Conditions: Acute Myeloid Leukemia (AML) Acute Myeloid Leukemia With FMS-like Tyrosine Kinase (FLT3) Mutation
Keywords: AML gilteritinib ASP2215 Acute Myeloid Leukemia FLT3
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 11
Healthy volunteers: no

Brief summary:
The purpose of this study was to determine the safety and tolerability of gilteritinib given in combination with atezolizumab in participants with relapsed or treatment refractory FMS-like tyrosine kinase 3 (FLT3) mutated AML and to determine the composite complete remission (CRc) rate for participants who either discontinued the study or completed 2 cycles of gilteritinib given in combination with atezolizumab.

This study also evaluated pharmacokinetics (PK), response to treatment, remission and survival. Adverse events (AEs), clinical laboratory results, vital signs, electrocardiograms (ECGs), and Eastern Cooperative Oncology Group (ECOG) performance status scores were also assessed.

Detailed description:
This study was planned to have 2 phases:

Phase 1:

The phase 1 portion of this study was to establish the recommended phase 2 dose (RP2D) of gilteritinib given in combination with atezolizumab.

Phase 2:

The phase 2 portion of the study was to treat participants with gilteritinib and atezolizumab at the RP2D and was to be enrolled in two stages. The first stage was to evaluate the remission rate and if a minimum rate was to be achieved, a second stage of enrollment was to be continued.

Arms:
arm 1: Participants received 120 milligrams (mg) giltertinib (3 tablets of 40 mg) orally, once a day in continuous 28-day cycles in combination with atezolizumab 420 mg adminstered by intravenous infusion (over 60 minutes) once every 2 weeks of 28-day cycle until the participant no longer received clinical benefit from therapy, unacceptable toxicity occurred or the participant met a treatment discontinuation criterion (Maximum treatment duration was 535 days for gilteritinib and 112 days for atezolizumab). arm 2: Participants received 120 mg giltertinib (3 tablets of 40 mg) orally, once a day in continuous 28-day cycles in combination with atezolizumab 840 mg administered by intravenous infusion (over 60 minutes) once every 2 weeks of 28-day cycle until the participant no longer received clinical benefit from therapy, unacceptable toxicity occurred or the participant met a treatment discontinuation criterion (Maximum treatment duration was 126 days for gilteritinib and 70 days for atezolizumab).

Interventions: intervention 1: gilteritinib intervention 2: atezolizumab
Intervention descriptions: intervention 1: Oral tablet intervention 2: Intravenous infusion

Protocol document:
Prot_000.pdf: 
Sponsor: APGD 
ISN/Protocol 2215-CL-1101 
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09 Dec 2020 
Astellas 
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Version 3.2 Incorporating Nonsubstantial Amendment 3 
Phase 1/2 Study of ASP2215 (Gilteritinib) Combined with 
Atezolizumab in Patients with Relapsed or Treatment Refractory 
FLT3 Mutated Acute Myeloid Leukemia (AML) 
Protocol for Phase 1/2 Study of ASP2215 
ISN/Protocol 2215-CL-1101 
Version 3.2 
Incorporating Nonsubstantial Amendment 3 [See Section 13] 
09 Dec 2020 
IND 117548 
Sponsor: 
Astellas Pharma Global Development, Inc. (APGD) 
1 Astellas Way 
Northbrook, IL 60062 
Protocol History: 
Version 1.0 Original [21Jun2018] 
Version 1.1 Incorporating Nonsubstantial Amendment 1 [17Oct2018] 
Version 2.0 Incorporating Substantial Amendment 1 [15Jan2019] 
Version 3.0 Incorporating Substantial Amendment 2 [05Dec2019] 
Version 3.1 Incorporating Nonsubstantial Amendment 2 [24Mar2020] 
The information contained in this document is supplied as a background for clinical investigations. This document contains 
confidential information which is the intellectual property of Astellas. By accepting or reviewing this document, you agree 
to hold this information in confidence and not copy or disclose it to others or use it for unauthorized purposes except (1) as 
otherwise agreed to in writing; (2) where required by applicable law; (3) where disclosure is directly related to the care and 
safety of the research participant; and (4) where disclosure of such information is made to a member of the investigator’s 
team who agrees to hold this information in confidence.  
NCT03730012


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Table of Contents  
I. 
SIGNATURES ······················································································ 8 
II. 
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL ···························· 10 
III. 
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS ·················· 11 
IV. 
SYNOPSIS ·························································································· 15 
V. 
FLOW CHARTS AND SCHEDULE OF ASSESSMENTS ······························· 25 
1 
INTRODUCTION ················································································· 29 
1.1 
Background ···················································································· 29 
1.2 
Nonclinical and Clinical Data ······························································· 31 
1.2.1 
Nonclinical Data – Gilteritinib ························································· 31 
1.2.2 
Nonclinical Data – Atezolizumab ····················································· 31 
1.2.3 
Clinical Data - Gilteritinib ······························································ 31 
1.2.3.1 
Studies Using Human Biomaterials ············································· 31 
1.2.3.2 
Clinical Pharmacokinetics and Pharmacodynamics ··························· 31 
1.2.3.3 
Clinical Safety······································································ 32 
1.2.3.4 
Clinical Efficacy ··································································· 33 
1.2.4 
Clinical Data – Atezolizumab ·························································· 33 
1.3 
Summary of Key Safety Information for Study Drugs ··································· 33 
1.3.1 
Key Safety Information - Gilteritinib ················································· 33 
1.3.2 
Key Safety Information - Atezolizumab ·············································· 35 
1.4 
Risk Benefit Assessment ····································································· 36 
2 
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS ·································· 37 
2.1 
Study Objective(s) ············································································ 37 
2.1.1 
Primary Objectives ······································································ 37 
2.1.2 
Secondary Objectives ··································································· 37 
2.1.3 
Exploratory Objectives ································································· 37 
2.2 
Study Design and Dose Rationale ··························································· 38 
2.2.1 
Study Design ············································································· 38 
2.2.2 
Dose Rationale ··········································································· 39 
2.3 
Endpoints ······················································································· 40 
2.3.1 
Primary Endpoints ······································································· 40 
2.3.2 
Secondary Endpoints ···································································· 40 
2.3.3 
Exploratory Endpoints ·································································· 40 


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3 
STUDY POPULATION ·········································································· 41 
3.1 
Selection of Study Population ······························································· 41 
3.2 
Inclusion Criteria ·············································································· 41 
3.3 
Exclusion Criteria ············································································· 42 
4 
TREATMENT(S) ·················································································· 44 
4.1 
Identification of Investigational Product(s) ················································ 44 
4.1.1 
Study Drug(s) ············································································ 44 
4.2 
Packaging and Labeling ······································································ 44 
4.3 
Study Drug Handling ········································································· 45 
4.4 
Blinding ························································································ 45 
4.5 
Assignment and Allocation ·································································· 45 
5 
TREATMENTS AND EVALUATION ························································ 46 
5.1 
Dosing and Administration of Study Drug(s) and Other Medication(s) ················ 46 
5.1.1 
Dose/Dose Regimen and Administration Period ···································· 46 
5.1.1.1 
Gilteritinib Dosing ································································· 46 
5.1.1.2 
Gilteritinib Subject Diary ························································· 46 
5.1.1.3 
Atezolizumab Dosing ····························································· 46 
5.1.1.4 
Combination Dosing ······························································ 47 
5.1.2 
Reduction in Dose of the Study Drug(s) ·············································· 47 
5.1.2.1 
Gilteritinib Dose Reduction ······················································ 47 
5.1.3 
Atezolizumab Dose Interruption ······················································· 48 
5.1.3.1 
Additional Dosing Interruption Guidelines ····································· 49 
5.1.4 
Previous and Concomitant Treatment (Medication and Non-Medication 
Therapy) ·················································································· 50 
5.1.5 
Treatment Compliance ·································································· 51 
5.1.6 
Criteria for Continuation of Treatment ··············································· 51 
5.1.7 
Restrictions During the Study ·························································· 51 
5.2 
Demographics and Baseline Characteristics ··············································· 51 
5.2.1 
Demographics ············································································ 51 
5.2.2 
Medical History ·········································································· 51 
5.2.3 
Diagnosis of the Target Disease, Severity, and Duration of Disease ·············· 51 
5.2.3.1 
Disease History ···································································· 51 
5.2.3.2 
FMS-like Tyrosine Kinase Mutation Status ···································· 51 
5.2.4 
Performance Status ······································································ 52 


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5.3 
Efficacy Assessments ········································································· 52 
5.3.1 
Bone Marrow Aspirate and Biopsy ··················································· 52 
5.3.2 
Response Assessments ·································································· 52 
5.3.2.1 
Composite Complete Remission (CRc) rate ···································· 52 
5.3.2.2 
Complete Remission (CR) ························································ 53 
5.3.2.3 
Complete Remission with Incomplete Platelet Recovery (CRp) ············· 53 
5.3.2.4 
Complete Remission with Incomplete Hematological Recovery (CRi) ····· 53 
5.3.2.5 
Complete Remission with Partial Hematologic Recovery (CRh) ············ 53 
5.3.2.6 
Partial Remission (PR) ···························································· 53 
5.3.2.7 
Relapse ·············································································· 53 
5.3.2.8 
Treatment Failure ·································································· 53 
5.3.2.9 
Best Response ······································································ 53 
5.3.3 
Survival Time, Duration of Response and Other Efficacy Endpoints ············· 54 
5.3.3.1 
Survival Status and Subsequent Antileukemic Treatments and Their 
Outcomes ··········································································· 54 
5.3.3.2 
Overall Survival ···································································· 54 
5.3.3.3 
Event-free Survival ································································ 54 
5.3.3.4 
Duration of Remission ···························································· 55 
5.4 
Safety Assessment ············································································ 55 
5.4.1 
Vital Signs ················································································ 55 
5.4.2 
Laboratory Assessments ································································ 55 
5.4.3 
Physical Examination ··································································· 56 
5.4.4 
Electrocardiogram ······································································· 56 
5.4.5 
Chest X-ray or Computed Tomography Scan ········································ 57 
5.4.6 
Multigated Acquisition Scan or Echocardiogram ··································· 57 
5.5 
Adverse Events and Other Safety Aspects ················································· 57 
5.5.1 
Definition of Adverse Events ·························································· 57 
5.5.1.1 
Abnormal Laboratory Findings ·················································· 57 
5.5.1.2 
Potential Cases of Drug-Induced Liver Injury ································· 58 
5.5.1.3 
Disease Progression and Study Endpoints ······································ 58 
5.5.2 
Definition of Serious Adverse Events (SAEs) ······································· 58 
5.5.2.1 
Always Serious Adverse Events ················································· 59 
5.5.3 
Criteria for Causal Relationship to Study Drug ······································ 59 
5.5.4 
Criteria for Defining the Severity of an Adverse Event ···························· 60 
5.5.5 
Reporting of Serious Adverse Events (SAEs) ······································· 60 


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5.5.6 
Follow-up of Adverse Events ·························································· 62 
5.5.7 
Monitoring of Common Serious Adverse Events ··································· 62 
5.5.8 
Adverse Events of Special Interest (AESI) (Immediately Reportable to the 
Sponsor) ·················································································· 62 
5.5.9 
Special Situations ········································································ 63 
5.5.9.1 
Pregnancy ··········································································· 63 
5.5.9.2 
Medication Error, Overdose and “Off-Label Use” ···························· 64 
5.5.9.3 
Misuse/Abuse ······································································ 64 
5.5.9.4 
Occupational Exposure ··························································· 64 
5.5.9.5 
Suspected Drug-Drug Interaction ················································ 64 
5.5.10 
Supply of New Information Affecting the Conduct of the Study ·················· 65 
5.5.11 
Urgent Safety Measures ································································ 65 
5.5.12 
Reporting Urgent Safety Measures ···················································· 65 
5.6 
Test Drug Concentration ····································································· 65 
5.6.1 
Pharmacokinetics ········································································ 65 
5.7 
Other Measurements, Assessments or Methods ··········································· 66 
5.7.1 
Blood and Buccal Swab Sample for Banked Pharmacogenomic Sample 
Analysis··················································································· 66 
5.7.2 
Exploratory Biomarker ································································· 66 
5.7.3 
Resource Utilization ···································································· 67 
5.8 
Total Amount of Blood ······································································· 67 
6 
DISCONTINUATION ············································································ 67 
6.1 
Discontinuation of Individual Subject(s) From Study Treatment ······················· 67 
6.1.1 
Lost to Follow Up ······································································· 69 
6.2 
Discontinuation of the Site ··································································· 69 
6.3 
Discontinuation of the Study································································· 69 
7 
STATISTICAL METHODOLOGY ··························································· 69 
7.1 
Sample Size ···················································································· 70 
7.2 
Analysis Sets ··················································································· 71 
7.2.1 
Full Analysis Set (FAS) ································································ 71 
7.2.2 
Per Protocol Set (PPS) ·································································· 71 
7.2.3 
Safety Analysis Set (SAF) ······························································ 71 
7.2.4 
Pharmacokinetics Analysis Set (PKAS) ·············································· 71 
7.2.5 
Biomarker Analysis Set (BMAS) ······················································ 72 


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7.3 
Demographics and Baseline Characteristics ··············································· 72 
7.3.1 
Demographics ············································································ 72 
7.3.2 
Subject Disposition ······································································ 72 
7.3.3 
Previous and Concomitant Medications ·············································· 72 
7.3.4 
Medical History ·········································································· 72 
7.3.5 
Disease History ·········································································· 72 
7.3.6 
Treatment Compliance ·································································· 72 
7.3.7 
Extent of Exposure ······································································ 72 
7.4 
Analysis of Efficacy ·········································································· 73 
7.4.1 
Analysis of Efficacy Variables ························································ 73 
7.5 
Analysis of Safety ············································································· 73 
7.5.1 
Adverse Events ·········································································· 73 
7.5.2 
Laboratory Assessments ································································ 73 
7.5.3 
Vital Signs ················································································ 74 
7.5.4 
Physical Examination ··································································· 74 
7.5.5 
Routine 12-lead Electrocardiograms ·················································· 74 
7.6 
Analysis of Pharmacokinetics ······························································· 74 
7.7 
Analysis of Pharmacodynamics ····························································· 74 
7.8 
Analysis of Biomarkers······································································· 74 
7.9 
Major Protocol Deviations and Other Analyses ··········································· 74 
7.10 
Interim Analysis (and Early Discontinuation of the Clinical Study) ···················· 75 
7.11 
Handling of Missing Data, Outliers, Visit Windows, and Other Information ········· 75 
8 
OPERATIONAL CONSIDERATIONS ······················································· 75 
8.1 
Data Collection ················································································ 75 
8.2 
Screen Failures ················································································ 76 
8.3 
Major Protocol Deviations ··································································· 76 
9 
END OF TRIAL ··················································································· 76 
10 
STUDY ORGANIZATION ······································································ 77 
10.1 
Independent Data-Monitoring Committee (IDMC) | Data and Safety Monitoring 
Board (DSMB) | Monitoring Committee | Adjudication Committee | Other 
Evaluation Committee(s) ····································································· 77 
10.2 
Other Study Organization ···································································· 77 
11 
REFERENCES ···················································································· 78 


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12 
APPENDICES ····················································································· 81 
12.1 
Ethical, Regulatory, and Study Oversight Considerations ······························· 81 
12.1.1 
Ethical Conduct of the Study ··························································· 81 
12.1.2 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ········ 81 
12.1.3 
Protocol Amendment and/or Revision ················································ 81 
12.1.4 
Financial Disclosure ···································································· 82 
12.1.5 
Informed Consent of Subjects ························································· 82 
12.1.5.1 
Subject Information and Consent ················································ 82 
12.1.5.2 
Supply of New and Important Information Influencing the Subject’s 
Consent and Revision of the Written Information ····························· 82 
12.1.6 
Source Documents ······································································ 83 
12.1.7 
Record Retention ········································································ 83 
12.1.8 
Subject Confidentiality and Privacy ··················································· 83 
12.1.9 
Arrangement for Use of Information and Publication of the Clinical Study ····· 84 
12.1.10 
Signatory Investigator for Clinical Study Report ···································· 84 
12.2 
Procedure for Clinical Study Quality Control ············································· 85 
12.2.1 
Clinical Study Monitoring ······························································ 85 
12.2.2 
Direct Access to Source Data/Documents ············································ 85 
12.2.3 
Data Management ······································································· 85 
12.2.4 
Quality Assurance ······································································· 85 
12.3 
Contraception Requirements ································································· 86 
12.4 
List of Prohibited and/or Concomitant Medications to be Use with Caution ·········· 88 
12.5 
Liver Safety Monitoring and Assessment ·················································· 92 
12.6 
Common Serious Adverse Events ··························································· 95 
12.7 
Adverse Events of Special Interest (AESI) for Atezolizumab ··························· 97 
12.8 
Laboratory Assessments ······································································ 98 
12.9 
Pharmacogenomic (PGx) Analysis With Banked Sample (Optional) ················ 100 
12.10 
Clinical Study Continuity ·································································· 102 
13 
ATTACHMENT 1:  NONSUBSTANTIAL AMENDMENT 3 ·························· 108 
14 
SPONSOR SIGNATURES ···································································· 118 
 


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I. 
SIGNATURES 
1.  SPONSOR’S SIGNATURES 
Required signatures (e.g., Protocol authors and contributors, etc.) are located in [Section 14 
Sponsor Signature]. 
 


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2.  INVESTIGATOR’S SIGNATURE 
Phase 1/2 Study of ASP2215 (Gilteritinib) Combined with Atezolizumab in 
Patients with Relapsed or Treatment Refractory FLT3 Mutated Acute Myeloid 
Leukemia (AML) 
ISN/Protocol 2215-CL-1101  
Version 3.2 Incorporating Nonsubstantial Amendment 3 
09 Dec 2020 
I have read all pages of this clinical study protocol for which Astellas is the sponsor. I agree to 
conduct the study as outlined in the protocol and to comply with all the terms and conditions set out 
therein. I confirm that I will conduct the study in accordance with International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical 
Practice (GCP) guidelines and applicable local regulations. I will also ensure that subinvestigator(s) 
and other relevant members of my staff have access to copies of this protocol and the ICH GCP 
guidelines to enable them to work in accordance with the provisions of these documents. 
Principal Investigator: 
Signature:  
 
 
 
Date (DD Mmm YYYY) 
Printed 
Name: 
 
  
<Insert name and qualification of the investigator> 
Address: 
 
 
 
 




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III. 
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS 
List of Abbreviations 
Abbreviations 
Description of abbreviations 
ADR 
adverse drug reaction 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUCinf 
area under the concentration-time curve from the time of dosing extrapolated to 
time infinity 
AUClast 
area under the concentration-time curve from the time of dosing up to the time of 
the last measurable concentration 
AUCtau 
area under the concentration-time curve from the time of dosing to the start of the 
next dosing interval at multiple dose conditions 
AUST 
Astellas United States Technologies (AUST) 
AXL 
a receptor tyrosine kinase encoded by the AXL gene 
BCRP 
breast cancer resistance protein 
BMAS 
biomarker analysis set 
CA 
Competent Authorities 
cEC 
Concerned Ethics Committee 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
creatine kinase 
CL/F 
apparent total clearance after extravascular dosing 
Cmax 
maximum concentration 
CR 
complete remission 
CRc 
composite complete remission 
CRh 
complete remission with partial hematologic recovery  
CRi 
complete remission with incomplete hematologic recovery 
CRp 
complete remission without platelet recovery 
CRF 
case report form 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
concentration immediately prior to dosing at multiple dosing 
CV 
coefficient of variation 


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Abbreviations 
Description of abbreviations 
CYP 
cytochrome P450 
DEC 
Dose Evaluation Committee 
DLT 
dose limiting toxicity 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EEA 
European Economic Area 
EFS 
event-free survival 
EOT 
end of treatment 
FAS 
full analysis set 
FEV1 
forced expiratory volume in the first second 
FLT3 
FMS-like tyrosine kinase 3 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practices 
GVHD 
graft-versus-host disease 
HSCT 
hematopoietic stem cell transplantation 
IB 
Investigator’s Brochure 
IC50 
concentration of an inhibitor where the response (or binding) is reduced by half 
ICF 
informed consent form 
ICH  
International Council for Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISN 
international study number 
ITD 
internal tandem duplication 
LA-CRF 
liver abnormality case report form 
LFT 
liver function tests 
MATE 
multidrug and toxin extrusion 
MDS 
myelodysplastic syndrome 
MRD 
minimal residual disease 
MTD 
maximum tolerated dose 
MUGA 
multigated acquisition 
NCI 
National Cancer Institute 
NYHA 
New York Heart Association 


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Abbreviations 
Description of abbreviations 
OCT 
organic cation transporter 
OATP 
organic anion transporting polypeptide 
OS 
overall survival 
P-gp 
P-glycoprotein 
PD-L1 
programmed death-ligand 1 
PGx 
pharmacogenomic 
PKAS 
pharmacokinetics analysis set 
PPS 
per protocol set 
PR 
partial remission 
q2w 
once every 2 weeks 
QTcF 
Fridericia-corrected QT interval 
RBC 
red blood cell 
RP2D 
recommended phase 2 dose 
SAE 
serious adverse event 
SAF 
safety analysis set 
SAP 
Statistical Analysis Plan 
SOP 
Standard Operating Procedures 
SPC 
summary of product characteristics 
SUSAR 
suspected unexpected serious adverse reactions 
t½ 
terminal elimination half-life 
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse event 
tmax 
time of the maximum concentration  
ULN 
upper limit of normal 
USM 
urgent safety measure 
Vz/F 
apparent volume of distribution during the terminal elimination phase after 
extravascular dosing 
WOCBP 
woman of childbearing potential 
 


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Definition of Key Study Terms 
Terms 
Definition of terms 
Baseline  
Assessments of subjects as they enter a study before they receive any 
treatment.  
Endpoint  
Variable that pertains to the efficacy or safety evaluations of a study. 
Enroll 
To register or enter a subject into a clinical study. NOTE: Once a subject has 
received the study drug or placebo, the clinical study protocol applies to the 
subject.  
Intervention 
The drug, device, therapy or process under investigation in a clinical study that 
is believed to have an effect on outcomes of interest in a study (e.g., health-
related quality of life, efficacy, safety and pharmacoeconomics).  
Investigational 
period 
Period of time where major interests of protocol objectives are observed, and 
where the test drug or comparative drug is usually given to a subject, and 
continues until the last assessment after completing administration of the test 
drug or comparative drug. 
Post investigational 
period 
Period of time after the last assessment of the protocol. Follow-up observations 
for sustained adverse events and/or survival are done in this period. 
Screening 
A process of active consideration of potential subjects for enrollment in a 
study. 
Screen failure 
Potential subject who did not meet 1 or more criteria required for participation 
in a study. 
Screening period 
Period of time before entering the investigational period, usually from the time 
when a subject signs the consent until just before the test drug or comparative 
drug is given to a subject.  
Study period 
Period of time from the first site initiation date to the last site completing the 
study. 
Variable 
Any entity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values. 
 


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IV. 
SYNOPSIS 
Date and Version No of Protocol Synopsis: 
09 Dec 2020, Version 3.2 
Sponsor:   
Astellas Pharma Global Development Inc. (APGD) 
Protocol Number:  
2215-CL-1101 
Name of Study Drug:  
ASP2215/Gilteritinib 
Phase of Development:   
Phase 1/2 
Title of Study:   
Phase 1/2 Study of ASP2215 (Gilteritinib) Combined with Atezolizumab in Patients with Relapsed or 
Treatment Refractory FLT3 Mutated Acute Myeloid Leukemia (AML) 
Planned Study Period:  
From 4Q2018 to 2Q2024. 
Study Objective(s):  
The primary objectives are to: 
• 
Determine the safety and tolerability of gilteritinib given in combination with atezolizumab in 
subjects with relapsed or treatment refractory FMS-like tyrosine kinase 3 (FLT3) mutated acute 
myeloid leukemia (AML). 
• 
Determine the composite complete remission (CRc) rate for subjects with relapsed or treatment 
refractory FLT3 mutated AML who either discontinued the study or completed  
2 cycles of gilteritinib given in combination with atezolizumab. CRc is defined as a complete 
remission (CR), complete remission without platelet recovery (CRp) or complete remission with 
incomplete hematologic recovery (CRi).  
The secondary objectives are to: 
• 
Characterize the pharmacokinetics of gilteritinib and its active metabolites (if appropriate) when 
given in combination with atezolizumab. 
• 
Evaluate the safety and efficacy of gilteritinib in combination with atezolizumab in terms of: 
o Gilteritinib trough plasma concentrations (Ctrough)  
o CR rate 
o CR with partial hematologic recovery (CRh) 
o Best response rate (CRc + partial remission [PR]) 
o Duration of remission 
o Event-free Survival (EFS) 
o Overall Survival (OS) 
o Adverse events (AEs), clinical laboratory results, vital signs, electrocardiograms (ECGs), and 
Eastern Cooperative Oncology Group (ECOG) performance status scores 
The exploratory objectives are to: 
• 
Evaluate efficacy of gilteritinib given in combination with atezolizumab in terms of minimal 
residual disease (MRD) 
• 
Evaluate potential genomic, proteomic and/or other biomarkers that may correlate with treatment 
outcome 
• 
Evaluate pharmacodynamic biomarkers of treatment effect  
• 
Evaluate immune cell populations and AML blasts by immunophenotyping in relation to 
treatment effects  
Planned Total Number of Study Centers and Location(s):   
15 sites in the United States 


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Study Population:   
Patients with relapsed or treatment refractory FLT3 mutated AML. 
Number of Subjects to be Enrolled:   
Up to 61 subjects who are evaluable for response including up to 12 subjects in the phase 1 portion 
and up to 49 subjects in the phase 2 portion. 
Study Design Overview:   
This is an open-label, single arm, phase 1/2 study to evaluate the safety and efficacy of combining 
gilteritinib with atezolizumab for subjects with relapsed or treatment refractory FLT3 mutated AML. 
This study will have 2 phases.  
Phase 1: 
The phase 1 portion of this study is a dose-escalation phase with a 3 + 3 design to establish the 
recommended phase 2 dose (RP2D) of gilteritinib given in combination with atezolizumab. Up to 
12 subjects will be enrolled in cohorts of 3 to 6 subjects to determine the RP2D following the dose 
levels of the combination treatment outlined in the table below. Dose escalation decisions will be 
made based on DLTs that occur during the first cycle of treatment. A cycle is defined as 28 days. The 
treatment will consist of 3 distinct periods; remission induction, consolidation and maintenance.  
The dose limiting toxicity (DLT) observation period will be from cycle 1/day 1 through 
cycle 1/day 28. Evaluable subjects are defined as subjects who experience a DLT or in the absence of 
DLT, receive at least 23/28 doses of gilteritinib and at least 1/2 doses of atezolizumab. Subjects who 
are later discovered not to meet eligibility criteria or are not evaluable for DLT may be replaced.  
Dose evaluation rules based on the 3 + 3 design and dose escalation rules are as follows: 
Number of Subjects with DLT at the Given Dose 
During the DLT Observation Period 
Escalation Decision Rules 
0 of 3 or ≤ 1 of 6 subjects 
Escalate and enter up to 3 subjects at the next dose 
level, if next dose level available. If at dose level 2, 
determine if RP2D. 
1 of 3 subjects 
Enter up to 3 subjects at the same dose level. 
≥ 2 subjects 
De-escalate or stop escalating. 
DLT: dose limiting toxicity; RP2D: recommended phase 2 dose  
The Dose Evaluation Committee (DEC) will consist of the sponsor, principal investigators, and if 
appropriate, expert consultants who will be responsible for the review of safety data through the DLT 
observation period for each cohort. The decision will be made by the DEC to escalate to the next 
planned dose level, to remain at the same dose level, de-escalate to the dose level below or stop 
escalation. The RP2D will be selected based on the DEC’s review of all available data at each dose 
level, including safety and pharmacokinetic data (if available), and the RP2D will become the 
minimum safe and biologically effective dose level. Additional details regarding responsibilities and 
membership requirements will be included in the Subject Enrollment and DEC Plan. The subjects in 
the first cohort will be treated with gilteritinib 120 mg orally once daily and atezolizumab 420 mg 
once every 2 weeks by intravenous infusion. The subjects in the second cohort will be dosed based on 
the results of the first cohort and according to the dose level table below. 


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Dose Level 
Dose- 
Atezolizumab 
Dose- 
Gilteritinib 
1 
420 mg q2w 
120 mg once daily 
-1 
420 mg q2w 
80 mg once daily 
2 
840 mg q2w  
120 mg once daily 
q2w: once every 2 weeks 
Phase 2: 
In the phase 2 portion with 2 stages, up to 49 subjects will be enrolled. The subjects will be treated 
with gilteritinib and atezolizumab at the RP2D. In the first stage, 22 subjects will be enrolled. The 
subjects enrolled at the first stage of phase 2 will be used to calculate the CRc rate for the first stage. 
If the minimum CRc rate criterion (i.e., at least 12 CRc responders out of 22 subjects) is met, an 
additional 27 subjects will be enrolled for the second stage. 
Inclusion/Exclusion Criteria:   
Inclusion:   
Subject is eligible for the study if all of the following apply: 
1. Institutional Review Board-/Independent Ethics Committee-approved written Informed Consent 
and privacy language as per national regulations (e.g., Health Insurance Portability and 
Accountability Act Authorization for United States sites) must be obtained from the subject or 
legally authorized representative prior to any study-related procedures (including withdrawal of 
prohibited medication, if applicable).   
2. Subject is considered an adult according to local regulation at the time of signing informed 
consent form (ICF).  
3. Subject has defined AML by the WHO criteria (2017) and fulfills one of the following: 
• 
Refractory to at least 1 cycle of induction chemotherapy 
• 
Relapsed after achieving remission with a prior therapy 
4. Subject is positive for FLT3 mutation in bone marrow or blood after completion of subject’s last 
interventional treatment as determined by the local institution.  
5. Subject has an ECOG performance status ≤ 2 at screening. 
6. Subject must meet the following criteria as indicated on the clinical laboratory tests: 
• Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper 
limit of normal (ULN) 
• Serum total bilirubin ≤ 1.5 x ULN 
• Serum creatinine ≤ 1.5 x ULN or an estimated glomerular filtration rate of > 50 mL/min as 
calculated by the Modification of Diet in Renal Disease equation. 
7. Subject is suitable for oral administration of study drug. 
8. A female subject is eligible to participate if she is not pregnant [see Appendix 12.3 Contraception 
Requirements] and at least one of the following conditions applies: 
• Not a woman of childbearing potential (WOCBP) as defined in [Appendix 12.3 
Contraception Requirements] 
OR 
• WOCBP who agrees to follow the contraceptive guidance as defined in [Appendix 12.3 
Contraception Requirements] throughout the treatment period and for at least 180 days after 
the final study drug administration. 
9. Female subject must agree not to breastfeed starting at screening and throughout the study period, 
and for at least 180 days after the final study drug administration. 


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10. Female subject must not donate ova starting at screening and throughout the study period, and for 
at least 180 days after the final study drug administration. 
11. A male subject must not donate sperm starting at screening and throughout the treatment period, 
and for at least 120 days after the final study drug administration. 
12. A male subject with female partner(s) of child-bearing potential must agree to use contraception 
as detailed in [Appendix 12.3 Contraception Requirements] during the treatment period, and for at 
least 120 days after the final study drug administration. 
13. Male subject 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 120 days after the final study drug administration 
14. Subject agrees not to participate in another interventional study while on treatment. 
Waivers to the inclusion criteria will NOT be allowed. 
Exclusion:   
Subject will be excluded from participation if any of the following apply: 
1. Subject was diagnosed as acute promyelocytic leukemia. 
2. Subject has BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast crisis). 
3. Subject has AML secondary to prior chemotherapy for other neoplasms (except for 
myelodysplastic syndrome [MDS]). 
4. Subject has clinically active central nervous system leukemia. 
5. Subject has uncontrolled or significant cardiovascular disease, including: 
• A myocardial infarction within 12 months 
• Uncontrolled angina within 6 months 
• History of clinically significant ventricular arrhythmias (such as ventricular tachycardia, 
ventricular fibrillation, torsades de pointes) or any history of arrhythmia  
• Uncontrolled hypertension 
6. Subject has baseline left ventricular ejection fraction (LVEF) that is < 45%.  
7. Subject has mean of triplicate Fridericia-corrected QT interval (QTcF) > 450 ms at screening 
based on central reading.  
8. Subject has congenital or acquired Long QT Syndrome at screening. 
9. Subject has hypokalemia and/or hypomagnesemia at screening (defined as values below 
institutional lower limit of normal). 
10. Subject has been diagnosed with another malignancy that requires concurrent treatment or hepatic 
malignancy regardless of the need for treatment.  
11. Subject has clinically significant coagulation abnormality unless secondary to AML in the 
opinion of the investigator. 
12. Subject is receiving or plans to receive concomitant chemotherapy or immunotherapy other than 
as specified in the protocol. 
13. Subject has had major surgery within 4 weeks prior to the first study dose. 
14. Subject has radiation therapy within 4 weeks prior to the first study dose. 
15. Subject requires treatment with concomitant drugs that are strong inducers of CYP3A. 
16. Subject has known pulmonary disease with diffusion capacity of lung for carbon monoxide 
≤ 65%, forced expiratory volume in the first second (FEV1) ≤ 65%, dyspnea at rest or requiring 
oxygen or any pleural neoplasm.  


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17. Subject with systemic fungal, bacterial, viral or other uncontrolled infection that is exhibiting 
ongoing signs/symptoms related to the infection without improvement despite appropriate 
antibiotics or other treatment. The patient needs to be off pressors and have negative blood 
cultures for 48 hours. 
18. Subject has not recovered from any prior therapy related toxicities, as determined by investigator. 
19. Subject is known to have human immunodeficiency virus infection.  
20. Subject has active hepatitis B or C or other active hepatic disorder. 
21. Subject has previously been treated with gilteritinib, quizartinib or crenolanib (will only apply to 
subjects enrolled in the phase 2 portion of the study). 
22. Subject has active clinically significant graft-versus-host disease (GVHD) or is on treatment with 
systemic corticosteroids for GVHD. 
23. Subject has relapsed after allogeneic HSCT. 
24. Subject has an active autoimmune disorder that in the opinion of the investigator makes the 
subject unsuitable for study treatment or participation. 
25. Subject has any condition, which, in the investigator’s opinion, makes the subject unsuitable for 
study participation, including any contraindications of atezolizumab listed in the current 
Investigator’s Brochure (IB). 
Waivers to the exclusion criteria will NOT be allowed. 
Investigational Product(s): 
Gilteritinib tablets containing 40 mg of active ingredients  
Atezolizumab vials containing 60 mg/mL (1200 mg/20 mL) of active ingredients   
Dose(s):   
Subjects will be treated with gilteritinib 120 mg or 80 mg once daily and atezolizumab 420 mg or 
840 mg once every 2 weeks for the phase 1 portion of the study. The primary objective will be to 
establish an RP2D of gilteritinib in combination with atezolizumab. The RP2D will be determined by 
the DEC and will be the minimum safe and biologically effective dose level based on data from the 
phase 1 portion of the study. 
In the phase 2 portion, the subjects will be treated with gilteritinib and atezolizumab at RP2D. 
Mode of Administration: 
Gilteritinib will be administered orally. 
Atezolizumab will be administered by intravenous infusion over 60 minutes, and if the first infusion 
is tolerated, all subsequent infusions may be delivered over 30 minutes. 
Comparative Drug(s): 
Not applicable 
Concomitant Medication Restrictions or Requirements:    
The following medications are prohibited during the course of the program: 
• 
Strong inducers of CYP3A. 
• 
Therapies to treat AML including, but not limited to: 
o Chemotherapy 
o Immunotherapy, cellular therapy or vaccines 
Exceptions: Hydroxyurea, intrathecal chemotherapy, cranial irradiation, localized radiation for 
palliation.  
• 
Any other investigational agent for AML. 


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Caution is advised when considering the concomitant use of the following medications: 
• 
Medications known to prolong QT or QTcF intervals. 
• 
Strong inhibitors or inducers of P-glycoprotein and concomitant drugs that target serotonin 
5HT2BR 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. If CYP3A inhibitors are used concomitantly, subjects should be closely 
monitored for AEs. 
Precaution is advised in the use of gilteritinib (ASP2215) with concomitant drugs that are substrates 
of breast cancer resistance protein, since the transporter has been shown to be inhibited by gilteritinib 
(ASP2215) in in vitro studies. 
Duration of Treatment:   
Subjects will be treated until they no longer derive clinical benefit in the judgment of the treating 
physician, have unacceptable toxicity, undergo hematopoietic stem cell transplantation (HSCT), or 
meet 1 of the discontinuation criteria; whichever occurs first. 
Definition of Dose Limiting Toxicity:   
In phase 1, a DLT is defined as any of the following events that occur within the observation period 
(cycle 1/day 1 through cycle 1/day 28) and that is considered to be possibly or probably related to 
study regimen. In phase 2, the DLT observation period is the first treatment cycle (cycle 1/day1 
through cycle 1/day28). 
• Confirmed Hy’s law case 
• Any Grade ≥ 3 non-hematologic or extramedullary toxicity with the following exceptions: 
o Anorexia or fatigue 
o Grade 3 nausea and/or vomiting if not requiring tube feeding or TPN, or diarrhea if not 
requiring or prolonging hospitalization that can be managed to grade ≤ 2 with standard 
antiemetic or antidiarrheal medications used at prescribed dose within 7 days of onset 
o Grade 3 mucositis that resolved to grade ≤ 2 within 7 days of onset 
o Grade 3 fever with neutropenia, with or without infection* 
o Grade 3 infection* 
o Grade 3 infusion-related toxicity, if successfully managed and resolves within 72 hours. 
*Toxicities are excluded only if the event is an expected direct complication of cytopenias due to the 
active underlying leukemia. 
Hematologic toxicity will not be considered as a DLT. However, prolonged myelosuppression defined 
as absolute neutrophil count (ANC) ≤ 0.5 × 109/L for more than 21 days from the onset of severe 
neutropenia in the absence of evidence of active leukemia in the marrow and blood will be considered 
as a DLT. 
Discontinuation of Treatment:  
Subjects who meet any of the following criteria during the study will be withdrawn from study 
treatment: 
• 
Subject declines further study participation (i.e., withdrawal of consent). 
• 
Subject is non-compliant with protocol based on the investigator or medical monitor assessment. 
• 
Subject is found to have significantly deviated from any one of the inclusion or exclusion criteria 
after enrollment (subjects having clinical benefit and no DLT may be kept in the study after 
discussion with the medical monitor). 


