancreatitis and pancreatic acute while being treated with gilteritinib. 
11.1.11 
Other Potential Risks 
Other 
potential 
risks 
of 
gilteritinib 
include 
gastrointestinal 
obstruction, 
gastrointestinal perforation, gastrointestinal hemorrhage, differentiation syndrome 
and squamous cell skin carcinoma. 
Please refer to the current Investigator’s Brochure for additional information. 
11.1.12 
Overdose 
Neither the effects of overdose of gilteritinib (defined as more than 300 mg for a 
single dose) nor an antidote to overdose are known. In the case of an overdose, the 
patient should be closely monitored for adverse reactions and supportive treatment 
should be administered. 
11.2 
Midostaurin21 
Midostaurin will be obtained by the individual study sites as standard of care treatments from 
commercial stock. Please refer to the commercial package insert for full prescribing 
information. 
11.2.1 
Other Names 
RYDAPT 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
51 
11.2.2 
Classification 
Midostaurin is a kinase inhibitor. 
11.2.3 
Storage and Stability 
Midostaurin is an oral drug that is available in 25 mg capsules. 
Store in the original package to protect from moisture at 25°C (77°F); excursions 
permitted to 15°C to 30°C (59°F to 86°F). 
11.2.4 
Dose Specifics 
Midostaurin 50 mg (two 25 mg capsules) twice a day by mouth on days 8-21. 
Patients should take their doses at approximately the same time each day, and 
approximately 12 hours should elapse between the morning and evening doses. 
Each daily dose should be given with food and a glass of water (~240 mL). Patients 
should be instructed to swallow capsules whole and not open, break or chew 
capsules. If vomiting occurs, no re-dosing is allowed prior to the next scheduled 
dose. 
Dose interruptions are permitted (Section 6). 
11.2.5 
Drug Interactions 
Midostaurin is metabolized by CYP3A4 to active compounds. Co-administration 
of drugs which are potent inducers (e.g., phenytoin) or, especially, potent inhibitors 
(e.g., itraconazole) of this isoenzyme could decrease or increase midostaurin 
concentrations, and, potentially, decrease the effectiveness or increase toxicity, 
respectively. 
Potent CYP3A4 inhibitors are thought to represent the most significant potential 
for drug interactions with midostaurin (Appendix V). 
11.2.6 
Side Effects 
Please refer to the Package Insert. 
11.3 
Daunorubicin40,41,42 
Daunorubicin will be obtained by the individual study sites as standard of care treatments from 
commercial stock. Daunorubicin is generic and may be obtained from multiple manufacturers. 
Please refer to the commercial package insert for full prescribing information. 
11.3.1 
Other Names 
Daunorubicin hydrochloride, Daunomycin, Rubidomycin, Cerubidine 
11.3.2 
Classification 
Anthracycline topoisomerase inhibitor. 
11.3.3 
Storage and Stability 
Store unopened vials in refrigerator, 2° to 8°C (36° to 46°F). Store prepared solution 
for infusion at room temperature, 15° to 30°C (59° to 86°F) for up to 24 hours. 
Contains no preservative. Discard unused portion. Protect from light. 
11.3.4 
Dose Specifics 
Induction: Daunorubicin 90 mg/m2/day will be administered IV per package insert 
or institutional guidelines or over 30-60 minutes Days 1, 2, and 3 (45 mg/m2/day if 
receives second cycle of induction). 
 