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• 
Subject develops an unacceptable study DLT or serious adverse event (SAE) requiring 
discontinuation of treatment. 
• 
Subject has not achieved PR or CRc, and in the opinion of the investigator, is no longer deriving 
clinical benefit after 6 cycles of therapy. 
• 
Gilteritinib dose is interrupted for greater than 15 days. Subjects may be allowed to continue 
treatment after discussions with the medical monitor if the interruption was not due to a 
gilteritinib related AE. 
• 
Subject receives any antileukemic therapy (including HSCT) other than the assigned treatment, 
with the exception of hydroxyurea up to 5 g daily for up to 2 weeks, prophylactic intrathecal 
chemotherapy or cranial irradiation. 
• 
Investigator/subinvestigator determines that the continuation of the study treatment will be 
detrimental to the subject. 
• 
Subject is lost to follow-up despite reasonable efforts by the investigator to locate the subject. 
• 
Female subject becomes pregnant. 
• 
Death. 
• 
Subject is receiving gilteritinib, atezolizumab, or the combination of gilteritinib + atezolizumab 
and has progressive disease, recurrence under treatment, and in the opinion of the investigator the 
subject is no longer deriving clinical benefit. 
The subject will be discontinued from the long term treatment period if any of the following occur: 
• 
Subject declines further study participation (i.e., withdraws consent) 
• 
Subject is lost to follow-up despite reasonable efforts by the investigator to locate the subject. 
• 
More than 3 years has passed from the End of Treatment (EOT) Visit. 
• 
Death 
Endpoints for Evaluation:   
Primary: 
• 
Safety and tolerability (development of DLTs and AEs and define RP2D) 
• 
CRc rate 
Secondary: 
• 
Gilteritinib trough plasma concentrations (Ctrough)  
• 
CR rate 
• 
CR with partial hematologic recovery (CRh) 
• 
Best response rate 
• 
Duration of remission 
• 
EFS 
• 
OS 
• 
AEs, clinical laboratory results, vital signs, ECGs and ECOG 
Exploratory: 
• 
MRD in relation to clinical outcomes 
• 
Evaluate potential genomic, proteomic and/or other biomarkers that may correlate with treatment 
outcome 
• 
Evaluate pharmacodynamic biomarkers of treatment effect  
• 
Evaluate immune cell populations and AML blasts by immunophenotyping in relation to 
treatment effects 
 


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Statistical Methods:  
Sample Size Justification:  
Phase 1 
The sample size in phase 1 is based on 3+3 design and not based on power calculation. 
Phase 2 
Simon’s 2-stage design [Simon, 1989] will be used in the study to evaluate the efficacy in terms of 
CRc rate for the selected combination dose level of gilteritinib and atezolizumab. The null hypothesis 
that the true CRc rate is 50% will be tested against a 1-sided alternative. In the first stage, the CRc of 
22 subjects will be evaluated. If there are 11 or fewer subjects with CRc from these 22 subjects by the 
end of cycle 2, the study will be stopped. Otherwise, 27 additional subjects will be accrued for a total 
of 49 subjects evaluable for calculation of CRc rate. The null hypothesis will be rejected if 32 or more 
subjects with CRc are observed in the 49 subjects by the end of cycle 2. This design yields a 1-sided 
type I error rate of 0.025 and power of 80% when the true CRc rate is 70%. The sample size was 
calculated in East® Version 6.4. 
Bayesian Posterior Probability for Safety Monitoring in Phase 2: 
A Bayesian posterior probability will be used for safety monitoring during the whole treatment 
period. Subjects in phase 1 and phase 2 cohorts who complete the DLT observation period or 
experience DLTs will be included in the model-fitting process to provide the complete safety 
information. The DLT rate will be reviewed as the last subject of each cohort of 7 DLT-evaluable 
subjects completes the first treatment cycle. The estimated DLT rates based on the Bayesian beta-
binomial model will be provided for safety monitoring in the dose expansion cohort. If the DLT rate 
for the expanded dose level is equal or higher than 20% with a posterior probability of 80%, then the 
enrollment to the expansion cohort will be paused and the safety will be reassessed by the DEC. If the 
reassessment warrants, enrollment to the expansion cohort may be continued at the current dose level 
or 1 lower dose level. Safety evaluation will be conducted separately for induction, consolidation and 
maintenance phases. 
With a non-informative prior, Beta(1,1) distribution, the numbers of DLTs for each cohort of 
7 DLT-evaluable subjects, which trigger the enrollment pause for toxicities review, are listed in the 
following table: 
DLT-evaluable Subjects 
Number of DLTs 
7 
3 
14 
4 
21 
6 
28 
8 
35 
9 
42 
11 
49 
12 
DLT: dose-limiting toxicity 


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Efficacy:   
Response to treatment will be defined per modified Cheson criteria [2003] as outlined below for up to 
the end of 2 cycles and end of treatment. 
Composite Complete Remission (CRc) rate 
Defined as the rate of all complete and incomplete remission (i.e., CR+ CRp + CRi). 
Complete Remission (CR) 
For subjects to be classified as being in CR, they must have bone marrow regenerating normal 
hematopoietic cells and achieve a morphologic leukemia-free state and must have an ANC 
> 1 × 109/L and platelet count ≥ 100 × 109/L, and normal marrow differential with < 5% blasts, and 
they must be red blood cell (RBC) and platelet transfusion independent (defined as 1 week without 
RBC transfusion and 1 week without platelet transfusion prior to disease assessment. There should be 
no evidence of extramedullary leukemia. 
Complete Remission with Incomplete Platelet Recovery (CRp) 
For subjects classified as being in CRp, they must achieve CR except for incomplete platelet recovery 
(< 100  109/L). 
Complete Remission with Incomplete Hematological Recovery (CRi) 
For subjects to be classified as being in CRi, they must fulfill all the criteria for CR except for 
incomplete hematological recovery with residual neutropenia < 1  109/L with or without complete 
platelet recovery. RBC and platelet transfusion independence is not required. 
Complete Remission with Partial Hematologic Recovery (CRh) 
For subjects classified as being in CR, except if their ANC is > 0.5 × 109/L and their platelets are 
> 50 × 109/L. 
Partial Remission (PR) 
For subjects to be classified as being in PR, they must have bone marrow regenerating normal 
hematopoietic cells with evidence of peripheral recovery with no (or only a few regenerating) 
circulating blasts and with a decrease of at least 50% in the percentage of blasts in the bone marrow 
aspirate/biopsy with the total marrow blasts between 5% and 25%. 
Relapse 
Relapse after CR, CRp or CRi is defined as a reappearance of leukemic blasts in the peripheral blood 
or ≥ 5% blasts in the bone marrow aspirate/biopsy not attributable to any other cause or reappearance 
or new appearance of extramedullary leukemia. 
Relapse after PR is similarly defined with reappearance of significant numbers of peripheral blasts 
and an increase in the percentage of blasts in the bone marrow aspirate/biopsy to > 25% not 
attributable to any other cause or reappearance or new appearance of extramedullary leukemia. 
Best Response 
Best response is defined as the best-measured response (CR, CRp, CRi or PR) post-treatment. Two 
best responses will be defined. 
Pharmacokinetics:   
Gilteritinib trough plasma concentrations (Ctrough) 
Pharmacodynamics:   
Changes in the activation status of FLT3 and AXL, a receptor tyrosine kinase (RTK), may be assessed 
before and after treatment. 


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Safety:   
The safety analysis set is defined as all enrolled subjects who received at least 1 dose of study 
treatment.  
The safety evaluation will be based mainly on AEs, clinical laboratory, vital signs, ECGs and ECOG 
performance status. Descriptive statistics will be used to summarize safety data. All safety data will 
be summarized by the actual treatment received. 
All summaries of AEs will include only treatment-emergent events unless otherwise stated. AEs will 
be categorized by SOC and preferred term using MedDRA and will be graded according to the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE)  
version 5.0. 
During phase 1, DLT assessment will occur during cycle 1 only. AEs (toxicities) will be graded 
according to the CTCAE version 5.0. 
Interim analyses:  
No interim analysis is planned. 
 


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V. 
FLOW CHARTS AND SCHEDULE OF ASSESSMENTS 
Phases 1 and 2 
 
AML: acute myeloid leukemia; EOT: end of treatment; FLT3: FMS-like tyrosine kinase 3; q2w: every 2 weeks; RP2D: recommended phase 2 dose. 
Enroll up to 12 subjects in 
phase 1 and up to 49 
subjects in phase 2 s with 
Relapsed or Treatment 
Refractory FLT3 mutated 
AML 
Phase 1: gilteritinib once daily plus 
420 or 840 mg atezolizumab q2w. 
Phase 2:  
gilteritinib once daily plus 
atezolizumab q2W at RP2D. 
28-day cycles in phases 1 and 2 until 
lack of clinical benefit or 
unacceptable toxicity. 
EOT 
Visit 
30-day 
follow-up 
visit 
Long-term 
follow-up for 
3 years or 
until subject 
death or 
withdrawal 


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Table 1 
Schedule of Assessments  
Assessments 
Screening 
C1D1 
C1D8 a 
C1 D15 a 
Subsequent 
Cycles D1 
Subsequent 
Cycles D15a  
EOTb 
30-Day 
Follow-up 
Long-term 
Follow-upc 
Windows 
Day -14 to -1 
 
± 1d 
 
 
 
± 7d 
+ 7d 
± 7d 
Signed ICF 
X 
 
 
 
 
 
 
 
 
Medical and Disease History 
X 
 
 
 
 
 
 
 
 
Enrollment 
 
X 
 
 
 
 
 
 
 
Physical Examinationd 
X 
X 
X 
X 
X 
X 
X 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
 
 
ECOG Performance Statuse 
X 
X 
 
X 
X 
X 
X 
 
 
12-lead ECGf  
X 
X 
X 
X 
X 
X 
X 
 
 
Chest X-ray (or CT of chest)  
X 
 
 
 
 
 
 
 
 
Pregnancy Test for WOCBPg 
X 
X 
 
 
X 
 
X 
 
 
MUGA or ECHO 
X 
 
 
 
 
 
 
 
 
Clinical Laboratory Tests (chemistry, hematology, coagulation, urinalysis)h,i 
Xh 
Xh,i 
Xi 
Xi 
X 
X 
X 
 
 
Thyroid Function Testj 
X 
 
 
 
Xj 
 
Xj 
 
 
Resource utilization 
 
X 
 
 
X 
 
X 
 
 
FLT3 Mutation Statusk 
Xk 
 
 
 
 
 
 
 
 
Bone Marrow Biopsy and/or Aspiration for disease assessment and MRDl 
Xl 
 
 
 
Xl 
 
Xl 
 
 
Pharmacokinetic Sample Collectionm 
 
X 
X 
X 
X 
X 
 
 
 
Blood Sample for FLT3 and AXLn 
 
X 
 
 
 
 
 
 
 
Blood Sample for Immune Cell Immunophenotypingo 
 
X 
 
X 
Xo 
 
X 
 
 
Blood Sample for Blast Cell Immunophenotypingo 
 
X 
 
X 
Xo 
 
X 
 
 
PGx (whole blood and buccal swab)p 
 
X 
 
 
 
 
 
 
 
AE/SAE Assessment 
X 
X 
X 
X 
X 
X 
X 
Xq 
Xr 
Prior and Concomitant Medicationss 
X 
X 
X 
X 
X 
X 
X 
Xr 
 
Survival and subsequent anti-leukemic treatments and their outcomes 
 
 
 
 
 
 
 
Xq 
X 
Gilteritinib Dosing at the Clinict 
 
X 
X 
X 
X 
X 
 
 
 
Subject Diary for Gilteritinibu 
 
X 
 
 
X 
 
 
 
 
Atezolizumab Dosing at the Clinic  
 
X 
 
X 
X 
X 
 
 
 
Footnotes appear on next page 


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AE: adverse event; CT: computed tomography; D: day; ECG: electrocardiogram; ECHO: echocardiogram; ECOG: Eastern Cooperative Oncology Group; EOT: end of treatment; 
FLT3: FMS-like tyrosine kinase 3; ICF: informed consent form; MRD: minimal residual disease; MUGA: multigated acquisition scan; PGx: pharmacogenomics;  
QTcF: Fridericia-corrected QT interval; SAE: serious adverse event; WOCBP: women of childbearing potential.  
a. Visits should be scheduled based on day 1. 
b. If subject permanently discontinues treatment, an EOT Visit should be conducted within 7 days of last dose of study drug.  
c. Telephone contact every 3 months, from the date of the 30-day follow-up visit additional contacts may be made to support key analyses. Subjects will be followed for up to 3 years 
after the 30-day follow-up visit. 
d. Height measurement performed only at screening. Weight measurement should be performed at screening and at day 1 of each cycle. 
e. Subject has an ECOG performance status ≤ 2 at screening to be eligible to enroll in study. 
f. ECG assessment will be evaluated at screening, predose on cycle 1 days 1, 8 and 15, and days 1 and 15 of each subsequent visit and at EOT. Predose assessments should be taken 
within 1 hour before drug administration. The 12-lead ECGs will be recorded in triplicate (3 separate ECGs with 10 min resting prior to first ECG and at least 5 min apart per time 
point), and transmitted electronically for central reading. The mean QTcF of the triplicate ECG tracings based on central reading will be used for all treatment decisions. If the mean 
triplicate QTcF is > 500 ms at any time point, the ECG will be repeated (within 2 h if identified on machine read or as soon as possible if identified by central read). See 
[Section 5.4.4] for further guidance on treatment decision.  
g. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin). 
h. Subjects may be screened and enrolled from local labs only. However, clinical laboratory samples must also be submitted for central read. Laboratory tests and/or ECGs can be 
repeated during the screening period. In the event that the central laboratory results received after randomization are not within eligibility parameters, the subject will still be 
considered eligible, if local labs met the eligibility criteria, and will not be considered a protocol deviation. Local laboratory results that support eligibility and dosing decisions 
must be entered into the clinical database. If local laboratory is to be used to support dosing decisions, local laboratory tests will include complete blood count with differential and 
clinical chemistries (e.g., potassium levels, magnesium levels, glucose, serum creatinine, alanine aminotransferase and aspartate aminotransferase). Additional assessments may be 
done centrally or locally to monitor AEs or as required by dose modification requirements.  
i. Urinalysis is only required at screening. Uric acid will be tested in cycle 1 only on days 1, 8 and 15. Additional laboratory tests may be performed according to institutional standard 
of care.  
j. Thyroid function tests will be repeated after every 2 cycles beginning at cycle 3 (cycle 3/day 1, cycle 5/day 1, cycle 7/day 1, etc.). 
k. Subject is positive for FLT3 mutation in bone marrow or blood after completion of the subject’s last interventional treatment as determined by the local institution.  
l. Bone marrow samples will be collected at screening, cycle 2/day 1, and cycle 3/day 1. For subjects who do not achieve a CR, CRp or CRi, the bone marrow assessments will be 
repeated on day 1 of every 2 subsequent cycles. For subjects who achieve a CRc (CR, CRp or CRi), bone marrow will be repeated 1 month after the date of remission and every 
3 subsequent cycles or if there is suspicion of relapse in the whole blood. Bone marrow samples are also required at the EOT Visit and as clinically indicated. If bone marrow 
aspirate is unobtainable due to technical difficulties such as dry tap, a tube of whole blood (EDTA) along with bone marrow biopsy should be collected instead. Remaining bone 
marrow aspirate and/or whole blood samples will be used for MRD analysis and may be used for other biomarker analyses in relation to treatment outcome. If bone marrow aspirate 
is unobtainable at relapse (e.g., dry tap), a peripheral blood smear should be collected along with bone marrow biopsy. All samples will be sent to the central lab for analysis.  
m. Trough pharmacokinetic samples will be collected for all subjects predose (within 1 h of dose administration) on cycle 1/days 1, 8 and 15, and on days 1 and 15 of each subsequent 
cycle up to 6 months. 
n. Blood samples for FLT3 and AXL samples will be collected on cycle 1/day 1 predose and postdose at 2 h, between 4 to 6 h, and 24 h. 
o. Blood samples for immune and blast cell immunophenotyping will be collected pre-dose at cycle 1 on days 1 and 15, cycle 2/day 1, cycle 3/day 1 and EOT. 
p. Whole blood and buccal swab will be collected pre-dose on day 1 for subjects who consent to participate in the PGx study.  
q. Telephone contact with the subject is sufficient unless any assessment must be repeated for resolution of treatment-related AEs. 
Footnotes continued on next page 


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r. Only SAE data that is possibly or probably related to study drug will be collected. Any concomitant medications related to SAEs will be collected. 
s. Includes medications taken within 28 days prior to day 1. 
t. Gilteritinib is taken once daily at home except for clinic days when it will be taken at the clinic. 
u. Subject diary for gilteritinib is to be given to the subject on day 1 of every cycle. Subjects should complete as instructed.  
 


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1 
INTRODUCTION 
1.1 
Background 
Over 90% of leukemia cases are diagnosed in adults 20 years of age and older, among whom 
the most common types are chronic lymphocytic leukemia (35%) and acute myeloid 
leukemia (AML; 32%) [American Cancer Society, 2014]. The median age at diagnosis for 
leukemia is 67 years of age, with 54% of patients diagnosed at 65 years or older [O’Donnell 
et al, 2012]. It was estimated that 18860 (11530 men and 7330 women) were to be diagnosed 
with and 10460 were to die of AML in 2014 in the United States [American Cancer Society, 
2014]. While 60% to 80% of younger patients achieve a complete remission (CR) with 
standard therapy, only 30% to 40% of such patients are alive and disease-free at 5 years 
because relapsing AML subsequent to CR is common [Tallman, 2005]. Outcomes are worse 
for patients aged 60 years or over, with CR rates in the range of 40% to 55% and poor 
long-term survival rates. Along with age, remission rates and overall survival (OS) depend on 
a number of other factors, including cytogenetics, previous bone marrow disorders (such as 
myelodysplastic syndromes) and comorbidities.  
FMS-like tyrosine kinase 3 (FLT3) is a member of the class III receptor tyrosine kinase 
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 [Schlenk & Döhner, 2009] transforming 
activity in cells [Yamamoto et al, 2001]. 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) [Patel et al, 2012; Gale et al, 2008; Yanada et al, 2005; Tiesmeier et 
al, 2004; Moreno et al, 2003]. 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) [Brunet et al, 2012]. Similar to their prognosis for 
first-line therapy, patients with relapsed/refractory FLT3-mutation positive AML have lower 
remission rates with salvage chemotherapy, shorter durations of remission to second relapse 
and decreased OS relative to FLT3-mutation negative patients [Konig & Levis, 2015; 
Chevallier et al, 2011; Levis et al, 2011].  
In a recent international randomized phase III study of elacytarabine versus investigator 
choice in patients with relapsed/refractory AML, the CR rate in the control arm was only 
12% [Roboz et al, 2014]. In this study, the treatment options available in the control arm 
(physician’s choice) reflect contemporary clinical practice, rather than a strict selection of 
only patients that are eligible for intensive salvage regimens. As a result, this control arm 
should more appropriately represent what can be expected in standard clinical practice. 


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AXL, a receptor tyrosine kinase, has been detected in AML and has been shown to play a 
role in mediating migration and invasiveness of cancer cells. Inhibition of AXL has been 
shown to increase apoptosis and inhibit proliferation of FLT3-ITD and FLT3 wild-type AML 
cell lines and primary AML cells in vitro and reduced tumor burden and prolonged survival 
in mouse models [Janning et al, 2015].  
Gilteritinib 
XOSPATA (gilteritinib) tablets have been approved by FDA, EMA and MHLW for the 
treatment of adult patients who have relapsed or refractory AML with a FLT3 mutation. 
Gilteritinib has an inhibitory effect on tyrosine kinases, mainly FLT3, AXL, LTK and ALK.  
Gilteritinib demonstrated favorable efficacy in a nonclinical AML model, with complete 
regression of tumors in the xenograft model mice transplanted with MV4-11, by repeated oral 
doses. In addition, gilteritinib inhibited the growth of Ba/F3 cells expressing either FLT3-
ITD, FLT3-D835Y or FLT3-ITD-D835Y with similar activities. Gilteritinib has been studied 
in relapsed or refractory AML patients in a phase 1/2 study. In the study, patients with FLT3 
mutated AML receiving 80 mg or higher dose had a complete composite remission (CRc) 
rate of 41% and median OS of 31 weeks [Perl et al, 2017]. Furthermore, 16% of the patients 
tested were in complete molecular remission by FLT3-ITD based minimal residual disease 
(MRD) assay [Levis 2018]. Based on promising activity observed in the phase 1/2 study in 
AML patients, a phase 3 study in relapsed or refractory AML is currently ongoing. 
Programmed Death-Ligand 1/PD-1 Inhibitors 
Agents that target the programmed death-ligand 1 (PD-L1)/PD-1 axis have shown broad 
activity and durable responses in multiple tumor types, holding the promise of delivering 
immune-based therapy to almost all patients with cancer. To date, patients with solid tumors 
have been the focus of most clinical studies that use immune checkpoint inhibitors; however, 
data are emerging that these therapeutics are active in hematological malignancies. 
Significant preliminary activity with nivolumab has been seen in relapsed/refractory 
Hodgkin’s lymphoma [Ansell et al, 2015]. In this ongoing phase I study, an overall response 
rate (ORR) of 87% was seen in patients with heavily pre-treated Hodgkin’s lymphoma 
(n = 23). Most patients had undergone prior autologous stem cell transplant and received 
brentuximab vedotin. Pembrolizumab has shown similar activity in Hodgkin’s lymphoma 
[Moskowitz et al, 2014]. Nivolumab has also been studied in a variety of relapsed/refractory 
lymphoid histologies (B-cell lymphoma, T-cell lymphoma, and multiple myeloma) [Lesokhin 
et al, 2014]. The most significant responses were seen in the diffuse large B-cell lymphoma 
and follicular lymphoma subgroups. Additionally, Nivolumab in combination with 
azacytadine achieved 22% CRc and median OS of 6.8 months in patients with relapsed or 
refractory AML [Daver et al, 2017]. 
Atezolizumab is a PD-L1 blocking antibody that previously received FDA accelerated 
approval for the treatment of locally advanced or metastatic urothelial carcinoma that has 
progressed after platinum-containing chemotherapy. On October 18, 2016, FDA approved 
atezolizumab for the treatment of patients with metastatic non-small cell lung cancer whose 


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disease progressed during or following platinum-containing chemotherapy. Currently, there 
have not been any results released of clinical studies with atezolizumab in AML. However, 
atezoluzimab monotherapy has been tested in patients with advanced myeloid malignancies 
[Gerds et al, 2018] and preliminary results showed an overall response rate of 62% for the 
atezolizumab-azacitidine arm at a dosing schedule of 840 mg intravenous every 2 weeks. 
Also, as previously described, studies with other checkpoint inhibitors have demonstrated 
clinical activity, including CRs in AML in the post-HSCT setting. Therefore, atezolizumab, 
as a typical PD-L1 inhibitor, was selected to be evaluated as combination therapy with 
gilteritinib to treat patients with relapsed/refractory FLT3 mutated AML. 
1.2 
Nonclinical and Clinical Data 
Nonclinical and clinical data for gilteritinib (ASP2215) available as of the writing of this 
protocol are summarized below. Please refer to the current version of the Gilteritinib 
(ASP2215) Investigator’s Brochure (IB). 
1.2.1 
Nonclinical Data – Gilteritinib 
Refer to the current IB for a summary of nonclinical data on gilteritinib. 
1.2.2 
Nonclinical Data – Atezolizumab 
Refer to the current IB for nonclinical data on atezolizumab. 
1.2.3 
Clinical Data - Gilteritinib 
1.2.3.1 Studies Using Human Biomaterials 
In Caco-2 cells, the permeability of gilteritinib was between that of known low and high 
permeability markers. Gilteritinib was a substrate for P-glycoprotein (P-gp), but not a 
substrate for breast cancer resistance protein (BCRP), organic anion transporting polypeptide 
(OATP)1B1, OATP1B3 or organic cation transporter (OCT)1. No major human-specific 
gilteritinib metabolites were formed by liver microsomes or hepatocytes. The main enzyme 
involved in the metabolism of gilteritinib was estimated to be cytochrome P450 (CYP)3A4. 
In in vitro studies, gilteritinib showed inhibitory effects on P-gp, BCRP, OATP1B1, OCT1, 
OCT2, multidrug and toxin extrusion (MATE)1 and MATE2-K. Gilteritinib showed direct 
inhibition of CYP2C19 and CYP3A4, and induction potential on CYP1A2, CYP2B6, 
CYP2C8, CYP2C9, CYP2C19, and CYP3A4/5. The interactions that may be clinically 
relevant include the potential to inhibit CYP3A, BCRP, and P-gp in the small intestine, 
OCT1 in the liver, and MATE1 in the kidney. Clinical assessments were performed to 
evaluate the effect of gilteritinib on a MATE1 substrate and a CYP3A substrate. Results are 
described in [Section 1.2.3.2 Clinical Pharmacokinetics and Pharmacodynamics]. 
1.2.3.2 Clinical Pharmacokinetics and Pharmacodynamics 
In study 2215-CL-0101, a phase 1/2 study in patients with relapsed/refractory AML, FLT3 
mutational status was collected locally from the patient’s record. 


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With regards to gilteritinib pharmacokinetics, median tmax was observed between 2 and 
6 hours following single and repeat dosing. At a dose of 120 mg, the median Cmax at day 15 
was approximately 282 ng/mL and the median AUC at day 15 was approximately 
6180 ng·h/mL. The estimated t1/2 across dose levels based on Rac ranged from 45 to 
159 hours. Approximately dose proportional pharmacokinetics were observed following once 
daily administration of gilteritinib over the range evaluated (20 to 450 mg). 
The effect of gilteritinib on the pharmacokinetics of midazolam, a CYP3A4 substrate, was 
investigated in patients with relapsed/refractory AML. Midazolam exposure was comparable 
when midazolam was administered alone or in combination with gilteritinib. The results 
suggest coadministration of gilteritinib and a CYP3A4 substrate is not expected to result in a 
clinically-relevant drug-drug interaction. 
An assessment of the effect of gilteritinib on the pharmacokinetics of cephalexin, a MATE1 
substrate, was also performed in patients with relapsed/refractory AML. Cephalexin exposure 
and renal excretion were comparable when cephalexin was administered alone or in 
combination with gilteritinib. These results indicated a clinically-relevant interaction is not 
expected when gilteritinib is coadministered with a MATE1 substrate. 
The potential for drug-drug interactions was investigated in healthy subjects or patients with 
relapsed/refractory AML. The effect of ITZ (a strong CYP3A4 inhibitor), FLZ (a moderate 
CYP3A4 inhibitor) and RIF (a strong CYP inducer) on the pharmacokinetics of gilteritinib, a 
CYP3A4 and P-gp substrate, were evaluated in healthy adult subjects. Coadministration of 
gilteritinib with ITZ significantly increased gilteritinib exposure (approximately 2.21-fold) via 
a reduction in CL/F. As anticipated, a smaller increase in gilteritinib systemic exposure 
(approximately 1.43-fold) was observed following coadministration gilteritinib with FLZ. 
Furthermore, RIF significantly decreased gilteritinib systemic exposure (approximately 70%). 
In summary, coadministration of gilteritinib with a strong CYP3A4 inhibitor or inducer may 
result in significantly greater or lesser, respectively, gilteritinib systemic exposure. 
The effect of food on gilteritinib pharmacokinetics was examined in phase 1 study 2215-CL-
0113 in healthy adult subjects. Although the geometric mean Cmax decreased approximately 
26% under fed conditions, overall exposure of gilteritinib was comparable under fasted and 
fed conditions as evidenced by the less than 10% difference in AUC. Indices of overall 
gilteritinib exposure decreased approximately 10% (AUCinf and AUClast) and absorption was 
delayed (2-hour increase in median tmax) when gilteritinib was administered with a high-fat 
meal relative to fasted conditions. Gilteritinib t1/2, CL/F and VZ/F were comparable in the 
fasted and fed treatment groups. Hence, gilteritinib can be administered without regard to 
food. 
1.2.3.3 Clinical Safety 
All patients receiving the study drug experienced at least 1 AE, and 91.7% (22/24) of patients 
experienced a drug-related AE. Common AEs, occurring in ≥ 20% of all patients, were 
hepatic function abnormal and blood creatine phosphokinase increased (37.5%, 9/24), blood 
lactate dehydrogenase increased (33.3%, 8/24), diarrhea and pyrexia (29.2%, 7/24) and 


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febrile neutropenia, stomatitis, renal impairment and hypertension (20.8%, 5/24). Of these 
common AEs, hepatic function abnormal, blood creatine phosphokinase increased and 
diarrhea appeared to have increased incidence with increasing doses. The majority of the 
common AEs were considered by the investigator to be related to study drug. 
1.2.3.4 Clinical Efficacy 
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 EOT in the 
191 FLT3 mutation-positive patients was 48.7% overall and 66.7%, 55.4%, 47.2%, 60.0% 
and 50.0% in the 80 mg, 120 mg, 200 mg, 300 mg and 450 mg dose groups, respectively. 
Of the 249 patients who received at least 1 dose of gilteritinib in study 2215-CL-0101 who 
were evaluated for efficacy, the majority of CRc and PR responses were observed in FLT3 
mutation-positive patients in dose groups of 80 mg and greater. The derived response rate 
(CRc + PR) at the end of treatment (EOT) in the 191 FLT3 mutation-positive patients was 
48.7% overall and 66.7%, 55.4%, 47.2%, 60.0% and 50.0% in the 80 mg, 120 mg, 200 mg, 
300 mg and 450 mg dose groups, respectively. 
After gilteritinib treatment at doses ranging from 20 mg to 300 mg per day, a CRc rate of 
36.8% and a response rate of 47.4% was attained. Patients in the 200 mg dose group had the 
highest CRc and response rate, of 57.1% (for both measures) at EOT. At EOT, 3 of the FLT3 
mutation-positive patients achieved CRc (60.0%) and the response rate in this group was 
80.0%. Across all dose groups, the median duration of CRc was 86.5 days and the median 
duration of remission was 113.5 days. 
Study 2215-CL-0301, is a phase 3, open-label, randomized study comparing the efficacy and 
safety of gilteritinib monotherapy to salvage chemotherapy in patients with FLT3- mutated 
AML who are refractory to or have relapsed after first-line AML therapy.  
As of the data cutoff date of 17 Sep 2018, OS was significantly longer in the gilteritinib arm 
(median, 9.3 months) compared with the salvage chemotherapy arm (median, 5.6 months) 
using a Kaplan-Meier estimate (HR: 0.637; 95% CI: 0.490, 0.830; 1-sided P-value 0.0004). 
The survival probability was higher in the gilteritinib arm compared with the salvage 
chemotherapy arm at 6 months (65.5% versus 48.9%) and 12 months (37.1% versus 16.7%). 
1.2.4 
Clinical Data – Atezolizumab 
Refer to the current IB for clinical data on atezolizumab. 
1.3 
Summary of Key Safety Information for Study Drugs 
1.3.1 
Key Safety Information - Gilteritinib 
The nonclinical and clinical studies, which are referred to in this section, are described in 
more detail in the ASP2215 IB.  


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Study 2215-CL-0101 demonstrated efficacy in FLT3 mutation-positive patients with 
relapsed/refractory AML, with a tolerable safety profile. 
Expected ADRs for gilteritinib include the preferred terms of diarrhea, edema peripheral, blood 
creatine phosphokinase increased, ALT increased, AST increased, myopathy, electro-
cardiogram (ECG), QT prolongation and posterior reversible encephalopathy syndrome. 
Refer to [Section 1.2.3.3 Clinical Safety] and the IB for a comprehensive summary of safety 
findings.  
The majority of patients (249 [98.8%]) in study 2215-CL-0101 experienced at least 
1 treatment-emergent adverse event (TEAE), and 188 (74.6%) of 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, 
thrombocytopenia, constipation, diarrhea, nausea, stomatitis, vomiting, asthenia, fatigue, 
peripheral edema, pyrexia, pneumonia, sepsis, fall, alanine aminotransferase (ALT) increased, 
AST increased, blood alkaline phosphatase (ALP) increased, blood creatinine increased, 
neutrophil count decreased, platelet count decreased, appetite decreased, hypoalbuminemia, 
hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia, arthralgia, AML, dizziness, 
dysgeusia, headache, cough, dyspnea, epistaxis, hypoxia and hypotension. Other than TEAEs 
that were determined to be ADRs, 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. Peripheral edema, increases in circulating creatine kinase (CK), increases in 
circulating ALT and AST, myopathy, diarrhea, prolonged QT and posterior reversible 
encephalopathy syndrome were identified as ADRs that may be expected for gilteritinib. 
Ninety-five patients experienced a TEAE with an outcome of death; of these, 1 event of each 
of the following: intracranial hemorrhage, pulmonary embolism, septic shock, neutropenia, 
ventricular fibrillation and hemoptysis were considered possibly related to gilteritinib and 
1 event of respiratory failure was considered probably related to gilteritinib by the 
investigator. Additionally, 1 event of bacteremia recorded as grade 3 with a fatal outcome 
was considered possibly related to gilteritinib by the investigator. Twenty-eight 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. 
As of the final analysis data cutoff date of 17 Sep 2018, 246 patients had received at least 
1 dose of gilteritinib 120 mg and 109 patients had received at least 1 dose of salvage 
chemotherapy in Study 2215-CL-0301. 100% (246/246) of patients in the gilteritinib arm and 
98.2% (107/109) of patients in the salvage chemotherapy arm experienced at least 1 TEAE. 
When adjusted for number of events (E) per patient year (PY) with PY defined as the total 
duration of exposures time in year, the E/PY of drug related TEAEs were higher in patients 
treated with salvage chemotherapy compared to patients treated with gilteritinib (47.23 vs 
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The most frequent TEAEs in the gilteritinib arm were anemia, febrile neutropenia, pyrexia, 
ALT increased, AST increased, diarrhea, nausea and constipation. The most frequent TEAEs 
in the salvage chemotherapy arm were febrile neutropenia, anemia, nausea, diarrhea and 
pyrexia. Diarrhea, blood creatine phosphokinase increased, ALT increased and AST 
increased and edema peripheral and myalgia have been identified as expected adverse 
reactions for gilteritinib.  
The data below is from a cutoff date of 17 Sep 2018:  
When adjusted for number of events (E) per patient year (PY) with PY defined as the total 
duration of exposures time in year, the E/PY of drug related TEAEs leading to death were 
higher in patients treated with salvage chemotherapy compared to patients treated with 
gilteritinib (0.67 vs 0.12). The most frequent TEAEs leading to death in the gilteritinib arm 
by PT were AML, septic, sepsis, cardiac arrest and lung infection and pneumonia.  
1.3.2 
Key Safety Information - Atezolizumab  
Detailed information on the toxicities and common AEs associated with atezolizumab can be 
found within the current IB. 
In a 15-day intravenous (dosing frequency days 1, 8 and 15) toxicity study in mice, the major 
toxicological finding was minimal sciatic neuropathy (vacuolation and lymphocytic 
infiltration) at doses ≥ 10 mg/kg observed at the end of dosing and 4-week recovery period.  
In repeated 8-week subcutaneous/intravenous and 26 week intravenous toxicity studies 
(dosing frequency: weekly) in cynomolgus monkeys, the major toxicological finding was 
minimal to mild multifocal arteritis/periarteritis in multiple organs including the heart, aorta, 
kidney, liver, pancreas, epididymis, gastrointestinal tract, skin, tongue, and female 
reproductive organs. The findings were reversible following a 3-month recovery period. In 
the 26-week study, female monkeys administered 50 mg/kg intravenous atezolizumab 
experienced irregular menstruation during the dosing period, including an increase in mean 
menstrual cycle length compared to controls and a corresponding lack of newly formed 
corpora lutea. 
The PD-1/PD-L1 pathway is known to play an important role to maintain immune tolerance 
to the fetal allograft and inhibiting this pathway could cause adverse effects on pregnancy 
such as abortion and/or stillbirth [Poulet et al, 2016]. 
Preliminary data in myelodysplastic syndrome (MDS) patients of atezolizumab 840 mg every 
2 weeks dose in combination with azacitidine [Gerds et al, 2018] showed that the most 
common adverse events (AEs) were febrile neutropenia (4/11), neutropenia (3/11) and 
anemia (1/11). Additionally, preliminary data of atezolizumab 840 mg every 2 weeks dose in 
combination with guadecitabine in MDS patients [O’Connell et al, 2018] showed that the 
most common AEs were again hematologic; neutropenia, thrombocytopenia and leukopenia. 


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1.4 
Risk Benefit Assessment 
Approximately 30% of adult AML subjects are refractory to induction therapy. Furthermore, 
of those who achieve CR, approximately 75% will relapse. Subjects with AML with FLT3 
mutations comprise an especially poor prognosis group. Generally, there is no established 
standard for relapsed subjects with FLT3 mutations and less than 20% will achieve CR with 
subsequent treatment. Duration of remission for the small minority who achieve remission is 
also limited with most of the subjects relapsing. 
In phase 1/2 Study 2215-CL-0101, ASP2215 has resulted in CRc in over 40% of subjects 
receiving 80 mg or higher dose. The median survival was over 7 months in 120 mg dose level. 
The majority of subjects in the study have received multiple treatments prior to receiving 
ASP2215. Furthermore, ASP2215 was well tolerated at the proposed doses in this study. 
The drug interaction potential of atezolizumab is unknown [TECENTRIQ® prescribing 
information, 2016]. Atezolizumab is not expected to have direct impact on CYP and other 
drug metabolizing enzymes or transporters. In addition, atezolizumab is not expected to 
modulate cytokine levels, which could exert an indirect impact on CYP450 activities. No 
significant or clinically meaningful drug-drug interaction is expected when atezolizumab is 
co-administered with ASP2215, a CYP3A and P-gp substrate. 
Given the lack of progress in AML drug development, the high, unmet medical need among 
all AML patient populations, and the promise of immune checkpoint inhibitors, the overall 
risk-benefit profile is favorable and justifies further exploration of atezolizumab in AML. On 
the basis of their mechanism of action, drugs such as atezolizumab have the potential to 
confer the benefits of a HSCT (i.e., GVL) with a much more tolerable side effect profile 
(i.e., lack of graft versus host disease).  
Subjects with AML who relapse or do not respond to initial treatment have a very poor 
prognosis. Although there are various chemotherapy options available, they are by no means 
curative. The response to salvage chemotherapy is poor, and especially for subjects with 
FLT3 mutation. Although it is not known whether combination of ASP2215 with 
atezolizumab would lead to longer survival, in light of the very poor prognosis of relapsed or 
refractory AML subjects with FLT3 mutations, the potential for combination treatment to 
improve outcome outweighs the risk of potential toxicities. 


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2 
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS 
2.1 
Study Objective(s) 
2.1.1 
Primary Objectives 
The primary objectives are to: 
● 
Determine the safety and tolerability of gilteritinib given in combination with 
atezolizumab in subjects with relapsed or treatment refractory FLT3 mutated AML. 
● 
Determine the CRc rate for subjects with relapsed or treatment refractory FLT3 mutated 
AML who either discontinued the study or completed 2 cycles of gilteritinib given in 
combination with atezolizumab. CRc is defined as a CR, complete remission without 
platelet recovery (CRp) or complete remission with incomplete hematologic recovery 
(CRi).  
2.1.2 
Secondary Objectives  
The secondary objectives are to: 
● 
Characterize the pharmacokinetics of gilteritinib and its active metabolites (if 
appropriate) when given in combination with atezolizumab. 
● 
Evaluate the safety and efficacy of gilteritinib in combination with atezolizumab in terms 
of: 
o Gilteritinib trough plasma concentrations (Ctrough) 
o CR rate 
o CR with partial hematologic recovery (CRh) 
o Best response rate (CRc + PR) 
o Duration of remission 
o Event-free Survival (EFS) 
o OS 
o AEs, clinical laboratory results, vital signs, ECGs and Eastern Cooperative 
Oncology Group (ECOG) performance status scores 
2.1.3 
Exploratory Objectives 
The exploratory objectives are to: 
● 
Evaluate efficacy of gilteritinib given in combination with atezolizumab in terms of 
MRD 
● 
Evaluate potential genomic, proteomic and/or other biomarkers that may correlate with 
treatment outcome 
● 
Evaluate pharmacodynamic biomarkers of treatment effect  
● 
Evaluate immune cell populations and AML blasts by immunophenotyping in relation to 
treatment effects  


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2.2 
Study Design and Dose Rationale 
2.2.1 
Study Design 
This is an open-label, single arm, phase 1/2 study to evaluate the safety and efficacy of 
combining gilteritinib with atezolizumab for subjects with relapsed or treatment refractory 
FLT3 mutated AML. This study will have 2 phases. Refer to [Section V Flow Charts and 
Schedule of Assessments] for details of design.  
Phase 1: 
The phase 1 portion of this study is a dose- escalation phase with a 3 + 3 design to establish 
the recommended phase 2 dose (RP2D) of gilteritinib given in combination with 
atezolizumab. Up to 12 subjects will be enrolled in cohorts of 3 to 6 subjects to determine the 
RP2D following the dose levels of the combination treatment outlined in the table below. 
Dose escalation decisions will be made based on DLTs that occur during the first cycle of 
treatment. A cycle is defined as 28 days. The treatment will consist of 3 distinct periods; 
remission induction, consolidation and maintenance.  
The DLT observation period will be from cycle 1/day 1 through cycle 1/day 28. Evaluable 
subjects are defined as subjects who experience a DLT or in the absence of DLT, receive at 
least 23/28 doses of gilteritinib and at least 1/2 doses of atezolizumab. Subjects who are later 
discovered not to meet eligibility criteria or are not evaluable for DLT may be replaced.  
Dose evaluation rules based on the 3 + 3 design and dose escalation rules are as follows: 
Number of Subjects with DLT at the Given Dose 
During the DLT Observation Period 
Escalation Decision Rules 
0 of 3 or ≤ 1 of 6 subjects 
Escalate and enter up to 3 subjects at the next dose level, 
if next dose level available. If at dose level 2, determine if 
RP2D. 
1 of 3 subjects 
Enter up to 3 subjects at the same dose level. 
≥ 2 subjects 
De-escalate or stop escalating. 
DLT: dose limiting toxicity 
The Dose Evaluation Committee (DEC) will consist of the sponsor, principal investigators, 
and if appropriate, expert consultants who will be responsible for the review of safety data 
through the DLT observation period for 3 or 6 evaluable subjects for each cohort. The 
decision will be made by the DEC to escalate to the next planned dose level, to remain at the 
same dose level, de-escalate to the dose level below or stop escalation. The RP2D will be 
selected based on the DEC’s review of all available data at each dose level, including safety 
and pharmacokinetic data (if available), and the RP2D will become the minimum safe and 
biologically effective dose level. Additional details regarding responsibilities and 
membership requirements will be included in the Subject Enrollment and DEC Plan.  
The subjects in the first cohort will be treated with gilteritinib 120 mg orally once daily and 
atezolizumab 420 mg once every 2 weeks by intravenous infusion. The subjects in the second 


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cohort phase will be dosed based on the results of the first cohort and according to the dose 
level table below. 
Dose Level 
Dose-Atezolizumab 
Dose-Gilteritinib 
1 
420 mg q2w 
120 mg once daily 
-1 
420 mg q2w 
80 mg once daily 
2 
840 mg q2w  
120 mg once daily 
Subjects will be administered treatment until a discontinuation criterion is met. If 1 treatment 
is discontinued due to toxicity, the subject may continue on the other as monotherapy until a 
discontinuation criterion is met. Subjects will have an (EOT) visit within 7 days after last 
dose of study drug, followed by a 30-day follow up for safety, after which the subjects will 
enter the long-term follow-up period of up to 3 years for collection of subsequent AML 
treatment, remission status and survival (cause of death and date of death).  
Phase 2: 
In the phase 2 portion with 2 stages, up to 49 subjects will be enrolled. The subjects will be 
treated with gilteritinib and atezolizumab at the RP2D. In the first stage, 22 subjects will be 
enrolled. The subjects enrolled at the first stage of phase 2 will be used to calculate the CRc 
rate for the first stage. If the minimum CRc rate criterion (i.e., at least 12 CRc responders out 
of 22 subjects) is met, an additional 27 subjects will be enrolled for the second stage. 
Subjects will enter the screening period up to 14 days prior to the start of treatment.  
Subjects will be administered treatment until discontinuation criterion is met. If 1 treatment is 
discontinued due to toxicity, the subject may continue on the other as monotherapy until 
discontinuation criteria is met. Subjects will have an (EOT) visit within 7 days after last dose 
of study drug, followed by a 30-day follow up for safety, after which the subjects will enter 
the long-term follow-up period of up to 3 years for collection of subsequent AML treatment, 
remission status and survival (cause of death and date of death).  
2.2.2 
Dose Rationale 
In the first-in-human phase 1/2 clinical study 2215-CL-0101, relapsed/refractory AML 
subjects were treated with gilteritinib at doses ranging from 20 to 450 mg administered once 
daily. The primary objectives for this study were to determine the safety and 
pharmacokinetics of gilteritinib following single and repeat dosing. In addition, preliminary 
efficacy as assessed by response rates was evaluated. 
Clinical safety data indicated an MTD of 300 mg. Clinical efficacy data supports doses of 
120 mg and greater to ensure efficacy in FLT3-mutation positive subjects. PIA has shown 
substantial reduction of phospho-FLT3, with > 90% inhibition at doses of 80 mg or greater. 
Although, none of the dose levels within the expansion cohort reached the threshold to stop 
enrollment (> 20% DLT with posterior probability of 80%), 120 mg and 200 mg doses 
especially had low DLT rates. However, CK and AST elevations correlating with increasing 
dose and increasing exposure were observed. Overall, 120 mg provides a good balance of 


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ensuring effective drug levels for virtually all subjects with a low incidence of safety 
concerns. 
Doses of 80 mg and 120 mg gilteritinib given in combination with atezolizumab is chosen as 
a starting dose for the escalation cohort to maintain a more efficacious gilteritinib dose while 
confirming the safety of the combination in a population that is not able to tolerate intense 
therapy.  
For atezolizumab, simulations [Bai et al, 2012] do not suggest any clinically meaningful 
differences in exposure following a fixed dose compared with a body weight-adjusted dose. 
On the basis of this analysis, a fixed dose of 1200 mg once every 3 weeks (equivalent to a 
weight based dose of 15 mg/kg once every 3 weeks) was defined as the RP2D. 
For the once every 2 weeks dosing interval, the fixed dose of 840 mg once every 2 weeks is 
expected to be equivalent to that of 1200 mg every 3 weeks, the approved dosage for 
atezolizumab [Tecentriq prescribing information, 2016]. A 2-week dosing schedule is being 
used to better align AML treatment and evaluation schedule with gilteritinib. The fixed dose 
of 1200 mg once every 3 weeks (equivalent to an average body-weight based dose of 
15 mg/kg once every 3 weeks) was selected on the basis of both nonclinical studies [Deng et 
al, 2016] and available clinical pharmacokinetic, efficacy and safety data (refer to the 
Atezolizumab IB for details).  
The initial dose of atezolizumab to be tested in combination with gilteritinib will be 420 mg 
once every 2 weeks to determine the RP2D following the dose levels of the combination 
treatment outlined in Section 2.2.1. Dose escalation decisions will be made based on DLTs 
that occur during the first cycle of treatment.  
2.3 
Endpoints  
2.3.1 
Primary Endpoints 
● 
Safety and tolerability (development of DLTs and AEs and define RP2D) 
● 
CRc rate 
2.3.2 
Secondary Endpoints  
● 
Gilteritinib trough plasma concentrations (Ctrough)  
● 
CR rate 
● 
CR with partial hematologic recovery (CRh) 
● 
Best response rate 
● 
Duration of remission 
● 
EFS 
● 
OS 
● 
AEs, clinical laboratory results, vital signs, ECGs and ECOG 
2.3.3 
Exploratory Endpoints 
● 
MRD in relation to clinical outcomes 
● 
Evaluate potential genomic, proteomic and/or other biomarkers that may correlate with 
treatment outcome 


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● 
Evaluate pharmacodynamic biomarkers of treatment effect  
● 
Evaluate immune cell populations and AML blasts by immunophenotyping in relation to 
treatment effects  
3 
STUDY POPULATION 
3.1 
Selection of Study Population  
The study population will consist of a total of up to 61 adults, male and female. Subjects with 
relapsed or treatment refractory FLT3 mutated AML will be enrolled in this study.  
Verification of inclusion and exclusion criteria for a subject’s participation in this study is to 
be determined by the principal or a sub-investigator. 
3.2 
Inclusion Criteria 
Subject is eligible for the study if all of the following apply: 
1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved written 
informed consent and privacy language as per national regulations (e.g., Health 
Insurance Portability and Accountability Act Authorization for US sites) must be 
obtained from the subject or legally authorized representative prior to any study-related 
procedures (including withdrawal of prohibited medication, if applicable). 
2. Subject is considered an adult according to local regulation at the time of signing 
informed consent form (ICF).  
3. Subject has defined AML by the WHO criteria (2017) and fulfills one of the following: 
● 
Refractory to at least 1 cycle of induction chemotherapy 
● 
Relapsed after achieving remission with a prior therapy 
4. Subject is positive for FLT3 mutation in bone marrow or blood after completion of the 
subject’s last interventional treatment as determined by the local institution.  
5. Subject has an ECOG performance status ≤ 2 at screening. 
6. Subject must meet the following criteria as indicated on the clinical laboratory tests: 
● 
Serum AST and ALT ≤ 2.5 x upper limit of normal (ULN) 
● 
Serum total bilirubin (TBL) ≤ 1.5 x ULN 
● 
Serum creatinine ≤ 1.5 x ULN or an estimated glomerular filtration rate of  
> 50 mL/min as calculated by the Modification of Diet in Renal Disease equation. 
7. Subject is suitable for oral administration of study drug. 
8. A female subject is eligible to participate if she is not pregnant [see Appendix 12.3 
Contraception Requirements] and at least one of the following conditions applies: 
● 
Not a woman of childbearing potential (WOCBP) as defined in [Appendix 12.3 
Contraception Requirements] 
OR 


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● 
WOCBP who agrees to follow the contraceptive guidance as defined in 
[Appendix 12.3 Contraception Requirements] throughout the treatment period 
and for at least 180 days after the final study drug administration. 
9. Female subject must agree not to breastfeed starting at screening and throughout the 
study period, and for at least 180 days after the final study drug administration. 
10. Female subject must not donate ova starting at screening and throughout the study 
period, and for at least 180 days after the final study drug administration. 
11. A male subject must not donate sperm starting at screening and throughout the treatment 
period, and for at least 120 days after the final study drug administration. 
12. A male subject with female partner(s) of child-bearing potential must agree to use 
contraception as detailed in [Appendix 12.3 Contraception Requirements] during the 
treatment period, and for at least 120 days after the final study drug administration. 
13. Male subject 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 120 days after the final study drug 
administration. 
14. Subject agrees not to participate in another investigational study while on treatment. 
Waivers to the inclusion criteria will NOT be allowed. 
3.3 
Exclusion Criteria 
Subject will be excluded from participation if any of the following apply: 
1. Subject was diagnosed as acute promyelocytic leukemia. 
2. Subject has BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast crisis). 
3. Subject has AML secondary to prior chemotherapy for other neoplasms (except for 
MDS). 
4. Subject has clinically active central nervous system leukemia. 
5. Subject has uncontrolled or significant cardiovascular disease, including: 
● 
A myocardial infarction within 12 months 
● 
Uncontrolled angina within 6 months 
● 
History of clinically significant ventricular arrhythmias (such as ventricular 
tachycardia, ventricular fibrillation, torsades de pointes) or any history of arrhythmia  
● 
Uncontrolled hypertension 
6. Subject has baseline left ventricular ejection fraction (LVEF) that is < 45%. 
7. Subject has mean triplicate Fridericia-corrected QT interval (QTcF) > 450 ms at 
screening based on central reading.  
8. Subject has congenital or acquired Long QT Syndrome at screening. 


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9. Subject has hypokalemia and/or hypomagnesemia at screening (defined as values below 
institutional lower limit of normal). 
10. Subject has been diagnosed with another malignancy that requires concurrent treatment 
or hepatic malignancy regardless of the need for treatment.  
11. Subject has clinically significant coagulation abnormality unless secondary to AML in 
the opinion of the investigator. 
12. Subject is receiving or plans to receive concomitant chemotherapy or immunotherapy 
other than as specified in the protocol. 
13. Subject has had major surgery within 4 weeks prior to the first study dose. 
14. Subject has radiation therapy within 4 weeks prior to the first study dose.  
15. Subject requires treatment with concomitant drugs that are strong inducers of CYP3A. 
16. Subject has known pulmonary disease with diffusion capacity of lung for carbon 
monoxide ≤ 65%, forced expiratory volume in the first second (FEV1) ≤ 65%, dyspnea at 
rest or requiring oxygen or any pleural neoplasm. 
17. Subject with systemic fungal, bacterial, viral or other uncontrolled infection that is 
exhibiting ongoing signs/symptoms related to the infection without improvement despite 
appropriate antibiotics or other treatment. The patient needs to be off pressors and have 
negative blood cultures for 48 hours. 
18. Subject has not recovered from any prior therapy related toxicities, as determined by 
investigator 
19. Subject is known to have human immunodeficiency virus infection.  
20. Subject has active hepatitis B or C or other active hepatic disorder. 
21. Subject has previously been treated with gilteritinib, quizartinib or crenolanib (will only 
apply to subjects enrolled in the phase 2 portion of the study).  
22. Subject has active clinically significant graft-versus-host disease (GVHD) or is on 
treatment with systemic corticosteroids for GVHD. 
23. Subject has relapsed after allogeneic HSCT. 
24. Subject has an active autoimmune disorder that in the opinion of the investigator makes 
the subject unsuitable for study treatment or participation. 
25. Subject has any condition, which, in the investigator’s opinion, makes the subject 
unsuitable for study participation, including any contraindications of atezolizumab listed 
in the current IB. 
Waivers to the exclusion criteria will NOT be allowed.  


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4 
TREATMENT(S) 
4.1 
Identification of Investigational Product(s) 
4.1.1 
Study Drug(s) 
Gilteritinib will be provided by the sponsor in high-density polyethylene bottles each 
containing 30 tablets of 40 mg gilteritinib (see Table 2). The study site personnel will fill out 
the label to indicate the number of tablets that need to be taken each day based on the 
assigned dose. Additional information and guidance is provided in the pharmacy manual.  
Table 2 
Test Drug (Gilteritinib Tablets, 40 mg) 
Test Drug 
Gilteritinib Tablets, 40 mg 
Code name 
ASP2215 
Active ingredient 
Chemical name: C29H44N8O3•1/2 C4H4O4 
Composition and dosage form 
One tablet contains 40 mg of gilteritinib in free form. 
gilteritinib tablets are round light-yellow film-coated tablets. 
Lot no. 
Described in separately prepared “Study Drug Handling Procedures” 
Storage 
Bottled gilteritinib should be stored according to labeled storage 
instructions. Store in original container. 
Atezolizumab will be provided by the sponsor as 1200 mg/20 mL solution in vials for 
intravenous infusion [Table 3]. Refer to the current IB. 
Table 3 
Test Drug (Atezolizumab) 
Comparative Drug 
Atezolizumab 
Code Name 
TECENTRIQ® 
Active ingredient 
Atezolizumab  
Composition and dosage form  
TECENTRIQ 1200 mg/20 mL solution for intravenous infusion 
Lot No.  
Refer to drug product. 
Storage 
Refer to current IB. 
4.2 
Packaging and Labeling 
Gilteritinib used in this study will be prepared, packaged, and labeled under the responsibility 
of qualified staff at Astellas Pharma Global Development, Inc. (APGD) – Astellas United 
States Technologies (AUST) or sponsor’s designee in accordance with APGD-AUST or 
sponsor’s designee Standard Operating Procedures (SOPs), Good Manufacturing Practice 
(GMP) guidelines, ICH Good Clinical Practice (GCP) guidelines, and applicable local 
laws/regulations. 
Each bottle of gilteritinib will bear a label conforming to regulatory guidelines, GMP and 
local laws and regulations that identifies the contents as investigational drug. 
Atezolizumab will be supplied by the sponsor and will be packaged and labeled under the 
responsibility of qualified staff at APGD – AUST or sponsor’s designee in accordance with 
APGD-AUST or sponsor’s designee SOPs, GMP guidelines, ICH GCP guidelines, and 
applicable local laws/regulations. 


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Each atezolizumab 1200 mg/20 mL vial will bear a label conforming to regulatory 
guidelines, GMP and local laws and regulations that identifies the contents as investigational 
drug. Each labeled vial of atezolizumab 1200 mg/20 mL will be packaged into a 1x carton 
that also bears a label conforming to regulatory guidelines, GMP and local laws and 
regulations that identifies the contents as investigational drug. 
4.3 
Study Drug Handling  
Current ICH GCP Guidelines require the investigator to ensure that study drug deliveries 
from the sponsor are received by the investigator or designee and that: 
● 
Such deliveries are recorded, 
● 
Study drug is handled and stored according to labeled storage conditions, 
● 
Study drug with appropriate expiry/retest only is dispensed to study subjects in 
accordance with the protocol, and 
● 
Any unused study drug is returned to the sponsor or standard procedures for the 
alternative disposition of unused study drug are followed. 
Study drug inventory and accountability records will be kept by the investigator or designee. 
Study drug accountability throughout the study must be documented and reconciled. The 
following guidelines are therefore pertinent: 
● 
The investigator or designee agrees not to supply study drugs to any persons except the 
eligible subjects in this study in accordance with the protocol. 
● 
The investigator or designee will keep the study drugs in a pharmacy or other locked and 
secure storage facility under controlled storage conditions, accessible only to those 
authorized by the investigator to dispense these study drugs. 
● 
A study drug inventory will be maintained by the investigator or designee. The inventory 
will include details of material received and a clear record of when they were dispensed 
and to which subject. 
● 
At the conclusion or termination of this study, the investigator or designee agrees to 
conduct a final drug supply inventory and to record the results of this inventory on the 
Drug Accountability Record. It must be possible to reconcile delivery records with those 
of used and/or returned study drug. Any discrepancies must be accounted for and 
documented. Appropriate forms of deliveries and returns must be signed by the site staff 
delegated this responsibility. 
● 
The site staff must return unused study drug including gilteritinib and atezolizumab supplied 
by the sponsor back to the sponsor or designee at the end of the study or upon expiration. 
4.4 
Blinding 
This section is not applicable as this is an open label study. 
4.5 
Assignment and Allocation 
Enrollment and study drug assignment will be performed via Interactive Response Technology 
(IRT). 


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5 
TREATMENTS AND EVALUATION 
5.1 
Dosing and Administration of Study Drug(s) and Other 
Medication(s) 
5.1.1 
Dose/Dose Regimen and Administration Period 
5.1.1.1 Gilteritinib Dosing 
Gilteritinib is an oral tablet that subjects will take once daily. Subjects will be instructed to 
take the daily gilteritinib dose with water as close to the same time each morning as possible. 
Dose reductions are permitted [see Section 5.1.2 Reduction in Dose of the Study Drug(s)]. 
Gilteritinib will be taken in the clinic on visit days, and self-administered at home when 
subjects are not scheduled for clinic visits. If a subject forgets to take a dose in the morning 
and is 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. 
Subjects will be treated with gilteritinib at either 120 mg or 80 mg once daily for the phase 1 
portion of the study. The primary objective will be to establish an RP2D of gilteritinib in 
combination with atezolizumab. The RP2D will be determined by the DEC and will be the 
minimum safe and biologically effective dose level based on data from the phase 1 portion of 
the study. 
In the phase 2 portion, the subjects will be treated with gilteritinib once daily at RP2D. All 
subjects will be treated until they no longer derive clinical benefit in the judgment of the 
treating physician, have unacceptable toxicity, undergo HSCT, or meet 1 of the 
discontinuation criteria; whichever occurs first. 
5.1.1.2 Gilteritinib Subject Diary 
Each subject will be given a subject diary on day 1 of each cycle. Subjects should complete 
the diary as instructed.  
5.1.1.3 Atezolizumab Dosing 
Atezolizumab at a dose of 420 mg or 840 mg via intravenous infusion will be administered 
once every 2 weeks for the phase 1 portion. Based on the results of the phase 1 portion, 
Atezolizumab may be dosed at 420 mg or 840 mg via intravenous infusion administered once 
every 2 weeks for the phase 2 portion of the study. 
Administer the assigned dose as an intravenous infusion over 60 minutes every 2 weeks. If 
the first infusion is tolerated, all subsequent infusions may be delivered over 30 minutes. 
Refer to the pharmacy manual and current IB for administration instructions. 
The route of administration of atezolizumab outside of label instructions is not recommended 
and is a clinical decision of the investigator.  


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Atezolizumab will be prepared according to the current IB.  
Atezolizumab treatment should continue until the subject no longer receives clinical benefit 
from therapy in the opinion of the investigator, unacceptable toxicity occurs or the subject 
meets a treatment discontinuation criterion.  
5.1.1.4 Combination Dosing 
On days where both gilteritinib and atezolizumab are dosed, gilteritinib is to be taken first, 
then atezolizumab second, when subject is in the clinic. It should be noted that trough 
pharmacokinetic samples should be collected within 1 hour prior to gilteritinib dosing, and 
time points for blood samples collected for FLT3 and AXL (cycle 1/day 1 – pre-dose and 
post-dose at 2 hours, between 4 to 6 hours and 24 hours) are relative to gilteritinib dose 
administration. If in the opinion of the investigator the subject no longer receives clinical 
benefit from or experiences unacceptable toxicity that is related to either gilteritinib or 
atezolizumab, then the subject may discontinue either gilteritinib or atezolizumab and 
continue to receive the other agent.  
5.1.2 
Reduction in Dose of the Study Drug(s) 
5.1.2.1 Gilteritinib Dose Reduction 
Gilteritinib dose cannot be reduced during the DLT observation period (cycle 1/day 1 through 
cycle 1/day 28) of the phase 1 portion of the study.  
Guidelines for gilteritinib dose interruption and reduction for the phase 2 portion are provided 
in [Table 5].  
The dose levels potentially used include the following [Table 4]: 
Table 4 
Gilteritinib Dose Levels 
Dose Level (DL) 
Gilteritinib Dose 
DL - 0 
120 mga 
DL – 1 
80 mg 
DL – 2 
40 mg 
a Starting dose for gilteritinib 
The gilteritinib dose may be initially reduced by 1 dose level per day. The gilteritinib dose 
can be further reduced by a second dose level if the subject has already experienced clinical 
benefit. Note that dose reductions should occur in a step-wise manner. Only 2 dose level 
reductions are permitted. Dose reduction can occur during the treatment cycle based on the 
dose reduction guideline in [Table 5]. 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 5]. In the unusual circumstance that dosing is interrupted or reduced for 
reasons not specified in the tables, the investigator should promptly inform the study medical 
monitor or his/her designee. If the gilteritinib dose has been reduced for related toxicities, it 
cannot be re-escalated. Any subjects that have been off treatment for more than 14 days other 


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than for HSCT or a study drug related AE, may only resume treatment after discussion with 
the medical monitor. 
Table 5 
Guidelines for Gilteritinib Dose Interruption or Reduction Event 
Gilteritinib Dosing Instructions 
Nonhematological Events 
Grade 3 toxicity at least possibly 
related to gilteritinib 
Dosing will be interrupted for up to 14 days. 
If the AE resolves to ≤ grade 1 within 14 days, the subject may resume 
dosing at the reduced dose. 
Grade 4 toxicity at least possibly 
related to gilteritinib 
Treatment will be discontinued. 
QTcF > 500 ms 
See [Section 5.4.4] 
Myelosuppression 
Myelosuppression in the 
presence of CR, CRp or CRi 
Dose may be reduced without interruption if the following criteria are met: 
Subject has received a minimum of 2 cycles of gilteritinib 
Platelets < 25 × 109/L and/or absolute neutrophil count (ANC) ≤ 0.5 × 109/L 
Marrow blasts < 5% 
No evidence of extramedullary disease 
Further dose reduction is permitted if dosing 1 full cycle at the reduced dose 
has not resulted in the desired hematologic recovery.  
AE: adverse event; CR: complete remission; CRc: composite complete remission; CRi: complete remission with 
incomplete hematologic recovery; CRp: complete remission with incomplete platelet recovery; ECG: 
electrocardiogram; QTcF: Fridericia-corrected QT interval 
5.1.3 
Atezolizumab Dose Interruption 
Refer to the following for atezolizumab dose modification recommendations:  
Table 6 
Recommended Dosage Modifications for Adverse Reactions (Atezolizumab) 
Adverse Reaction 
Severity of Adverse 
Reactiona 
Dosage Modifications 
Pneumonitis [see Warnings and 
Precautions (6.3) in the current 
IB] 
Grade 2 
Withhold dose until Grade 1 or resolved and 
corticosteroid dose is less than or equal to 
prednisone 10 mg per day (or equivalent) 
Grade 3 or 4 
Permanently discontinue 
Hepatitis [see Warnings and 
Precautions (6.3) in the current 
IB] 
AST or ALT > 3 and ≤ 8 x 
ULN or total bilirubin > 
1.5 and ≤ 3 x ULN 
Withhold dose until Grade 1 or resolved and 
corticosteroid dose is less than or equal to 
prednisone 10 mg per day (or equivalent) 
AST or ALT > 8 x ULN or 
total bilirubin > 3 x ULN 
Permanently discontinue 
Colitis or diarrhea [see Warnings 
and Precautions (6.3) in the 
current IB.] 
Grade 2 or 3 
Withhold dose until Grade 1 or resolved and 
corticosteroid dose is less than or equal to 
prednisone 10 mg per day (or equivalent) 
Grade 4 
Permanently discontinue 
Endocrinopathies (including but 
not limited to hypophysitis, 
adrenal insufficiency, 
hyperthyroidism, and type 1 
diabetes mellitus) [see Warnings 
and Precautions (6.3) in the 
current IB] 
Grade 2, 3, or 4 
Withhold dose until Grade 1 or resolved and 
clinically stable on hormone replacement 
therapy. 
Table continued on next page 


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Adverse Reaction 
Severity of Adverse 
Reactiona 
Dosage Modifications 
Other immune-mediated adverse 
reactions involving a major organ 
[see Warnings and Precautions 
(6.3) in the current IB] 
Grade 3 
Withhold dose until Grade 1 or resolved and 
corticosteroid dose is less than or equal to 
prednisone 10 mg per day (or equivalent) 
Grade 4 
Permanently discontinue 
Infections [see Warnings and 
Precautions (6.3) in the current 
IB] 
Grade 3 or 4 
Withhold dose until Grade 1 or resolved 
Infusion-Related Reactions [see 
Warnings and Precautions (6.3) in 
the current IB] 
Grade 1 or 2 
Interrupt or slow the rate of infusion 
Grade 3 or 4 
Permanently discontinue 
Persistent Grade 2 or 3 adverse 
reaction (excluding 
endocrinopathies) 
Grade 2 or 3 adverse 
reaction that does not 
recover to Grade 0 or 1 
within 12 weeks after last 
TECENTRIQ dose 
Permanently discontinue 
Inability to taper corticosteroid 
Inability to reduce to less 
than or equal to prednisone 
10 mg per day (or 
equivalent) within 12 
weeks after last 
TECENTRIQ dose 
Permanently discontinue 
Recurrent Grade 3 or 4 adverse 
reaction 
Recurrent Grade 3 or 4 
(severe or life- threatening) 
adverse reaction 
Permanently discontinue 
Previously experienced a skin 
adverse reaction on prior treatment 
with other immune-stimulatory 
anticancer agents 
Grade 3 or 4 (severe or 
life-threatening reaction) 
Caution when considering the use of 
atezolizumab 
Suspected cutaneous adverse 
reactions 
Grade 3 or 4 
Refer to a dermatologist for further diagnosis 
and management 
SJS or TEN 
Withhold dose until confirmation of diagnosis 
Confirmed SJS or TEN 
Any Grade 
Permanently discontinue 
SJS: Stevens-Johnson Syndrome; TEN: Toxic Epidermal Necrolysis 
a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 
 
Refer to the pharmacy manual or current IB for any updates. 
5.1.3.1 Additional Dosing Interruption Guidelines 
● 
Cycle 1: If the cycle 1/day 15 dose of atezolizumab is withheld due to, a treatment-
related AE then the cycle 1/day 15 dose should be skipped and atezolizumab 
administration resumed at day 1 of the next cycle, if the treatment-related event has 
resolved or returned to grade 1. 
● 
Subsequent cycles 2 and beyond: if the day 1 and/or day 15 dose of atezolizumab in a 
cycle is delayed due to a treatment-related AE, then atezolizumab administration should 
be skipped until the next scheduled atezolizumab dose (e.g., day 1 or day 15) of a cycle.  


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● 
In subsequent cycles, atezolizumab and gilteritinib may be interrupted for situations 
other than treatment related AEs such as medical/surgical events or logistical reasons not 
related to study therapy. Subjects should be placed back on study therapy within 14 days 
of the scheduled interruption, unless otherwise discussed with the medical monitor. The 
reason for interruption should be documented in the subject's study record. 
5.1.4 
Previous and Concomitant Treatment (Medication and Non-Medication 
Therapy) 
All medications and concomitant treatments administered from 28 days prior to cycle 1/day 1 
through the EOT Visit must be recorded in the electronic case report form (eCRF). 
Concomitant medications should be collected for reported or ongoing AE/serious adverse 
events (SAEs) through 30 days after the last dose of study drug for subjects who have 
discontinued treatment. For subjects who undergo HSCT, concomitant medications should be 
collected for reported or ongoing AE/SAEs through start of conditioning treatment or 30 days 
after the last dose of study drug, whichever comes first. Treatment with concomitant drugs 
that are strong inducers of CYP3A are prohibited. Treatment with concomitant drugs that are 
strong inhibitors or inducers 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. If CYP3A 
inhibitors are used concomitantly, subjects should be closely monitored for AEs. 
Precaution should be used in use of gilteritinib with concomitant drugs that are known to 
prolong QT or QTc intervals. 
Precaution should be used in use of gilteritinib with concomitant drugs that are substrates of 
BCRP, since the transporter has been shown to be inhibited by gilteritinib in in vitro studies. 
Common strong CYP3A inhibitors, strong CYP3A inducers, drugs targeting the serotonin 
receptor, P-gp inhibitors or inducers and drugs known to prolong QT or QTc intervals are 
listed in [Appendix 12.4 List of Prohibited and/or Cautionary Concomitant Medications]. 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. For concomitant drugs that have the 
potential to prolong QT or QTc intervals, a cardiology consult should be obtained as 
medically indicated. Any other treatments of AML (including but not limited to 
chemotherapy, radiotherapy, surgery, immunotherapy or cellular therapy) are prohibited 
during therapy with gilteritinib with the exception of hydroxyurea up to 5 g daily for up to 
2 weeks to keep the absolute blast count below 50 × 109/L, prophylactic intrathecal 
chemotherapy or cranial irradiation. Participation in another interventional study while on 
treatment is prohibited. 
Refer to [Appendix 12.4 List of Prohibited and/or Cautionary Concomitant Medications], as 
well as the country specific atezolizumab package insert for additional details on excluded or 
cautionary use of medications.  


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5.1.5 
Treatment Compliance 
Study subjects should be counseled on the need to meet 100% compliance with study drug. 
Investigator or designee should ensure that study subjects meet this goal throughout the study 
period. When study drug is administered at the research facility, it will be administered under 
the supervision of study personnel. 
Compliance of gilteritinib will be monitored by the accounting of unused medication returned 
by the subject at visits and the subject diary. Compliance will be documented in EDC and IRT. 
Reasons for dose reduction or interruption will also be recorded in the eCRF.  
Treatment compliance should be monitored closely and deviation in compliance should be 
reported to the sponsor, except in cases where directed by protocol or principal investigator 
(e.g., account for dose interruptions, adjustments, etc.). 
5.1.6 
Criteria for Continuation of Treatment  
Not applicable for this study. 
5.1.7 
Restrictions During the Study  
See Inclusion/Exclusion Criteria in [Sections 3.2 and 3.3]. 
5.2 
Demographics and Baseline Characteristics 
5.2.1 
Demographics 
Demographic information will be collected for all subjects and will include age, sex, race and 
ethnicity. 
5.2.2 
Medical History 
Medical history includes all significant medical conditions other than AML that have 
resolved prior to informed consent. Conditions that are ongoing at the time of consent will be 
collected as baseline conditions on the Medical History eCRF. Details that will be collected 
include the onset date, recovery date and CTCAE grade [National Cancer Institute, 2017], if 
applicable for ongoing conditions. 
5.2.3 
Diagnosis of the Target Disease, Severity, and Duration of Disease  
5.2.3.1 Disease History 
AML diagnosis and studies related to AML subtype classification will be collected and will 
include date, bone marrow evaluations, histopathology, cytogenetics, immunophenotyping 
and cytochemistry, lumbar puncture results if performed (RBCs, white blood cells with 
differential, cytospin results) and related genetic syndromes. Dates for diagnostic procedures 
will be collected. 
5.2.3.2 FMS-like Tyrosine Kinase Mutation Status 
All subjects must have documented FLT3 mutation by the local institution after completion 
of the subject’s last interventional treatment.  


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Bone marrow/blood sampling, processing, storage and shipment instructions will be provided 
in the Laboratory Manual. Refer to the Laboratory Manual for more detailed information. 
5.2.4 
Performance Status 
The ECOG Scale [Oken et al, 1982] will be used to assess performance status [Table 7] and 
will be obtained and recorded according to the Schedule of Assessments [Table 1].  
Table 7 
ECOG Performance Status 
Grade 
Description 
0 
Fully active, able to carry on all predisease performance without restriction. 
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. 
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. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 
Dead. 
ECOG: Eastern Cooperative Oncology Group 
5.3 
Efficacy Assessments 
5.3.1 
Bone Marrow Aspirate and Biopsy 
Bone marrow samples will be collected at screening, cycle 2/day 1 and cycle 3/day 1. For 
subjects who do not achieve a CR, CRp or CRi, the bone marrow assessments will be repeated 
on day 1 of every 2 subsequent cycles. For subjects who achieve a CRc (CR, CRp or CRi), 
bone marrow will be repeated 1 month after the date of remission and every 3 subsequent 
cycles or if there is suspicion of relapse in the whole blood. Bone marrow samples are also 
required at the EOT Visit and as clinically indicated. If bone marrow aspirate is unobtainable 
due to technical difficulties such as dry tap, a tube of whole blood (ethylenediaminetetraacetic 
acid [EDTA]) along with bone marrow biopsy should be collected instead. Remaining bone 
marrow aspirate and/or whole blood samples will be used for MRD analysis and may be used 
for other biomarker analyses in relation to treatment outcomes [described in Section 5.7] If 
bone marrow aspirate is unobtainable at relapse (e.g., dry tap), a peripheral blood smear 
should be collected along with bone marrow biopsy lab. All samples will be sent to the central 
lab. Refer to the laboratory manual for additional details.  
5.3.2 
Response Assessments 
Response to treatment will be defined per modified Cheson criteria [Cheson et al, 2003] as 
outlined below for up to the end of 2 cycles and end of treatment. 
5.3.2.1 Composite Complete Remission (CRc) rate 
Defined as the rate of all complete and incomplete remission (i.e., CR+ CRp + CRi). 