 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
52 
If patient does not achieve CR or CRi after first cycle of induction, then a second cycle 
of induction will be given. If second induction is needed, treatment will begin after day 
24 for midostaurin (i.e., ≥ 3 days after completing midostaurin) and day 28 for 
gilteritinib (i.e., ≥ 7 days after completing gilteritinib). 
Dose modifications are permitted (Section 6). 
11.3.5 
Preparation 
Daunorubicin is commercially available. Preparation will be per package insert and 
institutional guidelines. 
11.3.6 
Drug Interactions 
Use of daunorubicin in a patient who has previously received doxorubicin increases 
the risk of cardiotoxicity. Daunorubicin should not be used in patients who have 
previously received the recommended maximum cumulative doses of doxorubicin 
or daunorubicin. Cyclophosphamide used concurrently with daunorubicin may also 
result in increased cardiotoxicity. 
Hepatotoxic medications may impair liver function and increase the risk of toxicity. 
Daunorubicin may decrease the effect of ciprofloxacin absorption by altering the 
intestinal mucosa. 
11.3.7 
Side Effects 
Please refer to Package Insert. 
11.4 
Cytarabine43,44 
Cytarabine will be obtained by the individual study sites as standard of care treatments from 
commercial stock. Cytarabine is generic and may be obtained from multiple manufacturers. 
Please refer to the commercial package insert for full prescribing information. 
11.4.1 
Other Names 
Cytosar-U‚ Ara-C, Arabinosyl, cytosine arabinoside 
11.4.2 
Classification 
Antimetabolite. 
11.4.3 
Storage and Stability 
Store at 20°C to 25°C (68°F to 77°F). Protect from light. 
The dry powder is stored at room temperature. After reconstitution, cytarabine is 
stable for 7 days at room temperature and 15 days refrigerated. Solutions with a 
slight haze should be discarded. 
11.4.4 
Dose Specifics 
Induction: Cytarabine 100 mg/m2/day will be administered by continuous IV infusion 
for a total of 7 days beginning Day 1. 
If patient does not achieve CR or CRi after first cycle of induction, then a second cycle 
of induction will be given. If second induction is needed, treatment will begin after day 
24 for midostaurin (i.e., ≥ 3 days after completing midostaurin) or day 28 for gilteritinib 
(≥ 7 days after completing gilteritinib). 
Consolidation: Cytarabine 3 g/m2* over approximately 1-3 hours every 12 hours 
(+/- 2 hour window) on days 1, 3, and 5 or days 1-3 for a total of 6 doses for up to 4 
cycles. 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
53 
* For patients age ≥ 55 or patients with decreased creatinine clearance recommend 
reducing consolidation cytarabine dose to 1.5 g/m2. 
Dose interruptions are permitted (Section 6). 
11.4.5 
Preparation 
Cytarabine is commercially available. Preparation will be per package insert and 
institutional guidelines. 
11.4.6 
Drug Interactions 
Reversible decreases in steady-state plasma digoxin concentrations and renal 
glycoside excretion were observed in patients receiving beta-acetyldigoxin and 
chemotherapy regimens containing cyclophosphamide, vincristine and prednisone 
with or without cytarabine injection or procarbazine. 
Steady-state plasma digitoxin concentrations did not appear to change. Therefore, 
monitoring of plasma digoxin levels may be indicated in patients receiving similar 
combination chemotherapy regimens. The utilization of digitoxin for such patients 
may be considered as an alternative. 
An in vitro interaction study between gentamicin and cytarabine showed a cytarabine 
related antagonism for the susceptibility of K. pneumoniae strains. This study 
suggests that in patients on cytarabine being treated with gentamicin for a K. 
pneumoniae infection, the lack of a prompt therapeutic response may indicate the 
need for re-evaluation of antibacterial therapy. 
Clinical evidence in one patient showed possible inhibition of fluorocytosine efficacy 
during therapy with cytarabine injection. This may be due to potential competitive 
inhibition of its uptake. 
11.4.7 
Side Effects 
Please refer to Package Insert. 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
54 
12 
Statistical Considerations 
12.1 
Study Design & Sample Size Considerations 
This is a randomized, open-label Phase II study comparing gilteritinib to midostaurin in patients 
receiving standard induction therapy with cytarabine and daunorubicin in FLT3 mutated AML. 
Patients will be stratified according to FLT3-TKD vs. FLT3-ITD mutation. Patients with FLT3-
ITD mutation will undergo further stratification with NPM1 mutation status (positive vs. 
negative) and signal ratio (high [≥ 0.5] vs. low [<0.5] of FLT3 Wild Type). Patients will be 
randomized to receive standard induction treatment (cytarabine and daunorubicin) with either 
gilteritinib or midostaurin. If achieving CR or CRi, these patients will go on to receive standard 
consolidation treatment of high-dose cytarabine with the study drug received during induction 
(gilteritinib or midostaurin). Patients may proceed to allogeneic transplant after induction or 
after 0-4 cycles of chemotherapy consolidation. The primary objective of this study is to assess 
the FLT3 mutation negative CRc (includes CR and CRi) rate of patients who receive gilteritinib 
compared to those who receive midostaurin in addition to standard therapy with cytarabine 
and daunorubicin after induction. FLT3 mutation negativity is evaluated by PCR at the end of 
induction. 
Based on a retrospective study performed at John-Hopkins,45 we assume with the control arm 
of cytarabine, daunorubicin and midostaurin, the FLT3 mutation negative CRc rate after 
induction is 40%. With 170 eligible patients with allocation ratio of 1:1 to the two arms, the 
study will have 80% power to detect an improvement of 20% in the FLT3 mutation negative 
CRc rate in the gilteritinib arm (i.e., from 40% to 60%) at the one-sided significance level of 
0.05 based on Fisher’s exact test. Accounting for 5% ineligibility, we will need a total of 179 
patients. 
Assume 7 FLT3 mutated patients will be accrued each month, the accrual of the study will be 
completed in 2.1 years. 
12.2 
Statistical Analysis 
12.2.1 
Primary Objectives 
The primary endpoint of this study is the FLT3 mutation negative Composite 
Complete Response (CRc) [includes CR and CRi] rate. The cut points used for FLT3 
mutation negativity are 1% (equivalent to 10-2) for FLT3-TKD and 10-4 for FLT3-ITD 
(please see Sections 13.1.2.1 and 13.1.2.2 for details). The final analysis of FLT3 
mutation negative CRc rate will be performed after the last patient has completed 
the induction treatment and all patients have MRD response data available. Patients 
who drop out prior to MRD response assessment or without MRD assessment will 
be counted as non-responders in the analysis. The FLT3 mutation negative CRc 
rate will be compared between gilteritinib and midostaurin arms using Fisher’s exact 
test. All eligible and treated patients will be included into the analysis. Two-sided 
90% confidence interval on the difference in the FLT3 mutation negative CRc rate 
will be provided based on the normal approximation to the difference of two 
independent binomial proportions with continuity correction. 
12.2.2 
Secondary and Exploratory Objectives 
As a secondary objective, the FLT3 mutation negative Complete Response (CR) 
rate of patients with FLT3 mutated AML who receive gilteritinib will be compared to 
those who receive midostaurin in addition to standard therapy with cytarabine and 
daunorubicin after induction. The final analysis of FLT3 mutation negative CR rate 
will be performed after the last patient has completed the induction treatment and all 