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5.3.2.2 Complete Remission (CR) 
For subjects to be classified as being in CR, they must have bone marrow regenerating 
normal hematopoietic cells and achieve a morphologic leukemia-free state and must have an 
absolute neutrophil count (ANC) > 1 × 109/L and platelet count ≥ 100 × 109/L, and normal 
marrow differential with < 5% blasts, and they must be red blood cell (RBC) and platelet 
transfusion independent (defined as 1 week without RBC transfusion and 1 week without 
platelet transfusion). There should be no evidence of extramedullary leukemia. 
5.3.2.3 Complete Remission with Incomplete Platelet Recovery (CRp) 
For subjects classified as being in CRp, they must achieve CR except for incomplete platelet 
recovery (< 100 × 109/L). 
5.3.2.4 Complete Remission with Incomplete Hematological Recovery (CRi) 
For subjects to be classified as being in CRi, they must fulfill all the criteria for CR except for 
incomplete hematological recovery with residual neutropenia < 1 × 109/L with or without 
complete platelet recovery. RBC and platelet transfusion independence is not required. 
5.3.2.5 Complete Remission with Partial Hematologic Recovery (CRh) 
For subjects classified as being in CR, except if their ANC is > 0.5 × 109/L and their platelets 
are > 50 × 109/L. 
5.3.2.6 Partial Remission (PR) 
For subjects to be classified as being in PR, they must have bone marrow regenerating 
normal hematopoietic cells with evidence of peripheral recovery with no (or only a few 
regenerating) circulating blasts and with a decrease of at least 50% in the percentage of blasts 
in the bone marrow aspirate/biopsy with the total marrow blasts between 5% and 25%. 
5.3.2.7 Relapse 
Relapse after CR, CRp or CRi is defined as a reappearance of leukemic blasts in the 
peripheral blood or ≥ 5% blasts in the bone marrow aspirate/biopsy not attributable to any 
other cause or reappearance or new appearance of extramedullary leukemia.  
Relapse after PR is similarly defined with reappearance of significant numbers of peripheral 
blasts and an increase in the percentage of blasts in the bone marrow aspirate/biopsy to 
> 25% not attributable to any other cause or reappearance or new appearance of 
extramedullary leukemia. 
5.3.2.8 Treatment Failure 
Treatment failure is defined as lack of CR, CRp or CRi, and is determined at the EOT. 
5.3.2.9 Best Response 
Best response is defined as the best-measured response (CR, CRp, CRi or PR) post treatment. 
Two best responses will be defined. 


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5.3.3 
Survival Time, Duration of Response and Other Efficacy Endpoints 
5.3.3.1 Survival Status and Subsequent Antileukemic Treatments and Their Outcomes 
Information on survival status, subsequent antileukemic treatments (including HSCT) and 
outcomes will be collected for all subjects during long-term follow-up. 
The first survival status assessment will occur at the 30-day follow up. After the  
30-day follow up, the subject or caregiver will continue to be contacted via telephone by site 
personnel for follow-up every 3 months. Data may be supplemented by site records when 
available at the time of the contact (e.g., treatment records, outcomes). Follow-up will 
continue until the data cut-off date for final analysis, which is estimated to be up to 3 years of 
follow-up for some subjects. Additional contacts may be made to support key analyses 
(e.g., final analysis). 
Reasonable effort should be made to contact any subjects lost to follow-up during the course 
of the study in order to complete study-related assessments and retrieve any outstanding data 
and study drug. Following unsuccessful telephone contact, an effort to contact the subject by 
mail using a method that provides proof of receipt should be attempted. Contact via an 
alternate, preapproved contact is permissible if the subject is not reachable. Such efforts 
should be documented in the source documents. 
If a subject death occurs during the SAE reporting period or if the death occurs after the SAE 
reporting period but is determined by the investigator to be related to study regimen 
(gilteritinib and/or atezolizumab), then the associated AE with outcome of death will also be 
reported on the AE eCRF and SAE Worksheet. If a subject death does not meet the criteria of 
an SAE, then death and antileukemic treatment and outcome up through the date of death 
should be collected and entered in the eCRF. 
5.3.3.2 Overall Survival 
OS is defined as the time from the date of enrollment until the date of death from any cause. 
For a subject who is not known to have died by the end-of-study follow-up, OS is censored at 
the date of last contact. 
Date of last contact is defined as the death date or the latest of the following dates: treatment 
discontinuation date, last dosing administration date, last disease assessment date or the last 
follow-up date on which the subject was known to be alive. 
5.3.3.3 Event-free Survival 
EFS is defined as the time from the date of enrollment until the date of documented relapse 
from CR, CRp or CRi, treatment failure or death from any cause, whichever occurs first. 
If a subject experiences relapse or death the subject is defined as having an EFS event related 
to either “relapse” or “death,” and the event date is the date of relapse or death. 
If a subject who discontinues the treatment due to treatment failure during the first 
2 treatment cycles, and the subject has no previous response of CR, CRp or CRi, the subject 
is defined as having an EFS event and the event date is the date of enrollment. 


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If a subject who discontinues the treatment due to treatment failure after the 2 treatment 
cycles, and the subject has no previous response of CR, CRp or CRi, the subject is defined as 
having an EFS event and the event date is the date of end of the 2nd treatment cycle 
evaluation date (i.e., cycle 3/day 1 bone marrow evaluation).  
For a subject who is not known to have relapse or treatment failure or death, EFS is censored 
at the date of last relapse-free assessment date. Subject is not censored at HSCT. 
5.3.3.4 Duration of Remission 
Duration of remission includes duration of CRc, CR, CRi, CRp and response (CRc + PR). 
Duration of CRc is defined as the time from the date of first CRc until the date of 
documented relapse for subjects who achieve CRc. Subjects who die without report of 
relapse are considered nonevents and censored at their last relapse-free disease assessment 
date. Subjects who come off study for an allogeneic HSCT will be considered nonevents and 
censored at the time of HSCT. Other subjects who do not relapse on study are considered 
nonevents and censored at the last relapse-free disease assessment date. 
The duration of CR, CRp or CRi is defined similarly as duration of CRc. 
Duration of response is defined as the time from the date of either first CRc or PR until the 
date of documented relapse of any type for subjects who achieve CRc or PR. Subjects who 
die without report of relapse are considered nonevents and censored at their last relapse-free 
disease assessment date. Subjects who come off study for an allogeneic HSCT will be 
considered nonevents and censored at the time of HSCT. Other subjects who do not relapse 
on study are considered nonevents and censored at the last relapse-free assessment date. 
5.4 
Safety Assessment 
5.4.1 
Vital Signs 
Vital signs, including systolic and diastolic blood pressures (mmHg), radial pulse rate 
(beats/minute) and temperature will be obtained and recorded at the times specified in the 
Schedule of Assessments [Table 1]. All vital sign measurements will be obtained with the 
subject in the sitting or supine position. 
If clinically significant vital sign changes from baseline (pretreatment) are noted, the changes 
will be documented as AEs on the AE page of the eCRF. Clinical significance will be defined 
as a variation in vital signs, which has medical relevance that could result in an alteration in 
medical care. The investigator will continue to monitor the subject until the parameter returns 
to grade ≤ 1 or to the baseline (pretreatment) value or until the investigator determines that 
follow up is no longer medically necessary 
5.4.2 
Laboratory Assessments 
Refer to [Appendix 12.8 Laboratory Assessment] and laboratory manual for a list of the 
laboratory tests that will be performed during the conduct of the study. Refer to the Schedule 
of Assessments [Table 1] for study visit collection dates. Local laboratory tests can be used at 
screening for eligibility for serum chemistry, hematology, urinalysis and coagulation only. In 


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the event that the central laboratory results received after enrollment are not within eligibility 
parameters, the subject will still be considered eligible if local labs met the eligibility criteria 
and not considered a protocol deviation. Additional laboratory tests should be performed 
according to institutional standard of care. Local testing of hematology and bone marrow 
aspirate and/or biopsy at screening and day 1 of each cycle will be reported in the eCRF. 
Hematology results will need to be assessed prior to dosing.  
Clinical significance of out-of-range laboratory findings is to be determined and documented 
by the investigator/subinvestigator who is a qualified physician. 
5.4.3 
Physical Examination  
Standard, full physical examinations will be performed to assess general appearance, skin, 
eyes, ears, nose, throat, neck, cardiovascular, chest and lungs, abdomen, musculoskeletal, 
neurologic status, mental status and lymphatic systems. Genitourinary and rectal system 
examinations are to be performed only if clinically indicated. Physical examinations will be 
conducted at the visits outlined in the Schedule of Assessments [Table 1]. Each physical 
examination will include the observation and review of body system, weight at screening and 
on day 1 of each cycle. Height is only required at screening. If clinically significant 
worsening of findings from predose (day 1) is noted at any study visit, the changes will be 
documented as AEs on the AE page of the eCRF. Clinical significance is defined as any 
variation in physical findings, which has medical relevance that could result in an alteration 
in medical care. The investigator will continue to monitor the subject until the parameter 
returns to grade ≤ 1 or to the baseline (pretreatment) condition or until the investigator 
determines that follow up is no longer medically necessary. 
5.4.4 
Electrocardiogram  
A 12-lead ECG will be performed during the screening period, predose of cycle 1/day 1, 
cycle 1/day 8, cycle 1/day 15, day 1 of each subsequent cycle, day 15 of each subsequent 
cycle and at the EOT visit. Predose assessments should be taken within 1 hour before 
gilteritinib alone or in combination with atezolizumab administration on the days when the 
combination is given. The 12-lead ECGs will be recorded in triplicate (3 separate ECGs, 
10 minutes resting prior to first ECG and at least 5 minutes apart per time point) and 
transmitted electronically for central reading. The mean QTcF of the triplicate ECG tracings 
based on central reading will be used for all treatment interruption and reduction decisions.  
If the mean triplicate QTcF is > 500 ms at any time point, on local read, the ECG will be 
repeated (within 2 hours if identified on machine read or as soon as possible if identified 
from central read). Cardiology consult will be obtained as medically indicated. If  
QTcF > 500 ms is confirmed, then the investigator will interrupt and reduce gilteritinib per 
the interruption or reduction guidelines in [Section 5.1.2 Reduction in Dose of the Study 
Drug(s)]. 
ECGs are to be performed prior to obtaining the time-matched pharmacokinetic sample, 
therefore, the ECGs must be started at least 10 to 15 minutes before the pharmacokinetic 
draw. Whenever a study procedure coincides with the scheduled time point for an ECG 


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triplicate, the study activities will ideally be undertaken in a fixed sequence: ECG triplicate 
first, vital signs (blood pressure and heart rate) second and any type of blood draw as the last 
assessment. This order of events is not mandatory and can be changed if required in order to 
accommodate pharmacokinetic time points.  
5.4.5 
Chest X-ray or Computed Tomography Scan 
Chest X-ray or computed tomography (CT) scan is to be performed at screening. A chest 
X-ray (or CT of chest) does not need to be repeated if performed within 2 weeks prior to start 
of screening. 
5.4.6 
Multigated Acquisition Scan or Echocardiogram 
A multigated acquisition scan (MUGA) or ECHO (as per standard of care) is to be performed 
at screening for all subjects.  
5.5 
Adverse Events and Other Safety Aspects 
5.5.1 
Definition of Adverse Events  
An AE is any untoward medical occurrence in a subject administered a study drug, and which 
does not necessarily have to have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom or disease (new or exacerbated) temporally associated with the use of a medicinal 
product whether or not considered related to the medicinal product. 
In order to identify any events that may be associated with study procedures and could lead to 
a change in the conduct of the study, Astellas collects AEs even if the subject has not 
received study drug treatment. AE collection begins after the signing of the ICF and will be 
collected until 30 days after the last dose of study drug or the subject is determined to be a 
screen failure.  
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrences. 
5.5.1.1 Abnormal Laboratory Findings 
Any abnormal laboratory test result (e.g., hematology, clinical chemistry or urinalysis) or 
other safety assessment (e.g., ECGs, radiographic scans, vital signs measurements, physical 
examination), including those that worsen from baseline, that is considered to be clinically 
significant in the medical and scientific judgment of the investigator and not related to 
underlying disease, is to be reported as an SAE or AE (also referred to as an [S]AE). 
Any clinically significant abnormal laboratory finding or other abnormal safety assessment, 
which is associated with the underlying disease does not require reporting as an (S)AE, 
unless judged by the investigator to be more severe than expected for the subject’s condition. 


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Repeating an abnormal laboratory test or other safety assessment, in the absence of any of the 
above criteria, does not constitute an AE. Any abnormal test result that is determined to be an 
error does not require reporting as an AE. 
5.5.1.2 Potential Cases of Drug-Induced Liver Injury 
Refer to [Appendix 12.5 Liver Safety Monitoring and Assessment] for detailed instructions 
on Drug Induced Liver Injury (DILI). Abnormal values in aspartate transaminase (AST) 
and/or alanine transaminase (ALT) concurrent or with abnormal elevations in TBL that meet 
the criteria outlined in [Appendix 12.5 Liver Safety Monitoring and Assessment], in the 
absence of other causes of liver injury, are considered potential cases of drug-induced liver 
injury (potential Hy’s Law cases) and are always to be considered important medical events 
and reported per [Section 5.5.5 Reporting of Serious Adverse Events]. 
5.5.1.3 Disease Progression and Study Endpoints 
Under this protocol, the following event(s) will not be considered as an (S)AE: 
● 
Disease Progression: events including defined study endpoints that are clearly consistent 
with the expected pattern of progression of the underlying disease are not to be recorded 
as AEs. If there is any uncertainty as to whether an event is due to anticipated disease 
progression and/or if there is evidence suggesting a causal relationship between the study 
drug and the event, it should be reported as an (S)AE. All deaths up to 30 days after the 
last dose of study drug must be reported as an SAE, even if attributed to disease 
progression.  
● 
Pre-planned and elective hospitalizations or procedures for diagnostic, therapeutic or 
surgical procedures for a pre-existing condition that did not worsen during the course of 
the clinical study. These procedures are collected per the eCRF Completion Guidelines. 
5.5.2 
Definition of Serious Adverse Events (SAEs) 
An AE is considered “serious” if, in the view of either the investigator or sponsor, it results in 
any of the following outcomes:  
● 
Results in death 
● 
Is life-threatening (an AE is considered “life-threatening” if, in the view of either the 
investigator or sponsor, its occurrence places the subject at immediate risk of death. It 
does not include an AE that, had it occurred in a more severe form, might have caused 
death) 
● 
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions  
● 
Results in congenital anomaly or birth defect 
● 
Requires inpatient hospitalization (except for planned procedures as allowed per study) 
or leads to prolongation of hospitalization (except if prolongation of planned 
hospitalization is not caused by an AE). Hospitalization for 
treatment/observation/examination caused by AE is to be considered as serious.)  
● 
Other medically important events (defined in paragraph below) 


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Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. These events, including those that may result in disability/incapacity, 
usually are considered serious. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that 
do not result in hospitalization; or development of drug dependency or drug abuse.  
5.5.2.1 Always Serious Adverse Events 
The sponsor has a list of events that they classify as “always serious” events. If an AE is 
reported that is considered by the sponsor to be an SAE per this classification as “always 
serious”, additional information on the event (e.g., investigator confirmation of seriousness, 
causality) will be requested.  
5.5.3 
Criteria for Causal Relationship to Study Drug 
A medically qualified investigator is obligated to assess the relationship between each study 
drug and each occurrence of each (S)AE. This medically qualified investigator will use 
medical judgment, as well as the Reference Safety Information (RSI) to determine the 
relationship. The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
The medically qualified investigator is requested to provide an explanation for the causality 
assessment for each (S)AE and must document in the medical notes that he/she has reviewed 
the (S)AE and has provided an assessment of causality. 
Following a review of the relevant data, the causal relationship between the study drug and 
each (S)AE will be assessed by answering ‘yes’ or ‘no’ to the question “Do you consider 
that there is a reasonable possibility that the event may have been caused by the study 
drug”. 
When making an assessment of causality, the following factors are to be considered when 
deciding if there is evidence and/or arguments to suggest there is a ‘reasonable possibility’ 
that an (S)AE may have been caused by the study drug (rather than a relationship cannot be 
ruled out) or if there is evidence to reasonably deny a causal relationship: 
● 
Plausible temporal relationship between exposure to the study drug and (S)AE onset 
and/or resolution. Has the subject actually received the study drug? Did the (S)AE occur 
in a reasonable temporal relationship to the administration of the study drug?  
● 
Plausibility; i.e., could the event been caused by the study drug? Consider biologic 
and/or pharmacologic mechanism, half-life, literature evidence, drug class, preclinical 
and clinical study data, etc. 
● 
Dechallenge/Dose reduction/Rechallenge:  
○ Did the (S)AE resolve or improve after stopping or reducing the dose of the 
suspect drug? Also consider the impact of treatment for the event when evaluating 
a dechallenge experience.  


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○ Did the (S)AE reoccur if the suspected drug was reintroduced after having been 
stopped?  
● 
Laboratory or other test results; a specific lab investigation supports the assessment of 
the relationship between the (S)AE and the study drug (e.g., based on values pre-, during 
and post-treatment) 
● 
Available alternative explanations independent of study drug exposure; such as other 
concomitant drugs, past medical history, concurrent or underlying disease, risk factors 
including medical and family history, season, location, etc. and strength of the alternative 
explanation 
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the sponsor/delegated contract research 
organization (CRO). However, it is very important that the medically qualified investigator 
always make an assessment of causality for every event before the initial transmission of the 
SAE data to the sponsor/delegated CRO. With limited or insufficient information about the 
event to make an informed medical judgment and in absence of any indication or evidence to 
establish a causal relationship, a causality assessment of ‘no’ is to be considered. In such 
instance, the investigator is expected to obtain additional information regarding the event as 
soon as possible and to re-evaluate the causality upon receipt of additional information. The 
medically qualified investigator may revise his/her assessment of causality in light of new 
information regarding the SAE and shall send an SAE follow-up report and update the eCRF 
with the new information and updated causality assessment.  
5.5.4 
Criteria for Defining the Severity of an Adverse Event 
AEs, including abnormal clinical laboratory values, will be graded using the National Cancer 
Institute Common Terminology Criteria for Adverse Event (NCI-CTCAE) guidelines 
(version 5.0). The items that are not stipulated in the NCI-CTCAE version 5.0 will be 
assessed according to the criteria below and entered into the eCRF: 
Grade 
Assessment Standard 
1-Mild 
Asymptomatic or mild symptoms, clinical or diagnostic observations noted; 
intervention not indicated. 
2-Moderate 
Local or noninvasive intervention indicated. 
3-Severe 
Medically significant but not immediately life threatening, hospitalization or 
prolonged hospitalization. 
4-Life Threatening 
Life threatening consequences, urgent intervention indicated 
5-Death 
Death related to AE 
5.5.5 
Reporting of Serious Adverse Events (SAEs) 
The collection of AEs and the expedited reporting of SAEs will start following receipt of the 
ICF and will continue until 30 days after last administration of study drug or the subject is 
determined to be a screen failure.  
In the case of a SAE, the investigator must contact the sponsor/delegated CRO by fax or 
email immediately (within 24 hours of awareness). 


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The investigator must complete and submit an SAE worksheet containing all information that 
is required by local and/or regional regulations to the sponsor/delegated CRO by email or fax 
immediately (within 24 hours of awareness).  
The SAE worksheet must be signed by a medically qualified investigator (as identified on 
Delegation of Authority Log). Signature confirms accuracy and completeness of the SAE 
data, as well as the investigator causality assessment including the explanation for the 
causality assessment. 
For contact details, see [Section II Contact Details of Key Sponsor's Personnel]. Fax or email 
the SAE/Special Situations Worksheet to: 
Astellas Pharma Global Development, Inc. 
Global Pharmacovigilance 
Fax number 888-396-3750 
Alternate Fax: 847-317-1241 
Email: safety-us@astellas.com 
If there are any questions or if clarification is needed regarding the SAE, please contact the 
sponsor's medical monitor/study physician or his/her designee [Section II Contact Details of 
Key Sponsor’s Personnel].  
Follow-up information for the event should be sent promptly (within 7 days of the initial 
notification). 
Full details of the SAE should be recorded on the medical records, SAE/Special Situation 
Worksheet and on the (e)CRF. The following minimum information is required: 
● 
International Study Number (ISN)/Study number,  
● 
Subject number, sex and age, 
● 
The date of report, 
● 
A description of the SAE (event, seriousness criteria),  
● 
Causal relationship to the study drug (including reason), and 
● 
The drug provided (if any) 
The sponsor or sponsor’s designee will medically evaluate the SAE and determine if the 
report meets the requirements for expedited reporting based on seriousness, causality, and 
expectedness of the events (e.g., Suspected Unexpected Serious Adverse Reaction (SUSAR) 
reporting) according to current local/regional regulatory requirements in participating 
countries. The sponsor or sponsor's designee will submit expedited safety reports (e.g., IND 
Safety Reports, SUSAR, Council for International Organizations of Medical Sciences 
[CIOMS]-I) to Competent Authorities (CA) and concerned Ethics Committee (cEC) per 
current local regulations, and will inform the investigators of such regulatory reports as 
required. Investigators must submit safety reports as required by their IRB/local IEC within 
timelines set by regional regulations (e.g., EMA, FDA) where required. Documentation of the 
submission to and receipt by the IRB/local IEC of expedited safety reports should be retained 
by the site. 


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The sponsor/delegated CRO will notify all investigators responsible for ongoing clinical 
studies with the study drug of all SUSARs which require submission per local requirements 
IRB/local IEC. 
The investigators should provide written documentation of IRB/IEC notification for each 
report to the sponsor. 
The investigator may contact the sponsor's medical monitor/study physician for any other 
problem related to the safety, welfare or rights of the subject. 
5.5.6 
Follow-up of Adverse Events 
All AEs occurring during or after the subject has discontinued the study are to be followed up 
until resolved or judged to be no longer clinically significant, or until they become chronic to 
the extent that they can be fully characterized by the investigator.  
 If after the protocol defined AE collection period [see Section 5.5.1 Definition of Adverse 
Event], an AE progresses to a SAE or the investigator learns of any (S)AE including death, 
where he/she considers there is reasonable possibility it is related to the study drug treatment 
or study participation, the investigator must promptly notify the sponsor. 
5.5.7 
Monitoring of Common Serious Adverse Events 
Common SAEs are SAEs commonly anticipated to occur in the study population independent 
of drug exposure. SAEs classified as “common” are provided in [Appendix 12.6 Common 
Serious Adverse Events] for reference. The list does NOT change the investigator’s reporting 
obligations, nor his obligations to perform a causality assessment, or prevent the need to 
report an AE meeting the definition of an SAE as detailed above. The purpose of this list is to 
alert the investigator that some events reported as SAEs may not require expedited reporting 
to the regulatory authorities based on the classification of “common SAEs” as specified in 
[Appendix 12.6 Common Serious Adverse Events]. The sponsor will monitor these events 
throughout the course of the study for any change in frequency. Any changes to this list will 
be communicated to the participating investigational sites. Investigators must report 
individual occurrences of these events as stated in [Section 5.5.5 Reporting of Serious 
Adverse Events].  
5.5.8 
Adverse Events of Special Interest (AESI) (Immediately Reportable to the 
Sponsor) 
AEs of special interest (AESI) are required to be reported by the investigator to the sponsor 
immediately (i.e., no more than 24 hours after learning of the event). AEs of special interest 
are provided in the [Appendix 12.7 Adverse Events of Special Interest for Atezolizumab] for 
reference. 
After initiation of study treatment, AEs of special interest will continue to be reported until 
30 days after the last dose of study treatment. The AEs of special interest are to be collected 
via the SAE/Special Situation worksheet and reported within 24 hours as described in 
[Section 5.5.5 Reporting of SAEs]. 


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5.5.9 
Special Situations  
Certain Special Situations observed in association with the study drug(s), such as incorrect 
administration (e.g., wrong dose of study drug) are collected in the eCRF, as Protocol 
Deviation per [Section 8.3 Major Protocol Deviations] or may require special reporting, as 
described below. These Special Situations are not considered AEs, but do require to be 
communicated to Astellas as per the timelines defined below. 
If a Special Situation is associated with, or results in, an AE, the AE is to be assessed 
separately from the Special Situation and captured as an AE in the eCRF. If the AE meets the 
definition of a SAE, the SAE is to be reported as described in [Section 5.5.5 Reporting of 
Serious Adverse Events] and the details of the associated Special Situation are to be included 
in the clinical description on the SAE worksheet. 
The Special Situations are: 
● 
Pregnancy  
● 
Medication Error, Overdose and “Off-label use” 
● 
Misuse/abuse 
● 
Occupational exposure 
● 
Suspected Drug-Drug interaction 
5.5.9.1 Pregnancy 
If a female subject becomes pregnant during the study dosing period or within 180 days from 
the discontinuation of dosing, the investigator is to report the information to the 
sponsor/delegated CRO according to the timelines in [Section 5.5.5 Reporting of Serious 
Adverse Events] using the Pregnancy Reporting Form and in the eCRF. 
The investigator will attempt to collect pregnancy information on any female partner of a 
male subject who becomes pregnant during the study dosing period or within 180 days from 
the discontinuation of dosing and report the information to sponsor/delegated CRO according 
to the timelines in [Section 5.5.5 Reporting of Serious Adverse Events] using the Pregnancy 
Reporting Form.  
The expected date of delivery or expected date of the end of the pregnancy, last menstruation, 
estimated conception date, pregnancy result and neonatal data etc., should be included in this 
information. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
termination (including elective termination) of a pregnancy is to be reported for a female 
study subject as an AE in the eCRF or SAE per [Section 5.5.5 Reporting of Serious Adverse 
Events]. For (S)AEs experienced by a female partner of a male subject, (S)AEs are to be 
reported via the Pregnancy Reporting Form.  
Additional information regarding the outcome of a pregnancy when also categorized as an 
SAE is mentioned below: 
● 
“Spontaneous abortion” includes miscarriage, abortion and missed abortion. 


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● 
Death of a newborn or infant within 1 month after birth is to be reported as an SAE 
regardless of its relationship with the study drug. 
● 
If an infant dies more than 1 month after the birth, is to be reported if a relationship 
between the death and intrauterine exposure to the study drug is judged as "possible" by 
the investigator. 
● 
Congenital anomaly (including anomaly in miscarried fetus) 
Unless a congenital anomaly is identified prior to spontaneous abortion or miscarriage, the 
embryo or fetus should be assessed for congenital defects by visual examination. (S)AEs 
experienced by the newborn/infant should be reported via the Pregnancy Reporting Form. 
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery 
date. 
5.5.9.2 Medication Error, Overdose and “Off-Label Use” 
If a Medication Error, Overdose or “Off label Use” (i.e., use outside of what is stated in the 
protocol) is suspected, refer to Section 8.3 Major Protocol Deviations. Any associated 
(S)AEs are to be reported in the eCRF. If the AE meets the definition of a SAE, the SAE is 
also to be reported as described in [Section 5.5.5 Reporting of Serious Adverse Events] 
together with the details of the medication error, overdose and/or “Off-Label Use”. 
In the event of suspected gilteritinib overdose, the subject should receive supportive care and 
monitoring. The medical monitor should be contacted as applicable. 
In the event of suspected overdose of atezolizumab, refer to Section 6.10 in the current IB. 
5.5.9.3 Misuse/Abuse 
If misuse or abuse of the study drug(s) is suspected, the investigator must forward the Special 
Situation worksheet to the delegated CRO by fax or email immediately (within 24 hours of 
awareness). Any associated (S)AEs are to be reported in the eCRF. If the AE meets the 
definition of a SAE, the SAE is also to be reported as described in [Section 5.5.5 Reporting 
of Serious Adverse Events] together with details of the misuse or abuse of the study drug(s). 
5.5.9.4 Occupational Exposure 
If occupational exposure (e.g., inadvertent exposure to the study drug(s) of site staff whilst 
preparing it for administration to the subject) to the study drug(s) occurs, the investigator 
must forward the Special Situation worksheet to delegated CRO by fax or email immediately 
(within 24 hours of awareness). Any associated (S)AEs occurring to the individual associated 
with or resulting from the Special Situation are to be reported on the Special Situations 
worksheet. 
5.5.9.5 Suspected Drug-Drug Interaction 
If a suspected drug-drug interaction associated with the study drug(s) is suspected, the 
investigator must forward the Special Situation worksheet to the delegated CRO by fax or 
email immediately (within 24 hours of awareness). Any associated (S)AEs are to be reported 
in the eCRF. If the AE meets the definition of a SAE, the SAE is also to be reported as 


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described in [Section 5.5.5 Reporting of Serious Adverse Events] together with details of the 
suspected drug-drug interaction. 
5.5.10 Supply of New Information Affecting the Conduct of the Study 
When new information becomes available necessary for conducting the clinical study 
properly, the sponsor will inform all investigators involved in the clinical study, as well as 
the regulatory authorities. Investigators should inform the IRB/IEC of such information when 
needed.  
The investigator will also inform the subjects, who will be required to sign an updated ICF in 
order to continue in the clinical study. 
5.5.11 Urgent Safety Measures  
An Urgent Safety Measure (USM) is an intervention, which is not defined by the protocol 
and can be put in place with immediate effect without needing to gain prior approval by the 
sponsor, relevant CA, IRB/IEC, where applicable, in order to protect study participants from 
any immediate hazard to their health and/or safety. Either the investigator or the sponsor can 
initiate an USM. The cause of an USM can be safety, product or procedure related.  
5.5.12 Reporting Urgent Safety Measures 
In the event of a potential USM, the investigator must contact the Astellas Study Physician 
(within 24 hours of awareness). Full details of the potential USM are to be recorded in the 
subject’s medical records. The sponsor may request additional information related to the 
event to support their evaluation.  
If the event is confirmed to be an USM the sponsor will take appropriate action to ensure the 
safety and welfare of the subjects. These actions may include, but are not limited to, a change 
in study procedures or study treatment, halting further enrollment in the study or stopping the 
study in its entirety. The sponsor or sponsor's designee will notify the cEC within the 
timelines required per current local regulations, and will inform the investigators as required. 
When required, investigators must notify their IRB/IEC within timelines set by regional 
regulations. 
5.6 
Test Drug Concentration 
5.6.1 
Pharmacokinetics 
Pharmacokinetic samples will be collected at predose for all subjects to evaluate gilteritinib 
plasma concentrations as outlined in the Schedule of Assessments [Table 1]. 
For each sample, 2 mL of blood will be collected and processed. 
Blood sampling, processing, storage and shipment instructions will be provided in the 
Laboratory Manual. Samples will be shipped to and analyzed by a sponsor-designated 
analytical laboratory. Please refer to the Laboratory Manual for more detailed information on 
this topic.  


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5.7 
Other Measurements, Assessments or Methods 
5.7.1 
Blood and Buccal Swab Sample for Banked Pharmacogenomic Sample 
Analysis 
Pharmacogenomic (PGx) research may be conducted in the future to analyze or determine 
genes of relevance to clinical response, pharmacokinetics and toxicity/safety issues. After 
enrollment, a whole blood and buccal swab sample will be collected for subjects who provide 
separate consent. Samples will be shipped to a sponsor-designated banking CRO. 
Labels should uniquely identify each sample and contain at least: 
● 
Protocol number (i.e., 2215-CL-1101) 
● 
Subject number and 
● 
Purpose and biological matrix (i.e., “biobanking,” “buccal sample”) 
Details on sample collection, labeling, storage and shipment procedures will be provided in a 
separate Laboratory Manual. See [Appendix 12.7 Adverse Events of Special Interest (AESI) 
for Atezolizumab] for further details on the banking procedures. 
5.7.2 
Exploratory Biomarker 
Bone marrow aspirate samples 
Samples will be analyzed for MRD at any time point. Samples will be analyzed for FLT3 
mutational status at screening/baseline and EOT, and may be analyzed for FLT3 mutational 
status at other time points. Samples may be analyzed for mutations in AML related genes and 
changes in proteins in relation to treatment effects at screening/baseline and EOT, and may 
be analyzed for mutations in AML related genes and changes in proteins in relation to 
treatment effects at other time points. Samples may be used for method development or 
validation of diagnostic assays related to study treatment.  
Blood samples 
Samples may be analyzed for MRD at any time point. Samples may be analyzed for FLT3 
mutational status at screening/baseline and EOT, and may be analyzed for FLT3 mutational 
status at other time points. Samples may be analyzed for mutations in AML related genes and 
changes in proteins in relation to treatment effects at screening/baseline and EOT, and may 
be analyzed for mutations in AML related genes and changes in protein expression in relation 
to treatment effects at other time points.  
Samples will be assessed for activation status of FLT3 and AXL, AML blast cell 
phenotyping and immunophenotyping for immune cell populations including, but not limited 
to, lymphocyte subsets, dendritic cells, natural killer cells, regulatory T cells and 
T lymphocyte subsets. Samples may be used for method development or validation of 
diagnostic assays related to study treatments.  
Bone marrow/blood sampling, processing, storage and shipment instructions will be provided 
in the Laboratory Manual. Samples will be shipped to and analyzed by a sponsor-designated 
analytical laboratory. Samples will be stored for a period up to 15 years following study 


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database hard lock. Please refer to the Laboratory Manual for more detailed information on 
this topic. 
5.7.3 
Resource Utilization 
Resource utilization in this study population will include analysis of data on hospitalization, 
blood transfusion, antibiotic IV infusions, medication for AEs and opioid usage. Details on 
hospitalizations and other relevant resource utilization will be collected at each study visit as 
indicated in the Schedule of Assessments [Table 1].  
For each hospitalization, reason, admission and discharge dates, ward type (normal vs 
intensive care unit) will be recorded in the eCRF. 
The following other resource utilization will be recorded in the eCRF: number of blood 
transfusions, number of units of each transfusion, number of antibiotic IV infusions, type of 
antibiotic, start/end dates of antibiotic treatment, type of medication for AEs, mode of 
administration of medication for AEs (oral, IV, etc.), start/end dates of medication for AEs, 
type of opioid medication, mode of administration of opioids, (oral, IV, etc.), start/end dates 
of opioids. 
5.8 
Total Amount of Blood 
The total amount of blood collected for study assessments for each subject will vary 
depending on how long they stay on treatment.  
At any time during the study, if any laboratory abnormalities are found for a subject, if results 
are needed before central laboratory results are available or for disease assessment, then 
additional blood may be drawn for monitoring.  
Additional blood beyond standard monitoring that will be drawn for this study will include 
draws for eligibility assessment, serum chemistry, hematology, coagulation and pregnancy 
test at specific study defined time points, pharmacokinetics and bioanalytical sampling.  
The maximum amount of blood collected for study specific assessments during the screening 
and cycle 1 period is approximately 42 mL. 
The maximum amount of blood collected for study specific assessments in cycle 2 and 
beyond is approximately 36 mL per cycle.  
6 
DISCONTINUATION 
6.1 
Discontinuation of Individual Subject(s) From Study Treatment  
A discontinuation from treatment is a subject who enrolled in the study and for whom both 
study treatments are permanently discontinued for any reason. If one treatment is 
discontinued due to toxicity, the subject may continue on the other as monotherapy until 
discontinuation criteria is met. The reason for discontinuation from study treatment must be 
documented in the subject’s medical records. 


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All subjects who discontinue study treatment will remain in the study and must continue to 
be followed for protocol specific follow-up procedures as outlined in [Table 1 Schedule of 
Assessments]. The only exception to this is when the subject specifically withdraws consent 
for any further contact with him/her or persons previously authorized by the participant to 
provide this information. 
All participants who discontinue study treatment are to be followed for up to 3 years after 
their EOT, death or the final analysis, whichever occurs first per [Table 1 Schedule of 
Assessments]. 
The subject is free to withdraw from the study treatment and/or study for any reason and at 
any time without giving reason for doing so and without penalty or prejudice. The 
investigator is also free to discontinue the subject from study treatment or to terminate a 
subject's involvement in the study at any time if the subject's clinical condition warrants it. 
If a subject is discontinued from the study with an ongoing AE or an unresolved laboratory 
result that is significantly outside of the reference range, the investigator will attempt to 
provide follow-up until the condition stabilizes or no longer is clinically significant.  
Subjects who meet any of the following criteria during the study will be withdrawn from 
study treatment: 
● 
Subject declines further study participation (i.e., withdrawal of consent). 
● 
Subject is non-compliant with protocol based on the investigator or medical monitor 
assessment. 
● 
Subject is found to have significantly deviated from any one of the inclusion or exclusion 
criteria after enrollment (subjects having clinical benefit and no DLT may be kept in the 
study after discussion with the medical monitor). 
● 
Subject develops an unacceptable study drug-related toxicity (DLT) or SAE requiring 
discontinuation of treatment. 
● 
Subject receives any antileukemic therapy (including HSCT) other than the assigned 
treatment, with the exception of hydroxyurea up to 5 g daily for up to 2 weeks, 
prophylactic intrathecal chemotherapy or cranial irradiation. 
● 
Subject has not achieved a PR or CRc, and in the opinion of the investigator, is no longer 
deriving clinical benefit after 6 cycles of therapy. 
● 
Investigator/subinvestigator determines that the continuation of the study treatment will 
be detrimental to the subject. 
● 
Subject is lost to follow-up despite reasonable efforts by the investigator to locate the 
subject. 
● 
Female subject becomes pregnant. 
● 
Death 
● 
Subject is receiving gilteritinib, atezolizumab, or the combination of gilteritinib + 
atezolizumab and has progressive disease, recurrence under treatment, or no response, 
and in the opinion of the investigator the subject is no longer deriving clinical benefit. 


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Discontinuation criteria from long term follow-up for individual subjects: 
● 
Subject declines further study participation (i.e., withdraws consent) 
● 
Subject is lost to follow-up despite reasonable efforts by the investigator to locate the 
subject. 
● 
More than 3 years has passed from the EOT Visit. 
● 
Death 
6.1.1 
Lost to Follow Up 
Every reasonable effort is to be made to contact any subject lost to follow up during the 
course of the study to complete study-related assessments, record outstanding data, and 
retrieve study drug.  
6.2 
Discontinuation of the Site 
If an investigator intends to discontinue participation in the study, the investigator must 
immediately inform the sponsor. 
6.3 
Discontinuation of the Study 
The sponsor may terminate this study prematurely, either in its entirety or at any study site, 
for reasonable cause provided that written notice is submitted in advance of the intended 
termination. Advance notice is not required if the study is stopped due to safety concerns. If 
the sponsor terminates the study for safety reasons, the sponsor will immediately notify the 
investigator and subsequently provide written instructions for study termination.  
7 
STATISTICAL METHODOLOGY 
A statistical analysis plan (SAP) will be written to provide details of the analysis, along with 
specifications for tables, listings and figures to be produced. The SAP will be finalized before 
the database soft lock at the latest. Any changes from the analyses planned in SAP will be 
justified in the clinical study report. 
In general, continuous data will be summarized with descriptive statistics (number of subjects, 
mean, SD, minimum, median and maximum), and frequency and percentage for categorical 
data. 
Baseline will be defined as the last observation prior to first dose, unless otherwise specified. 
Prior to database lock, a Final Review of Data and Tables, Listings and Figures Meeting will 
be held to allow a review of the clinical study data and to verify the data that will be used for 
analysis set classification. If required, consequences for the statistical analysis will be 
discussed and documented. A meeting to determine analysis set classifications may also be 
held prior to database lock. 


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7.1 
Sample Size 
This is an open-label, single arm study. No interim analysis and 1 final analysis are planned. 
Phase 1 
The sample size in phase 1 is based on 3+3 design and not based on power calculation. 
Phase 2 
Simon’s 2-stage design [Simon, 1989] will be used in the study to evaluate the efficacy in 
terms of CRc rate for the selected combination dose level of gilteritinib and atezolizumab. 
The null hypothesis that the true CRc rate is 50% will be tested against a 1-sided alternative. 
In the first stage, the CRc of 22 subjects will be evaluated. If there are 11 or fewer subjects 
with CRc from these 22 subjects by the end of cycle 2, the study will be stopped. Otherwise, 
27 additional subjects will be accrued for a total of 49 subjects evaluable for calculation of 
CRc rate. The null hypothesis will be rejected if 32 or more subjects with CRc are observed 
in the 49 subjects by the end of cycle 2. This design yields a 1-sided type I error rate of 0.025 
and power of 80% when the true CRc rate is 70%. The sample size was calculated in East® 
Version 6.4. 
Bayesian Posterior Probability for Safety Monitoring in Phase 2: 
A Bayesian posterior probability will be used for safety monitoring during the whole 
treatment period. Subjects in phase 1 and phase 2 cohorts who complete the DLT observation 
period or experience DLTs will be included in the model-fitting process to provide the 
complete safety information. The DLT rate will be reviewed as the last subject of each cohort 
of 7 DLT-evaluable subjects completes the first treatment cycle. The estimated DLT rates 
based on the Bayesian beta-binomial model will be provided for safety monitoring in the 
dose expansion cohort. If the DLT rate for the expanded dose level is equal or higher than 
20% with a posterior probability of 80%, then the enrollment to the expansion cohort will be 
paused and the safety will be reassessed by the DEC. If the reassessment warrants, 
enrollment to the expansion cohort may be continued at the current dose level or 1 lower dose 
level. Safety evaluation will be conducted separately for induction, consolidation and 
maintenance phases. 
With a non-informative prior, Beta(1,1) distribution, the numbers of DLTs for each cohort of 
7 DLT-evaluable subjects, which trigger the enrollment pause for toxicities review, are listed 
in the following table: 


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DLT-evaluable Subjects 
Number of DLTs 
7 
3 
14 
4 
21 
6 
28 
8 
35 
9 
42 
11 
49 
12 
DLT: dose-limiting toxicity 
7.2 
Analysis Sets 
Detailed criteria for analysis sets will be laid out in Classification Specifications and the 
allocation of subjects to analysis sets will be determined prior to database hard-lock.  
7.2.1 
Full Analysis Set (FAS) 
The full analysis set (FAS) will consist of all subjects who are enrolled in the study and took 
at least 1 dose of study drug. The FAS will be used for efficacy analyses. Subjects will be 
analyzed based on the actual treatment received. 
7.2.2 
Per Protocol Set (PPS) 
The per protocol set (PPS) will consist of the subset of the FAS who do not meet criteria for 
PPS exclusion. These criteria are to capture relevant non-adherence to the protocol and will 
be defined in the SAP. The sensitivity analyses for the primary and some secondary 
endpoints may be performed on the PPS. Select demographic and baseline characteristics will 
also be summarized for the PPS. 
7.2.3 
Safety Analysis Set (SAF) 
For the statistical summary of the safety data, the safety analysis set (SAF) will be used. The 
SAF consists of all subjects who took at least 1 dose of study drug (gilteritinib or 
atezolizumab) and will be used for safety analyses. The subjects will be analyzed based on 
the actual treatment received. The FAS and SAF are the same for this study. 
7.2.4 
Pharmacokinetics Analysis Set (PKAS) 
The pharmacokinetics analysis set (PKAS) consists of the administered population for which 
sufficient plasma concentration data is available to facilitate derivation of at least one 
pharmacokinetic parameter and for whom at least 1 plasma concentration datum is available 
and both the date and time of dosing on the day of pharmacokinetic sampling and the date 
and time of sampling are known. Additional subjects may be excluded from the PKAS at the 
discretion of the pharmacokineticist. Any formal definitions for exclusion of subjects or time-
points from the PKAS will be documented in the in the Classification Specifications and 
determined the Classification Meeting.  


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7.2.5 
Biomarker Analysis Set (BMAS) 
The biomarker analysis set (BMAS) will include the subjects from the administered 
population for whom sufficient biomarker measurements were collected.  
7.3 
Demographics and Baseline Characteristics  
7.3.1 
Demographics 
Demographics and baseline characteristics will be summarized by treatment group for the 
SAF. Descriptive statistics will include number of subjects, mean, standard deviation, 
minimum, median and maximum for continuous endpoints and frequency and percentage for 
categorical endpoints. 
7.3.2 
Subject Disposition  
The number and percentage of all subjects during the study will be reported per treatment 
group, study drug administration, subject completion, premature discontinuation and major 
protocol violations.  
7.3.3 
Previous and Concomitant Medications  
The frequency of concomitant medications (prescription, over-the-counter and nutritional 
supplements) will be summarized by treatment group and PT for SAF. Medications will be 
coded using the WHO drug dictionary. Medications will be counted by the number of 
subjects who took each medication. A subject taking the same medication multiple times will 
only be counted once for that medication. Medications will be presented in decreasing order 
of frequency based on the total number of subjects who took each medication. 
7.3.4 
Medical History  
A detailed medical history for each subject will be obtained during screening period and will 
be summarized by treatment group for the SAF 
7.3.5 
Disease History 
Each subject’s complete cancer history will be listed. The number and percentage of subjects 
will be used to summarize the AML subtype and FLT3 mutation status. 
7.3.6 
Treatment Compliance 
Treatment compliance is defined as the total number of doses of gilteritinib in combination 
with atezolizumab actually taken by the subject divided by the number of doses of study drug 
expected to be taken during the study multiplied by 100. Descriptive statistics for study drug 
compliance will be presented by dose for the entire study period for the SAF by treatment 
group. 
7.3.7 
Extent of Exposure 
Drug exposure including duration of exposure, cumulative dose, average daily dose, dose 
intensity and relative dose intensity will be summarized by treatment group. The number and 


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proportion of subjects with dose reduction, dose escalation and dose interruption will be 
tabulated. Details of the calculation will be provided in SAP.  
7.4 
Analysis of Efficacy  
Efficacy analysis will be conducted on the FAS and PPS in which FAS will be considered as 
primary and PPS as supportive. 
7.4.1 
Analysis of Efficacy Variables 
CRc rate, CR rate, best response rate, duration of remission, EFS and OS, will be 
summarized using descriptive statistics. The CRc rate, CR rate, best response rate with the 
corresponding 95% confidence interval will be reported by treatment group. The survival 
curve and median time for time-to-event variables will be estimated using the Kaplan-Meier 
method and will be reported along with the corresponding 95% confidence interval by 
treatment group. 
7.5 
Analysis of Safety 
The safety evaluation will be based mainly on AEs, clinical laboratory results, vital sign 
measurements, ECGs and ECOG performance scores. Descriptive statistics will be used to 
summarize safety data. All safety data will be summarized by treatment received and the 
analyses will be performed on the SAF. 
7.5.1 
Adverse Events  
All AEs recorded on treatment including within 30 days from the last study treatment will be 
summarized. AEs will be categorized by SOC and PT using the MedDRA dictionary and will 
be graded according to the NCI CTCAE version 5.0. 
The number and percent of subjects experiencing 1 or more AE(s) will be summarized by 
treatment group, SOC and PT. The number and percentage of subjects with at least one grade 
3 or higher AE will be summarized by treatment group, SOC and PT.  
Distribution of the maximum severity (grade) and treatment-related AEs will be summarized 
by treatment group, SOC and PT. Distribution of SAEs, discontinuations due to AE and 
deaths on study will be presented for each treatment group. 
Additional summary tables will be generated for the following population subsets: subjects 
with SAEs including deaths, subjects who discontinue due to AEs and investigator-attributed 
relationship to study drug for AEs and SAEs. 
All summaries of AEs will include only TEAEs unless otherwise stated. Listings of AEs, 
SAEs, deaths and withdrawals due to AEs will be presented. 
7.5.2 
Laboratory Assessments  
Clinical laboratory evaluations (including serum chemistry, hematology, coagulation and 
urinalysis) and their changes from baseline will be summarized by treatment group using 
descriptive statistics. Clinically significant abnormalities in laboratory values will be 
presented for each treatment. Shift tables will present shift from baseline to worst grade for 


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selected variables using the NCI-CTCAE grade and laboratory reference range indicator. 
Frequency of subjects with laboratory values outside normal range will be generated in 
addition to tabulation of worst toxicity grade. 
7.5.3 
Vital Signs  
Descriptive statistics will be used to summarize vital sign results and changes from baseline 
by treatment group and time point.  
7.5.4 
Physical Examination  
Physical examination findings will be listed by the actual treatment received. All clinically 
significant abnormal findings will be recorded as medical history or AEs and graded using 
NCI-CTCAE guidelines. 
7.5.5 
Routine 12-lead Electrocardiograms 
The 12-lead ECG results will be summarized by the actual treatment received and time point. 
Overall ECG interpretation will be summarized for each time point. A shift analysis table 
showing shifts from baseline in overall ECG (normal, abnormal) will be provided. ECG 
parameters and their change from baseline will be summarized by treatment group using 
descriptive statistics. 
7.6 
Analysis of Pharmacokinetics 
Descriptive statistics (e.g., N, mean, standard deviation, minimum, median, maximum, 
coefficient of variation [CV], geometric mean, and geometric CV) will be provided for 
trough plasma concentrations (Ctrough) of gilteritinib and possible metabolite(s), if appropriate, 
by treatment, visit and time point.  
7.7 
Analysis of Pharmacodynamics 
Changes in the activation status of FLT3 and AXL may be assessed before and after 
treatment. 
7.8 
Analysis of Biomarkers  
MRD will be assessed in relation to the following efficacy variables: CRc rate, CR rate, EFS, 
Duration of remission and OS. 
FLT3 mutational status at baseline and EOT, as well as mutations in other AML related 
genes and protein expression will be assessed in relation to CRc rate, CR rate, EFS, Duration 
of remission and OS.  
Baseline levels and changes from baseline in immune cell populations and AML blasts by 
immunophenotyping will be assessed in relation to CRc rate, CR rate and OS.  
7.9 
Major Protocol Deviations and Other Analyses 
Major protocol deviations as defined in [Section 8.3 Major Protocol Deviations] will be 
provided in a data listing. 


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The major protocol deviation criteria will be uniquely identified as follows: 
PD1 - Entered into the study even though they did not satisfy entry criteria,  
PD2 - Developed withdrawal criteria during the study and was not withdrawn, 
PD3 - Received wrong treatment or incorrect dose, 
PD4 - Received excluded concomitant treatment.  
7.10 
Interim Analysis (and Early Discontinuation of the Clinical Study) 
No formal interim analysis is planned. 
7.11 
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information 
Imputation methods for missing data, if applicable, and the definitions for windows to be 
used for analyses by visit will be outlined in the SAP. 
8 
OPERATIONAL CONSIDERATIONS 
8.1 
Data Collection 
The investigator or site designee will enter data collected using an Electronic Data Capture 
system. In the interest of collecting data in the most efficient manner, the investigator or site 
designee should record data (including laboratory values, if applicable) in the eCRF within 
5 days after the subject’s visit. 
The investigator or site designee is responsible to ensure that all data in the eCRFs and 
queries are accurate and complete and that all entries are verifiable with source documents. 
These documents should be appropriately maintained by the site. 
The monitor should verify the data in the eCRFs with source documents and confirm that 
there are no inconsistencies between them. 
Certain laboratory tests are performed at a central laboratory per the Schedule of Assessments 
[Table 1]. Laboratory data performed at a central laboratory will be transferred electronically 
to the sponsor or designee at predefined intervals during the study. The Central laboratory 
will provide the sponsor or designee with a complete and clean copy of the data. 
ECG results will be read at a central ECG reading laboratory. Central ECG read data will be 
transferred electronically to the sponsor or designee at predefined intervals during the study. 
The central ECG laboratory will provide the sponsor or designee with a complete and clean 
copy of the data. 
The investigator or designee will be responsible for eCRF completion and that all data and 
queries are accurate, complete and are verifiable with the source. The source should be 
appropriately maintained by the clinical unit. 
Electronic data sources and any supporting documents should be available for 
review/retrieval by the sponsor/designee at any given time. 


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8.2 
Screen Failures 
For screen failures the demographic data, reason for failing, informed consent, inclusion and 
exclusion criteria and AEs will be collected in the eCRF. 
8.3 
Major Protocol Deviations 
A major protocol deviation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change. The investigator is responsible for ensuring 
the study is conducted in accordance with the procedures and evaluations described in this 
protocol and must protect the rights, safety, and welfare of subjects. The investigator should 
not implement any deviation from, or changes of, the protocol, unless it is necessary to 
eliminate an immediate hazard to study subjects.  
A protocol waiver is a documented prospective approval of a request from an investigator to 
deviate from the protocol. Protocol waivers are strictly prohibited. 
The major protocol deviation criteria are as follows: 
PD1 - Entered into the study even though they did not satisfy entry criteria,  
PD2 - Developed withdrawal criteria during the study and was not withdrawn, 
PD3 - Received wrong treatment or incorrect dose, 
PD4 - Received excluded concomitant treatment. 
When a major deviation from the protocol is identified for an individual subject, the 
investigator or designee must ensure the sponsor is notified. The sponsor will follow-up with 
the investigator, as applicable, to assess the deviation and the possible impact to the safety 
and/or efficacy of the subject to determine subject continuation in the study.  
If a major deviation impacts the safety of a subject, the investigator must contact the sponsor 
immediately.  
The investigator will also assure that deviations meeting IRB/IEC and applicable regulatory 
authorities’ criteria are documented and communicated appropriately. All documentation and 
communications to the IRB/IEC and applicable regulatory authorities will be provided to the 
sponsor and maintained within the trial master file.  
9 
END OF TRIAL  
The end of the study is defined as the last visit or scheduled procedure shown in the Schedule 
of Assessments [Table 1] for the last study participant in the study.  


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10 
STUDY ORGANIZATION 
10.1 
Independent Data-Monitoring Committee (IDMC) | Data and Safety 
Monitoring Board (DSMB) | Monitoring Committee | Adjudication 
Committee | Other Evaluation Committee(s) 
This section is not applicable to this study. 
10.2 
Other Study Organization 
A DEC consisting of sponsor representatives and investigators will convene once a dose level 
cohort completes the DLT observation period and the data are available for review.   
Additional details regarding responsibilities, membership requirements and safety review 
time points will be included in the DEC Plan. 
 


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11 
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Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, et al. PD-1 Blockade with 
Nivolumab in Relapsed or Refractory Hodgkin's Lymphoma. N Engl J Med. 2015;372(4):311-19. 
ASP2215 Investigator’s Brochure, 2017. 
Atezolizumab Investigator’s Brochure, 2018. 
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Brunet S, Labopin M, Esteve J, Cornelissen J, Socié G, Iori AP, et al. Impact of FLT3 internal tandem 
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Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH, et al. Revised 
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Chevallier P, Labopin M, Turlure P, Prebet T, Pigneux A, Hunault M, et al. A new Leukemia 
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Daver N, Garcia-Manero G, Basu S, Cortes JE, Ravandi F, Jabbour EJ, et al. Nivolumab (Nivo) with 
Azacytidine (AZA) in Patients (pts) with Relapsed Acute Myeloid Leukemia (AML) or 
Frontline Elderly AML. Blood. 2017;130:1345. 
Deng R, Bumbaca D, Pastuskovas CV, Boswell CA, West D, Cowan KJ, et al. Preclinical 
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Gerds AT, Scott BL, Greenberg PL, Khaled SK, Lin TL, Pollyea DA, et al. 466 PD-L1 blockade with 
atezolizumab in higher-risk myelodysplastic syndrome: an initial safety and efficacy analysis. 
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Hematology (ASH); 02 Dec 2018; San Diego, CA.  
Janning M, Ben-Batalla, I, Loges S. Axl inhibition: a potential road to a novel acute myeloid leukemia 
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Konig H, Levis M. Targeting FLT3 to treat leukemia. Expert Opin Ther Targets. 2015;19:37-54. 
Lesokhin AM, Ansell SM, Armand P, Scott EC, Halwani A, Gutierrez M, et al. Preliminary Results 
of a Phase I Study of Nivolumab (BMS-936558) in Patients with Relapsed or Refractory 
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Levis M, Perl AE, Altman JK, Gocke C, Bahceci E, Hill J, et al. A next-generation sequencing-based 
assay for minimal residual disease assessment in AML patients with FLT3-ITD mutations. 
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of FLT3 internal tandem duplication and D835 mutations in acute myeloid leukemia. 
Haematologica. 2003;88:19-24. 
Moskowitz CH, Ribrag V, Michot JM, Martinelli G, Zinzani PL, Gutierrez M, et al. PD-1 Blockade 
with the Monoclonal Antibody Pembrolizumab (MK-3475) in Patients with Classical Hodgkin 
Lymphoma after Brentuximab Vedotin Failure: Preliminary Results from a Phase 1b Study 
(KEYNOTE-013). Blood. 2014;124:290.  
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atezolizumab, an immune checkpoint inhibitor, in patients with relapsed or refractory 
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San Diego, CA. 
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leukemia. J Natl Compr Canc Netw. 2012;10:984-1021. 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response 
criteria of the Eastern Cooperative Oncology Group. AM J Clin Oncol. 1982;5:649-55. 
Patel JP, Gönen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J, et al. Prognostic relevance of 
integrated genetic profiling in acute myeloid leukemia. New Eng J Med. 2012;366:1079-89. 
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reproductive safety of therapeutic PD-1 inhibitors, Birth Defects Res (Part B) 2016;107:108-19. 
Perl AE, Altman JK, Cortes J, Smith C, Litzow M, Baer MR, et al. Selective Inhibition of FLT3 by 
Gilteritinib in Relapsed/Refractory Acute Myeloid Leukemia. Lancet Oncol. 2017 
Aug;18(8):1061-75. 
Roboz G J, Rosenblat T, Arellano M, Gobbi M, Altman JK, Montesinos P, et al. International 
Randomized Phase III Study of Elacytarabine Versus Investigator Choice in Patients With 
Relapsed/Refractory Acute Myeloid Leukemia. J Clin Oncol. 2014;32(18):1919-26. 
Schlenk RF, Döhner K. Impact of new prognostic markers in treatment decisions in acute myeloid 
leukemia. Curr Opin Hematol. 2009;16:98-104. 
Simon R. Optimal two-stage designs for phase II clinical trials. Biometric Research Branch, National 
Cancer Institute, Bethesda, Maryland. 1989:1-10. 
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Tumours of Haematopoietic and Lymphoid tissues. 4th ed. Revised. World Health 
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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. 
TECENTRIQ (prescribing information). Genentech, Inc., South San Francisco, CA. December 2019. 
Available at: https://www.gene.com/download/pdf/tecentriq_prescribing.pdf. Accessed on 
20 March 2020. 
Tiesmeier J, Müller-Tidow C, Westermann A, Czwalinna A, Hoffmann M, Krauter J, et al. Evolution 
of FLT3-ITD and D835 activating point mutations in relapsing acute myeloid leukemia and 
response to salvage therapy. Leuk Res. 2004;28:1069-74. 
Yamamoto Y, Kiyoi H, Nakano Y, Suzuki R, Kodera Y, Miyawaki S, et al. Activating mutation of 
D835 within the activation loop of FLT3 in human hematologic malignancies. Blood. 
2001;97:2434-39. 
Yanada M, Matsuo K, Suzuki T, Kiyoi H, Naoe T. Prognostic significance of FLT3 internal tandem 
duplication and tyrosine kinase domain mutations for acute myeloid leukemia: a meta-analysis. 
Leukemia. 2005;19:1345-49.  


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12 
APPENDICES 
12.1 
Ethical, Regulatory, and Study Oversight Considerations 
12.1.1 Ethical Conduct of the Study 
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing clinical study conduct and the ethical principles that 
have their origin in the Declaration of Helsinki.  
12.1.2 Institutional Review Board (IRB)/Independent Ethics Committee (IEC)  
GCP requires that the clinical protocol, any protocol amendments, the IB, the ICF and all 
other forms of subject information related to the study (e.g., advertisements used to recruit 
subjects) and any other necessary documents be reviewed by an IRB/IEC. The IRB/IEC will 
review the ethical, scientific and medical appropriateness of the study before it is conducted. 
IRB/IEC approval of the protocol, ICF and subject information and/or advertising, as 
relevant, will be obtained prior to the authorization of drug shipment to a study site. 
Any substantial amendments to the protocol will require IRB/IEC approval before 
implementation, except for changes necessary to eliminate an immediate hazard to subjects. 
The investigator will be responsible for the following: 
● 
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
● 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
● 
Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable), and all other applicable local regulations 
12.1.3 Protocol Amendment and/or Revision 
Any changes to the study that arise after approval of the protocol must be documented as 
protocol amendments: substantial amendments and/or non-substantial amendments. 
Depending on the nature of the amendment, either IRB/IEC or notification may be required. 
The changes will become effective only after the approval of the sponsor, the investigator, 
the regulatory authority and the IRB/IEC (if applicable). 
Amendments to this protocol must be signed by the sponsor and the investigator. Written 
verification of IRB/IEC approval will be obtained before any amendment is implemented 
which affects subject safety or the evaluation of safety, and/or efficacy. Modifications to the 
protocol that are administrative in nature do not require IRB/IEC approval, but will be 
submitted to the IRB/IEC for their information, if required by local regulations. 
If there are changes to the ICF, written verification of IRB/IEC approval must be forwarded 
to the sponsor. An approved copy of the new ICF must also be forwarded to the sponsor. 


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12.1.4  Financial Disclosure 
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study. 
12.1.5 Informed Consent of Subjects 
12.1.5.1 Subject Information and Consent 
The investigator or his/her representative will explain the nature of the study to the subject or 
his/her legal representative, and answer all questions regarding this study. Prior to any study-
related screening procedures being performed on the subject, the informed consent statement 
will be reviewed and signed and dated by the subject or his/her guardian or legal 
representative, the person who administered the informed consent and any other signatories 
according to local requirements. A copy of the signed ICF will be given to the subject and the 
original will be placed in the subject’s medical record. An entry must also be made in the 
subject’s dated source documents to confirm that informed consent was obtained prior to any 
study-related procedures and that the subject received a signed copy. 
The signed consent forms will be retained by the investigator and made available (for review 
only) to the study monitor and auditor regulatory authorities and other applicable individuals 
upon request. 
12.1.5.2 Supply of New and Important Information Influencing the Subject’s Consent 
and Revision of the Written Information 
1. The investigator or his/her representative will immediately inform the subject orally 
whenever new information becomes available that may be relevant to the subject’s 
consent or may influence the subject’s willingness to continue to participate in the study 
(e.g., report of serious drug ADR). The communication must be documented in the 
subject’s medical records and whether the subject is willing to remain in the study or not 
must be confirmed and documented.  
2. The investigator must update their ICF and submit it for approval to the IRB/IEC. The 
investigator or his/her representative must obtain written informed consent from the 
subject on all updated ICFs throughout their participation in the study. The investigator 
or his/her designee must re-consent subjects with the updated ICF even if relevant 
information was provided orally. The investigator or his/her representative who obtained 
the written informed consent and the subject should sign and date the ICF. A copy of the 
signed ICF will be given to the subject and the original will be placed in the subject’s 
medical record. An entry must be made in the subject’s records documenting the 
re-consent process. 


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12.1.6 Source Documents 
Source data must be available at the site to document the existence of the study subjects and 
to substantiate the integrity of study data collected. Source data must include the original 
documents relating to the study, as well as the medical treatment and medical history of the 
subject. 
The investigator is responsible for ensuring the source data are attributable, legible, 
contemporaneous, original, accurate and complete whether the data are hand-written on paper 
or entered electronically. If source data are created (first entered), modified, maintained, 
achieved, retrieved or transmitted electronically via computerized systems (and/or other kind 
of electric devices) as part of regulated clinical study activities, such systems must be 
compliant with all applicable laws and regulations governing use of electronic records and/or 
electronic signatures. Such systems may include, but are not limited to, electronic 
medical/health records, protocol related assessments, AE tracking, and/or drug 
accountability.  
Paper records from electronic systems used in place of electronic format must be certified 
copies. A certified copy must be an exact copy and must have all the same attributes and 
information as the original. Certified copies must include signature and date of the individual 
completing the certification. Certified copies must be a complete and chronological set of 
study records (including notes, attachments, and audit trail information (if applicable). All 
printed records must be kept in the subject file and available for archive.  
12.1.7 Record Retention 
The investigator will archive all study data (e.g., subject identification code list, source data, 
eCRFs and investigator's file) and relevant correspondence. These documents are to be kept 
on file for the appropriate term determined by local regulation (for US sites, 2 years after 
approval of the NDA or discontinuation of the IND). The investigator agrees to obtain the 
sponsor's agreement prior to disposal, moving, or transferring of any study-related records. 
The sponsor will archive and retain all documents pertaining to the study according to local 
regulations. 
Data generated by the methods described in the protocol will be recorded in the subjects' 
medical records and/or study progress notes. 
12.1.8 Subject Confidentiality and Privacy 
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited unless otherwise the subject provides 
written consent or approval. Additional medical information may be given only after 
approval of the subject to the investigator or to other appropriate medical personnel 
responsible for the subject's well-being. 
The sponsor shall not disclose any confidential information on subjects obtained during the 
performance of their duties in the clinical study without justifiable reasons. 


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Even though any individuals involved in the study, including the study monitors and auditors, 
may get to know matters related to subject's privacy due to direct access to source documents, 
or from other sources, they may not leak the content to third parties.  
The sponsor affirms the subject's right to protection against invasion of privacy. Only a 
subject identification number will identify subject data retrieved by the sponsor. However, 
the sponsor requires the investigator to permit the sponsor, sponsor's representative(s), the 
IRB/IEC and when necessary, representatives of the regulatory health authorities to review 
and/or to copy any medical records relevant to the study. 
The sponsor agrees to comply and process personal data in accordance with all applicable 
privacy laws and regulations, including, without limitation, the Personal Information 
Protection Law in Japan and Privacy laws in the US. If the services will involve the 
collection or processing of personal data (as defined by applicable data protection legislation) 
within the European Economic Area (EEA), then sponsor shall serve as the controller of such 
data, as defined by the EU Data Protection Directive, and investigator and/or third party shall 
act only under the instructions of the sponsor in regard to personal data If sponsor is not 
based in the EEA, sponsor must appoint a third party to act as its local data protection 
representative or arrange for a co-controller established in the EU for data protection 
purposes in order to comply with the Directive. 
12.1.9 Arrangement for Use of Information and Publication of the Clinical Study 
Information concerning the study drug, patent applications, processes, unpublished scientific 
data, the IB and other pertinent information is confidential and remains the property of the 
sponsor. Details should be disclosed only to the persons involved in the approval or conduct 
of the study. The investigator may use this information for the purpose of the study only. It is 
understood by the investigator that the sponsor will use the information obtained during the 
clinical study in connection with the development of the drug and therefore may disclose it as 
required to other clinical investigators or to regulatory agencies. In order to allow for the use 
of the information derived from this clinical study, the investigator understands that he/she 
has an obligation to provide the sponsor with all data obtained during the study. 
Publication of the study results is discussed in the clinical study agreement. 
12.1.10 Signatory Investigator for Clinical Study Report 
ICH E3 guidelines recommend and EU Directive 2001/83/EC requires that a final study 
report which forms part of a marketing authorization application be signed by the 
representative for the coordinating investigator(s) or the principal investigator(s). The 
representative for the coordinating investigator (s) or the principal investigator(s) will have 
the responsibility to review the final study results to confirm to the best of his/her knowledge 
it accurately describes the conduct and results of the study. The representative for 
coordinating investigator(s) or the principal investigator(s) will be selected from the 
participating investigators by the sponsor prior to database lock. 


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12.2 
Procedure for Clinical Study Quality Control 
12.2.1 Clinical Study Monitoring 
The sponsor or delegated CRO is responsible for monitoring the clinical study to ensure that 
subject's human rights, safety, and well-being are protected, that the study is properly 
conducted in adherence to the current protocol and GCP, and study data reported by the 
investigator/subinvestigator are accurate and complete and that they are verifiable with study-
related records such as source documents. The sponsor is responsible for assigning study 
monitor(s) to this study for proper monitoring. They will monitor the study in accordance 
with planned monitoring procedures.  
12.2.2 Direct Access to Source Data/Documents 
The investigator and the study site must accept monitoring and auditing by the sponsor or 
delegated CRO as well as inspections from the IRB/IEC and relevant regulatory authorities. 
In these instances, they must provide all study-related records including source documents 
when they are requested by the sponsor monitors and auditors, the IRB/IEC, or regulatory 
authorities. The confidentiality of the subject's identities shall be well protected consistent 
with local and national regulations when the source documents are subject to direct access. 
12.2.3 Data Management 
Data Management will be coordinated by the Global Data Science department of the sponsor 
in accordance with the SOPs for data management. All study specific processes and 
definitions will be documented by Data Management. Completion of the eCRF will be 
described in the eCRF Completion Guidelines. Coding of medical terms and medications will 
be performed using MedDRA and WHO Drug Dictionary respectively. 
12.2.4 Quality Assurance 
The sponsor is implementing and maintaining quality assurance and quality control systems 
with written SOPs to ensure that studies are conducted and data are generated, documented, 
recorded, and reported in compliance with the protocol, GCP, and applicable regulatory 
requirement(s). Where applicable, the quality assurance and quality control systems and 
written SOPs of the CRO will be applied. 
The sponsor or sponsor's designee may arrange to audit the clinical study at any or all 
investigational sites and facilities. The audit may include on-site review of regulatory 
documents, case report forms, and source documents. Direct access to these documents will 
be required by the auditors. 


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12.3 
Contraception Requirements 
WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Schedule of Assessments. 
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND METHODS OF 
CONTRACEPTION DEFINITIONS (WOCBP) 
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 FSH measurements of at least > 40 IU/L (or higher per local institutional 
guidelines), is required.  
Females on 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 administrationa 
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 


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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 
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 
180 days after final drug administration. 


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12.4 
List of Prohibited and/or Concomitant Medications to be Use with 
Caution 
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 
Source: Table 4 in FDA Draft Guidance for Industry – Drug Interaction Studies – Study Design, Data Analysis, 
Implications for Dosing, and Recommendations (February 2012) 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm292362.pdf. 
CYP: cytochrome P450. 
The following list describes medications and foods that are common strong inhibitors of 
CYP3A and should be used with caution. This list should not be considered all inclusive. 
Consult individual drug labels for specific information on a compound’s propensity to inhibit 
CYP3A. 
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 
Clarithromycin 
Conivaptan 
Itraconazole 
Ketoconazole 
Nefazodone 
Posaconazole 
Telaprevir 
Telithromycin 
Voriconazole 
Source: Table 3 in FDA Draft Guidance for Industry – Drug Interaction Studies – Study Design, Data Analysis, 
Implications for Dosing, and Recommendations (February 2012) 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm292362.pdf. 
CYP: cytochrome P450. 


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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. 
Drugs Targeting Serotonin Receptors  
Drug Type 
Generic Drug Name 
Affinity or function to 5HT2BR 
Eletriptan Hydrobromide 
5HT2BR: 5-hydroxytryptamine receptor 2B 
The following list describes medications and foods that are common inhibitors or inducers of 
P-gp and should be used with caution. 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. 
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: Table 12 in http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ 
DrugInteractionsLabeling/ucm093664 htm#major 
Drugs Targeting Sigma (nonspecific) Receptor (sigma R) 
No list of drugs that target sigma nonspecific receptor is provided. Please consult individual 
drug labels for specific information on whether a compound targets sigma nonspecific 
receptors. 


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Drugs That May Prolong QT or QTc 
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. 
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 
Antipsychotics 
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 
Azole antifungals  
Ketoconazole 
Fluconazole 
Itraconazole 
Posaconazole 
Voriconazole 
Table continued on next page 


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Drug Type 
Generic Drug Name 
Antimalarials 
Amodiaquine 
Atovaquone 
Chloroquine 
Doxycycline 
Halofantrine 
Mefloquine  
Proguanil 
Primaquine 
Pyrimethamine 
Quinine 
Sulphadoxine 
Antiprotozoals 
Pentamidine 
Antiemetics 
Droperidol 
Dolasetron 
Granisetron 
Ondansetron 
Antiestrogens 
Tamoxifen 
Immunosuppressants 
Tacrolimus 
Source: 
Yap GY, Camm AJ. Drug induced qt prolongation and torsades de pointes. Heart. 2003;89:1363-1372. 
 


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12.5 
Liver Safety Monitoring and Assessment 
Any subject enrolled in a clinical study with active drug therapy and reveals an increase of 
serum aminotransferases to > 3 x ULN or TBL > 2 x ULN should undergo detailed testing 
for liver enzymes (including at least ALT, AST, ALP, and TBL). Testing should be repeated 
within 72 hours of notification of the test results. For studies for which a central laboratory is 
used, alerts will be generated by the central laboratory regarding moderate and severe liver 
abnormality to inform the investigator and study team. Subjects should be asked if they have 
any symptoms suggestive of hepatobiliary dysfunction. 
Definition of Liver Abnormalities 
Confirmed abnormalities will be characterized as moderate and severe where ULN: 
 
ALT or AST 
 
TBL 
Moderate 
> 3 x ULN  
or 
> 2 x ULN 
Severe 
> 3 x ULN 
and 
> 2 x ULN 
In addition, the subject should be considered to have severe hepatic abnormalities for any of 
the following: 
● 
ALT or AST > 8 x ULN. 
● 
ALT or AST > 5 x ULN for more than 2 weeks.  
● 
ALT or AST > 3 x ULN and International Normalized Ratio (INR) > 1.5 (If INR testing 
is applicable/evaluated). 
● 
ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%).  
The investigator may determine that abnormal liver function results, other than as described 
above, may qualify as moderate or severe abnormalities and require additional monitoring 
and follow-up. 
Follow-up Procedures 
Confirmed moderate and severe abnormalities in hepatic functions should be thoroughly 
characterized by obtaining appropriate expert consultations, detailed pertinent history, 
physical examination and laboratory tests. The site staff is to complete the liver abnormality 
case report form (LA-CRF). Subjects with confirmed abnormal liver function testing should 
be followed as described below. 
Confirmed moderately abnormal liver function tests (LFTs) should be repeated 2 to 3 times 
weekly then weekly or less if abnormalities stabilize or the study drug has been discontinued 
and the subject is asymptomatic.  
Severe hepatic liver function abnormalities as defined above, in the absence of another 
etiology, may be considered an important medical event and may be reported as a SAE. The 
sponsor should be contacted and informed of all subjects for whom severe hepatic liver 
function abnormalities possibly attributable to study drug are observed. 


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To further assess abnormal hepatic laboratory findings, the investigator is expected to: 
● 
Obtain a more detailed history of symptoms and prior or concurrent diseases. Symptoms 
and new-onset diseases is to be recorded as “AEs” within the (e)CRF. Illnesses and 
conditions such as hypotensive events, and decompensated cardiac disease that may lead 
to secondary liver abnormalities should be noted. Nonalcoholic steatohepatitis is seen in 
obese hyperlipoproteinemic and/or diabetic subjects, and may be associated with 
fluctuating AT levels. The investigator should ensure that the medical history form 
captures any illness that predates study enrollment that may be relevant in assessing 
hepatic function.  
● 
Obtain a history of concomitant drug use (including nonprescription medication, 
complementary and alternative medications), alcohol use, recreational drug use and 
special diets. Medications, is to be entered in the (e)CRF. Information on alcohol, other 
substance use and diet should be entered on the LA-CRF or an appropriate document. 
● 
Obtain a history of exposure to environmental chemical agents. 
● 
Based on the subject’s history, other testing may be appropriate including:  
○ Acute viral hepatitis (A, B, C, D, E or other infectious agents),  
○ Ultrasound or other imaging to assess biliary tract disease, 
○ Other laboratory tests including INR, direct bilirubin. 
● 
Consider gastroenterology or hepatology consultations. 
● 
Submit results for any additional testing and possible etiology on the LA-CRF or an 
appropriate document. 
Study Treatment Discontinuation 
In the absence of an explanation for increased LFT’s, such as viral hepatitis, preexisting or 
acute liver disease, or exposure to other agents associated with liver injury, the subject may 
be discontinued from study treatment. The investigator may determine that it is not in the 
subject’s best interest to continue study treatment. Discontinuation of study treatment should 
be considered if: 
● 
ALT or AST > 8 x ULN. 
● 
ALT or AST > 5 x ULN for more than 2 weeks. 
● 
ALT or AST > 3 x ULN and TBL > 2 x ULN or INR > 1.5) (If INR testing is 
applicable/evaluated). 
● 
ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%).  
In addition, if close monitoring for a subject with moderate or severe hepatic laboratory tests 
is not possible, study treatment should be discontinued. 
*Hy’s Law Definition: 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).  