patients have MRD response data available. Patients who drop out prior to MRD 
response assessment will be counted as non-responders in the analysis. The FLT3 
mutation negative CR rate will be compared between gilteritinib and midostaurin 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
55 
arms using Fisher’s exact test. Two-sided 90% confidence interval on the difference 
in the FLT3 mutation negative CR rate will be provided based on the normal 
approximation to the difference of two independent binomial proportions with 
continuity correction. 
The MRD- CRc rate of patients with FLT3 mutated AML who receive gilteritinib will 
be compared to those who receive midostaurin. MRD will be measured by flow 
cytometry. The MRD- CRc rate will be compared using Fisher’s exact test. Two-
sided 90% confidence interval on the difference in the MRD- CRc rate will be 
provided based on the normal approximation to the difference of two independent 
binomial proportions with continuity correction. 
The CRc (CR or CRi, as defined in Section 9) rate of patients with FLT3 mutated 
AML who receive gilteritinib will also be compared to those who receive midostaurin. 
The CRc rate will be compared using Fisher’s exact test. Two-sided 90% confidence 
interval on the difference in the CRc rate will be provided based on the normal 
approximation to the difference of two independent binomial proportions with 
continuity correction. One of the secondary objectives of this study is to compare 
event free survival (EFS) of patients who receive gilteritinib to those who receive 
midostaurin in addition to cytarabine and daunorubicin after induction and high-dose 
cytarabine after consolidation. EFS is defined as time from study randomization to 
the date of induction treatment failure, relapse after CRc or to death from any cause 
after CRc, whichever comes first. For patients alive without induction treatment 
failure or relapse after CRc, EFS will be censored at the date of the last disease 
evaluation. The main analysis of EFS is to set the event date for induction treatment 
failure on day 1 of randomization. 
We assume with the control arm of cytarabine/daunorubicin plus midostaurin, for 
FLT3 mutated patients, the cure rate of EFS is 25% and the median EFS for the 
non-cure patients is 6 months. With approximately 170 eligible patients, the study 
will have 80% power to detect 38% reduction in hazard rate in EFS in the gilteritinib 
arm, using one-sided log rank test at the significance level of 0.05 and assuming 2 
years of follow-up. The number of EFS events needed is about 110. 
We will also assess OS of patients who receive gilteritinib to those who receive 
midostaurin in addition to cytarabine and daunorubicin after induction and high-dose 
cytarabine after consolidation. OS is defined as the time between randomization and 
death from any cause. The censored follow-up time for patients without death 
information is the date of last contact. 
The final analysis of EFS and OS will be performed when the full information of EFS 
is reached (i.e., 110 events have occurred). Estimates of EFS and OS, including 
medians and confidence intervals, will be calculated using the Kaplan-Meier method. 
Comparison of EFS and OS between treatment arms will be conducted using the 
one-sided stratified log-rank test with FLT3 mutation (TKD vs ITD), FLT3-ITD 
mutation signal ratio (high [≥ 0.5] vs. low [<0.5] of FLT3 Wild Type), and NPM1 
mutation status, the same stratification factors used in randomization. Cox 
proportional hazards models, stratified on the same factors above, will also be used 
to assess the treatment effect. 
A sensitivity analysis of EFS will be performed where follow-up will be censored at 
the start of transplantation. 
Comparison of CRc rate, EFS and OS between treatment arms will also be 
conducted in patients with de novo AML, t-AML and AML-MRC separately; and in 
patients with favorable, intermediate, and adverse risk separately, determined by 
2017 ELN risk classification. 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
56 
To determine the predictive value of Minimal Residual Disease (MRD) positivity and 
negativity post induction therapy. EFS and OS of the patients who achieved MRD 
negative after induction will be compared with those who did not. All CRc patients 
who have MRD response evaluated post induction will be included into this analysis. 
The interaction of treatment and MRD status will be tested in the Cox regression 
model. If a strong interaction effect is detected, the treatment effect will be looked at 
within MRD+ and MRD- patients separately. 
The correlation between MRD by molecular studies and morphology will be 
assessed. McNemar's test will be used to assess the concordance of the 
measurements. 
For patients who are FLT3 mutation positive after induction and administered 
consolidation, the FLT3 mutation negative CRc rate after first cycle of consolidation 
and their corresponding 90% confidence intervals will be given by treatment arm. 
To assess the correlation of FLT3 mutation with outcome, the EFS and OS of those 
patients with FLT3-TKD mutation will be compared with patients with FLT3-ITD 
mutation. Among those patients with FLT3-ITD mutation, EFS and OS will be 
compared among those with ITD signal ratio >0.5 with those ≤ 0.5 of FLT3 Wild 
Type. 
As per NCI CTCAE Version 5.0, the term toxicity is defined as adverse events that 
are classified as either possibly, probably, or definitely related to study treatment. 
The maximum grade for each type of toxicity will be recorded for each patient, and 
frequency tables will be reviewed to determine toxicity patterns during induction and 
consolidation separately by treatment arm. 
12.3 
Planned Interim Futility Analyses 
12.3.1 
Interim Analysis of FLT3 Mutation Negative CRc Rate and EFS 
An interim futility analysis of FLT3 mutation negative CRc rate will be performed 
when 90 (i.e., 50% of 179) patients have MRD response data available. The 
PrECOG Data Safety Monitoring Board (DSMB) may consider stopping the study 
for inefficacy if the observed FLT3 mutation negative CRc rate in the gilteritinib arm 
is lower than the control arm. The FLT3 mutation negative CRc rate (and CR rate) 
with two treatment arms combined will also be calculated. Upon the approval of the 
DSMB, it may be released to the study team to guide the design in other AML Phase 
III trials. 
When the last patient has completed the induction treatment and all patients have 
MRD response data available, the final analysis of FLT3 mutation negative CRc rate 
will be performed. At that time, if the information fraction of EFS >50% (i.e., more 
than 55 EFS events have occurred), an interim futility analysis of EFS will be 
performed as well. Otherwise, the interim analysis of EFS will be performed later 
until 50% of information is reached. In the interim analysis of EFS time, the Kaplan-
Meier curve for each arm and the point estimate and two-sided 90% confidence 
interval of hazard ratio (gilteritinib arm vs. control arm) will be provided. If the lower 
bound of the 90% confidence interval of HR is above 1, the study may be 
permanently terminated for inefficacy in EFS. 
The interim futility analysis of FLT3 mutation negative CRc rate is complete and 
stopping criteria was not met. The study will continue as planned. 
 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
57 
12.3.2 
Study and Safety Monitoring Plan 
This study will be monitored by the PrECOG DSMB. The DSMB meets twice each 
year. For each meeting, all monitored studies are reviewed for toxicity and progress 