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The 2 “requirements” for Hy’s Law are:  
1) Evidence that a drug can cause hepatocellular-type injury, generally shown by an increase 
in transaminase elevations higher 3 x ULN (“2 x ULN elevations are too common in treated 
and untreated patients to be discriminating”).  
2) Cases of increased bilirubin (at least 2 x ULN) with concurrent transaminase elevations at 
least 3 x ULN and no evidence of intra- or extra-hepatic bilirubin obstruction (elevated ALP) 
or Gilbert’s syndrome [Temple, 2006]. 
FDA Guidance for Industry, “Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation”2009: 
1. The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold 
or greater elevations above the ULN of ALT or AST than the (nonhepatotoxic) control 
drug or placebo. 
2. Among study subjects showing such AT elevations, often with ATs much greater than 
3 x ULN, one or more also show elevation of serum TBL to > 2 x ULN, without initial 
findings of cholestasis (elevated serum ALP). 
3. No other reason can be found to explain the combination of increased AT and TBL, such 
as viral hepatitis A, B, or C; preexisting or acute liver disease; or another drug capable of 
causing the observed injury. [Guidance for Industry titled “Drug-Induced Liver Injury: 
Premarketing Clinical Evaluation” issued by FDA on July 2009] 
References 
Temple R. Hy’s law: Predicting Serious Hepatotoxicity. Pharmacoepidemiol Drug Saf. 2006 
April;15(Suppl 4):241-3. 
Guidance for Industry titled “Drug-Induced Liver Injury: Premarketing Clinical Evaluation” issued by 
FDA on July 2009.  


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12.6 
Common Serious Adverse Events 
The following is a list of SAEs that the sponsor considers to be associated with the disease 
state being studied. The list does NOT change your reporting obligations or prevent the need 
to report an AE meeting the definition of an SAE as detailed in [Section 5.5.2 Definition of 
Serious Adverse Events]. The purpose of this list is to alert the investigator that some events 
reported as SAEs may not require expedited reporting to the regulatory authorities based on 
the classification of “common SAEs”. The investigator is required to follow the requirements 
detailed in [Section 5.5.5 Reporting of Serious Adverse Events].  
For IND safety reporting, single occurrences of the following events may be excluded from 
expedited reporting to the FDA. If aggregate analysis of these events indicate they occur 
more frequently with study drug, an expedited IND safety report may be submitted to the 
FDA.  
Serious Adverse Events Caused by AML 
Grades Usually 
Observed with AML 
Hematologic AE 
Anemia 
0 - 4 
Bone marrow hypocellular 
0 - 4 
CD4 lymphocytes decreased 
0 - 4 
Disseminated intravascular coagulation 
0 - 3 
Leukocytosis 
0 - 4 
Lymphocyte count decreased 
0 - 4 
Lymphocyte count increased 
0 - 4 
Neutropenia 
0 - 4 
Neutrophil count decreased 
0 - 4 
Platelet count decreased 
0 - 4 
Purpura 
0 - 3 
Thrombocytopenia 
0 - 4 
White blood cell decreased 
0 - 4 
Infection-related AE 
Bacterial infection (regardless of organ-system involved or specific bacterial cause) 
0 - 3 
Chills 
0 - 3 
Cough 
0 - 3 
Febrile neutropenia (without infection) 
0 - 4 
Fever 
0 - 5 
Flu-like symptoms 
0 - 3 
Fungal infections (regardless of organ-system involved or fungal cause) 
0 - 3 
Mucositis 
0 - 4 
Periodontal disease 
0 - 3 
Pneumonia 
0 - 5 
Sepsis/septicemia/bacteremia (all causes) 
0 - 5 
Sinusitis 
0 - 4 
Sore throat 
0 - 3 
Psychiatric and Nervous System Related AE 
Anxiety 
0 - 2 
Cognitive disturbance 
0 - 3 
Confusion 
0 - 5 
Depressed level of consciousness 
0 - 5 
Depression 
0 - 3 
Table continued on next page 


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Serious Adverse Events Caused by AML 
Grades Usually 
Observed with AML 
Libido decreased 
0 - 2 
Meningismus 
0 - 5 
Seizure 
0 - 5 
Somnolence 
0 - 5 
Syncope 
3 
Other AEs 
Activated partial thromboplastin time prolonged 
0 - 2 
Alanine aminotransferase increased 
0 - 2 
Alkaline phosphatase increased 
0 - 2 
Anorexia 
0 - 2 
Aspartate aminotransferase increased 
0 - 2 
Blood bilirubin increased 
0 - 2 
Bone and/or joint pain 
0 - 2 
Bruising 
0 - 2  
Bleeding/hemorrhage 
0 - 5 
Diarrhea 
0 - 2 
Dyspnea 
0 - 5 
Fatigue 
0 - 3 
Flushing 
0 - 2 
Gamma-glutamyltransferase increased 
0 - 1 
GVHD-acute and chronic 
0 - 2 
Hypertrophied gums 
0 - 1 
Hyperuricemia 
0 - 1 
Hypokalemia 
0 - 2 
Hypotension 
0 - 2 
Hypoxia 
0 - 3 
INR increased 
0 - 1 
Lactate dehydrogenase increased 
0 - 2 
Malaise 
0 - 2 
Multiorgan failure 
0 - 5 
Nausea 
0 - 2 
Oral dysesthesia 
0 - 2 
Petichiae 
0 - 2 
Pruritus 
0 - 3 
Skin and subcutaneous tissue disorders 
0 - 3 
Transient ischemic attacks 
0 - 2 
Tumor lysis syndrome 
3 - 5 
Vasculitis 
0 - 5 
Vomiting 
0 - 2 
Weight loss 
0 - 2 
AE: adverse event; AML: acute myeloid leukemia; GVHD: graft-versus-host disease;  
INR: international normalization ratio 


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12.7 
Adverse Events of Special Interest (AESI) for Atezolizumab  
Adverse events of special interest (AESI) are required to be reported by the investigator to 
the sponsor immediately (i.e., no more than 24 hours after learning of the event). AEs of 
special interest are as follows: 
● 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's 
Law (see Section 5.5.1.2 Potential Cases of Drug-Induced Liver Injury) 
● 
Suspected transmission of an infectious agent by the study treatment, as defined below: 
○ Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent. A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an infection 
in a subject exposed to a medicinal product. This term applies only when a 
contamination of study treatment is suspected. 
● 
Pneumonitis 
● 
Colitis 
● 
Pneumonitis 
● 
Colitis 
● 
Endocrinopathies: diabetes mellitus, pancreatitis, adrenal insufficiency, hyperthyroidism, 
and hypophysitis 
● 
Hepatitis, including AST or ALT  10  ULN 
● 
Systemic lupus erythematosus 
● 
Neurological disorders: Guillain-Barré syndrome, myasthenic syndrome or myasthenia 
gravis, and meningoencephalitis 
● 
Events suggestive of hypersensitivity, infusion-related reactions, cytokine-release 
syndrome, influenza-like illness, systemic inflammatory response syndrome, and 
systemic immune activation 
● 
Nephritis 
● 
Ocular toxicities (e.g., uveitis, retinitis, optic neuritis) 
● 
Myositis 
● 
Myopathies, including rhabdomyolysis 
● 
Grade  2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis) 
● 
Vasculitis 
● 
Autoimmune hemolytic anemia 
● 
Severe cutaneous reactions are a known risk (e.g., Stevens-Johnson syndrome, dermatitis 
bullous, toxic epidermal necrolysis) 


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12.8 
Laboratory Assessments 
Panel/Assessment 
Parameters to be Analyzed 
Hematology 
White Blood Cell Counta 
White Blood Cell Differentiala 
Red Blood Cell Count 
Hemoglobina 
Hematocrita 
Mean Corpuscular Volume 
Platelet Counta 
Mean Corpuscular Hemoglobin Concentration 
Mean Corpuscular Hemoglobin 
Blast count 
Chemistry 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Blood Urea Nitrogen 
Creatinine 
Uric Acidb 
Glucose 
Calcium 
Phosphate 
Magnesium 
Albumin 
Total Protein 
Alkaline Phosphatase 
Lactate Dehydrogenase 
Creatine Kinase 
Triglycerides 
Total Cholesterol 
Liver Function Tests including: 
Total Bilirubin 
Alanine Aminotransferase 
Aspartate Aminotransferase 
Thyroid Function Tests including TSH and Free T4 
Serum Pregnancy Test 
Human Chorionic Gonadotropin 
Coagulation Profile (PT/INR, 
D-dimer, fibrinogen)
INR (with PT if reported) 
aPTT 
Fibrinogen (screening only) 
D-dimer (screening only)
Table continued on next page 
Footnotes


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Panel/Assessment 
Parameters to be Analyzed 
Urinalysis 
Color 
Appearance 
Specific Gravity 
pH 
Bilirubin 
Blood 
Glucose 
Ketones 
Leukocyte Esterase 
Nitrite 
Protein 
Urobilinogen 
Bone Marrow 
Blast Count and Cell Countsa  
Flow Cytometry for Blasts 
Minimal Residual Disease  
Exploratory biomarkers (protein or genomic) related to study 
treatment 
Pharmacokinetics 
Gilteritinib concentration 
Pharmacogenomics (For subjects who 
provide separate PGx consent) 
PGx analyses to be determined. 
FLT3 and AXL 
Phospho-FLT3 and Phospho-AXL 
Immune cell population 
immunophenotyping 
Lymphocyte subsets, dendritic cells, natural killer cells,  
T-cell subsets, T-regulatory cells 
Blast cell immunophenotyping 
Blast cell immunophenotyping  
aPTT: activated partial thromboplastin time; FLT3: FMS-like tyrosine kinase;  
INR: international normalized ratio; PGx: pharmacogenomic; PT: prothrombin time; T4: thyroxine;  
TSH: thyroid stimulating hormone. 
a. In addition to the central read of these values, available local results will also be entered into the electronic 
case report form. 
b. On days 1, 8 and 15 in cycle 1. 


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12.9 
Pharmacogenomic (PGx) Analysis With Banked Sample (Optional)  
INTRODUCTION 
PGx research aims to provide information regarding how naturally occurring differences in a 
subject’s gene and/or expression of genes based on genetic variation may impact what 
treatment options are best suited for the subject. Through investigation of PGx by 
technologies such as genotyping, gene sequencing, statistical genetics and Genome-Wide 
Association Studies, the relationship between gene profiles and a drug’s kinetics, efficacy or 
toxicity may be better understood. As many diseases may be influenced by 1 or more genetic 
variations, PGx research may identify which genes are involved in determining the way a 
subject may or may not respond to a drug. 
OBJECTIVES 
The PGx research that may be conducted in the future with acquired blood samples is 
exploratory. The objective of this research will be to analyze or determine genes of relevance 
to clinical response, pharmacokinetics and/or toxicity/safety issues. 
By analyzing genetic variations, it may be possible to predict an individual subject’s response 
to treatment in terms of efficacy and/or toxicity. 
SUBJECT PARTICIPATION 
Subjects who have consented to participate in this study may participate in this  
PGx sub-study. Subjects must provide written consent prior to providing any blood samples 
that may be used at a later time for PGx analysis. 
SAMPLE COLLECTION AND STORAGE 
Subjects who consent to participate in this sub-study will provide one tube of whole blood of 
approximately 4 – 6 mL per Astellas’ instructions. Each sample will be identified by the 
unique subject number. Samples will be shipped to a designated banking CRO as directed by 
Astellas. 
PGx ANALYSIS 
Details on the potential PGx analysis cannot be established yet. Astellas may initiate the PGx 
analysis if evidence suggests that genetic variants may be influencing the drug’s kinetics, 
efficacy and/or safety.  
DISPOSAL OF PGx SAMPLES/DATA 
All PGx samples collected will be stored for a period of up to 15 years following study 
database hardlock. If there is no requirement for analysis, the whole blood sample will be 
destroyed after the planned storage period. The subject has the right to withdraw consent at 
any time. When a subject’s withdraw notification is received, the PGx sample will be 
destroyed. The results of any PGx analysis conducted on a sample prior to its withdrawal will 
be retained at Astellas indefinitely unless otherwise specified by local regulation. 


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INFORMATION DISCLOSURE TO THE SUBJECTS 
Exploratory PGx analysis may be conducted following the conclusion of the clinical study, if 
applicable. The results of the PGx analysis will not be provided to any investigators or 
subjects, nor can the results be requested at a later date. Any information that is obtained 
from the PGx analysis will be the property of Astellas.  
 


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12.10 Clinical Study Continuity 
INTRODUCTION 
The purpose of this appendix is to provide acceptable alternate methods to assess safety and 
efficacy parameters, as appropriate, in the event the clinical study is interrupted at the 
country, state, site or participant level during any crisis (e.g., natural disaster, pandemic).    
BENEFIT-RISK RATIONALE 
Maintaining the safety of clinical study participants and delivering continuity of care in the 
clinical study setting is paramount during any crisis. The site is expected to follow the 
protocol and associated Schedule of Assessments [Table 1] unless the site principal 
investigator discusses the need with the Astellas medical monitor to implement the alternate 
measures.  
The approach outlined within this appendix defines which assessments are required to 
maintain a favorable benefit/risk to the participant, to maintain overall study integrity and to 
provide acceptable alternate methods to complete the study required assessments and 
procedures if study activities are unable to be performed as described in Section 5 due to a 
crisis. 
INFORMED CONSENT 
Participants who need to follow any or all of the alternate measures outlined in this Appendix 
will be required to provide informed consent, which explicitly informs them of the nature of 
and rationale for these changes, and gain their agreement to continue participation in the 
study prior to the implementation of any of these changes. In the event the urgency of 
implementing the alternate measures does not allow for the participant to provide written 
consent prior to implementation, the principal investigator or designee will obtain oral 
agreement from the subject followed by written documentation as soon as is feasible. A 
separate addendum to the study informed consent will be provided to document the 
participant’s consent of the changes. 
PARTICIPANT PROCEDURES ASSESSMENT 
Sites with participants who are currently enrolled into this clinical study may consider 
implementing the alternate methods outlined below if one or more of the following 
conditions are met due to the crisis: 
• Regional or local travel has been restricted, inclusive of mandatory shelter in place 
measures, which makes participant travel to/from the study site nearly impossible 
• Site facilities have been closed for clinical study conduct  
• Site has been restricted to treating patients with conditions outside of the scope of the 
study 
• Site personnel have temporarily relocated the conduct of the study to a location that place 
a burden on the participant with respect to time and travel 


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• Participant(s) have temporarily relocated from the current study site to an alternate study 
site to avoid placing a burden on the participant with respect to travel 
• Participant(s) have temporarily relocated from their home location and the new distances 
from the site would cause undue burden with respect to time and travel 
• Participant has risk factors for which traveling to the site poses an additional risk to the 
participant’s health and safety 
Adherence to the original protocol as reflected in the Schedule of Assessment [Table 1] is 
expected, where plausible, in the case of a crisis. The alternate measures as noted in [Table 8] 
below are only permissible in the event of a crisis, and after discussing the need with the 
Astellas medical monitor or designee to implement the alternate measures. This is to allow 
for continuity of receiving study drug and maintaining critical safety and efficacy 
assessments for patients participating in the study at a time of crisis. 
If one or more of the alternate measures noted below is implemented for a participant, the site 
should document in the participant’s source document the justification for implementing the 
alternate measure and the actual alternate measures that were implemented, along with the 
corresponding time point(s). 
All other assessments should be completed as outlined in [Table 1].  
 


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Table 8 
 Alternative Schedule of Assessments in Response to a Crisis  
Critical Assessments 
Alternate Approach(es) 
Critical Time points 
Follow-up 
Cycle Day 
 
C1D1 
C1D8 
C1D1 
Subsequent 
Cycles D1 
Subsequent 
Cycles D15  
EOT 
30-Day 
Follow-up 
Long-term 
Follow-up 
General Study Procedures 
Weight 
Can be obtained at local clinic 
X 
 
 
X 
 
 
 
 
Physical Examination 
Since atezolizumab needs to be given every 2 weeks in the 
clinic, this will be captured in the clinic. In the event the visit 
is missed, this can be captured during the telehealth visit. 
X 
X 
X 
X 
X 
X 
 
 
Vital Signs 
Since atezolizumab needs to be given every 2 weeks in the 
clinic, this will be captured in the clinic. In the event the visit 
is missed, information may be captured during telehealth visits 
if a patient has adequate monitoring instruments and 
knowledgeable and able to obtain measurements 
X 
X 
X 
X 
X 
X 
 
 
ECOG Performance Status 
Since atezolizumab needs to be given every 2 weeks in the 
clinic, this will be captured in the clinic. In the event the visit 
is missed, information can be captured during telehealth visits. 
X 
 
X 
X 
X 
X 
 
 
AE/SAE Assessment 
Since atezolizumab needs to be given every 2 weeks in the 
clinic, this will be obtained in the clinic. In the event the visit 
is missed or the patient cannot come to the clinic, telehealth 
visits will be allowed for non-dosing visits. Please refer to 
protocol schedule of assessments. 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and Concomitant 
Medications 
Since atezolizumab needs to be given every 2 weeks in the 
clinic, this will be obtained in the clinic. In the event the visit 
is missed or the patient cannot come to the clinic, telehealth 
visits will be allowed for non-dosing visits. Please refer to 
protocol schedule of assessments. 
X 
X 
X 
X 
X 
X 
X 
 
Electrocardiograms 
12-lead ECG 
Since atezolizumab needs to be given every 2 weeks in the 
clinic, this will be obtained in the clinic. In the event the visit 
is missed or cannot be made, ECG in triplicates performed in 
local facility is acceptable if results can be made available to 
investigative site. 
X 
X 
X 
X 
X 
X 
 
 
Table continued on next page 


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Critical Assessments 
Alternate Approach(es) 
Critical Time points 
Follow-up 
Cycle Day 
 
C1D1 
C1D8 
C1D1 
Subsequent 
Cycles D1 
Subsequent 
Cycles D15  
EOT 
30-Day 
Follow-up 
Long-term 
Follow-up 
Blood and Urine Collection 
Clinical Laboratory Tests 
(chemistry, hematology, 
coagulation, urinalysis) 
Since atezolizumab needs to be given every 2 weeks in the 
clinic, this will be obtained in the clinic. In the event the visit 
is missed, or the patient cannot come to the clinic, the 
collection of samples at local facility is acceptable if the results 
can be made available to investigative site. 
X 
X 
X 
X 
X 
X 
 
 
Thyroid Function Test 
Since atezolizumab needs to be given every 2 weeks in the 
clinic, this will be obtained in the clinic. In the event the visit 
is missed, or the patient cannot come to the clinic, the 
collection of samples at local facility is acceptable if the results 
can be made available to investigative site. 
 
 
 
X 
 
X 
 
 
Pharmacokinetic Sample 
Collection 
Since atezolizumab needs to be given every 2 weeks in the 
clinic. This will be obtained in the clinic. 
X 
X 
X 
X 
X 
 
 
 
Blood Sample for FLT3 and AXL 
This is an exploratory endpoint. There are no alternative 
approaches for this assessment. If the 24 post-dose sample is 
not feasible, it is okay. 
X 
 
 
 
 
 
 
 
Blood Sample for Immune Cell 
Immunophenotyping 
In general biomarker samples are collected on atezolizumab 
treatment days and do not require a unique visit to the study 
site. These samples cannot be stored. If samples cannot be 
received by central lab then they should not be collected 
X 
 
X 
X 
 
X 
 
 
Blood Sample for Blast Cell 
Immunophenotyping 
In general biomarker samples are collected on atezolizumab 
treatment days and do not require a unique visit to the study 
site. These samples cannot be stored. If samples cannot be 
received by central lab then they should not be collected 
X 
 
X 
X 
 
X 
 
 
PGx (whole blood and buccal 
swab) 
This samples are collected on an atezolizumab treatment day. 
If the samples can be collected but the central lab cannot 
receive samples, samples can be stored at sites until shipping is 
accepted again 
X 
 
 
 
 
 
 
 
Table continued on next page 


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Critical Assessments 
Alternate Approach(es) 
Critical Time points 
Follow-up 
Cycle Day 
 
C1D1 
C1D8 
C1D1 
Subsequent 
Cycles D1 
Subsequent 
Cycles D15  
EOT 
30-Day 
Follow-up 
Long-term 
Follow-up 
Pregnancy Test for WOCBP 
Since atezolizumab needs to be given every 2 weeks in the 
clinic, this will be obtained in the clinic. In the event the visit 
is missed, or the patient cannot come to the clinic, the 
collection of samples at local facility is acceptable if the results 
can be made available to investigative site. 
X 
 
 
X 
 
X 
 
 
Treatment 
Gilteritinib Dosing at the Clinic 
Patient will be taken off study and the patient can take 
commercially available gilteritinib off study or receive other 
alternative therapies for R/R AML albeit the options are 
limited and not very effective. Delivery from site to patient if 
the patient is just on gilteritinib monotherapy is also possible. 
X 
X 
X 
X 
X 
 
 
 
Atezolizumab Dosing at the Clinic  
All atezolizumab dose needs to be administered in the clinic at 
every 2 week intervals. The protocol allows for patients to 
continue treatment with gilteritinib alone if the patient had 
issues related to tolerability of other clinical considerations 
related to atezolizumab. 
X 
 
X 
X 
X 
 
 
 
Tissue Collection 
Bone Marrow Biopsy and/or 
Aspiration for disease assessment 
and MRD 
Bone marrow assessment to be performed in the clinic. In the 
event this is not possible, bone marrow biopsy performed in a 
local facility is acceptable if results can be made available to 
investigative site. 
 
 
 
X 
 
X 
 
 
Diary 
Subject Diary for Gilteritinib 
Diary can be shipped directly to the patient. Accountability can 
be performed during the telehealth visit. 
X 
 
 
X 
 
 
 
 
AE: adverse event; AML: acute myeloid leukemia; AXL; a receptor tyrosine kinase encoded by the AXL gene; C: cycle; D: day; ECG: electrocardiogram; ECOG: Eastern Cooperative 
Oncology Group; EOT: end of treatment; FLT3: FMS-like tyrosine kinase 3; MRD: minimal residual disease; PGx: pharmacogenomics; R/R: relapsed or refractory; SAE: serious 
adverse event; WOCBP: women of childbearing potential.  
 


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INVESTIGATIONAL PRODUCT SUPPLY 
If any of the conditions outlined above in the Participants Procedures Assessment are met, 
one or all of the following mitigating strategies will be employed, as needed, to ensure 
continuity of study supply to the participants:   
● 
Increase stock of study drug on site to reduce number of shipments required, if site space 
will allow 
● 
Use of locally available atezolizumab brands 
● 
Direct-to-Participant shipments of study drug from the site to the participant’s home 
(ASP2215 only)  
DATA COLLECTION REQUIREMENTS 
Additional data may be collected in order to indicate how participation in the study may have 
been affected by a crisis and to accommodate data collection resulting from alternate 
measures implemented to manage the conduct of the study and participant safety.  
● 
Critical assessments for safety and efficacy based on study endpoints to be identified as 
missing or altered (performed virtually, at alternative locations, out of window, or other 
modifications) due to the crisis 
 
 
 


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13 
ATTACHMENT 1:  NONSUBSTANTIAL AMENDMENT 3 
I.  The purpose of this amendment is:  
Nonsubstantial Changes 
1. Update Key Sponsor Personnel 
DESCRIPTION OF CHANGE:  
Contact details for clinical research contact are revised. 
 
RATIONALE: 
Contact details of sponsor personnel are updated based on changes to study personnel. 
 
2. Update Recommended Dose Modifications for Adverse Reactions 
DESCRIPTION OF CHANGE:  
Table 6 is expanded to add rows for the following adverse reactions: 
• Skin adverse reaction while on prior treatment with another immune-stimulatory 
anticancer agent 
• Suspected cutaneous adverse reaction 
• Confirmed Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis 
 
RATIONALE: 
To include appropriate management of severe dermatological events, as well as to specify 
severe cutaneous adverse reactions to be a known risk with atezolizumab. 
 
3. Update Definition of Pharmacokinetics Analysis Set (PKAS) 
DESCRIPTION OF CHANGE: 
The definition of PKAS is revised to include and for whom at least 1 plasma concentration 
datum is available and both the date and time of dosing on the day of pharmacokinetic 
sampling and the date and time of sampling are known. 
 
RATIONALE: 
Only the plasma concentration sample with both date and time of sampling and date and time 
of dosing available is valid for pharmacokinetic analysis. 
 
4. Note that Severe Cutaneous Reactions are Known Risk 
DESCRIPTION OF CHANGE: 
In Section 12.7, it is noted that severe cutaneous reactions are a known risk. 
 
RATIONALE: 
Severe cutaneous reactions is upgraded from a potential risk to an identified risk by the 
Atezolizumab manufacturer. 


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5. Add Appendix for Clinical Study Continuity 
DESCRIPTION OF CHANGE: 
A Clinical Study Continuity appendix is added to the protocol. This appendix contains 
procedures for continuity of care during a crisis. An alternative schedule of assessments is 
provided.  
 
RATIONALE: 
This appendix is added to provide acceptable alternate methods to assess safety and efficacy 
parameters in the event the clinical study is interrupted at the country, state, site or 
participant level during any crisis (e.g., natural disaster or pandemic). 
 
6. Minor Administrative-type Changes 
DESCRIPTION OF CHANGE:  
Include minor administrative-type changes (e.g., typos, format, numbering and consistency 
throughout the protocol). 
 
RATIONALE: 
To provide clarifications to the protocol and to ensure better definition of the study 
procedures. 
 


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II.  Amendment Summary of Changes: 
II Contact Details of Key Sponsor’s Personnel 
 
WAS: 
Clinical Research Contact: 
Jason Moresco, MBA 
Clinical Study Manager on assignment with Astellas 
Phone: 262-331-1613 
Email: jason.moresco@astellas.com 
 
IS AMENDED TO: 
Clinical Research Contact: 
Dhruva PatelJason Moresco, MBA 
Clinical Study Manager on assignment with Astellas 
Phone: 1-224-205-8837262 331 1613 
Email: dhruva.pateljason.moresco@astellas.com 
 
5 Treatments and Evaluation 
5.1.3 Atezolizumab Dose Interruption, Table 6 Recommended Dosage Modifications for 
Adverse Reactions (Atezolizumab) 
ADDED: 
Adverse Reaction 
Severity of Adverse 
Reactiona 
Dosage Modifications 
Previously experienced a skin 
adverse reaction on prior 
treatment with other immune-
stimulatory anticancer agents 
Grade 3 or 4 (severe or 
life-threatening reaction) 
Caution when considering the use of 
atezolizumab 
Suspected cutaneous adverse 
reactions 
Grade 3 or 4 
Refer to a dermatologist for further 
diagnosis and management 
SJS or TEN 
Withhold dose until confirmation of 
diagnosis 
Confirmed SJS or TEN 
Any Grade 
Permanently discontinue 
SJS: Stevens-Johnson Syndrome; TEN: Toxic Epidermal Necrolysis 
 
IV Synopsis and 5 Treatments and Evaluation 
5.3.2 Response Assessments 
WAS: 
Response to treatment will be defined per modified Cheson criteria [Cheson et al, 2003] as 
outlined below. 
 
IS AMENDED TO: 
Response to treatment will be defined per modified Cheson criteria [Cheson et al, 2003] as 
outlined below for up to the end of 2 cycles and end of treatment. 
 


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IV Synopsis and 5 Treatments and Evaluation 
5.3.2.5 Complete Remission with Partial Hematologic Recovery (CRh) 
WAS: 
For subjects classified as being in CR, except if their ANC is > 0.5 Gi/L and their platelets 
are > 50 Gi/L. 
 
IS AMENDED TO: 
For subjects classified as being in CR, except if their ANC is > 0.5 × Gi109/L and their 
platelets are > 50 × Gi109/L. 
 
IV Synopsis and 5 Treatments and Evaluation 
5.3.2.9 Best Response 
WAS: 
Two best responses, up to the time of 2 cycles of treatment period and the EOT Visit will be 
defined. 
 
IS AMENDED TO: 
Two best responses, up to the time of 2 cycles of treatment period and the EOT Visit will be 
defined. 
 
7 Statistical Methodology 
7.2.4 Pharmacokinetics Analysis Set (PKAS) 
WAS: 
The pharmacokinetics analysis set (PKAS) consists of the administered population for which 
sufficient plasma concentration data is available to facilitate derivation of at least one 
pharmacokinetic parameter and for whom the time of dosing on the day os sampling is 
known. 
 
IS AMENDED TO: 
The pharmacokinetics analysis set (PKAS) consists of the administered population for which 
sufficient plasma concentration data is available to facilitate derivation of at least one 
pharmacokinetic parameter and for whom at least 1 plasma concentration datum is 
available and both the date and time of dosing on the day of pharmacokinetic sampling 
and the date and time of sampling are known the time of dosing on the day os sampling is 
known. 
 
12 Appendices 
12.7 Adverse Events of Special Interest (AESI) for Atezolizumab 
WAS: 
• Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, toxic 


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epidermal necrolysis) 
 
IS AMENDED TO: 
• Severe cutaneous reactions are a known risk (e.g., Stevens-Johnson syndrome, 
dermatitis bullous, toxic epidermal necrolysis) 
 
12 Appendices 
 
ADDED: 
12.10 Clinical Study Continuity 
INTRODUCTION 
The purpose of this appendix is to provide acceptable alternate methods to assess safety 
and efficacy parameters, as appropriate, in the event the clinical study is interrupted at 
the country, state, site or participant level during any crisis (e.g., natural disaster, 
pandemic).    
BENEFIT-RISK RATIONALE 
Maintaining the safety of clinical study participants and delivering continuity of care in 
the clinical study setting is paramount during any crisis. The site is expected to follow 
the protocol and associated Schedule of Assessments [Table 1] unless the site principal 
investigator discusses the need with the Astellas medical monitor to implement the 
alternate measures.  
The approach outlined within this appendix defines which assessments are required to 
maintain a favorable benefit/risk to the participant, to maintain overall study integrity 
and to provide acceptable alternate methods to complete the study required assessments 
and procedures if study activities are unable to be performed as described in Section 5 
due to a crisis. 
INFORMED CONSENT 
Participants who need to follow any or all of the alternate measures outlined in this 
Appendix will be required to provide informed consent, which explicitly informs them 
of the nature of and rationale for these changes, and gain their agreement to continue 
participation in the study prior to the implementation of any of these changes. In the 
event the urgency of implementing the alternate measures does not allow for the 
participant to provide written consent prior to implementation, the principal 
investigator or designee will obtain oral agreement from the subject followed by written 
documentation as soon as is feasible. A separate addendum to the study informed 
consent will be provided to document the participant’s consent of the changes. 
PARTICIPANT PROCEDURES ASSESSMENT 
Sites with participants who are currently enrolled into this clinical study may consider 
implementing the alternate methods outlined below if one or more of the following 
conditions are met due to the crisis: 


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• Regional or local travel has been restricted, inclusive of mandatory shelter in place 
measures, which makes participant travel to/from the study site nearly impossible 
• Site facilities have been closed for clinical study conduct  
• Site has been restricted to treating patients with conditions outside of the scope of 
the study 
• Site personnel have temporarily relocated the conduct of the study to a location that 
place a burden on the participant with respect to time and travel 
• Participant(s) have temporarily relocated from the current study site to an alternate 
study site to avoid placing a burden on the participant with respect to travel 
• Participant(s) have temporarily relocated from their home location and the new 
distances from the site would cause undue burden with respect to time and travel 
• Participant has risk factors for which traveling to the site poses an additional risk to 
the participant’s health and safety 
Adherence to the original protocol as reflected in the Schedule of Assessment [Table 1] 
is expected, where plausible, in the case of a crisis. The alternate measures as noted in 
[Table 8] below are only permissible in the event of a crisis, and after discussing the 
need with the Astellas medical monitor or designee to implement the alternate 
measures. This is to allow for continuity of receiving study drug and maintaining 
critical safety and efficacy assessments for patients participating in the study at a time 
of crisis. 
If one or more of the alternate measures noted below is implemented for a participant, 
the site should document in the participant’s source document the justification for 
implementing the alternate measure and the actual alternate measures that were 
implemented, along with the corresponding time point(s). 
All other assessments should be completed as outlined in [Table 1].  
 


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12 Appendices 
 
ADDED: 
Table 8  Alternative Schedule of Assessments in Response to a Crisis 
Critical Assessments 
Alternate Approach(es) 
Critical Time points 
Follow-up 
Cycle Day 
 
C1D1 
C1D8 
C1D1 
Subsequent 
Cycles D1 
Subsequent 
Cycles D15  
EOT 
30-Day 
Follow-up 
Long-term 
Follow-up 
General Study Procedures 
Weight 
Can be obtained at local clinic 
X 
 
 
X 
 
 
 
 
Physical Examination 
Since atezolizumab needs to be given every 2 weeks in the 
clinic, this will be captured in the clinic. In the event the 
visit is missed, this can be captured during the telehealth 
visit. 
X 
X 
X 
X 
X 
X 
 
 
Vital Signs 
Since atezolizumab needs to be given every 2 weeks in the 
clinic, this will be captured in the clinic. In the event the 
visit is missed, information may be captured during 
telehealth visits if a patient has adequate monitoring 
instruments and knowledgeable and able to obtain 
measurements 
X 
X 
X 
X 
X 
X 
 
 
ECOG Performance Status 
Since atezolizumab needs to be given every 2 weeks in the 
clinic, this will be captured in the clinic. In the event the 
visit is missed, information can be captured during 
telehealth visits. 
X 
 
X 
X 
X 
X 
 
 
AE/SAE Assessment 
Since atezolizumab needs to be given every 2 weeks in the 
clinic, this will be obtained in the clinic. In the event the 
visit is missed or the patient cannot come to the clinic, 
telehealth visits will be allowed for non-dosing visits. 
Please refer to protocol schedule of assessments. 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and Concomitant 
Medications 
Since atezolizumab needs to be given every 2 weeks in the 
clinic, this will be obtained in the clinic. In the event the 
visit is missed or the patient cannot come to the clinic, 
telehealth visits will be allowed for non-dosing visits. 
Please refer to protocol schedule of assessments. 
X 
X 
X 
X 
X 
X 
X 
 
Electrocardiograms 


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12-lead ECG 
Since atezolizumab needs to be given every 2 weeks in the 
clinic, this will be obtained in the clinic. In the event the 
visit is missed or cannot be made, ECG in triplicates 
performed in local facility is acceptable if results can be 
made available to investigative site. 
X 
X 
X 
X 
X 
X 
 
 
Blood and Urine Collection 
Clinical Laboratory Tests 
(chemistry, hematology, 
coagulation, urinalysis) 
Since atezolizumab needs to be given every 2 weeks in the 
clinic, this will be obtained in the clinic. In the event the 
visit is missed, or the patient cannot come to the clinic, the 
collection of samples at local facility is acceptable if the 
results can be made available to investigative site. 
X 
X 
X 
X 
X 
X 
 
 
Thyroid Function Test 
Since atezolizumab needs to be given every 2 weeks in the 
clinic, this will be obtained in the clinic. In the event the 
visit is missed, or the patient cannot come to the clinic, the 
collection of samples at local facility is acceptable if the 
results can be made available to investigative site. 
 
 
 
X 
 
X 
 
 
Pharmacokinetic Sample 
Collection 
Since atezolizumab needs to be given every 2 weeks in the 
clinic, this will be obtained in the clinic. 
X 
X 
X 
X 
X 
 
 
 
Blood Sample for FLT3 and 
AXL 
This is an exploratory endpoint. There are no alternative 
approaches for this assessment. If the 24 post-dose sample 
is not feasible, it is okay. 
X 
 
 
 
 
 
 
 
Blood Sample for Immune Cell 
Immunophenotyping 
In general biomarker samples are collected on 
atezolizumab treatment days and do not require a unique 
visit to the study site. These samples cannot be stored. If 
samples cannot be received by central lab then they 
should not be collected 
X 
 
X 
X 
 
X 
 
 
Blood Sample for Blast Cell 
Immunophenotyping 
In general biomarker samples are collected on 
atezolizumab treatment days and do not require a unique 
visit to the study site. These samples cannot be stored. If 
samples cannot be received by central lab then they 
should not be collected 
X 
 
X 
X 
 
X 
 
 
PGx (whole blood and buccal 
swab) 
This samples are collected on an atezolizumab treatment 
day. If the samples can be collected but the central lab 
cannot receive samples, samples can be stored at sites 
until shipping is accepted again 
X 
 
 
 
 
 
 
 
Pregnancy Test for WOCBP 
Since atezolizumab needs to be given every 2 weeks in the 
clinic, this will be obtained in the clinic. In the event the 
visit is missed, or the patient cannot come to the clinic, the 
collection of samples at local facility is acceptable if the 
results can be made available to investigative site. 
X 
 
 
X 
 
 
 
 
X 
 
 


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Treatment 
Gilteritinib Dosing at the Clinic 
Patient will be taken off study and the patient can take 
commercially available gilteritinib off study or receive 
other alternative therapies for R/R AML albeit the 
options are limited and not very effective. Delivery from 
site to patient if the patient is just on gilteritinib 
monotherapy is also possible. 
X 
X 
X 
X 
X 
 
 
 
Atezolizumab Dosing at the 
Clinic  
All atezolizumab dose needs to be administered in the 
clinic at every 2 week intervals. The protocol allows for 
patients to continue treatment with gilteritinib alone if the 
patient had issues related to tolerability of other clinical 
considerations related to atezolizumab. 
X 
 
X 
X 
X 
 
 
 
Tissue Collection 
Bone Marrow Biopsy and/or 
Aspiration for disease 
assessment and MRD 
Bone marrow assessment to be performed in the clinic. In 
the event this is not possible, bone marrow biopsy 
performed in a local facility is acceptable if results can be 
made available to investigative site. 
 
 
 
X 
 
X 
 
 
Diary 
Subject Diary for Gilteritinib 
Diary can be shipped directly to the patient. 
Accountability can be performed during the telehealth 
visit. 
X 
 
 
X 
 
 
 
 
AE: adverse event; AML: acute myeloid leukemia; AXL; a receptor tyrosine kinase encoded by the AXL gene; C: cycle; D: day; ECG: electrocardiogram; ECOG: Eastern 
Cooperative Oncology Group; EOT: end of treatment; FLT3: FMS-like tyrosine kinase 3; MRD: minimal residual disease; PGx: pharmacogenomics; R/R: relapsed or 
refractory; SAE: serious adverse event; WOCBP: women of childbearing potential.   


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INVESTIGATIONAL PRODUCT SUPPLY 
If any of the conditions outlined above in the Participants Procedures Assessment are 
met, one or all of the following mitigating strategies will be employed, as needed, to 
ensure continuity of study supply to the participants:   
● 
Increase stock of study drug on site to reduce number of shipments required, if site 
space will allow  
● 
Use of locally available atezolizumab brands 
● 
Direct-to-Participant shipments of study drug from the site to the participant’s 
home (ASP2215 only)  
DATA COLLECTION REQUIREMENTS 
Additional data may be collected in order to indicate how participation in the study 
may have been affected by a crisis and to accommodate data collection resulting from 
alternate measures implemented to manage the conduct of the study and participant 
safety.  
● 
Critical assessments for safety and efficacy based on study endpoints to be 
identified as missing or altered (performed virtually, at alternative locations, out of 
window, or other modifications) due to the crisis 
 
III.  Nonsubstantial Amendment Rationale: 
Rationale for Nonsubstantial Designation 
All revisions made to the protocol are administrative in nature and do not impact the safety or 
scientific value of the clinical study. 
 


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14 
SPONSOR SIGNATURES 
 
Astellas Signatories 
(Electronic signatures are attached at the end of the document.)  
, MD 
 
Medical Sciences 
, PhD 
 
Data Science 
 
 
 
PPD
PPD
PPD
PPD

SAP_001.pdf: 
Sponsor: Astellas Pharma Global Development, Inc. 
SAP Draft Version 1.0 
ISN/Protocol 2215-CL-1101 
20-Aug-2021
Astellas 
Page 1 of 38 
STATISTICAL ANALYSIS PLAN 
Draft Version 1.3, dated 20 Aug-2021 
A Phase 1/2 Study of ASP2215 (Gilteritinib) Combined with Atezolizumab in Patients with 
Relapsed or Treatment Refractory FLT3 Mutated Acute Myeloid Leukemia (AML)  
ISN/Protocol: 2215-CL-1101 
IND number: 117,548 
Sponsor: 
Astellas Pharma Global Development, Inc. (APGD) 
1 Astellas Way 
Northbrook, IL 60062 
This confidential document is the property of the sponsor.  No unpublished information 
contained in this document may be disclosed without prior written approval of the sponsor. 
NCT03730012


Sponsor: Astellas Pharma Global Development, Inc. 
SAP Draft Version 1.0 
ISN/Protocol 2215-CL-1101 
20-Aug-2021 
Astellas 
Page 2 of 38 
Table of Contents 
I. 
LIST OF ABBREVIATIONS AND KEY TERMS ································
···········
 5 
1 
INTRODUCTION ································
································
··················
 8 
2 
FLOW CHART AND VISIT SCHEDULE ································
····················
 9 
3 
STUDY OBJECTIVES AND DESIGN ································
························
 12 
3.1 
Study Objectives ································
································
··············
 12 
3.1.1 
Primary Objectives ································
································
······  12 
3.1.2 
Secondary Objectives ································
································
···  12 
3.1.3 
Exploratory Objectives ································
································
· 12 
3.2 
Study Design ································
································
···················
 12 
3.2.1 
Study Design ································
································
·············
 12 
3.2.2 
Reduction in Dose of the Study Drug(s) ································
··············
 14 
3.3 
Randomization ································
································
·················
 17 
4 
SAMPLE SIZE································
································
·····················
 17 
5 
ANALYSIS SETS ································
································
·················
 18 
5.1 
Full Analysis Set (FAS) ································
································
······  18 
5.2 
Safety Analysis Set (SAF) ································
································
···  18 
5.3 
Pharmacokinetics Analysis Set (PKAS) ································
····················
 18 
5.4 
Biomarker Analysis Set (BMAS) ································
···························
 18 
6 
ANALYSIS VARIABLES ································
································
·······  18 
6.1 
Efficacy Endpoints ································
································
············
 18 
6.1.1 
Primary Efficacy Endpoint ································
·····························
 18 
6.1.2 
Secondary Efficacy Endpoint ································
··························
 18 
6.1.3 
Response Definition ································
································
·····  19 
6.1.4 
Definition of Other Efficacy Variables ································
···············
 20 
6.1.5 
Definition of Biomarker Variables ································
····················
 21 
6.2 
Safety Variables ································
································
···············
 22 
6.2.1 
Definition of DLT ································
································
·······  22 
6.2.2 
Definition of MTD ································
································
······  23 
6.2.3 
Bayesian Posterior Probability for Safety Monitoring in Phase 2 ·················
 23 
6.2.4 
Adverse Events ································
································
··········
 23 
6.2.5 
Other Variables ································
································
··········
 23 
6.3 
Pharmacokinetics Variables································
································
··  23 


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6.4 
Pharmacodynamics Variables ································
·······························
 24 
6.5 
Other Variables ································
································
················
 24 
7 
STATISTICAL METHODOLOGY ································
···························
 25 
7.1 
General Considerations ································
································
·······  25 
7.2 
Study Population ································
································
··············
 25 
7.2.1 
Disposition of Subjects ································
································
· 25 
7.2.2 
Protocol Deviations ································
································
·····  25 
7.2.3 
Demographic and Other Baseline Characteristics ································
···  26 
7.2.4 
Previous and Concomitant Medications ································
··············
 26 
7.2.5 
Previous and Concomitant Non-Medication Therapy ·······························
 27 
7.3 
Study Drugs ································
································
····················
 27 
7.3.1 
Exposure ································
································
··················
 27 
7.3.2 
Treatment Compliance ································
································
··  27 
7.4 
Analysis of Efficacy ································
································
··········
 28 
7.4.1 
Analysis of Primary Efficacy Endpoint ································
···············
 28 
7.4.2 
Analysis of Secondary Efficacy Endpoint ································
············
 28 
7.4.3 
Analysis of Exploratory Efficacy Endpoint ································
··········
 29 
7.5 
Analysis of Safety ································
································
·············
 29 
7.5.1 
Adverse Events ································
································
··········
 29 
7.5.2 
Clinical Laboratory Evaluation ································
························
 30 
7.5.3 
Vital Signs ································
································
················
 32 
7.5.4 
Electrocardiograms (ECGs) ································
····························
 32 
7.5.5 
Pregnancies ································
································
···············
 33 
7.5.6 
Eastern Cooperative Oncology Group (ECOG) Performance Scores ·············
 33 
7.6 
Analysis of PK ································
································
·················
 34 
7.7 
Analysis of Biomarkers································
································
·······  34 
7.8 
Subgroups of Interest ································
································
·········  34 
7.9 
Other Analyses ································
································
················
 34 
7.10 
Interim Analysis (and Early Discontinuation of the Clinical Study) ····················
 34 
7.11 
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········  34 
7.11.1 
Missing Data ································
································
·············
 34 
7.11.2 
Outliers ································
································
···················
 35 
7.11.3 
Visit Windows ································
································
···········
 35 


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7.11.4 
Covid-19 Impact Assessment ································
··························
 36 
8 
DOCUMENT REVISION HISTORY ································
·························
 37 
9 
REFERENCES ································
································
····················
 37 
10 
APPENDICES ································
································
·····················
 38 
10.1 
Appendix 1: Signatures ································
································
·······  38 
 


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I. 
LIST OF ABBREVIATIONS AND KEY TERMS 
List of Abbreviations 
Abbreviations 
Description of abbreviations 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AML 
Acute Myeloid Leukemia 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the Concentration-time Curve 
AXL 
A Receptor Tyrosine Kinase Encoded by the AXL Gene 
BMAS 
Biomarker Analysis Set 
BMI 
Body Mass Index 
BOIN 
Bayesian Optimal Interval Design 
CA 
Competent Authorities 
Cmax 
Maximum Concentration 
CR 
Complete Remission 
CRc 
Composite Complete Remission 
CRh 
complete remission with partial hematologic recovery  
CRi 
Complete Remission with Incomplete Hematologic Recovery 
CRp 
Complete Remission without Platelet Recovery 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
Concentration Immediately Prior to Dosing at Multiple Dosing 
CV 
Coefficient of Variation 
DBP 
Diastolic Blood Pressure 
DEC 
Dose Evaluation Committee 
DL 
Dose Level 
DLT 
Dose Limiting Toxicity 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EFS 
Event-free survival 
EOT 
End of Treatment 


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Abbreviations 
Description of abbreviations 
FAB 
French-American-British 
FAS 
Full Analysis Set 
FLT3 
FMS-like Tyrosine Kinase 3 
HSCT 
Hematopoietic Stem Cell Transplantation 
ICF 
Informed Consent Form 
ICH  
International Council for Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
INR 
International Normalized Ratio 
IRT 
Interactive Response Technology 
ISN 
International Study Number 
MRD 
Minimal Residual Disease 
MTD 
Maximum Tolerated Dose 
MUGA 
Multigated Acquisition 
NCI 
National Cancer Institute 
OS 
Overall Survival 
PGx 
Pharmacogenomic 
PKAS 
Pharmacokinetics Analysis Set 
PR 
Partial Remission 
PT 
Preferred Term  
q2w 
Once Every 2 Weeks 
QTcF 
Fridericia-Corrected QT Interval 
RBC 
Red Blood Cell 
RP2D 
Recommended Phase 2 Dose 
RTK 
Receptor Tyrosine Kinase 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
ULN 
Upper Limit of Normal 
WHO 
World Health Organization 
WHO – DD 
World Health Organization – Drug Dictionary 
WOCBP 
Woman of Childbearing Potential 
 


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List of Key Terms 
Terms 
Definition of terms 
Baseline  
Assessments of subjects as they enter a study before they receive any 
treatment.  
Endpoint  
Variable that pertains to the efficacy or safety evaluations of a study. 
Enroll 
To register or enter a subject into a clinical study. NOTE: Once a subject has 
received the study drug or placebo, the clinical study protocol applies to the 
subject.  
Intervention 
The drug, device, therapy or process under investigation in a clinical study 
that is believed to have an effect on outcomes of interest in a study. (e.g., 
health-related quality of life, efficacy, safety and pharmacoeconomics).  
Investigational 
period 
Period of time where major interests of protocol objectives are observed, and 
where the test drug or comparative drug is usually given to a subject, and 
continues until the last assessment after completing administration of the test 
drug or comparative drug. 
Post investigational 
period 
Period of time after the last assessment of the protocol. Follow-up 
observations for sustained adverse events and/or survival are done in this 
period. 
Screening 
A process of active consideration of potential subjects for enrollment in a 
study. 
Screen failure 
Potential subject who did not meet 1 or more criteria required for 
participation in a studyl. 
Screening period 
Period of time before entering the investigational period, usually from the 
time when a subject signs the consent until just before the test drug or 
comparative drug is given to a subject.  
Study period 
Period of time from the first site initiation date to the last site completing the 
study. 
Variable 
Any entity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values. 
 


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1 
INTRODUCTION 
This Statistical Analysis Plan (SAP) contains a more technical and detailed elaboration of the 
principal features of the analysis described in the protocol, and includes detailed procedures 
for executing the statistical analysis of the primary, secondary and exploratory endpoints and 
other data.  
The SAP is finalized and signed prior to any of the following: study unblinding, database 
hard lock, interim analysis, or accumulation of substantial amount of data in an open-label 
study to ensure lack of bias. For operational efficiency an earlier time is usually targeted. If 
needed, revisions to the approved SAP may be made prior to database hard lock. Revisions 
will be version controlled. 
This statistical analysis is coordinated by the responsible biostatistician of GD-US. Any 
changes from the analyses planned in the SAP will be justified in the Clinical Study Report 
(CSR). 
Prior to database hard lock, a final review of data and TLFs meeting will be held to allow a 
review of the clinical trial data and to verify the data that will be used for analysis set 
classification. If required, consequences for the statistical analysis will be discussed and 
documented. A meeting to determine analysis set classifications may also be held prior to 
database hard lock. 
 


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2 
FLOW CHART AND VISIT SCHEDULE 
phases 1 and 2
 
 
AML: acute myeloid leukemia; EOT: end of treatment; FLT3: FMS-like tyrosine kinase 3; q2w: every 2 weeks; RP2D: recommended phase 2 dose. 
 
 
 
Enroll up to 12 subjects in 
phase 1 and up to 49 
subjects in phase 2 s with 
Relapsed or Treatment 
Refractory FLT3 mutated 
AML 
Phase 1: gilteritinib once daily plus 
420 or 840 mg atezolizumab q2w. 
Phase 2:  
gilteritinib once daily plus 
atezolizumab q2W at RP2D. 
28-day cycles in phases 1 and 2 
until lack of clinical benefit or 
unacceptable toxicity. 
EOT 
Visit 
30-day 
follow-up 
visit 
Long-term 
follow-up for 
3 years or 
until subject 
death or 
withdrawal 


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Table 1 
Schedule of Assessments  
Assessments 
Screening 
C1D1 C1D8 a 
C1 D15 a 
Subsequent 
Cycles D1 
Subsequent 
Cycles D15a  
EOTb 
30-Day 
Follow-up 
Long-term 
Follow-upc 
Windows 
Day -14  
to -1 
 
± 1d 
 
 
 
± 7d 
+ 7d 
± 7d 
Signed ICF 
X 
 
 
 
 
 
 
 
 
Medical and Disease History 
X 
 
 
 
 
 
 
 
 
Enrollment 
 
X 
 
 
 
 
 
 
 
Physical Examinationd 
X 
X 
X 
X 
X 
X 
X 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
 
 
ECOG Performance Statuse 
X 
X 
 
X 
X 
X 
X 
 
 
12-lead ECGf  
X 
X 
X 
X 
X 
X 
X 
 
 
Chest X-ray (or CT of chest)  
X 
 
 
 
 
 
 
 
 
Pregnancy Test for WOCBPg 
X 
X 
 
 
X 
 
X 
 
 
MUGA or ECHO 
X 
 
 
 
 
 
 
 
 
Clinical Laboratory Tests (chemistry, hematology, coagulation, urinalysis)h,i 
Xh 
Xh,i 
Xi 
Xi 
X 
X 
X 
 
 
Thyroid Function Testj 
X 
 
 
 
Xj 
 
Xj 
 
 
Resource utilization 
 
X 
 
 
X 
 
X 
 
 
FLT3 Mutation Statusk 
Xk 
 
 
 
 
 
 
 
 
Bone Marrow Biopsy and/or Aspiration for disease assessment and MRDl 
Xl 
 
 
 
Xl 
 
Xl 
 
 
Pharmacokinetic Sample Collectionm 
 
X 
X 
X 
X 
X 
 
 
 
Blood Sample for FLT3 and AXLn 
 
X 
 
 
 
 
 
 
 
Blood Sample for Immune Cell Immunophenotypingo 
 
X 
 
X 
Xo 
 
X 
 
 
Blood Sample for Blast Cell Immunophenotypingo 
 
X 
 
X 
Xo 
 
X 
 
 
PGx (whole blood and buccal swab)p 
 
X 
 
 
 
 
 
 
 
AE/SAE Assessment 
X 
X 
X 
X 
X 
X 
X 
Xq 
Xr 
Prior and Concomitant Medicationss 
X 
X 
X 
X 
X 
X 
X 
Xr 
 
Survival and subsequent anti-leukemic treatments and their outcomes 
 
 
 
 
 
 
 
Xq 
X 
Gilteritinib Dosing at the Clinict 
 
X 
X 
X 
X 
X 
 
 
 
Subject Diary for Gilteritinibu 
 
X 
 
 
X 
 
 
 
 
Atezolizumab Dosing at the Clinic  
 
X 
 
X 
X 
X 
 
 
 
AE: adverse event; CT: computed tomography; D: day; ECG: electrocardiogram; ECHO: echocardiogram; ECOG: Eastern Cooperative Oncology Group; EOT: end of treatment; 
FLT3: FMS-like tyrosine kinase 3; ICF: informed consent form; MRD: minimal residual disease; MUGA: multigated acquisition scan; PGx: pharmacogenomics;  
QTcF: Fridericia-corrected QT interval; SAE: serious adverse event; WOCBP: women of childbearing potential.  
Footnotes continued on next page 


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a  Visits should be scheduled based on day 1. 
b  If subject permanently discontinues treatment, an EOT Visit should be conducted within 7 days of last dose of study drug.  
c  Telephone contact every 3 months, from the date of the 30-day follow up visit additional contacts may be made to support key analyses. Subjects will be followed for up to 3 years 
after the 30-day follow-up visit. 
d  Height measurement performed only at screening. Weight measurement should be performed at screening and at day 1 of each cycle. 
e  Subject has an ECOG performance status ≤ 2 at screening to be eligible to enroll in study. 
f  ECG assessment will be evaluated at screening, predose on cycle 1 days 1, 8 and 15, and days 1 and 15 of each subsequent visit and at EOT. Predose assessments should be taken 
within 1 hour before drug administration. The 12-lead ECGs will be recorded in triplicate (3 separate ECGs with 10 min resting prior to first ECG and at least 5 min apart per time 
point), and transmitted electronically for central reading. The mean QTcF of the triplicate ECG tracings based on central reading will be used for all treatment decisions. If the mean 
triplicate QTcF is > 500 ms at any time point, the ECG will be repeated (within 2 h if identified on machine read or as soon as possible if identified by central read). See [Protocol 
Section 5.4.4] for further guidance on treatment decision.   
g  WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin). 
h  Subjects may be screened and enrolled from local labs only. However, clinical laboratory samples must also be submitted for central read. Laboratory tests and/or ECGs can be 
repeated during screening period. In the event that the central laboratory results received after randomization are not within eligibility parameters, the subject will still be considered 
eligible, if local labs met the eligibility criteria, and will not be considered a protocol deviation. Local laboratory results that support eligibility and dosing decisions must be entered 
into the clinical database. If local laboratory is to be used to support dosing decisions, local laboratory tests will include complete blood count with differential and clinical 
chemistries (e.g., potassium levels, magnesium levels, glucose, serum creatinine, alanine aminotransferase and aspartate aminotransferase). Additional assessments may be done 
centrally or locally to monitor AEs or as required by dose modification requirements.   
i  Urinalysis is only required at screening. Uric acid will be tested in cycle 1 only on days 1, 8 and 15. Additional laboratory tests may be performed according to institutional standard 
of care.  
j  Thyroid function tests will be repeated after every 2 cycles beginning at cycle 3 (cycle 3/day 1, cycle 5/day 1, cycle 7/day 1, etc.). 
k  Subject is positive for FLT3 mutation in bone marrow or blood after completion of the subject’s last interventional treatment as determined by the local institution.   
l  Bone marrow samples will be collected at screening, cycle 2/day 1, and cycle 3/day 1. For subjects who do not achieve a CR, CRp or CRi, the bone marrow assessments will be 
repeated on day 1 of every 2 subsequent cycles. For subjects who achieve a CRc (CR, CRp or CRi), bone marrow will be repeated 1 month after the date of remission and every 
3 subsequent cycles or if there is suspicion of relapse in the whole blood. Bone marrow samples are also required at the EOT Visit and as clinically indicated. If bone marrow 
aspirate is unobtainable due to technical difficulties such as dry tap, a tube of whole blood (EDTA) along with bone marrow biopsy should be collected instead. Remaining bone 
marrow aspirate and/or whole blood samples will be used for MRD analysis and may be used for other biomarker analyses in relation to treatment outcome. If bone marrow aspirate 
is unobtainable at relapse (e.g., dry tap), a peripheral blood smear should be collected along with bone marrow biopsy. All samples will be sent to the central lab for analysis.   
m  Trough pharmacokinetic samples will be collected for all subjects predose (within 1 h of dose administration) on cycle 1/days 1, 8 and 15, and on days 1 and 15 of each subsequent 
cycle up to 6 months. 
n  Blood samples for FLT3 and AXL samples will be collected on cycle 1/day 1 predose and postdose at 2 h, between 4 to 6 h, and 24 h. 
o  Blood samples for immune and blast cell immunophenotyping will be collected pre-dose at cycle 1 on days 1 and 15, cycle 2/day 1, cycle 3/day 1 and EOT. 
p  Whole blood and buccal swab will be collected pre-dose on day 1 for subjects who consent to participate in the PGx study.   
q  Telephone contact with the subject is sufficient unless any assessment must be repeated for resolution of treatment-related AEs. 
r  Only SAE data that is possibly or probably related to study drug will be collected.  Any concomitant medications related to SAEs will be collected. 
s  Includes medications taken within 28 days prior to day 1. 
t  Gilteritinib is taken once daily at home except for clinic days when it will be taken at the clinic. 
u  Subject diary for gilteritinib is to be given to the subject on day 1 of every cycle. Subjects should complete as instructed 


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3 
STUDY OBJECTIVES AND DESIGN 
3.1 
Study Objectives 
3.1.1 
Primary Objectives 
● 
Determine the safety and tolerability of gilteritinib given in combination with 
atezolizumab in subjects with relapsed or treatment refractory FLT3 mutated AML. 
● 
Determine the CRc rate for subjects with relapsed or treatment refractory FLT3 mutated 
AML who either discontinued the study or completed 2 cycles of gilteritinib given in 
combination with atezolizumab.  CRc is defined as a CR, complete remission without 
platelet recovery (CRp) or complete remission with incomplete hematologic recovery 
(CRi).  
3.1.2 
Secondary Objectives 
● 
Characterize the pharmacokinetics of gilteritinib and its active metabolites (if 
appropriate) when given in combination with atezolizumab. 
● 
Evaluate the safety and efficacy of gilteritinib in combination with atezolizumab in terms 
of: 
o Gilteritinib trough plasma concentrations (Ctrough) 
o CR rate 
o CR with partial hematologic recovery (CRh) 
o Best response rate (CRc + PR) 
o Duration of remission 
o Event-free Survival (EFS) 
o OS 
o AEs, clinical laboratory results, vital signs, ECGs and Eastern Cooperative 
Oncology Group (ECOG) performance status scores 
3.1.3 
Exploratory Objectives 
● 
Evaluate efficacy of gilteritinib given in combination with atezolizumab in terms of MRD 
● 
Evaluate potential genomic, proteomic and/or other biomarkers that may correlate with 
treatment outcome 
● 
Evaluate pharmacodynamic biomarkers of treatment effect  
● 
Evaluate immune cell populations and AML blasts by immunophenotyping in relation to 
treatment effects  
3.2 
Study Design 
3.2.1 
Study Design 
This is an open-label, single arm, phase 1/2 study to evaluate the safety and efficacy of 
combining gilteritinib with atezolizumab for subjects with relapsed or treatment refractory 
FLT3 mutated AML. This study will have 2 phases. Refer to [Section 2 Flow Charts and 
Table 1 Schedule of Assessments] for details of design.   


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Phase 1: 
The phase 1 portion of this study is a dose- escalation phase with a 3 + 3 design to establish 
the recommended phase 2 dose (RP2D) of gilteritinib given in combination with 
atezolizumab.  Up to 12 subjects will be enrolled in cohorts of 3 to 6 subjects to determine 
the RP2D following the dose levels of the combination treatment outlined in Table 1. Dose 
escalation decisions will be made based on DLTs that occur during the first cycle of 
treatment. The treatment will consist of 3 distinct periods; remission induction, consolidation 
and maintenance.   
The DLT observation period will be from cycle 1/day 1 through cycle 1/day 28. Evaluable 
subjects are defined as subjects who experience a DLT or in the absence of DLT, receive at 
least 23/28 doses of gilteritinib and at least 1/2 doses of atezolizumab. Subjects who are later 
discovered not to meet eligibility criteria or are not evaluable for DLT may be replaced.  
Dose evaluation rules based on the 3 + 3 design and dose escalation rules are as follows: 
Number of Subjects with DLT at the 
Given Dose During the DLT Observation 
Period 
Escalation Decision Rules 
0 of 3 or ≤ 1 of 6 subjects 
Escalate and enter up to 3 subjects at the next dose 
level, if next dose level available.  If at dose level 
2, determine if RP2D. 
1 of 3 subjects 
Enter up to 3 subjects at the same dose level. 
≥ 2 subjects 
De-escalate or stop escalating. 
DLT: dose limiting toxicity 
The Dose Evaluation Committee (DEC) will consist of the sponsor, principal investigators, 
and if appropriate, expert consultants who will be responsible for the review of safety data 
through the DLT observation period for 3 or 6 evaluable subjects for each cohort.  The 
decision will be made by the DEC to escalate to the next planned dose level, to remain at the 
same dose level, de-escalate to the dose level below or stop escalation.  The RP2D will be 
selected based on the DEC’s review of all available data at each dose level, including safety 
and pharmacokinetic data, and the RP2D will become the minimum safe and biologically 
effective dose level. Additional details regarding responsibilities and membership 
requirements will be included in the Subject Enrollment and DEC Plan.  
The subjects in the first cohort will be treated with gilteritinib 120 mg orally once daily and 
atezolizumab 420 mg once every 2 weeks by intravenous infusion. The subjects in the second 
cohort will be dosed based on the results of the first cohort and according to the dose level 
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Dose Level 
Dose-Atezolizumab 
Dose-Gilteritinib 
1 
420 mg q2w 
120 mg once daily 
-1 
420 mg q2w 
80 mg once daily 
2 
840 mg q2w  
120mg once daily 
Subjects will be administered treatment until a discontinuation criterion is met. If 1 treatment 
is discontinued due to toxicity, the subject may continue on the other as monotherapy until a 
discontinuation criterion is met. Subjects will have an (EOT) visit within 7 days after last 
dose of study drug, followed by a 30-day follow up for safety, after which the subjects will 
enter the long-term follow-up period of up to 3 years for collection of subsequent AML 
treatment, remission status and survival (cause of death and date of death). 
Phase 2: 
In the phase 2 portion with 2 stages, up to 49 subjects will be enrolled. The subjects will be 
treated with gilteritinib and atezolizumab at the RP2D. In the first stage, 22 subjects will be 
enrolled. The subjects enrolled at the first stage of phase 2 will be used to calculate the CRc 
rate for the first stage. If the minimum CRc rate criterion (i.e., at least 12 CRc responders out 
of 22 subjects) is met, an additional 27 subjects will be enrolled for the second stage. 
Subjects will enter the screening period up to 14 days prior to the start of treatment.  
Subjects will be administered treatment until discontinuation criterion is met. If 1 treatment is 
discontinued due to toxicity, the subject may continue on the other as monotherapy until 
discontinuation criteria is met.  Subjects will have an (EOT) visit within 7 days after last dose 
of study drug, followed by a 30-day follow-up for safety, after which the subjects will enter 
the long-term follow-up period of up to 3 years for collection of subsequent AML treatment, 
remission status and survival (cause of death and date of death).  
3.2.2 
Reduction in Dose of the Study Drug(s) 
3.2.2.1 Gilteritinib Dose Reduction 
Gilteritinib dose cannot be reduced during the DLT observation period (cycle 1/ day 1 
through cycle 1 /day 28 ) of the phase 1 portion of the study.   
Guidelines for gilteritinib dose interruption and reduction for the phase 2 portion are 
provided in [Table 3].  
The dose levels potentially used include the following [Table 2]: 
Table 2 
Gilteritinib Dose Levels 
Dose Level (DL) 
Gilteritinib Dose 
DL - 0 
120 mga 
DL – 1 
80 mg 
DL – 2 
40 mg 
a Starting dose for gilteritinib 
 


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The gilteritinib dose may be initially reduced by 1 dose level per day. The gilteritinib dose 
can be further reduced by a second dose level if the subject has already experienced clinical 
benefit. Note that dose reductions should occur in a step-wise manner. Only 2 dose level 
reductions are permitted. Dose reduction can occur during the treatment cycle based on the 
dose reduction guideline in [Table 3]. 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 3]. In the unusual circumstance that dosing is interrupted or reduced for 
reasons not specified in the tables, the investigator should promptly inform the study medical 
monitor or his/her designee. If the gilteritinib dose has been reduced for related toxicities, it 
cannot be re-escalated. Any subjects that have been off treatment for more than 14 days other 
than for HSCT or a study drug related AE, may only resume treatment after discussion with 
the medical monitor. 
Table 3 
Guidelines for Gilteritinib Dose Interruption or Reduction Event  
Gilteritinib Dosing Instructions 
Nonhematological Events 
Grade 3 toxicity at least 
possibly related to gilteritinib 
Dosing will be interrupted for up to 14 days. 
If the AE resolves to ≤ grade 1 within 14 days, the subject may resume 
dosing at the reduced dose. 
Grade 4 toxicity at least 
possibly related to gilteritinib 
Treatment will be discontinued. 
QTcF > 500 ms 
See [Protocol Section 5.4.4] 
Myelosuppression 
Myelosuppression in the 
presence of CR, CRp or CRi 
Dose may be reduced without interruption if the following criteria are 
met: 
Subject has received a minimum of 2 cycles of gilteritinib 
Platelets < 25 × 109/L and/or absolute neutrophil count (ANC) 
≤ 0.5 × 109/L 
Marrow blasts < 5% 
No evidence of extramedullary disease 
Further dose reduction is permitted if dosing 1 full cycle at the reduced 
dose has not resulted in the desired hematologic recovery.  
AE: adverse event; CR: complete remission; CRc: composite complete remission; CRi: complete remission with 
incomplete hematologic recovery; CRp: complete remission with incomplete platelet recovery; ECG: 
electrocardiogram; QTcF: Fridericia-corrected QT interval 
 


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3.2.2.2 Atezolizumab Dose Interruption 
Refer to the following for atezolizumab dose modification recommendations:  
Table 4 
Recommended Dosage Modifications for Adverse Reactions 
(Atezolizumab) 
Adverse Reaction 
Severity of Adverse Reactiona Dosage Modifications 
Pneumonitis [see Warnings and 
Precautions (5.1) in the package 
insert] 
Grade 2 
Withhold dose until Grade 1 or resolved 
and corticosteroid dose is less than or 
equal to prednisone 10 mg per day (or 
equivalent) 
Grade 3 or 4 
Permanently discontinue 
Hepatitis [see Warnings and 
Precautions (5.2) in the package 
insert] 
AST or ALT > 3 and ≤ 8 x 
ULN or total bilirubin > 1.5 and 
≤ 3 x ULN 
Withhold dose until Grade 1 or resolved 
and corticosteroid dose is less than or 
equal to prednisone 10 mg per day (or 
equivalent) 
AST or ALT > 8 x ULN or total 
bilirubin > 3 x ULN 
Permanently discontinue 
Colitis or diarrhea [see Warnings 
and Precautions (5.3) in the 
package insert] 
Grade 2 or 3 
Withhold dose until Grade 1 or resolved 
and corticosteroid dose is less than or 
equal to prednisone 10 mg per day (or 
equivalent) 
Grade 4 
Permanently discontinue 
Endocrinopathies (including but 
not limited to hypophysitis, 
adrenal insufficiency, 
hyperthyroidism, and type 1 
diabetes mellitus) [see Warnings 
and Precautions (5.4) in the 
package insert] 
Grade 2, 3, or 4 
Withhold dose until Grade 1 or resolved 
and clinically stable on hormone 
replacement therapy. 
Other immune-mediated adverse 
reactions involving a major organ 
[see Warnings and Precautions 
(5.5) in the package insert] 
Grade 3 
Withhold dose until Grade 1 or resolved 
and corticosteroid dose is less than or 
equal to prednisone 10 mg per day (or 
equivalent) 
Grade 4 
Permanently discontinue 
Infections [see Warnings and 
Precautions (5.6) in the package 
insert] 
Grade 3 or 4 
Withhold dose until Grade 1 or resolved 
Infusion-Related Reactions [see 
Warnings and Precautions (5.7) 
in the package insert] 
Grade 1 or 2 
Interrupt or slow the rate of infusion 
Grade 3 or 4 
Permanently discontinue 
Persistent Grade 2 or 3 adverse 
reaction (excluding 
endocrinopathies) 
Grade 2 or 3 adverse reaction 
that does not recover to Grade 0 
or 1 within 12 weeks after last 
TECENTRIQ dose 
Permanently discontinue 
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Adverse Reaction 
Severity of Adverse Reactiona Dosage Modifications 
Inability to taper corticosteroid 
Inability to reduce to less than 
or equal to prednisone 10 mg 
per day (or equivalent) within 
12 weeks after last 
TECENTRIQ dose 
Permanently discontinue 
Recurrent Grade 3 or 4 adverse 
reaction 
Recurrent Grade 3 or 4 (severe 
or life- threatening) adverse 
reaction 
Permanently discontinue 
Previously experienced a skin 
adverse reaction on prior 
treatment with other immune-
stimulatory anticancer agents 
Grade 3 or 4 (severe or life-
threatening reaction) 
Caution when considering the use of 
Atezolizumab 
Suspected cutaneous adverse 
reactions 
Grade 3 or 4 
Refer to a dermatologist for further 
diagnosis and management 
SJS or TEN 
Withhold dose until confirmation of 
diagnosis  
Confirmed SJS or TEN 
Any Grade 
Permanently discontinue 
a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 
Refer to the pharmacy manual and package insert for any updates. 
3.3 
Randomization 
This is a non-randomized study. Patient assignment will be performed via Interactive 
Response Technology (IRT). Prior to the initiation of the study treatment, the site staff will 
contact the IRT in order to assign the subject to treatment. Specific procedures for 
assignment, enrollment and registration through the IRT are contained in the study 
procedures manual. 
4 
SAMPLE SIZE 
This is an open-label, single arm study. No interim analysis and 1 final analysis are planned. 
Phase 1 
The sample size in phase 1 is based on 3+3 design and not based on power calculation. Up to 
12 subjects will be enrolled in cohorts of 3 to 6 subjects to determine the RP2D following the 
dose levels of the combination treatment outlined in Table 2. 
Phase 2 
Simon’s 2-stage design [Simon, 1989] will be used in the study to evaluate the efficacy in 
terms of CRc rate for the selected combination dose level of gilteritinib and atezolizumab. 
The null hypothesis that the true CRc rate is 50% will be tested against a 1-sided alternative. 
In the first stage, the CRc of 22 subjects will be evaluated. If there are 11 or fewer subjects 
with CRc from these 22 subjects by the end of cycle 2, the study will be stopped. Otherwise, 
27 additional subjects will be accrued for a total of 49 subjects evaluable for calculation of 
CRc rate. The null hypothesis will be rejected if 32 or more subjects with CRc are observed 
in the 49 subjects by the end of cycle 2. This design yields a 1-sided type I error rate of 0.025 


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and power of 80% when the true CRc rate is 70%. The sample size was calculated in East® 
Version 6.4. 
5 
ANALYSIS SETS 
Detailed criteria for analysis sets will be laid out in Classification Specifications and the 
allocation of subjects to analysis sets will be determined prior to database hard-lock. 
5.1 
Full Analysis Set (FAS) 
The full analysis set (FAS) will consist of all subjects who are enrolled in the study andtook 
at least 1 dose of study drug. The FAS will be used for efficacy analyses. Subjects will be 
analyzed based on the actual treatment received. 
5.2 
Safety Analysis Set (SAF) 
For the statistical summary of the safety data, the safety analysis set (SAF) will be used. The 
SAF consists of all subjects who took at least 1 dose of study drug (gilteritinib or 
atezolizumab) and will be used for safety analyses. The subjects will be analyzed based on 
the actual treatment received. The FAS and SAF are the same for this study. 
5.3 
Pharmacokinetics Analysis Set (PKAS) 
The pharmacokinetics analysis set (PKAS) consists of the administered population for which 
sufficient plasma concentration data is available to facilitate derivation of at least one 
pharmacokinetic parameter and for whom at least 1 plasma concentration datum is available 
and both the date and time of dosing on the day of pharmacokinetic sampling and the date 
and time of sampling are known. Additional subjects may be excluded from the PKAS at the 
discretion of the pharmacokineticist. Any formal definitions for exclusion of subjects or time-
points from the PKAS will be documented in the in the Classification Specifications and 
determined the Classification Meeting.  
5.4 
Biomarker Analysis Set (BMAS) 
The biomarker analysis set (BMAS) will include the subjects from the administered 
population for whom sufficient biomarker measurements were collected.  
6 
ANALYSIS VARIABLES 
6.1 
Efficacy Endpoints 
Efficacy analysis will be conducted on the FAS. 
6.1.1 
Primary Efficacy Endpoint 
Composite complete remission (CRc) rate is the primary efficacy endpoint. The definition 
will be defined in Section 6.1.4. 
6.1.2 
Secondary Efficacy Endpoint 
● 
Complete remission (CR) rate 
● 
CR with partial hematologic recovery (CRh) rate 


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● 
Duration of remission 
● 
Best response rate 
● 
Event-free survival (EFS) 
● 
Overall survival (OS) 
The definition of secondary efficacy endpoint will be defined in Section 6.1.3 and 
Section 6.1.4.  
6.1.3 
Response Definition 
Response to treatment will be defined per modified Cheson criteria [2003] as outlined below. 
● 
Complete Remission (CR)  
For subjects to be classified as being in CR, they must have bone marrow regenerating normal 
hematopoietic cells and achieve a morphologic leukemia-free state and must have an ANC  
> 1 x 109/L and platelet count ≥ 100 x 109/L, and normal marrow differential with < 5% 
blasts, and they must be red blood cell (RBC) and platelet transfusion independent (defined as 
1 week without RBC transfusion and 1 week without platelet transfusion prior to disease 
assessment. There should be no evidence of extramedullary leukemia. 
● 
Complete Remission with Incomplete Platelet Recovery (CRp) 
For subjects classified as being in CRp, they must achieve CR except for incomplete platelet 
recovery (< 100  109/L). 
● 
Complete Remission with Incomplete Hematological Recovery (CRi) 
For subjects to be classified as being in CRi, they must fulfill all the criteria for CR except for 
incomplete hematological recovery with residual neutropenia < 1  109/L with or without 
complete platelet recovery. RBC and platelet transfusion independence is not required. 
● 
Composite Complete Remission (CRc)  
For subjects to be classified as being in CRc at a post-baseline visit, they must either achieve 
CR, CRp or CRi at the visit.  
● 
Complete Remission with Partial Hematological Recovery (CRh) 
For subjects classified as being in CR, except if their ANC is > 0.5 Gi/L and their platelets are 
> 50 Gi/L.  
● 
Partial Remission (PR) 
For subjects to be classified as being in PR, they must have bone marrow regenerating normal 
hematopoietic cells with evidence of peripheral recovery with no (or only a few regenerating 
<=2%) circulating blasts and with a decrease of at least 50% in the percentage of blasts in the 
bone marrow aspirate/biopsy with the total marrow blasts between 5% and 25%. 