toward completion. When appropriate, the DSMB will also review interim analyses 
of outcome data. Only the study statistician and the DSMB members will have 
access to interim analyses of outcome data. Prior to completion of this study, any 
use of outcome data will require approval of the DSMB. 
 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
58 
13. 
Laboratory and Pathology Correlative Studies 
13.1 
Correlative Studies: Mandatory Bone Marrow Samples 
13.1.1 
Overview 
13.1.1.1 
Central Biorepository Pathology Facility (CBPF) 
Prescreening: Central Biorepository Pathology Facility (CBPF) will 
perform the following: 
• 
Baseline immunophenotype for later MRD assessment. 
Additional testing will be done for DNMT3A mutation status testing 
using next generation sequencing on all FLT3 mutated patients. 
Bone marrow samples will be sent to the CBPF after induction to 
perform: 
• 
AML MRD by flow cytometry on all patients. 
• 
MRD for FLT3-TKD mutation analysis on FLT3-TKD mutated 
patients. 
Bone marrow samples will also be sent to the CBPF after first 
consolidation cycle to perform: 
• 
MRD for FLT3-TKD mutation analysis on FLT3-TKD mutated 
patients. 
Additional analyses performed will depend on resources, sample quality 
and availability: 
• 
Assess correlation between MRD by molecular studies and 
morphology (blast count). 
• 
Assess outcomes of patients who are MRD positive/negative by 
morphology vs. flow cytometry. 
• 
Assess outcomes of patients who have mutations in NPM1. 
• 
Assess outcomes of patients who have FLT3 mutations and 
mutations in NPM1 and DNMT3A. 
Any left-over samples will be stored at the CBPF for future research. 
13.1.1.2 
Invivoscribe 
Prescreening: Invivoscribe will perform the following: 
• 
FLT3 ITD and TKD testing, includes signal ratio. 
• 
NPM1 mutation status 
• 
Prescreening results will be returned to the site (no other research 
sample results will be returned to sites) 
End of Induction (First and Second Induction, as applicable) 
• 
FLT3-ITD MRD testing 
End of First Consolidation Cycle 
• 
FLT3-ITD MRD testing 
Any left-over samples will be batched and shipped to CBPF for future 
research. 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
59 
13.1.2 
Methodology 
13.1.2.1 
CBPF: Baseline Immunophenotype, DNMT3A and MRD 
Prescreening Flow Cytometry 
Flow cytometry will be performed at baseline. 
Multicolor, multiparameter flow cytometric immunophenotyping will be 
performed using antibodies to CD2, surface CD3, cytoplasmic CD3, 
CD4, CD5, CD7, CD13, CD14, CD15, CD19, CD25, CD33, CD34, 
CD36, CD38, CD45, CD54, CD56,CD64, CD117, CD123, CD133, HLA-
DR, MPO, TdT to characterize the immunophenotype of the blasts. 
Approximately 50,000 events will be collected for this assay. 
Baseline DNMT3A 
DNMT3A will be interrogated using next generation sequencing 
technology. Sequencing libraries will be prepared from genomic DNA 
obtained from bone marrow aspirate or peripheral blood samples using 
hybridization capture-based target enrichment of the genomic regions 
of interest [DNMT3A (NM_022552) exons 8-22 (codons 286-862), exon 
23 (codons 866-913)]. Bidirectional paired-end sequencing will be 
performed using a next generation sequencing (NGS) platform to 
screen for single nucleotide variants and insertions/deletions (up to 52 
base-pairs). The genomic reference sequence used is genome 
GRCh37/hg19. 
Analytical Sensitivity: 5% (one mutant allele in the background of 
nineteen wild type alleles). 
Variants are reported per the standardized mutation nomenclature 
guidelines by the 
human genome 
variation society (HGVS, 
www.hgvs.org <http://www.hgvs.org>). 
Post-Induction 
Flow Cytometry (all patients) 
Minimal residual acute myeloid leukemia will be detected using 
multicolor, multiparameter flow cytometry using antibodies to CD4, 
CD5, CD7, CD13, CD14, CD15, CD19, CD25, CD33, CD34, CD36, 
CD38, CD45, CD54, CD56, CD64, CD117, CD123, CD133, HLA-DR. 
Myeloid blasts will be characterized using this panel of antibodies to 
detect immunophenotypic variations compared with normal myeloid 
progenitors. This assay has been validated to a sensitivity level of 0.01 
to 0.1% (1 cell in 1,000 to 10,000). The sensitivity may vary in individual 
patients due to a number of factors that are either intrinsic to the AML 
blasts, and/or bone marrow specimen quality. This requires an 
adequate specimen, with acquisition of at least 200,000 events, for a 
valid negative result. Note that positive results may be obtained with 
fewer events. 
Post-Induction and Post First Consolidation Cycle MRD 
FLT3-TKD (on FLT3-TKD patients) 
Polymerase chain reaction (PCR)-based DNA analysis will be 
performed to detect codon 835/836 (tyrosine kinase domain, TKD) point 
mutation in FLT3. A multiplex PCR using fluorescently-labeled primers 
will be performed, followed by detection and sizing of PCR products 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
60 
using capillary electrophoresis. For detecting point mutations in codons 
835/836 (TKD), a restriction enzyme digestion of the PCR products will 
be performed prior to capillary electrophoresis. The lower limit of 
detection (analytical sensitivity) of this assay is approximately 1% of 
mutant DNA in a background of wild type DNA (equivalent to 10-2). 
When a mutation is detected, the ratio of area under the peak of mutant 
over total (mutant+wild-type) FLT3 is reported for monitoring the mutant 
allele burden. 
13.1.2.2 
Invivoscribe: FLT3, NPM1 and FLT3 MRD 
Prescreening FLT3 and Signal Ratio46 
Primers flanking exons 14, 15 and the activation loop region of exon 20 
of the FLT3 gene are used to amplify DNA extracted from a patient 
sample. The forward and reverse PCR primers are fluorescently labeled 
with different flurophores that serve to confirm the presence of sample 
signal. 
The size of the FLT3 ITD PCR is determined by capillary electrophoresis 
and the signal ratio compares the signal intensity of the mutant to the 
wild type. 
The FLT3-TKD PCR product is digested with EcoRV and the presence 
of the mutation is further assessed using capillary electrophoresis and 
the signal ratio compares the signal intensity of the mutant to the wild-
type. 
FLT3 and signal ratio results will be returned to sites. 
Prescreening NPM147 
Primers targeting the area surrounding exon 12 of the NPM1 gene are 
used to amplify the patient’s DNA. The size of the NPM1 PCR product 
is determined by capillary electrophoresis. 
NPM1 results will be returned to sites. 
Post-Induction and Post First Consolidation Cycle FLT3-ITD MRD 
Testing (on FLT3-ITD patients)48 
The FLT3-ITD MRD test is an amplicon-based NGS assay. This assay 
can detect mutations with a mutant cell sensitivity of 10-4 (1 mutant cell 
in a background of ten thousand normal cells; equivalent to an allelic 
sensitivity of 5x10-5 when a single mutant allele is present). 
The following three controls are included in every test: 
1. A positive control with a FLT3 mutant allelic concentration of 5x10- 5 
(a mutant cell concentration of approximately 10-4). 
2. A negative control with a wild-type FLT3 gene. 
3. A no template control with water in place of the DNA sample in the 
PCR reaction. 
The sequencing output data is analyzed using an Invivoscribe 
developed proprietary FLT3-ITD MRD Data Analysis software. 
 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
61 
13.1.3 
Bone Marrow Sample Collection 
Mailers and kits will be supplied. Instructions and shipping address will be provided. 
Refer to the Invivoscribe Lab Manual for the mailer and the PrE0905 Lab Manual for 
kit details. 
• 
Prescreening 
○ 
Invivoscribe 
- 
One 4 mL Sodium Heparin green top tube (need approximately .75 mL 
of bone marrow) 
 
If bone marrow sample (preferred) is not available and patient has 
any circulating blasts, then one 4 mL Sodium Heparin green top 
tube of peripheral blood (need approximately 3 mL) will be allowed. 
○ 
CBPF 
- 
Two 10 mL EDTA tube (request 6 mL (ideal amount) of bone marrow in 
each) 
 
If diagnostic bone marrow was done prior to study enrollment or 
patient is inaspirable, then two 10 mL EDTA tubes of peripheral 
blood will be allowed if patient has any circulating blasts. 
• 
Post Induction (First Cycle and Second Cycle, as applicable) 
○ 
Invivoscribe 
- 
If FLT3 ITD+, one 4 mL EDTA tube bone marrow 
○ 
CBPF 
- 
All patients (ITD+ and/or TKD+), one 10 mL EDTA tube (bone marrow) 
- 
If FLT3 TKD+, one additional 10 mL EDTA tube (bone marrow) 
- 
Request 6 mL (ideal amount) of bone marrow in each 
• 
Post First Consolidation Cycle 
○ 
Invivoscribe 
- 
If FLT3 ITD+, one 4 mL EDTA tube bone marrow 
o 
CBPF 
- 
All patients (ITD+ and/or TKD+), one 10 mL EDTA tube (bone marrow) 
- 
If FLT3 TKD+, one additional 10 mL EDTA tube (bone marrow) 
- 
Request 6 mL (ideal amount) of bone marrow in each 
• 
Relapse (Optional) 
○ 
CBPF 
- 
Two 10 mL EDTA tubes (request 6 mL (ideal amount) of bone marrow 
in each) 
Left-over derivatives from Invivoscribe will be shipped to the CBPF. 
13.1.4 
Bone Marrow Sample Processing and Shipment 
All samples collected will be labeled with a unique numeric identifier that will be 
coded for patient privacy protection. 
Invivoscribe 
Ship one 4 mL Sodium Heparin green top tube to Invivoscribe at Prescreening (bone 
marrow or blood). 
Post Induction (first cycle and second cycle, as applicable) and Post First 
Consolidation Cycle ship one 4 mL EDTA tube to Invivoscribe (bone marrow). 
 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
62 
CBPF 
Ship two 10 mL EDTA tubes to CBPF at Prescreening. 
Post Induction, Post First Consolidation Cycle and Relapse (as applicable) bone 
marrow samples will be shipped to CBPF. 
Samples should be shipped the same day they are obtained except as noted in the 
Invivoscribe Lab Manual and PrE0905 Lab Manual (i.e., samples cannot be received 
on Sunday). Samples will be shipped on a cold pack via overnight courier. 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
63 
14 
Administrative 
14.1 
Protocol Compliance 
The study shall be conducted as described in this protocol. All revisions to the protocol must 
be discussed with, and be prepared by PrECOG and/or representatives. The Investigator 
should not implement any deviation or change to the protocol or consent without prior review 
and documented approval from PrECOG and/or representatives and the Institutional Review 
Board (IRB) of an amendment, except where necessary to eliminate an immediate hazard(s) 
to study patients. 
If a deviation or change to the approved protocol is implemented to eliminate an immediate 
hazard(s) prior to obtaining IRB approval, notification will be submitted to the IRB for review 
and approval as soon as possible afterward. Documentation of approval signed by the 
chairperson or designee of the IRB(s) should be in the study records. If PrECOG and/or 
representatives provides an amendment that substantially alters the study design or increases 
the potential risk to the patient; the consent form must be revised and submitted to the IRB(s) 
for review and approval; the revised form must be used to obtain consent from patients 
currently enrolled in the study if they are affected by the Amendment; and the new form must 
be used to obtain consent from new patients prior to study entry. Information as to who 
investigators should send correspondence will be provided in additional study documents. 
14.2 
Institutional Review Board (IRB) 
Before study initiation, the Investigator must have written and dated approval from their 
respective IRB for the protocol, consent form, patient recruitment materials/process and any 
other written information to be provided to patients. The Investigator should also provide the 
IRB with a copy of the Investigator Brochure or product labeling, and any updates. 
The Investigator should provide the IRB with reports, updates, and other information (e.g., 
Safety Updates, amendments, and administrative letters) according to regulatory 
requirements, IRB or study site procedures. 
14.3 
Informed Consent Procedures 
Investigators must ensure that patients who volunteer for clinical trials or their legally 
acceptable representative are clearly and fully informed about the purpose, potential risks and 
other information. 
A protocol specific informed consent form (ICF) template will be provided to sites. Preparation 
of the site-specific consent form is the responsibility of the site Investigator and must include 
all applicable regulatory and IRB requirements, and must adhere to Good Clinical Practices 
(GCP) and to the ethical principles that have their origin in the Declaration of Helsinki. All 
changes to the ICF template will be approved by PrECOG and/or their representatives prior to 
implementation. 
In accordance with the Health Information Portability and Accountability Act (HIPAA), the 
consent process will also include written authorization by patients to release medical 
information to allow PrECOG and/or its agents, regulatory authorities, and the IRB of record at 
the study site for access to patient records and medical information relevant to the study, 
including the medical history. This will be documented in the informed consent form or other 
approved form obtained at the time of informed consent per institutional policies. This form 
should also be submitted to PrECOG and/or its agents for review prior to its implementation. 
The Investigator must provide the patient or legally acceptable representative with a copy of 
the consent form and written information about the study in the language in which the patient 
is most proficient. The language must be non-technical and easily understood. The Investigator 
should allow time necessary for patient or patient's legally acceptable representative to inquire 
about the details of the study, then informed consent must be signed and personally dated by 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
64 
the patient or the patient's legally acceptable representative and by the person who conducted 
the informed consent discussion. The patient or legally acceptable representative should 
receive a copy of the signed informed consent and any other written information provided to 
study patients prior to patient's participation in the trial. The investigator is responsible for 
assuring adequate documentation of this process and for storage and maintenance of the 
original signed consent form for each patient/subject.  
The informed consent and any other information provided to patients or the patient's legally 
acceptable representative, should be revised whenever important new information becomes 
available that is relevant to the patient's consent, and should receive IRB approval prior to use. 
The Investigator, or a person designated by the Investigator should inform the patient or the 
patient's legally acceptable representative of all pertinent aspects of the study and of any new 
information relevant to the patient's willingness to continue participation in the study. This 
communication should be documented in the patient record. During a patient's participation in 
the trial, any updates to the consent form and any updates to the written information will be 
provided to the patient. 
14.4 
Safety Communication 
Investigators will be notified of all AEs that are serious, unexpected, and definitely, probably, 
or possibly related to the investigational product. Upon receiving such notices, the Investigator 
must review and retain the notice with the Investigator Brochure and submit a copy of this 
information to the IRB according to local regulations. The Investigator and IRB will determine 
if the informed consent requires revision. The Investigator should also comply with the IRB 
procedures for reporting any other safety information. All revisions should be submitted to 
PrECOG and/or agents for review. 
14.5 
Monitoring 
Representatives and agents of PrECOG and, as applicable to the study, the manufacturer of 
investigational product must be allowed to visit all study site locations periodically to assess 
the data, quality and study integrity. The purpose of this visit is to review study records and 
directly compare them with source documents and discuss the conduct of the study with the 
Investigator, and verify that the facilities remain acceptable. Monitoring of drug accountability 
will also occur. 
The study may be evaluated by other auditors and government inspectors who must be 
allowed access to electronic Case Report Forms (eCRFs), source documents and other study 
files. The Investigator must notify PrECOG of any scheduled visits by regulatory authorities, 
and submit copies of all reports. Information as to who investigators should notify of an audit 
or where to address questions will be provided in additional study materials. 
14.6 
Study Records 
An Investigator is required to maintain adequate regulatory files with corresponding 
communication and approvals, accurate histories, observations and other data on each 
individual treated. Full details of required regulatory documents will be provided in additional 
study materials. Data reported on the eCRFs must be consistent with the source documents 
as part of the patient record. 
The confidentiality of records that could identify patients must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s). 
A study specific signature record will be maintained to document signatures and initials of all 
persons at a study site who are authorized to make entries and/or corrections on eCRFs as 
well as document other study-specific roles. 
 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
65 
14.7 
Electronic Case Report Form (eCRF) Information 
Additional information regarding eCRF instructions, timelines for data entry/ submission and 
query completion can be found in supplemental materials provided to the site. Sites will be 
expected to complete eCRFs as per the schedule provided and submit all relevant data as per 
the specified timelines. All items recorded on eCRFs must be found in source documents. 
The completed eCRF must be promptly reviewed, electronically signed, and dated by the 
Principal Investigator. 
Instructions for management of patients who do not receive any protocol therapy: 
If a patient is registered and does not receive any assigned protocol treatment, baseline, 
Serious Adverse Event and follow-up data will still be entered and must be submitted according 
to the eCRF instructions. Document the reason for not starting protocol treatment on the 
appropriate electronic end of treatment form. 
14.8 
Records Retention 
FDA Regulations (21CFR 312.62) require clinical investigators to retain all trial-related 
documentation, including source documents for the periods described below for studies 
performed under a US Investigational New Drug (IND): 
• two years after the FDA approves the marketing application, or 
• two years after the FDA disapproves the application for the indication being studied, or 
• two years after the FDA is notified by the sponsor of the discontinuation of trials and that an 
application will not be submitted. 
The Investigator must retain investigational product disposition records, copies of eCRFs (or 
electronic files), and source documents for the maximum period required by applicable 
regulations and guidelines, or Institution procedures, whichever is longer. The Investigator 
must contact PrECOG and/or representatives prior to destroying any records associated with 
the study. 
Information as to who investigators should contact for questions will be provided in additional 
study documents. PrECOG and/or representatives will notify the Investigator when the trial 
records for this study are no longer needed. 
 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
66 
15 
References 
1. American Cancer Society Key Statistics for Acute Myeloid Leukemia. https://www.cancer.org/ 
cancer/acute-myeloid-leukemia/about/key-statistics.html; last accessed 3/26/2018. 
2. O'Donnell MR, Abboud CN, Altman J, et al. Acute myeloid leukemia. J Natl Compr Canc Netw. 
2012; 10:984-1021. 
3. Tallman MS. New strategies for the treatment of acute myeloid leukemia including antibodies and 
other novel agents. Hematology Am Soc Hematol Educ Program. 2005:143-50. 
4. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus Chemotherapy for Acute Myeloid 
Leukemia with a FLT3 mutation. N Engl J Med. 2017 Aug 3; 377(5):454-464. 
5. Kondo, M., et al., Prognostic value of internal tandem duplication of the FLT3 gene in childhood 
acute myelogenous leukemia. Med Pediatr Oncol, 1999. 33(6): p. 525-9. 
6. Iwai, T., et al., Internal tandem duplication of the FLT3 gene and clinical evaluation in childhood 
acute myeloid leukemia. The Children's Cancer and Leukemia Study Group, Japan. Leukemia, 
1999. 13(1): p. 38-43. 
7. Kiyoi, H., et al., Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid 
leukemia. Blood, 1999. 93(9): p. 3074-80. 
8. Weisberg, E., et al., Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule 
tyrosine kinase inhibitor PKC412. Cancer Cell, 2002. 1(5): p. 433-43. 
9. Gilliland, D.G. and J.D. Griffin, The roles of FLT3 in hematopoiesis and leukemia. Blood, 
2002.100(5): p. 1532-42. 
10. Schlenk RF, Döhner K. Impact of new prognostic markers in treatment decisions in acute myeloid 
leukemia. Curr Opin Hematol. 2009; 16:98-104. 
11. Yamamoto Y, Kiyoi H, Nakano Y, et al. Activating mutation of D835 within the activation loop of 
FLT3 in human hematologic malignancies. Blood. 2001; 97:2434-9. 
12. Patel JP, Gönen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute 
myeloid leukemia. New Eng J Med. 2012; 366:1079-89. 
13. Gale RE, Green C, Allen C, et al. The impact of FLT3 internal tandem duplication mutant level, 
number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with 
acute myeloid leukemia. Blood. 2008; 111:2776-84. 
14. Yanada M, Matsuo K, Suzuki T, et al. Prognostic significance of FLT3 internal tandem duplication 
and tyrosine kinase domain mutations for acute myeloid leukemia: a meta-analysis. Leukemia. 
2005; 19:1345-9. 
15. Tiesmeier J, Müller-Tidow C, Westermann A, et al. Evolution of FLT3-ITD and D835 activating 
point mutations in relapsing acute myeloid leukemia and response to salvage therapy. Leuk Res. 
2004 Oct; 28(10):1069-74. 
16. Moreno I, Martín G, Bolufer P, et al. Incidence and prognostic value of FLT3 internal tandem 
duplication and D835 mutations in acute myeloid leukemia. Haematologica. 2003; 88:19-24. 
17. Brunet S, Labopin M, Esteve J, Cornelissen J, et al. Impact of FLT3 internal tandem duplication on 
the outcome of related and unrelated hematopoietic transplantation for adult myeloid leukemia in 
first remission : a retrospective analysis. J Clin Oncol. 2012 Mar 1; 30(7):735-41. 
18. Konig H, Levis M. Targeting FLT3 to treat leukemia. Expert Opin Ther Targets. 2015 Jan; 19(1):37-
54. 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
67 
19. Chevallier P, Labopin M, Turlure P, et al. A new Leukemia Prognostic Scoring System for 
refractory/relapsed adult acute myelogenous leukaemia patients: a GOELAMS Study. Leukemia. 
2011 Jun; 25(6):939-44. 
20. Levis M, Ravandi F, Wang ES, et al. Results from a randomized trial of salvage chemotherapy 
followed by lestaurtinib for patients with FLT3 mutant AML in first relapse. Blood. 2011 Mar 24; 
117(12):3294-301. 
21. RYDAPT® (midostaurin) capsules, for oral use; Initial US Approval: 2017; Highlights of Prescribing 
Information; Revised 4/2017. 
22. Linger RM, Keating AK, Earp HS, et al. TAM receptor tyrosine kinases: biologic functions, 
signaling, and potential therapeutic targeting in human cancer. Adv Cancer Res. 2008; 100:35-83. 
23. Hong CC, Lay JD, Huang JS, et al. Receptor tyrosine kinase AXL is induced by chemotherapy 
drugs and overexpression of AXL confers drug resistance in acute myeloid leukemia. Cancer Lett. 
2008 Sep 18; 268(2):314-24. 
24. Ben-Batalla I, Schultze A, Wroblewski M, et al. Axl, a prognostic and therapeutic target in acute 
myeloid leukemia mediates paracrine crosstalk of leukemia cells with bone marrow stroma. Blood. 
2013 Oct 3; 122(14):2443-52. 
25. Rochlitz C, Lohri A, Bacchi M, Schmidt M, et al. Axl expression is associated with adverse 
prognosis and with expression of Bcl-2 and CD34 in de novo acute myeloid leukemia (AML): results 
from a multicenter trial of the Swiss Group for Clinical Cancer Research (SAKK). Leukemia. 1999 
Sep; 13(9):1352-8. 
26. Park IK, Mishra A, Chandler J, et al. Inhibition of the receptor tyrosine kinase Axl impedes activation 
of the FLT3 internal tandem duplication in human acute myeloid leukemia: implications for Axl as 
a potential therapeutic target. Blood. 2013 Mar 14; 121(11):2064-73. 
27. Astellas. Gilteritinib (ASP2215) Investigator’s Brochure. For the Treatment of Acute Myeloid 
Leukemia. Edition 5, Edition Date: 20Sept2017. 
28. Perl AE, Altman JK, Cortes J, et al. Selective inhibition of FLT3 by gilteritinib in relapsed or 
refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1–2 study. 
Lancet Oncol. 2017 Aug; 18(8):1061-1075. 
29. Pratz KW, et al. Updated Results from a Phase 1 Study of Gilteritinib in Combination with Induction 
and Consolidation Chemotherapy in Subjects with Newly Diagnosed Acute Myeloid Leukemia 
(AML). Blood 132, no. Suppl 1 (2018): 564. Accessed March 28, 2019. doi: 10.1182/blood-2018-
99-110975. 
30. Perl AE, et al. Selective Inhibition of FLT3 by Gilteritinib in Relapsed or Refractory Acute Myeloid 
Leukaemia; a Multicentre, First-in-Human, Open-Label, Phase 1-2 Study. Lancet Oncol. 2017 Aug; 
18(8):1061-1075. doi: 10.1016/S1470-2045(17)30416-3. Epub 2017 June 20. 
31. Moreno I, Martin G, Bolufer P. Incidence and prognostic value of FLT3 internal tandem duplication 
and D835 mutations in acute myeloid leukemia. Haematologica. 2003 Jan; 88(1):19-24. 
32. Fernandez HF, Sun Z, Yao X, et al. Anthracycline Dose Intensification in Acute Myeloid Leukemia. 
New England Journal of Medicine. 2009. 361(13):1249-59. 
33. Luskin MR, Lee JW, Fernandez HF, et al. Benefit of high-dose daunorubicin in AML induction 
extends across cytogenetic and molecular groups. Blood. 2016 Mar 24; 127 (12):1551-8. 
34. DeZern AE, Sung A, Kim S, et al. Role of Allogeneic Transplantation for FLT3/ITD Acute Myeloid 
Leukemia: Outcomes from 133 Consecutive Newly Diagnosed Patients from a Single Institution. 
Biology of Blood and Marrow Transplantation. 
35. Temple R. Hy's law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug Saf. 2006; 15:241-
3. 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
68 
36. Döhner H1, Estey E2, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN 
recommendations from an international expert panel. Blood. 2017 Jan 26; 129 (4):424-447. 
37. Sagie A, Larson MG, Goldberg RJ, Bengston JR, Levy D. An improved method for adjusting the 
QT interval for heart rate (the Framingham Heart Study) The American Journal of Cardiology 1992; 
70; 797-801. 
38. Luo S, Michler K, Johnton P, Macfarlane PW. A Comparison of Commonly Used QT Correction 
Formulae: The Effect of Heart Rate on the QTc of Normal ECGs. J Electrocardiol. 2004;37 
Suppl:81-90. 
39. Calculate 
by 
QxMD; 
ECG- 
Corrected 
QT; 
2020 
QxMD 
Software, 
Inc.; 
https://qxmd.com/calculate/calculator_48/ecg-corrected-qt; last accessed 2/3/2020. 
40. Daunorubicin Hydrochloride; Teva Parenteral Medicines Inc.; Package Insert; Revised 12/2012; 
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4b8a5ad9-9e34-4f88-997c-244d9a0ef 
2 c2; last accessed 4/11/2018. 
41. Daunorubicin Monograph; BC Cancer Agency Cancer Drug Manual; Developed September 1994; 
Limited Revision 01 February 2017; http://www.bccancer.bc.ca/drug-database-site/Drug%20 
Index/Daunorubicin_monograph_1Feb2017.pdf; last accessed 4/11/2018. 
42. Daunorubicin-FDA Prescribing Information, Side Effects and Uses; Drugs.com; Revised 3/2018; 
https://www.drugs.com/pro/daunorubicin.html; last accessed 4/11/2018. 
43. Cytarabine; Hospira Inc.; Package Insert; Revised 12/2017; https://dailymed.nlm.nih.gov/ 
dailymed/fda/fdaDrugXsl.cfm?setid=bc2fa221-ea56-48b8-8304-42cd81b 
8463b&type=display; 
last accessed 4/11/2018. 
44. Cytarabine-FDA Prescribing Information, Side Effects and Uses; Drugs.com; Revised 12/2017; 
https://www.drugs.com/pro/cytarabine.html; last accessed 4/11/2018. 
45. Rebechi M, DeZern AE, Kagan A, et al. FLT3 ITD AML Outcomes Are Impacted By Exposure to 
One Cycle of Cytarabine Based Consolidation, Pre- and Post-Transplant TKI Therapy, and 
Presence of Minimal Residual Disease (MRD) Prior to Allogeneic Blood or Marrow Transplant, 
Blood (2017) 130 (Supplement 1): 2593. 
46. LeukoStrat CDx FLT3 Mutation Assay. https://invivoscribe.com/uploads/products/informational 
Downloads/LabPMM-Flyer_Leukostrat-CDx_FLT3_8.5x11_20170420.pdf; 
last 
accessed 
7/17/2018. 
47. NPM1 Mutation Assay. https://www.invivoscribe.com/clinical-services/npm1-mutation-detection-
by-pcr; last accessed 7/17/2018. 
48. FLT3 ITD MRD Testing. https://www.invivoscribe.com/clinical-services/flt3-itd-mrd-testing-by-
ngs?solution[]=FLT3%20ITD&; last accessed 7/18/2018. 
 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
69 
Appendix I: 
ECOG Performance Status 
 
PS 0 
Fully active, able to carry on all pre-disease performance 
without restriction 
PS 1 
Restricted in physically strenuous activity but ambulatory 
and able to carry out work of a light or sedentary nature e.g. 
light house work, office work. 
PS 2 
Ambulatory and capable of all self-care but unable to carry 
out any work activities. Up and about more than 50% of 
waking hours. 
PS 3 
Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours. 
PS 4 
Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair. 
Source: Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
70 
Appendix II: Calculation of Creatinine Clearance Using the Cockcroft-Gault Formula 
 
 
(140 - age [years]) (body wt [kg]) 
Creatinine clearance for males =  
————————————————— 
(72) (serum creatinine [mg/dL]) 
 
 
(140 - age [years]) (body wt [kg]) 
Creatinine clearance for females =  
————————————————— x 0.85 
(72) (serum creatinine [mg/dL]) 
 
NOTE: Actual body weight (wt) in kg. 
 
Source: Gault MH, Longerich LL, Harnett JD, et al. Predicting glomerular function from adjusted serum 
creatinine (editorial). Nephron 1992; 62:249 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
71 
Appendix III: Contraceptive Requirements 
Women of Childbearing Potential (WOCBP) participants may choose complete abstinence and have 
pregnancy test, as specified in Schedule of Assessments. 
WOCBP DEFINITIONS AND METHODS OF CONTRACEPTION DEFINITIONS 
A woman is considered fertile following menarche and until becoming post-menopausal unless permanently 
sterile. 
Women in the following categories are not considered WOCBP: 
● 
Premenarchal 
● 
Premenopausal female with 1 of the following (at least 1 month prior to screening): 
○ 
Documented hysterectomy 
○ 
Documented bilateral salpingectomy 
○ 
Documented bilateral oophorectomy 
● 
Post-menopausal 
Documentation of any of these categories can come from the site personnel’s review of the female subject’s 
medical records, medical examination, or medical history interview. 
A postmenopausal state is defined as at least 12 months after last regular menstrual bleeding without an 
alternative medical cause. 
● 
In case the last regular menstrual bleeding cannot be clearly determined, confirmation with repeated 
follicle-stimulating hormone (FSH) measurements of at least >40 IU/L (or higher per local institutional 
guidelines), is required. 
Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to 
use one of the non-estrogen hormonal 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 
by repeated FSH measurements before study enrollment. 
CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD BEARING POTENTIAL 
One of the highly effective methods of contraception listed below is required at the time of informed consent 
and until the end of relevant systemic exposure, defined as 180 days after the final study drug administration.a 
Highly Effective Contraceptive Methods (Failure rate of <1% per year when used consistently and 
correctly.)b 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulation 
● 
oral 
● 
intravaginal 
● 
transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
● 
oral 
● 
injectable 
● 
implantable  
Hormonal methods of contraception containing a combination of estrogen and progesterone, vaginal ring, 
injectables, implants and intrauterine hormone-releasing system (IUS) 
● 
intrauterine device (IUD) 
● 
bilateral tubal occlusion 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
72 
Male is sterile due to a bilateral orchiectomy. 
Vasectomized partner: (A vasectomized partner is a highly effective contraception method provided that the 
partner is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, 
an additional highly effective method of contraception should be used.) 
Sexual abstinence: Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the participant. It is not necessary to use any other method of contraception when complete abstinence is 
elected. 
a Local laws and regulations may require use of alternative and/or additional contraception methods. 
b Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical 
studies. 
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) OF CHILD BEARING 
POTENTIAL 
Male participants with female partners of childbearing potential are eligible to participate if they agree to the 
following during treatment and until the end of relevant systemic exposure defined as 120 days after final drug 
administration. 
● 
Inform any and all partner(s) of their participation in a clinical drug study and the need to comply with 
contraception instructions as directed by the investigator. 
● 
Male participants are required to remain abstinent use a condom during treatment and until end of 
relevant systemic exposure defined as 120 days after final drug administration. 
● 
Female partners of male participants who have not undergone a vasectomy with the absence of sperm 
confirmed or a bilateral orchiectomy should consider use of effective methods of contraception until 
the end of relevant systemic exposure, defined as 120 days after final drug administration. 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
73 
Appendix IV: NYHA Classification 
 
Class 
Symptoms 
Class I 
Patients with cardiac disease but without resulting limitation of 
physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation, dyspnea (shortness of breath), or 
anginal pain. 
Class II 
Patients with cardiac disease resulting in slight limitation of 
physical activity. Comfortable at rest. Ordinary physical activity 
results in fatigue, palpitation, dyspnea or anginal pain. 
Class III 
Patients with cardiac disease resulting in marked limitation of 
physical activity. Comfortable at rest. Less than ordinary 
physical activity causes fatigue, palpitation, dyspnea or anginal 
pain. 
Class IV 
Patients with cardiac disease resulting in inability to carry out 
any physical activity without discomfort. Symptoms of cardiac 
insufficiency or the anginal syndrome may be present even at 
rest. If any physical activity is undertaken, discomfort is 
increased. 
Source: Oxford Textbook of Internal Medicine. Vol. 2, pp 2228. Oxford University Press. 1997 
 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
74 
Appendix V: Additional Excluded and Cautionary Medications 
The following list describes medications and foods that are common strong inhibitors of CYP3A. This list should 
not be considered all inclusive. Consult individual drug labels for specific information on a compound’s 
propensity to inhibit CYP3A. 
NOTE: Treatment with concomitant drugs that are strong inhibitors of CYP3A should be avoided with the 
exception of antibiotics, antifungals and antivirals that are used as standard of care to prevent or treat 
infections. 
Strong CYP3A Inhibitors 
Drug Type 
Generic Drug Name 
Human Immunodeficiency Virus Protease 
Inhibitors 
Indinavir 
Nelfinavir 
Lopinavir/ritonavir 
Ritonavir 
Saquinavir 
Food/Juice 
Grapefruit juice 
Others 
Boceprevir 
Telaprevir 
Clarithromycin 
Telithromycin 
Conivaptan 
Itraconazole 
Ketoconazole 
Posaconazole 
Voriconazole 
Nefazodone 
CYP: Cytochrome P450. 
Source: Table 3 in FDA Draft Guidance for Industry – Drug Interaction Studies – Study Design, Data Analysis, 
Implications for Dosing, and Recommendations: 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm292362.pdf 
Treatment with concomitant drugs that are strong inducers of CYP3A are prohibited. The following list 
describes medications and foods that are common strong inducers of CYP3A. This list should not be 
considered all inclusive. Consult individual drug labels for specific information on a compound’s propensity to 
induce CYP3A. 
Strong CYP3A Inducers 
Drug Type 
Generic Drug Name 
Antiepileptic, Anticonvulsant 
Carbamazepine 
Phenytoin 
Antibiotic 
Rifampicin 
Food/Juice Supplement 
St. John’s Wort 
CYP: Cytochrome P450. 
Source: Table 4 in FDA Draft Guidance for Industry – Drug Interaction Studies – Study Design, Data Analysis, 
Implications for Dosing, and Recommendations: 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm292362.pdf 
*Continued on next page 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
75 
The following list describes medications that target serotonin receptors. This list should not be considered all 
inclusive. Consult individual drug labels for specific information on whether a compound targets serotonin 
receptors. 
NOTE: Treatment with concomitant drugs that target serotonin 5HT2BR or sigma nonspecific receptor should 
be avoided with the exception of drugs that are considered absolutely essential for the care of the 
patient. 
Drugs Targeting Serotonin Receptors 
Drug Type 
Generic Drug Name 
Affinity or function to 5HT2BR 
Eletriptan Hydrobromide 
Escitalopram 
Fluoxetine 
Sertraline 
 
5HT2BR: 5-Hydroxytryptamine Receptor 2B. 
 
 
 
The following list describes medications and foods that are common inhibitors or inducers of P-gp. This list 
should not be considered all inclusive. Consult individual drug labels for specific information on a compound’s 
propensity to inhibit or induce P-gp. 
NOTE: Treatment with concomitant drugs that are strong inhibitors or inducers of P-gp should be avoided with 
the exception of drugs that are considered absolutely essential for the care of the patient. 
P-gp Inhibitors or Inducers 
Transporter 
Gene 
Inhibitor 
Inducer 
P-gp 
ABCB1 
Amiodarone, azithromycin, captopril, 
carvedilol, clarithromycin, conivaptan, 
cyclosporine, diltiazem, dronedarone, 
erythromycin, felodipine, itraconazole, 
ketoconazole, lopinavir and ritonavir, 
quercetin, 
quinidine, 
ranolazine, 
verapamil 
Avasimibe, 
carbamazepine, 
phenytoin, rifampin, St. John’s 
wort, tipranavir/ritonavir  
P-gp: P-glycoprotein. 
Source:https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-
substrates-inhibitors-and-inducers 
 
 
 
 
 
 
*Continued on next page 
 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
76 
The following list describes drugs that are known to prolong QT or QTc. This list should not be considered all 
inclusive. Consult individual drug labels for specific information on whether a compound is known to prolong 
QT or QTc. 
Drugs That May Prolong QT or QTc 
Drug Type 
Generic Drug Name 
Class IA antiarrhythmics 
Quinidine 
Procainamide 
Disopyramide 
Class IC antiarrhythmics 
Flecainide  
Propafenone  
Moricizine 
Class III antiarrhythmics 
Amiodarone 
Sotalol 
Bretylium 
Ibutilide 
Dofetilide 
Antipsychotics 
Thioridazine 
Mesoridazine 
Chlorpromazine 
Prochlorperazine 
Trifluoperazine 
Fluphenazine 
Perphenazine 
Pimozide 
Risperidone 
Ziprasadone 
Lithium 
Haloperidol 
Tricyclic/tetracyclic antidepressants 
Amitriptyline 
Desipramine 
Doxepin 
Dosulepin hydrochloride 
Imipramine 
Maprotiline 
Selective serotonin and norepinephrine reuptake 
inhibitors (SSNRIs) antidepressants 
Venlafaxine 
Macrolide antibiotics 
Azithromycin 
Erythromycin 
Clarithromycin 
Dirithromycin 
Roxithromycin 
Tulathromycin 
Fluoroquinolone antibiotics 
Moxifloxacin 
Gatifloxacin 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
77 
Drugs That May Prolong QT or QTc 
Drug Type 
Generic Drug Name 
Azole antifungals 
Ketoconazole 
Fluconazole 
Itraconazole 
Posaconazole 
Voriconazole 
Antimalarials 
Amodiaquine 
Atovaquone 
Chloroquine 
Doxycycline 
Halofantrine 
Mefloquine  
Proguanil 
Primaquine 
Pyrimethamine 
Quinine 
Sulphadoxine 
Antiprotozoals 
Pentamidine 
Antiemetics 
Droperidol 
Dolasetron 
Granisetron 
Ondansetron 
Antiestrogens 
Tamoxifen 
Immunosuppressants 
Tacrolimus 
 

PrECOG Protocol Number: PrE0905 
IND Number: 143257 
Confidential 
Date: 10/5/2022 
 
78 
Appendix VI: Investigator’s Statement 
1. 
I have carefully read this protocol entitled “Randomized Trial of Gilteritinib vs 
Midostaurin in FLT3 Mutated Acute Myeloid Leukemia (AML)”, Version 3.0 dated 
10/5/2022 (Protocol Number PrE0905) and agree that it contains all the necessary 
information required to conduct the study. I agree to conduct the study as outlined in 
the protocol. 
2. 
I agree to conduct this study according to the moral, ethical and scientific principles 
governing clinical research as set out in the Declaration of Helsinki, the principles of 
Good Clinical Practice (GCP) as described in 21 Code of Federal Regulations (CFR) 
and any applicable local requirements. 
3. 
I understand that this trial and any subsequent changes to the trial will not be initiated 
without approval of the appropriate Institutional Review Board, and that all 
administrative requirements of the governing body of the institution will be complied 
with fully. 
4. 
Informed written consent will be obtained from all participating patients in accordance 
with institutional and Food and Drug Administration (FDA) requirements as specified in 
Title 21, CFR, Part 50. 
5. 
I understand that my signature on the electronic Case Report Form (eCRF) indicates 
that I have carefully reviewed each page and accept full responsibility for the contents 
thereof. 
6. 
I understand that the information presented in this study protocol is confidential, and I 
hereby assure that no information based on the conduct of the study will be released 
without prior consent from PrECOG, LLC unless this requirement is superseded by the 
FDA. 
Principal Investigator (PI): 
PI Name: 
 
 
 
 
 
 
 
 
 
 
Site Name: 
 
 
 
 
 
 
 
 
 
 
Signature of PI: 
 
 
 
 
 
 
 
 
 
Date of Signature: 
 
 
\ 
 
\ 
 
 
 
 
 
 
 
MM 
 
DD 
 
YYYY