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● 
Relapse 
Relapse after CR, CRp or CRi is defined as a reappearance of leukemic blasts in the 
peripheral blood or ≥ 5% blasts in the bone marrow aspirate/biopsy not attributable to any 
other cause or reappearance or new appearance of extramedullary leukemia. 
Relapse after PR is similarly defined with reappearance of significant numbers of peripheral 
blasts (>2%) or an increase in the percentage of blasts in the bone marrow aspirate/biopsy to 
> 25% not attributable to any other cause or reappearance or new appearance of 
extramedullary leukemia. 
● 
Best Response 
Best response is defined as the best-measured response (CR, CRp, CRi or PR) post-treatment.  
Two best responses, up to the time of 2 cycles of treatment period and the EOT Visit will be 
defined. 
● 
Treatment Failure 
Treatment failure is defined as lack of CR, CRp or CRi, and is determined at the EOT.  
6.1.4 
Definition of Other Efficacy Variables 
● 
CR rate - Defined as the number of subjects with CR divided by the number of subjects 
in the analysis population. Subjects with unknown or missing response, or who provide 
no information on response at the end of study will be treated as non-responders and will 
be included in the denominator when calculating rates.  
● 
CRp rate, CRi rate, CRh rate, PR rate – Defined similarly as CR rate. 
● 
Best response rate – Defined as the number of subjects with CR or CRp or CRi or PR 
divided by the number of subjects in the analysis population (i.e., CR+ CRp + CRi + 
PR). Subjects with unknown or missing response, or who provide no information on 
response at the end of study will be treated as non-responders and will be included in the 
denominator when calculating rates. 
● 
Duration of remission – This includes duration of CRc, duration of CR, duration of 
CR/CRh, and duration of response (CRc + PR) by the EOT. 
o Duration of CRc – Defined as the time from the date of either first CRc until the date 
of documented relapse of any type for subjects who achieve CRc. Subjects who die 
without report of relapse are considered non-events and censored at their last 
relapse-free disease assessment date. Subjects who come off study for an allogeneic 
HSCT will be considered nonevents and censored at the time of HSCT. Other subjects 
who do not relapse on study are considered non-events and censored at the last 
relapse-free assessment date.  
o Duration of CR, and CR/CRh – Defined similarly as duration of CRc. 
o Duration of response – Defined as the time from the date of either first CRc or PR 
until the date of documented relapse of any type for subjects who achieve CRc or PR. 
Subjects who die without report of relapse are considered nonevents and censored at 
their last relapse-free disease assessment date. Subjects who come off study for an 


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allogeneic HSCT will be considered nonevents and censored at the time of HSCT. 
Other subjects who do not relapse on study are considered nonevents and censored at 
the last relapse-free assessment date.  
● 
Event-free survival (EFS) – The time from the date of first dose until the date of 
documented relapse from CR, CRp or CRi, treatment failure or death from any cause, 
whichever occurs first.  
o If a subject experiences relapse or death the subject is defined as having an EFS event 
related to either “relapse” or “death,” and the event date is the date of relapse or 
death. 
o If a subject who discontinues the treatment due to treatment failure during the first 
2 treatment cycles, and the subject has no previous response of CR, CRp or CRi, the 
subject is defined as having an EFS event and the event date is the date of first dose. 
o If a subject who discontinues the treatment due to treatment failure after the 2 
treatment cycles, and the subject has no previous response of CR, CRp or CRi, the 
subject is defined as having an EFS event and the event date is the date of end of the 
2nd treatment cycle evaluation date (i.e., cycle 3/day 1 bone marrow evaluation).  
o For a subject who is not known to have relapse or treatment failure or death, EFS is 
censored at the date of last relapse-free assessment date. Subject is not censored at 
HSCT. 
● 
Overall survival (OS) - The time from the date of first dose until the date of death from 
any cause. For a subject who is not known to have died by the end-of-study follow-up, 
OS is censored at the date of last contact. Date of last contact is defined as the death date 
or the latest of the following dates: treatment discontinuation date, last dosing 
administration date, last disease assessment date or the last follow-up date on which the 
subject was known to be alive. 
6.1.5 
Definition of Biomarker Variables 
● 
Minimal Residual Disease (MRD) 
MRD will be analyzed from bone marrow and blood samples by a Sponsor-designed central 
laboratory. Samples will be analyzed for FLT3 mutational status at screening/baseline and 
EOT, and may be analyzed for FLT3 mutational status at other time points. Samples may be 
analyzed for mutations in AML related genes and changes in proteins in relation to treatment 
effects at screening/baseline and EOT, and may be analyzed for mutations in AML related 
genes and changes in proteins in relation to treatment effects at other time points. 
FLT3/ITD mutation ratio will be measured in relation to total FLT3. For a subject with 
multiple ITD mutations, the overall FLT3/ITD mutation ratio will be calculated from the sum 
of all ITD mutations. Changes in FLT3/ITD mutation ratio from baseline will be compared. 
At each visit, the presence of MRD will be “Present” if log10-transformed overall FLT3/ITD 
mutation ratio is greater than -4; otherwise, the presence of MRD will be “Absent”. For 
subjects with multiple ITD mutations detected, the ratios will be summed. 


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Additional absolute cut points (e.g., log10-transformed overall FLT3/ITD to total FLT3 ratio 
of -2, -3, etc.) may be evaluated, as well as the log10 transformed change in FLT3/ITD to total 
FLT3 ratio at each visit compared to baseline. 
Further details of biomarker variables will be specified in a separate biomarker analysis plan.  
6.2 
Safety Variables 
Safety (Development of DLTs and AEs) are the primary endpoints of the study. 
The safety and tolerability of ASP2215 will be assessed using: 
● 
Development of DLT 
● 
Adverse events 
● 
Clinical laboratory results (chemistry, hematology, coagulation, urinalysis, serum 
pregnancy test and bone marrow)  
● 
Vital signs (systolic and diastolic blood pressure, pulse rate and body temperature) 
● 
12-lead electrocardiogram (ECG) 
● 
Eastern Cooperative Oncology Group (ECOG) performance status scores 
6.2.1 
Definition of DLT  
In Phase 1, a DLT is defined as any of the following events that occur during the observation 
period (cycle 1/day 1 through cycle 1/day 28) and that is considered to be possibly or 
probably related to study regimen. In Phase 2, the DLT observation period is the first 
treatment cycle (cycle 1/day 1 through cycle 1/day 28).  
● 
Confirmed Hy’s law case 
● 
Any Grade ≥ 3 non-hematologic or extramedullary toxicity with the following 
exceptions: 
o Anorexia or fatigue 
o Grade 3 nausea and/or vomiting if not requiring tube feeding or TPN, or diarrhea if 
not requiring or prolonging hospitalization that can be managed to grade ≤ 2 with 
standard antiemetic or antidiarrheal medications used at prescribed dose within 
7 days of onset 
o Grade 3 mucositis that resolved to grade ≤ 2 within 7 days of onset 
o Grade 3 fever with neutropenia, with or without infection* 
o Grade 3 infection* 
o Grade 3 infusion-related toxicity, if successfully managed and resolves within 72 
hours. 
*Toxicities are excluded only if the event is an expected direct complication of cytopenias 
due to the active underlying leukemia. 
Hematologic toxicity will not be considered as a DLT. However, prolonged 
myelosuppression defined as absolute neutrophil count (ANC) ≤ 0.5 x 109/ L for more than 
21 days from the onset of severe neutropenia in the absence of evidence of active leukemia in 
the marrow or blood will be considered as a DLT. 


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6.2.2 
Definition of MTD 
MTD is defined as the highest dose level where no more than one subject out of six eligible 
subjects has experienced DLT during the DLT observation period.  
6.2.3 
 Bayesian Posterior Probability for Safety Monitoring in Phase 2 
A Bayesian posterior probability will be used for safety monitoring during the whole 
treatment period. Subjects in phase 1 and phase 2 cohorts who complete the DLT observation 
period or experience DLTs will be included in the model-fitting process to provide the 
complete safety information. The estimated DLT rates based on the Bayesian beta-binomial 
model will be provided for safety monitoring in the dose expansion cohort. If the DLT rate 
for the expanded dose level is equal or higher than 25% with a posterior probability of 80%, 
then the enrollment to the expansion cohort will be paused and the safety will be reassessed 
by the DEC. If the reassessment warrants, enrollment to the expansion cohort may be 
continued at the current dose level or 1 lower dose level. Safety evaluation will be conducted 
separately for induction, consolidation and maintenance phases. 
6.2.4 
Adverse Events 
Any adverse event (AE) recorded on treatment including within 30 days from the last study 
treatment will be classified as treatment-emergent AE (TEAE) and will be summarized.  
A drug-related TEAE is defined as any TEAE with at least possible relationship (possibly or 
probably related) to study treatment as assessed by the investigator or with missing 
assessment of the causal relationship 
Serious adverse events (SAEs) include adverse events that are flagged as serious by the 
investigator or sponsor on eCRF, or upgraded by the Sponsor based on review of the 
Sponsor’s list of Always Serious term.  
Adverse events of special safety interest (AESI) are defined in the Safety Review Plan for 
ASP2215.  
6.2.5 
Other Variables 
● 
Clinical laboratory variables (hematology, chemistry, coagulation, urinalysis, serum 
pregnancy test and bone marrow) 
● 
Vital signs (systolic and diastolic blood pressure, pulse rate and body temperature) 
● 
12-lead electrocardiogram (ECG) 
● 
Eastern Cooperative Oncology Group (ECOG) performance status scores 
6.3 
Pharmacokinetics Variables 
Gilteritinib trough plasma concentrations (Ctrough) samples will be collected for all subjects 
predose (within 1 h of dose administration) on cycle 1/day 1, 8 and 15, and on days 1 and 15 
of each subsequent cycle up to 6 months.  


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6.4 
Pharmacodynamics Variables  
Blood samples for FLT3 and AXL will be collected on cycle 1/day 1 predose and postdose at 
2 h, between 4 to 6 h, and 24 h.Changes in the activation status of FLT3 and AXL, a receptor 
tyrosine kinase (RTK), may be assessed before and after treatment. 
6.5 
Other Variables 
● 
Body Mass Index (BMI)  
BMI = weight (kg) / [height (m)]2 
● 
Duration of exposure 
Duration of exposure to a study drug will be calculated in days, using the following 
formula: 
Date of last dose of study drug – Date of first dose + 1 – number of days without drug 
administration in between. 
When the start or stop date is missing, then the exposure will be treated as missing. 
● 
Number of dosing days is defined as the number of days with non-zero dosing 
● 
Cumulative Dose 
Cumulative dose (mg) = sum of all doses of study drug taken during the study.  
● 
Average daily dose is defined as (cumulative dose)/(number of dosing days) in “mg/day” 
● 
Dose intensity is defined as (cumulative dose/duration of exposure) in “mg/day” for 
Gilteritinib and (cumulative dose/duration of exposure*14 days for Atezolizumb.  
● 
Relative dose intensity is defined as (dose intensity/planned dose intensity)*100%.  
● 
Treatment compliance 
Treatment compliance of Gilteritinib is defined as:  
Total number of doses of gilteritinib actually taken by the number of study drug 
expected to be taken during the study multiplied by 100.  
Treatment compliance of Atezolizumab is defined as: 
Total amount of Atezolizumab actually consumed by amount of study drug should 
been taken multiplied by 100.  
● 
Duration of AML 
Duration of AML will be calculated in days using the following formula: 
(Enrollment date – date of initial diagnosis of AML) + 1 
● 
Previous and concomitant medication 
Previous medication is defined as medication with at least one dose taken before the date 
of the first dose of study drug.  
Concomitant medication is defined as medication with at least one dose taken between 
the date of first exposure (inclusive) and the date of last exposure (inclusive) of study 


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drug. The first exposure is from 28 days prior to cycle 1 day 1. The last exposure date is 
max (the last dosing date for study drug, initial dosing date of the last cycle + 30).  
7 
STATISTICAL METHODOLOGY 
7.1 
General Considerations 
For continuous variables, descriptive statistics will include the number of subjects (n), mean, 
standard deviation, median, minimum and maximum. When needed, the use of other 
percentiles (e.g., 10%, 25%, 75% and 90%) will be mentioned in the relevant section. In 
addition, for continuous PK parameters, the coefficient of variation will be calculated and for 
Cmax and AUC the geometric mean will also be calculated. Frequencies and percentages will 
be displayed for categorical data. Percentages by categories will be based on the number of 
subjects with no missing data, i.e. will add up to 100%. Kaplan-Meier survival curves will be 
displayed for time-to-event variables and median survival time will be estimated with 2-sided 
95% confidence interval (CI). 
Safety analysis and other summaries based on SAF will be presented by actual treatment 
received. Pharmacokinetic summaries based on will be presented by actual treatment 
received.  For subjects with dose change, actual treatment refers to the first dose received 
before dose change.  
All data processing, summarization, and analyses will be performed using SAS® Version 9.3 
or higher on Unix. Specifications for table, figure, and data listing formats can be found in 
the TLF specifications for this study. 
Baseline is defined as the last available measurement prior to the first dose of study drug. 
Unless otherwise specified, all summaries and analysis will be presented by phase.   
7.2 
Study Population 
7.2.1 
Disposition of Subjects 
The following subject data will be presented: 
● 
Number and percentage of subjects with informed consent, discontinued before 
allocation to treatment, allocated to treatment (overall only); 
● 
Number and percentage of subjects allocated to treatment in each analysis set; 
● 
Number and percentage of subjects completed and discontinued treatment, by primary 
reason for treatment discontinuation;  
● 
Number and percentage of subjects completed and discontinued the study, by primary 
reason for study discontinuation;  
● 
Number and percentage of subjects completed and discontinued the post-study period, by 
primary reason for post-study period discontinuation; 
7.2.2 
Protocol Deviations 
Protocol deviations as defined in the study protocol (Section 8.3 Major Protocol Deviations) 
will be assessed for all subjects allocated to treatment. The number and percentage of 


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subjects meeting any criteria will be summarized for each criterion and overall as well as by 
study site. Subjects deviating from a criterion more than once will be counted once for the 
corresponding criterion. Any subjects who have more than one protocol deviation will be 
counted once in the overall summary. A data listing will be provided by site and subject.  
The protocol deviation criteria will be uniquely identified in the summary table and listing. 
The unique identifiers will be as follows: 
PD1 - Entered into the study even though they did not satisfy entry criteria,  
PD2 - Developed withdrawal criteria during the study and was not withdrawn, 
PD3 - Received wrong treatment or incorrect dose, 
PD4 - Received excluded concomitant treatment.   
7.2.3 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics will be summarized for the SAF. Descriptive 
statistics will include number of subjects, mean, standard deviation, minimum, median and 
maximum for continuous endpoints and frequency and percentage for categorical endpoints. 
Number and percentage of subjects allocated to treatment in each country and site will be 
presented for the SAF.  
Descriptive statistics for age, weight, body mass index (BMI), height, and prior FLT3 
inhibitor (gilteritinib, quizartinib, crenolanib) at study entry will be presented. Frequency 
tabulations for sex, ethnicity, region, age group (< 65 years vs. >=65 years) and race will be 
presented. Demographics and baseline characteristics will be summarized for the SAF.  
Frequency tabulations for AML disease history including AML subtype as classified by 
World Health Organization (WHO) classification and French-American-British (FAB) 
classification, risk status, antecedent hematological disorder, central nervous system 
leukemia, FLT3 mutation status will be presented for the SAF.  
Medical history other than AML and conditions existing at baseline will be coded in 
MedDRA and summarized by System Organ Class (SOC) and Preferred Term (PT) as well as 
by PT alone for the SAF. Baseline conditions are defined as those ongoing at the time of 
informed consent or arise following the time of informed consent and before the first dose of 
study drug. For ongoing medical conditions, Common Terminology Criteria for Adverse 
Events (CTCAE) grade will be provided in listing. 
Results from lumbar puncture and MUGA scan, if performed, will be provided in listing. 
7.2.4 
Previous and Concomitant Medications 
Previous medications are coded with World Health Organization – Drug Dictionary 
(WHO-DD), and will be summarized by therapeutic subgroup (Anatomical Therapeutic 
Chemical [ATC] 2nd level) and chemical subgroup (ATC 4th level) and preferred WHO 
name for the SAF. 


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As with previous medication, concomitant medication will be summarized by therapeutic 
subgroup (ATC 2nd level), chemical subgroup (ATC 4th level) and preferred WHO name for 
the SAF. Subjects taking the same medication multiple times will be counted once per 
medication. A medication which can be classified into several chemical and/or therapeutic 
subgroups is presented in all chemical and therapeutic subgroups. 
Concomitant medication will also be summarized for SAF and presented in decreasing order 
of frequency based on the total number of subjects who took each medication.  
7.2.5 
Previous and Concomitant Non-Medication Therapy 
Frequency tabulations of subjects with previous non-medication therapy and reason for use 
will be presented for SAF. Number of previous non-medication therapy received per subject 
will be summarized using descriptive statistics. 
Concomitant non-medication therapy will also be summarized as previous non-medication 
therapy.  
7.3 
Study Drugs 
7.3.1 
Exposure 
The following information on drug exposure will be presented for the SAF: 
● 
Descriptive statistics for cumulative amount of the drug subject was exposed to and 
average daily dose; and 
● 
Number and percent of subject with dose increase, decrease or interruptions. 
Duration of exposure will be summarized in two ways. 
● 
Descriptive statistics will be presented. 
● 
Exposure time will be categorized according to the following categories: 
o less than 3 months 
o at least 3 months, less than 6 months 
o at least 6 months, less than 12 months  
o at least 12 months, less than 24 months 
o 24 months or more 
o Unknown. 
Counts and percentages of subjects in each of these categories will be summarized for the 
SAF. 
Listing of subjects with dose reduction and interruption will also be provided for SAF. 
Descriptive statistics for duration of exposure, cumulative amount of the drug subject was 
exposed to average daily dose, dose intensity and relative dose intensity will be presented for 
study drug.  
7.3.2 
Treatment Compliance 
Treatment compliance of gilteritinub is defined as the total number of doses of 
gilteritinub actually taken by the subject divided by the number of doses of study drug 


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expected to be taken during the study multiplied by 100. Treatment compliance of 
Atezolizumab is defined as total amount of Atezolizumab actually consumed by 
amount of study drug should been taken multiplied by 100. Descriptive statistics for 
study drug compliance will be presented by dose for the entire study period for the 
SAF. Overall compliance will be examined for subjects in the SAF whose total study 
drug count and first and last days of treatment are known.  
Percent overall compliance will be summarized in two ways for the SAF: 
● 
Descriptive statistics will be presented by cohort and dose level. 
● 
Percent compliance will be categorized according to the following categories: 
o less than 50% 
o at least 50%, less or equal to 80% 
o greater than 80% 
o Unknown. 
Overall compliance will be provided in listing.  
7.4 
Analysis of Efficacy  
Efficacy analysis will be conducted on the FAS.  
7.4.1 
Analysis of Primary Efficacy Endpoint 
The CRc rate will be evaluated according to Simon’s minimax two-stage design (Simon, 
1989). The null hypothesis that the true CRc rate is 50% will be tested against a one-sided 
alternative.  
In stage I, a total of 22 subjects will be evaluated. If there are 11 or fewer subjects with CRc 
from these 22 subjects by the end of cycle 2, the study will be stopped. Otherwise, 
27 additional subjects will be accrued for a total of 49 subjects evaluable for calculation of 
CRc rate. The null hypothesis will be rejected if 32 or more subjects with CRc are observed 
in the 49 subjects by the end of cycle 2. This design yields a one-sided type I error rate of 
0.025 and power of 80% when the true CRc rate is 70%.  
The CRc (CR + CRp + CRi) rate will be summarized and its 95% confidence interval will be 
constructed by Clopper-Pearson method.  
7.4.2 
Analysis of Secondary Efficacy Endpoint 
CR rate, best response rate, duration of remission, OS and EFS will be summarized using 
descriptive statistics. The CR rate, best response rate with the corresponding 95% confidence 
interval will be reported. The survival curve and the median time for time to event variables 
will be estimated using the Kaplan-Meier method and will be reported along with the 
corresponding 95% confidence interval. 
The SAS code used to produce median from Kaplan-Meier estimates and corresponding 95% 
CI will be similar to that shown below: 
proc lifetest data=adtte plots=(s) outsurv=surv; 
time survtime*censor(0); 


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run; 
7.4.3 
Analysis of Exploratory Efficacy Endpoint 
● 
Evaluate efficacy of gilteritinib given in combination with atezolizumab in terms of 
minimal residual disease (MRD). MRD analysis will be conducted on the BMAS. MRD 
will be assessed in relation to the following efficacy variables: 
o CR rate 
o CRc rate 
o EFS 
o Duration of remission 
o OS 
● 
Evaluate potential genomic, proteomic and/or other biomarkers that may correlate with 
treatment outcome 
● 
Evaluate pharmacodynamic biomarkers of treatment effect 
● 
Evaluate immune cell populations and AML blasts by immunophenotyping in relation to 
treatment effects 
7.5 
Analysis of Safety 
All analysis of safety will be performed on the SAF, unless specified otherwise.  
7.5.1 
Adverse Events 
Any adverse event (AE) recorded on treatment including within 30 days from the last study 
treatment will be classified as treatment-emergent AE (TEAE) and will be summarized.  
Summaries and listings of TEAEs and Serious TEAEs include SAEs upgraded by the 
Sponsor based on review of the Sponsor’s list of Always Serious terms if any upgrade was 
done.  
The number and percent of subjects experiencing one or more AE(s) will be summarized by 
SOC and PT using MedDRA and will be graded according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. The number 
and percentage of subjects with at least one grade 3 or higher AE will also be summarized by 
SOC and PT.  
An overview table will include the following details: 
● 
Number and percentage of subjects with TEAEs, 
● 
Number and percentage of subjects with causally drug related TEAEs, 
● 
Number and percentage of subjects with serious TEAEs and Astellas upgraded serious 
TEAE, 
● 
Number and percentage of subjects with serious drug related TEAEs and Astellas 
upgraded serious drug related TEAE, 
● 
Number and percentage of subjects with TEAEs leading to permanent discontinuation of 
study drug, 
● 
Number and percentage of subjects with drug related TEAEs leading to permanent 
discontinuation of study drug, 


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● 
Number of deaths, and 
● 
Number and percentage of subjects with grade 3 or higher TEAEs. 
The number and percentage of subjects with TEAEs, as classified by SOC and PT will be 
summarized by period, cohort and dose level. Summaries will be provided for: 
● 
TEAEs 
● 
Drug related TEAEs,  
● 
Serious TEAEs and Astellas upgraded serious TEAE,  
● 
Drug related serious TEAEs and drug related Astellas upgraded serious TEAE,  
● 
TEAEs leading to permanent discontinuation of study drug,  
● 
Drug related TEAEs leading to permanent discontinuation of study drug,  
● 
TEAEs excluding serious adverse events that equal to or exceed a threshold of 5% in any 
dose level, 
● 
Common TEAEs that equal to or exceed a threshold of 5% in any dose level, and 
● 
Grade 3 or higher TEAEs. 
The number and percentage of subjects with TEAEs, as classified by PT only, will be 
summarized.  
AE summary tables will include subject counts as opposed to AE counts. If a subject 
experiences more than one episode of a particular AE, the subject will be counted only once 
for that AE. If a subject has more than one AE that code to the same preferred term, the 
subject will be counted only once for that preferred term. Similarly, if a subject has more than 
one AE within a SOC, the subject will be counted only once in that SOC.   
The number and percentage of subjects with TEAEs, as classified by SOC and PT will also 
be summarized by NCI-CTCAE severity grade and by relationship to study drug. In the 
subject count, if a subject has multiple TEAEs with the same SOC or PT, but with differing 
severity grade or relationship, then the subject will be counted only once with the worst 
severity grade and highest degree of relationship, however, if any of the severity grade or 
relationship values are missing then the subject will be counted only once with missing 
severity grade or relationship. Drug related TEAEs will be presented in a similar way by 
severity grade only. 
The number and percentage of subjects with adverse events of special safety interest 
(AESIs)for Atezolizumab will be summarized by PT. See [Appendix 12.7 Adverse Events of 
Special Interest (AESI) for Atezolizumab] for further details. 
All summaries of AEs will include only TEAEs unless otherwise stated. All AEs, deaths, 
SAEs and withdrawals due to adverse events will be displayed in listings.  
7.5.2 
Clinical Laboratory Evaluation 
The baseline visit is the last measurement taken prior to initial study drug administration.   
Quantitative clinical laboratory variables, i.e., hematology, serum chemistry, coagulation and 
urinalysis will be summarized using mean, standard deviation, minimum, maximum and 
median at each visit. Additionally, change from baseline will be calculated as the 


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post-baseline value minus the baseline value and summarized in the same way. Each 
laboratory result will be classified as low (L), normal (N), or high (H) at each visit according 
to the laboratory supplied reference ranges.  
The number and percentage of subjects below and above reference range will be summarized 
at each visit.  
Frequency tabulations of qualitative clinical laboratory variables (urinalysis) will be 
presented at each visit.  
Clinically significant abnormalities in laboratory values will be presented.  
For hematology and chemistry two types of shift tables will be presented:  
● 
Shift tables of changes based on reference range defined category (low, normal, high) 
from baseline to each visit as well as worst finding during the treatment period, and 
● 
Summary shifts of changes based on reference range defined category from baseline to 
each visit as well as worst finding during the treatment period (shift from high or 
normal 
to low, shift from low or normal to high, categorized increase [shift from low to 
normal 
or from normal to high], categorized no change [value stays in the same reference 
range], 
categorized decrease [shift from high to normal or from normal to low]). 
Laboratory results will also be graded using NCI-CTCAE v5.0, where possible. Parameters 
that have criteria available for both low and high values, i.e., hypo- and hyper-, will be 
summarized for both criteria. The same subject can be counted for both values if the subject 
has different laboratory values meeting each criterion. NCI-CTCAE grade of laboratory 
evaluations will be summarized by number and percentage of subjects for each visit. Shift 
tables of NCI-CTCAE grade change from baseline to worst post-baseline grade will also be 
presented. 
Laboratory results based on central assessment will be used for summaries as described 
above. Laboratory results based on local assessment and bone marrow results will be listed 
only. The laboratory results may be displayed in figures. 
7.5.2.1 Liver Enzymes and Total Bilirubin  
The following potentially clinically significant criteria in liver function tests for Alkaline 
Phosphatase (ALP), Alanine Transaminase (ALT), total bilirubin, Aspartate Transaminase 
(AST) and their combination are defined. The subject’s highest value during the study will be 
used.   


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Parameter 
 
 
 
 
Criteria 
ALT 
  
 
 
 
 
> 3xULN 
 
  
 
 
 
 
> 5xULN 
 
 
 
 
 
 
> 8xULN 
 
AST 
 
 
 
 
 
> 3xULN 
 
  
 
 
 
 
> 5xULN 
> 8xULN 
 
ALT or AST   
 
 
 
> 3xULN 
Total Bilirubin  
 
 
 
> 2xULN 
ALP 
 
 
  
 
 
> 1.5xULN 
ALT and/or AST AND Total Bilirubin(*) 
(ALT and/or AST > 3xULN) and  
total bilirubin > 2xULN 
(*) Combination of values measured within same sample 
The number and percentage of subjects with potentially clinically significant values in liver 
enzymes and total bilirubin will be presented. 
7.5.3 
Vital Signs 
The baseline visit is the last measurement taken prior to initial study drug administration.   
Vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], pulse rate and 
body temperature) will be summarized using mean, standard deviation, minimum, maximum 
and median by visit. Additionally, change will be calculated as the post-baseline value minus 
the baseline value and summarized by visit.   
Tables for potentially clinically significant vital signs will be generated using baseline value 
and highest value.  
The following potentially clinically significant criteria are defined: 
Vital Sign Variable 
Criteria 
SBP 
≥180 mmHg AND ≥20 mmHg change from baseline 
DBP 
≥105 mmHg AND ≥15 mmHg change from baseline 
Pulse Rate 
≥120 bpm AND ≥15 bpm change from baseline 
7.5.4 
Electrocardiograms (ECGs) 
12-lead ECGs will be recorded in triplicate at the scheduled time points. Each ECG tracing 
will be taken at least 5 minutes apart and transmitted electronically to central reading. The 
mean of the triplicate ECGs from central read should be used for all final treatment decisions, 
AE reporting and in the summary for analysis at each visit.  
ECG variables including changes from baseline will be summarized using mean, standard 
deviation, minimum, maximum and median at each visit.  


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Number and percentage of subjects with normal and abnormal results as assessed by central 
read for the overall interpretation will be tabulated at each visit. A shift analysis table 
showing shift in overall ECG interpretation from baseline to each time point will be 
provided. The worst of the three overall ECG interpretations will be used as the time-specific 
overall ECG interpretation for a subject. 
The QT interval corrected for heart rate by Fridericia’s formula, QTcF, is defined as: QTc (F) 
= QT/(RR)0.33, where RR interval is inversely proportional to heart rate (approximately RR = 
60/heart rate). 
The QTcF interval will be summarized using frequency tables at each visit for values of 
clinical importance using the range criteria below. 
 
QTc Interval Criteria Value (msec) 
Cumulative Category 
Interval Category 
Normal 
Borderline 
Prolonged 
Clinically significant 
≤ 450 
> 450 
> 480 
> 500 
≤ 450 
> 450 to ≤ 480 
> 480 to ≤ 500 
> 500 
The QTcF interval will also be summarized by the frequencies of subjects with a change 
from baseline of clinical importance using the criteria identified below. These summaries will 
be provided at each visit.   
Variable 
Change from Baseline 
 
Cumulative Category 
Interval Category 
QTc Interval (msec) 
<0 
≥ 0 
> 30 
> 60 
<0 
≥ 0 to ≤ 30 
> 30 to ≤ 60 
> 60 
Number and percentage of subjects with 12 lead ECG abnormalities at each visit as well as 
number and percentage of subjects whose 12 lead ECG reading shift from baseline to each 
visit will be tabulated.  
7.5.5 
Pregnancies 
A detailed listing of all pregnancies will be provided. 
7.5.6 
Eastern Cooperative Oncology Group (ECOG) Performance Scores 
Number of percent of subjects for each category of the ECOG performance status at each 
assessment time will be provided. Negative change scores indicate an improvement and 
positive scores indicate a decline in performance. 
ECOG performance scores will also be summarized using shift table from baseline to post-
baseline assessments. 


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7.6 
Analysis of PK 
PK analysis will be conducted on the PKAS.  
Descriptive statistics (e.g., N, mean, standard deviation, minimum, median, maximum, 
coefficient of variation [CV], geometric mean, and geometric CV) will be provided for 
trough plasma concentrations (Ctrough) of gilteritinib, if appropriate, by visit and time point.  
7.7 
Analysis of Biomarkers 
The activation status of FLT3 and AXL will be summarized by dose and change from 
baseline at each time point. 
Immune cell immunophenotyping and blast cell immunophenotyping biomarkers will be 
summarized by dose and change from baseline at each time point by both absolute number 
and percentage.  
7.8 
Subgroups of Interest  
Not applicable for this study. 
7.9 
Other Analyses 
Not applicable for this study.  
7.10 
Interim Analysis (and Early Discontinuation of the Clinical Study) 
Not applicable for this study. 
7.11 
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information 
7.11.1 Missing Data  
Every effort will be made to resolve incomplete dates for death and disease relapse. If a 
partial date cannot be resolved, the most conservative imputation methods will be used to 
complete the missing information.  
For OS and EFS, missing or incomplete death date will be imputed as the earliest feasible 
date on or after the date of last contact as the examples shown in the table below. The date of 
last contact will be obtained as described in Section 6.1.2. 
Incomplete Date of Death 
(YYYY MMM DD) 
Date of Last Contact  
(YYYY MMM DD)  
Imputed Date of Death  
(YYYY MMM DD) 
2005 APR ?? 
2005 MAR 31 
2005 APR 01 
2005 ??? 13 
2005 MAR 31 
2005 APR 13 
2005 ??? ?? 
2005 MAR 31 
2005 MAR 31 
???? APR ?? 
2005 MAR 31 
2005 APR 01 
???? APR 13 
2005 MAR 31 
2005 APR 13 
???? ??? ?? 
2005 MAR 31 
2005 MAR 31 
 


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Partial relapse dates will be imputed to the first day of the month of the missing parameter 
but not earlier than the last disease assessment date. A month and year must be present or the 
date will remain missing. 
Missing or partial start and stop dates of adverse events and concomitant medication will be 
imputed using the following algorithm: 
● 
Imputation rules for partial or missing stop dates: 
o If the month and year are present, then impute as the last day of that month. 
o If only the year is present, impute as December 31 of that year. 
o If the stop date is entirely missing, assume the event or medication is ongoing. 
● 
Imputation rules for partial or missing start dates: 
 
The imputed dates will be used to determine whether an AE is/is not treatment emergent. 
Listings of AEs and concomitant medications will present the actual partial dates; imputed 
dates will not be shown. 
7.11.2 Outliers 
All values will be included in the analyses.  
7.11.3 Visit Windows 
Visit windows are allowed for certain visits per the schedule of assessments. Subject data 
will not be excluded from analyses due to the subject’s failure to comply with the visit 
schedule. The visit windows for assessments are described in the following table. 


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CRF visit 
Visit Window 
Screening 
D-14 to D-1 
Cycle 1 Day 1 
No Window 
Cycle 1 Day 8 
C1D8± 1 
Cycle 1 Day 15 
No Window 
Cycle 2 Day 1 
No Window 
Cycle 2 Day 15 
No Window 
Cycle X Day 1 
No Window 
Cycle X Day 15 
No Window 
End of Treatment Visit 
Last dose date + 7 
 
Scheduled visit will be calculated using number of days relative to the first dose based on 
28-day cycles. In the case of multiple observations at a specific visit, the observation which is 
closest to the target date will be used. If the observations have the same distance to the target 
visit, the latest one will be used.   
7.11.4 Covid-19 Impact Assessment 
Assessments affected by the Covid-19 pandemic will be listed for visit-based assessments 
and for non-visit-based assessments.  
For visit-based assessments affected by Covid-19, the listing shows if an assessment was not 
performed due to Covid-19, if it was out of window, if the assessment was performed at an 
alternative location or if it was a virtual assessment. Other information and comments 
reported on assessments affected by Covid-19 are also included. 
For non-visit-based assessments affected by Covid-19, subjects who experience any of the 
following items: treatment discontinuation due to Covid-19, Covid-19 medical history, 
Covid-19 adverse event, hospitalization due to Covid-19, dose changing due to Covid-19, or 
Covid-19 death, will be flagged in a listing.   
Any events like discontinuation of treatment, medical history, adverse events, hospitalization, 
dose changing, or death, which are related to Covid-19, will be flagged in the corresponding 
listing. 
 


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8 
DOCUMENT REVISION HISTORY  
Version 
Date 
Changes 
Comment/rationale for change 
1.0 
26-Nov-2018 
NA 
Initial SAP draft 
1.1  
21-June-2019 
NA 
SAP updates based on Protocol 
Amendment 1  
1.2 
3-June-2020 
Remove BSA, Add 
Prior FLT3 Inhibitor 
 
1.3 
20-Aug-2020 
Remove MRD analysis 
of biomarker 
Revise treatment 
compliance for 
Atezolizumab  
 
 
9 
REFERENCES 
Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH, et al. Revised 
recommendations of the International Working Group for Diagnosis, Standardization of 
Response Criteria, Treatment Outcomes and Reporting Standards for Therapeutic Trials in 
Acute Myeloid Leukemia. J Clin Oncol. 2003;21(24):4642-9. 
ICH Harmonized Tripartite Guideline E 3. Structure and Content of Clinical Study Reports, 
November 1995. (www.ich.org; Guidelines; "Efficacy" Topics) 
ICH Harmonized Tripartite Guideline E 9. Statistical Principles for Clinical Trials, February 1998. 
(www.ich.org; Guidelines; "Efficacy" Topics) 
Simon R. Optimal two-stage designs for phase II clinical trials. Biometric Research Branch, National 
Cancer Institute, Bethesda, Maryland. 1989:1-10 


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10 
APPENDICES 
10.1 
Appendix 1: Signatures 
 
 
 
 
 
 
 
 
Prepared by: 
 
Date: 
 
 
, MS 
 
Global Data Science 
Astellas Pharma Global Development USA 
 
Date (DD Mmm YYYY) 
 
 
 
 
 
 
 
 
Approved by: 
 
Date: 
 
 
 MD 
,  
 
Medical Science-Hematology 
Astellas Pharma Global Development USA 
 
Date (DD Mmm YYYY) 
 
 
 
 
 
 
 
 
 
 
Date: 
 
 
, PHD 
 
Global Data Science 
Astellas Pharma Global Development USA 
 
Date (DD Mmm YYYY) 
 
 
 
 
 
 
 
 
 
 
Date: 
 
 
 
  
 
Date (DD Mmm YYYY) 
 
Clinical Project management 
Astellas Pharma Global Development USA 
 
 
 
 
 
 
 
 
 
Date: 
 
 
 PHD 
 
 
Clinical Pharmacology and Exploratory Development 
 
Date (DD Mmm YYYY) 
 
Astellas Pharma Global Development USA 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 PHD 
 
Clinical Pharmacology and Exploratory Development 
 
Date (DD Mmm YYYY) 
 
Astellas Pharma Global Development USA 
 
 
 
 
 
 
 
 
 
 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD