Conditions: Acute Myeloid Leukemia
Keywords: Acute Myeloid Leukemia Gilteritinib ASP2215
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 265
Healthy volunteers: no

Brief summary:
The objective of this study was to assess the safety and tolerability, including the maximum tolerated dose, of gilteritinib in participants with relapsed or treatment-refractory acute myeloid leukemia (AML). This study also determined the pharmacokinetic (PK) parameters of gilteritinib.

Detailed description:

Arms:
arm 1: Participants received a single dose of 20 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study. arm 2: Participants received a single dose of 40 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study. arm 3: Participants received a single dose of 80 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study. arm 4: Participants received a single dose of 120 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study. arm 5: Participants received a single dose of 200 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study. arm 6: Participants received a single dose of 300 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study. arm 7: Participants received a single dose of 450 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study. arm 8: Participants received 20 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. Starting on day 16 of cycle 1, participants also received 200 mg voriconazole orally every 12 hours through day 1 of cycle 2. arm 9: Participants received 40 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. arm 10: Participants received 80 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. arm 11: Participants received 120 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. arm 12: Participants received 200 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, certain participants also received 500 mg cephalexin as a single oral dose. arm 13: Participants received 300 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, participants also received 2 mg midazolam as a single oral dose.

Interventions: intervention 1: Gilteritinib intervention 2: Voriconazole intervention 3: Midazolam intervention 4: Cephalexin
Intervention descriptions: intervention 1: Participants received gilteritinib oral tablets (10 mg, 40 mg or 100 mg, depending on the dose) once daily without food allowed for at least 2 hours before and 1 hour after dosing starting from day -2 and day of cycle 1, for continuous 28-day cycles. intervention 2: Participants received 200 mg voriconazole tablets daily every 12 hours starting from day 16 of cycle 1 through day 1 of cycle 2. intervention 3: Participants received a single oral dose of 2 mg of midazolam syrup on day -1 and day 15 of cycle 1. intervention 4: Participants received a single oral dose of 500 mg cephalexin tablet or capsule on day -1 and day 15 of cycle 1.

Protocol document:
Prot_000.pdf: 
A Phase 1/2 Open-Label, Dose Escalation Study Investigating the 
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics 
of ASP2215 in Patients with Relapsed or Refractory Acute 
Myeloid Leukemia
ISN/Protocol 2215-CL-0101
ClinicalTrials.gov Identifier: NCT02014558
Date of Protocol Version 12.0: 02 June 2017
Sponsor: Astellas Pharma Global Development (APGD), Inc.
1 Astellas Way
Northbrook, IL 60062


Sponsor: APGD
ISN/Protocol 2215-CL-0101
EudraCT number 2014-002217-31
- CONFIDENTIAL -
02 Jun 2017
Astellas
Page 1 of 133
Version 12.0, Incorporating Substantial Amendment 11
A Phase 1/2 Open-Label, Dose Escalation Study 
Investigating the Safety, Tolerability, Pharmacokinetics, 
and Pharmacodynamics of ASP2215 in Patients with Relapsed 
or Refractory Acute Myeloid Leukemia
Protocol for Phase 1/2 Study of ASP2215
ISN/Protocol 2215-CL-0101
Version 12.0
Incorporating Substantial Amendment 11 [See Attachment 1]
02 June 2017
IND 117,548
EudraCT 2014-002217-31
Sponsor: 
Astellas Pharma Global Development, Inc. (APGD)
1 Astellas Way
Northbrook, IL 60062
Protocol History:
Version 11.0 Incorporating Substantial Amendment 10 [18Aug2015]
Version 10.0 Incorporating Substantial Amendment 9 [26May2015]
Version 9.0 Incorporating Substantial Amendment 8 (FR and DE) [16Apr2015]
Version 8.0 Incorporating Substantial Amendment 7 [15Dec2014]
Version 7.0 Incorporating Substantial Amendment 6 [23Sep2014]
Version 6.0 Incorporating Substantial Amendment 5 [07Jul2014]
Version 5.0 Incorporating Substantial Amendment 4 [19May2014]
Version 4.0 Incorporating Substantial Amendment 3 [28Jan2014]
Version 3.0 Incorporating Substantial Amendment 2 [21Jan2014]
Version 2.0 Incorporating Substantial Amendment 1 [16Jul2013]
Version 1.0 Original [23Apr2013]
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.


Sponsor: APGD
ISN/Protocol 2215-CL-0101
EudraCT number 2014-002217-31
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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 CHART AND SCHEDULE OF ASSESSMENTS·································27
1
INTRODUCTION·················································································39
1.1
Background ················································································39
1.2
Non-clinical and Clinical Data ··························································40
1.2.1
Non-clinical Studies·····································································40
1.2.1.1
Nonclinical Pharmacology························································40
1.2.1.2
Nonclinical Pharmacokinetics····················································44
1.2.1.3
Nonclinical Toxicology···························································45
1.3
Summary of Key Safety Information for Study Drugs ·······························46
1.3.1
Pre-Clinical Data ········································································46
1.3.2
ASP2215 Clinical Data ·································································47
1.4
Risk-Benefit Assessment·································································48
2
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS ··································49
2.1
Study Objectives ··········································································49
2.1.1
Primary Objectives······································································49
2.1.2
Secondary Objectives ···································································49
2.2
Study Design and Dose Rationale·······················································49
2.2.1
Study Design·············································································49
2.2.2
Dose Rationale···········································································55
2.3
Endpoints ··················································································55
2.3.1
Primary Endpoints·······································································55
2.3.1.1
Definition of DLT ·································································55
2.3.2
Secondary Endpoints····································································55
2.3.3
Exploratory Endpoints ··································································56
3
STUDY POPULATION··········································································56
3.1
Selection of Study Population ···························································56
3.2
Inclusion Criteria··········································································56
3.3
Exclusion Criteria·········································································58


Sponsor: APGD
ISN/Protocol 2215-CL-0101
EudraCT number 2014-002217-31
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4
TREATMENT(S)··················································································59
4.1
Identification of Investigational Product(s)············································59
4.1.1
Test Drug(s)··············································································59
4.2
Packaging and Labeling··································································60
4.3
Study Drug Handling ·····································································60
4.4
Blinding ····················································································61
4.5
Assignment and Allocation ······························································61
5
TREATMENTS AND EVALUATION························································61
5.1
Dosing and Administration of Study Drug(s) and Other Medication(s)············61
5.1.1
Dose/Dose Regimen and Administration Period ····································61
5.1.1.1
Dose Escalation Phase (Cohort 1) ···············································62
5.1.1.2
Expansion Phase (Cohort 2)······················································62
5.1.2
Increase or Reduction in Dose of the Study Drug(s)································64
5.1.3
Previous and Concomitant Treatment (Medication and Non-Medication 
Therapy) ··················································································66
5.1.4
Resumption of treatment after Hematopoietic Stem Cell Transplantation 
(HSCT) ···················································································67
5.1.5
Treatment Compliance··································································68
5.2
Demographics and Baseline Characteristics ···········································68
5.2.1
Demographics············································································68
5.2.2
Medical History··········································································68
5.2.3
Diagnosis of the Target Disease, Severity, and Duration of Disease··············68
5.2.4
Performance Status······································································68
5.3
Efficacy | Pharmacodynamics | Pharmacokinetics | Immunogenicity 
Assessment·················································································69
5.3.1
Response Definitions ···································································69
5.3.1.1
Composite Complete Remission Rate (CRc)···································69
5.3.1.2
Complete Remission (CR)························································69
5.3.1.3
Complete Remission with Incomplete Platelet Recovery (CRp)·············69
5.3.1.4
Complete Remission with Incomplete Hematological Recovery (CRi)·····69
5.3.1.5
Partial Remission (PR)····························································69
5.3.1.6
Relapse··············································································70
5.3.1.7
Best Response······································································70
5.4
Safety Assessment ········································································70


Sponsor: APGD
ISN/Protocol 2215-CL-0101
EudraCT number 2014-002217-31
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02 Jun 2017
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5.4.1
Vital Signs················································································70
5.4.2
Adverse Events ··········································································70
5.4.2.1
Adverse Events during HSCT····················································70
5.4.2.2
Adverse Events of Possible Hepatic Origin ····································70
5.4.3
Laboratory Assessments································································71
5.4.4
Physical Examination···································································73
5.4.5
Electrocardiogram (ECG) ······························································74
5.4.6
Ophthalmologic Exam ··································································74
5.5
Adverse Events and Other Safety Aspects·············································75
5.5.1
Definition of Adverse Events (AEs) ··················································75
5.5.2
Definition of Serious Adverse Events (SAEs) ·······································75
5.5.3
Criteria for Causal Relationship to the Study Drug ·································76
5.5.4
Criteria for Defining the Severity of an Adverse Event ····························77
5.5.5
Reporting of Serious Adverse Events (SAEs) ·······································77
5.5.6
Follow-up of Adverse Events··························································78
5.5.7
Monitoring of Common Serious Adverse Events ···································78
5.5.8
Procedure in Case of Pregnancy·······················································79
5.5.9
Emergency Procedures and Management of Overdose ·····························79
5.5.10
Supply of New Information Affecting the Conduct of the Study··················79
5.6
Test Drug Concentration ·································································80
5.6.1
Pharmacokinetics········································································80
5.7
Other Measurements, Assessments or Methods·······································81
5.7.1
Pharmacodynamics······································································81
5.7.2
Samples for Exploratory Analyses ····················································82
5.7.3
Sample for the Pharmacogenomics Sub-study (Optional)··························82
5.8
Total Amount of Blood···································································83
6
DISCONTINUATION············································································83
6.1
Discontinuation of Individual Subject(s)···············································83
6.2
Discontinuation of the Site·······························································84
6.3
Discontinuation of the Study ····························································84
7
STATISTICAL METHODOLOGY ···························································85
7.1
Sample Size················································································85
7.2
Analysis Set················································································85
7.2.1
Full Analysis Set (FAS) ································································85


Sponsor: APGD
ISN/Protocol 2215-CL-0101
EudraCT number 2014-002217-31
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02 Jun 2017
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7.2.2
Per Protocol Set (PPS) ··································································85
7.2.3
Safety Analysis Set (SAF)······························································86
7.2.4
Pharmacokinetic Analysis Set (PKAS) ···············································86
7.2.5
Pharmacodynamic Analysis Set (PDAS) ·············································86
7.3
Demographics and Other Baseline Characteristics····································86
7.3.1
Demographics············································································86
7.3.2
Medical History··········································································86
7.3.3
Disease History ··········································································86
7.3.4
Previous and Concomitant Medications ··············································86
7.3.5
Subject Disposition······································································87
7.3.6
Treatment Compliance··································································87
7.3.7
Extent of Exposure ······································································87
7.4
Analysis of Efficacy ······································································87
7.4.1
Analysis of Efficacy Variables ························································87
7.5
Analysis of Safety·········································································87
7.5.1
Bayesian Logistic Regression Modeling in Dose Escalation and Expansion 
Phases·····················································································88
7.5.2
Subject Assignment in Cohort 2 Dose Expansion Cohort··························88
7.5.3
Determination of DLT and MTD······················································89
7.5.4
Adverse Events ··········································································89
7.5.5
Laboratory Assessments································································90
7.5.6
Vital Signs················································································90
7.5.7
Physical Examination···································································90
7.5.8
ECGs······················································································90
7.5.9
Ophthalmologic Assessment···························································90
7.6
Analysis of Pharmacokinetics ···························································90
7.6.1
Estimation of Pharmacokinetic Parameters ··········································90
7.6.2
Concentration-Response Relationship Analysis ·····································91
7.7
Analysis of Pharmacodynamics ·························································91
7.7.1
·················································91
7.7.2
····················································································91
7.8
Protocol Deviations and Other Analyses···············································92
7.9
Interim Analysis (and Early Discontinuation of the Clinical Study)················92
7.10
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·····92
7.11
Analysis of Re-Enrolled Subjects·······················································92


Sponsor: APGD
ISN/Protocol 2215-CL-0101
EudraCT number 2014-002217-31
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02 Jun 2017
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8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS ····················92
8.1
Procedure for Clinical Study Quality Control ·········································92
8.1.1
Data Collection ··········································································92
8.1.2
Specification of Source Documents···················································93
8.1.3
Clinical Study Monitoring······························································93
8.1.4
Direct Access to Source Data/Documents············································93
8.1.5
Data Management ·······································································94
8.1.6
Protocol Deviations ·····································································94
8.1.7
End of Trial in All Participating Countries···········································95
8.2
Ethics and Protection of Subject Confidentiality······································95
8.2.1
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) / 
Competent Authorities (CA) ···························································95
8.2.2
Ethical Conduct of the Study···························································95
8.2.3
Informed Consent of Subjects ·························································96
8.2.3.1
Subject Information and Consent················································96
8.2.3.2
Supply of New and Important Information Influencing the Subject’s 
Consent and Revision of the Written Information ·····························96
8.2.4
Subject Confidentiality ·································································96
8.3
Administrative Matters···································································97
8.3.1
Arrangement for Use of Information and Publication of the Clinical Study ·····97
8.3.2
Documents and Records Related to the Clinical Study ·····························97
8.3.3
Protocol Amendment and/or Revision················································97
8.3.4
Signatory Investigator for Clinical Study Report····································98
9
QUALITY ASSURANCE········································································98
10
STUDY ORGANIZATION······································································98
10.1
Independent Data-Monitoring Committee (IDMC) | Data and Safety 
Monitoring Board (DSMB) | Monitoring Committee | Other Evaluation 
Committee(s) ··············································································98
10.2
Other Study Organization-  Dose Escalation Committee ····························99
11
REFERENCES ·················································································· 100
12
APPENDICES ··················································································· 101
12.1
List of Excluded Concomitant Medications ········································· 101
12.2
Liver Safety Monitoring and Assessment············································ 106
12.3
Common Serious Adverse Events ···················································· 109


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12.4
Retrospective PGx Sub-Study ························································· 111
13
ATTACHMENT 1:  SUBSTANTIAL AMENDMENT 11······························· 113
14
SPONSOR’S SIGNATURES·································································· 133
List of In-text Tables
Table 2A
Schedule of Assessments for Dose Escalation Phase (Cohort 1)························28
Table 2B
Schedule of Assessments for Expansion Phase with CYP3A4 Inhibitor 
Voriconazole Study (Cohort 2, Starting Dose Level)·····································30
Table 2C
Schedule of Assessments for Expansion Cohort without DDI Studies (Cohort 2, 
Intermediate Dose Levels) ···································································32
Table 2D
Schedule of Assessments for Expansion Phase with CYP3A4 Induction Study 
(Cohort 2, MTD Level)·······································································34
Table 2E
Schedule of Assessments for Expansion Phase with MATE1 Substrate Study 
(Cohort 2, MATE1 Sub-study) ······························································36
Table 2F
Post-Treatment Schedule of Assessments··················································38
Table 1
Inhibitory Effect of ASP2215 on Various Tyrosine Kinases ····························40
Table 2
Inhibition Effect of ASP2215 on Radioligand Binding to Various Receptors, Ion 
Channels and Transporters···································································41
Table 3
Inhibition Effect of ASP2215 on Various Enzymes ······································41
Table 4
Effect of Once-daily Oral Administration of ASP2215 on Tumor Growth and 
Regression in an MV4-11 Xenograft Model···············································43
Table 5
Dose Levels····················································································54
Table 6
Guidelines for ASP2215 Dose Reduction Event ··········································65
Table 7
Guidelines for ASP2215 Dose Escalation Event ··········································66
Table 8
COG Performance Status·····································································68
List of In-text Figures
Figure 1
Study Flow Chart··············································································27
Figure 2
Inhibitory Effect of ASP2215 on FLT3 Phosphorylation in MV4-11 Cells ···········42
Figure 3
Antitumor Effect of ASP2215 in an MV4-11 Xenograft Model ························43
Figure 4
Optimal Dose Escalation and Expansion···················································53
Figure 5
Optimal Efficacy Expansion of Cohort 2···················································54


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I.
SIGNATURES
1.
SPONSOR’S SIGNATURES
Required signatures (e.g., Protocol authors, Sponsor’s reviewers and contributors, etc.) are 
located in Section 14, Sponsor’s Signatures; e-signatures (when applicable) are located at the 
end of this document.  


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2.
INVESTIGATOR’S SIGNATURE
A Phase 1/2 Open-Label, Dose Escalation Study Investigating the Safety, 
Tolerability, Pharmacokinetics, and Pharmacodynamics of ASP2215 in Patients 
with Relapsed or Refractory Acute Myeloid Leukemia
ISN/Protocol 2215-CL-0101
Version 12.0 / Incorporating Substantial Amendment 11
02 June 2017
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 ICH GCP guidelines and applicable 
local regulations. I will also ensure that sub-investigator(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:
Printed Name:
Date (DD Mmm YYYY)
Address:




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III.
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS
List of Abbreviations
Abbreviations
Description of abbreviations
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase (SGPT)
AML
Acute myeloid leukemia
ANC
Absolute neutrophil count
APGD
Astellas Pharma Global Development, Inc.
APL
Acute promyelocytic leukemia
aPTT
Activated partial thromboplastin time
ASP2215
Compound code for study drug
AST
Aspartate aminotransferase (SGOT)
AUC
Area under the plasma concentration time curve
BCL-ABL
Chronic myelogenous leukemia in blast crisis
BCVA
Best-corrected visual acuity
Ca
Calcium
Cmax
Maximum concentration
CFR
Code of Federal Regulations
CI
Confidence interval
CRF
Case report form
CR
Complete remission
CRc
Composite complete remission
CRi
Complete remission with incomplete hematologic recovery
CRO
Contract research organization
CRp
Complete remission with incomplete platelet recovery
CSR
Clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
Minimum concentration
CV
Coefficient of variation
CYP3A4
Cytochrome P450-isozyme3A4
DDI
Drug-drug interaction
DFS
Disease-free survival
DIC
Disseminated intravascular coagulation
DL
Dose level
DLI
Donor lymphocytes infusion
dL
Deciliter
DILI
Drug-induced liver injury
DNA
Deoxyribonucleic acid
DLT
Dose-limiting toxicity
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form


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Abbreviations
Description of abbreviations
EDTA
Ethylenediaminetetraacetic acid
eGFR
Estimated glomerular filtration rate
FAS
Full analysis set
FDA
Food and Drug Administration
FLT3
FMS-like tyrosine kinase
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
GVHD
Graft-versus-host disease
hCG
Human chorionic gonadotropin
hERG
Human ether-a-go-go-related gene
HIPAA
Health Insurance Portability and Accountability Act
HSCT
Hematopoietic stem cell transplant
HNSTD
Highest non-severely toxic dose
IB
Investigator Brochure
ICF
Informed consent form
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IND
Investigational new drug
INR
International normalization ratio
IRB
Institutional Review Board
IRT
Interactive response technology
ISN
International study number
ITD
Internal tandem duplication
IUD
Intrauterine device
IU
International unit
IUS
Intrauterine system
K
Potassium
kg
Kilogram
L
Liter
LA-CRF
Liver abnormality case report form
LFT
Liver function test
LLN
Lower limit of normal
LVEF
Left ventricular ejection fraction
MAO-A
Monoamine oxidase A
MAO-B
Monoamine oxidase B
MATE1
Multidrug and toxin extrusion 1
MDRD
Modification of Diet in Renal Disease
MDS
Myelodysplastic syndrome
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
min
Minute
mL
Milliliter
mmHG
Millimeters mercury


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Abbreviations
Description of abbreviations
ms
Millisecond
MTD
Maximum tolerated dose
MUGA
Multigated acquisition scan
NCE
New chemical entity
NCI
National Cancer Institute
NDA
New Drug Application
NOAEL
No observed adverse effect level
NPM1
Nucleophosmin-1 gene
NYHA
New York Heart Association
OCT
Optical coherence tomography
OS
Overall survival
PAF
Platelet activating factor
PD
Pharmacodynamic
PDAS
Pharmacodynamic analysis set
PGx
Pharmacogenomics
PIA
Plasma inhibitory assay
PK
Pharmacokinetic
PKAS
Pharmacokinetic analysis set
PPS
Per protocol set
PR
Partial remission
PTT
Partial thromboplastin time
QTc
QT interval corrected
QTcF
Fridericia-corrected QT interval
RBC
Red blood cell
SAE
Serious adverse event
SAF
Safety analysis set
SAP
Statistical analysis plan
SOC
System organ class
SOP
Standard operating procedure
STD10
Severely toxic dose in 10% of animals
TBL
Total bilirubin
TK
Tyrosine kinase
tmax
Time to attain Cmax
ULN
Upper limit of normal
VA
Visual acuity
WBC
White blood cell
WHO
World Health Organization
WOCBP
Woman of childbearing potential


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Definition of Key Study Terms
Terms
Definition of terms
Baseline
Observed values/findings which are regarded as the starting point for 
comparison. 
Enroll
To register or enter into a clinical trial. NOTE: Once a subject has been 
enrolled, the clinical trial protocol applies to the subject. 
Intervention
The drug, 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, pharmacoeconomics). 
Investigational 
period
Period of time where major interests of protocol objectives are observed, and 
where the test drug or comparative drug (sometimes without randomization) 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 period
Period of time before entering the investigational period, usually from the time 
of starting a subject signing consent until just before the test drug or 
comparative drug (sometimes without randomization) is given to a subject. 
Randomization
The process of assigning trial subjects to treatment or control groups using an 
element of chance to determine assignments in order to reduce bias.
Screening
A process of active consideration of potential subjects for enrollment in a trial.
Screen failure
Potential subject who did not meet one or more criteria required for 
participation in a trial.
Study period
Period of time from the first site initiation date to the last site completing the 
study.
Variable
Any quantity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values.


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IV.
SYNOPSIS
Date and Version # of Protocol Synopsis:
02 June 2017 / Version 12.0
Sponsor:  
Astellas Pharma Global Development Inc (APGD)
Protocol Number:  
2215-CL-0101
Name of Study Drug: 
ASP2215
Phase of Development:  
Phase 1/2
Title of Study:
A Phase 1/2 Open-Label, Dose Escalation Study Investigating the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of ASP2215 in Patients with Relapsed or Refractory Acute 
Myeloid Leukemia (AML)
Planned Study Period: 
From 4Q2013 to 3Q2017
Study Objective(s): 
The primary objectives of this study are to:
Assess the safety and tolerability, including determination of the maximum tolerated dose (MTD), 
of oral ASP2215 in subjects with relapsed or treatment-refractory acute myeloid leukemia (AML).
Determine the pharmacokinetic (PK) parameters of ASP2215.
The secondary objectives of this study are to:
Investigate the anti-leukemic activity of various doses of ASP2215 in subjects with AML. 
Evaluate the effect of strong or moderate cytochrome P450- isozyme3A4 (CYP3A4) inhibitors on 
the PK of ASP2215.
Evaluate the potential induction of CYP3A4 by ASP2215 by assessment of midazolam PK.
Evaluate the effect of ASP2215 on MATE1 substrates by assessment of cephalexin PK.
Planned Total Number of Study Centers and Location(s):  
Approximately 35 centers
United States, Italy, France and Germany
Study Population:  
Patients with AML who relapsed after or are refractory to induction or salvage treatment.
Number of Subjects to be Enrolled/Randomized:  
Up to 40 subjects in dose escalation cohort and up to 250 subjects in dose expansion cohort.
Study Design Overview:  
This study is an open-label, dose escalation, first-in-human study in subjects with relapsed or 
refractory AML, with concomitant expansion cohort for multiple doses. One cycle is   defined as 
28 days and the subject will receive oral ASP2215 daily. The study treatment will continue until one 
of the discontinuation criteria is met or until rollover into the 2215-CL-0109 study. 
The starting dose level of ASP2215 is 20 mg daily and the decision to dose escalate to the next dose 
level will be made based on the assessment of safety variables including occurrence of grade 2 
adverse events (AE) or DLTs.
Study Design Overview continued:  


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This study will have two cohorts of subjects (Figure 1 and Figure 2):  
1.
Cohort 1: Dose escalation cohort
2.
Cohort 2: Dose expansion cohort
Cohort 1 
Cohort 1 will comprise the initial dose escalation cohort with up to 10 dose levels (Table 1). This 
cohort will be run at approximately 5 centers which will only participate in the dose expansion cohort 
(Cohort 2) if the enrollment in the dose escalation cohort (Cohort 1) is on a pause (i.e., dose level 
being tested at the time is fully enrolled and the one higher dose level has not yet been opened) . 
Subjects will be treated daily in 28 day cycles (with the exception of Cycle 1 where subjects will 
receive 29 doses). The DLT observation period is 30 days starting with the first dose taken on Day -2, 
and including the first 28 day treatment cycle. Subjects in Cycle 1 will have PK sampling performed 
prior to start of the first cycle and after receiving a single dose of the study drug on Day -2. 
This study will follow an accelerated titration design. Dose levels are set at around 50% increments. 
One subject will be treated at the starting dose level of 20 mg. If no DLT is identified, the next subject 
will be enrolled at double the dose level, i.e. dose level 3 (40 mg see Table 1). This dose escalation 
approach will continue wherein only odd numbered dose levels (1, 3, 5) are tested until the first 
instance of a DLT or second instance (observed in two subjects at any of these dose levels) of a 
grade 2 AE judged by the investigator to be related (e.g., possibly, probably, or definitely) to study 
drug (except for hematologic toxicities) occur.  
When a DLT or second instance (observed in two subjects) of grade 2 AE related to study drug is 
observed in a subject, the dose escalation schedule will stop the double-dose level method and follow 
the next consecutive dose level in Table 1 utilizing the modified 3+3 design. Modified 3+3 design 
testing each consecutive dose level may also be followed if recommended by dose escalation 
committee based on the review of pharmacokinetics data.  After dose level 5 (80 mg), each 
subsequent dose level (6-10) will be tested using the 3+3 design. In this phase, 3 subjects will be 
treated at each dose level. If no DLTs are observed, the subsequent subjects will be treated at the next 
dose level. If one DLT is observed in a dose level, 3 more subjects will be enrolled at that dose level. 
If the 3 additional subjects do not experience a DLT, the next dose level will be initiated. If 2 or more 
DLTs occur in a dose level the next lower dose level will be declared the maximum tolerated dose 
(MTD).
Subject replacement in the dose escalation cohort (Cohort 1)
A subject that receives less than 80% of the intended dose during Cycle 1 (e.g., misses 6 daily doses 
or leaves the study for reasons other than a DLT), will not be evaluable for DLT and will be replaced 
by another subject in the dose level. In addition, if after enrollment any subject is found not to fulfill 
any inclusion/exclusion criteria that would adversely affect safety or efficacy evaluation of that 
subject, they may be replaced after discussion between the Principal Investigator and Medical 
Monitor.
Cohort 2
Cohort 2 is the dose expansion cohort. This cohort will be conducted at approximately 35 additional 
centers that will not participate in the dose escalation cohort (Cohort 1). However, those centers 
participating in the dose escalation cohort (Cohort 1) may participate in the dose expansion cohort 
(Cohort 2) after the completion of the dose escalation phase (Cohort 1). Cohort 1 centers may also 
enroll patients in Cohort 2 if the enrollment in Cohort 1 is on a pause (i.e., dose level being tested at 
the time is fully enrolled and the one higher dose level has not yet been opened). Subjects will be 
treated daily in 28 day cycles. The DLT observation period is based on one completed cycle starting 
with the first dose taken on C1 D1. 
In the dose expansion phase (Cohort 2), a dose level may be expanded as follows: 


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If one subject in the dose escalation cohort (Cohort 1) at any dose level achieves complete 
remission (CR), complete remission with low platelets (CRp) or complete remission with 
incomplete hematologic recovery (CRi) then this dose level will continue to enroll a minimum of 
3 subjects. After the decision is made to escalate to the next dose level (0/3 or 1/6 DLTs observed), 
the dose level will be expanded to enroll up to 17 additional subjects. All subsequent dose levels 
will also be expanded following a dose escalation decision for the dose level in the dose escalation 
cohort (Cohort 1). When more than one dose levels are expanded in the dose expansion cohort 
(Cohort 2), the newly enrolled patients will be randomized to all open expanded dose levels).
In the absence of a CR, if the median decrease of FMS-like tyrosine kinase (FLT3) 
phosphorylation in plasma inhibitory assay (PIA) is equal or greater than 90% in a dose level with 
at least 3 subjects, then this dose level and the subsequent levels will be expanded following a dose 
escalation decision for the dose level (0/3 or 1/6 DLTs observed) in the dose escalation cohort 
(Cohort 1).
Subjects will be assigned in the dose escalation cohort (Cohort 1) or randomized in the dose 
expansion cohort (Cohort 2) to one of the open dose escalation levels as defined in the statistical 
methodology section [Section 7]. At least 10 subjects with FLT3 mutations (internal tandem 
duplication [ITD] or activating point mutations) will be enrolled to each expanded dose level 
(including the subjects in the dose escalation cohort). Dose levels at and above 120 mg will be further 
expanded (when found to be tolerable in Cohort 1) based on the efficacy results observed in 
escalation and expansion cohorts as described in the Statistical section.  At least 42 evaluable subjects 
with FLT3 mutations will be enrolled in dose levels selected for further expansion (Figure 2).  The 
safety in the dose expansion cohort (Cohort 2) will be monitored using Bayesian logistic regression 
modeling, as described in Section 7, based on the DLT rate observed in subjects from both the dose 
escalation and expansion cohorts.
In the dose expansion cohort (Cohort 2), and for the first dose level only, the effect of CYP3A4 
inhibition for strong inhibitor voriconazole (Schedule 2B) will be evaluated in all subjects in the dose 
level. In the dose expansion cohort (Cohort 2), and at the highest dose level of ASP2215 (MTD or one 
level below MTD), the effect of ASP2215 on midazolam pharmacokinetics (Schedule 2D) will be 
evaluated. After completion of the CYP3A4 inhibition expansion (Schedule 2B) and until MTD is 
determined, Cohort 2 subjects will participate without the drug-drug interaction (DDI) component 
(Schedule 2C). DDI studies (Schedules 2B, 2D and 2E) will be conducted in the United States only.  
European sites whose patients are randomized to the DDI arms of the study will follow Schedule 2C 
and will not administer their patients these medications. In addition, US sites approved by the sponsor 
to join the trial who cannot conduct the DDI portion of the trial will also be allowed to follow 
Schedule 2C even if patients are randomized to Schedule 2B or 2D.
Patients who have a contraindication to voriconazole or midazolam can participate in the trial without 
the DDI component (Schedule 2C) after discussion with the medical monitor. 
If the first dose level closes prior to 12 patients completing the DDI component with voriconazole, the 
next lowest dose level open for enrollment will participate according to Schedule 2B to evaluate the 
effect of CYP3A4 inhibition for strong inhibitor voriconazole.
To further evaluate DDI, a sub-study with a MATE1 substrate will be conducted [Table 2E].  This 
cohort will have approximately 20 subjects and will be enrolled at 200 mg.  The goal of this sub-study 
is to evaluate the effect of ASP2215 on the MATE1 transporter.  The pharmacokinetics of 500 mg 
cephalexin will be investigated prior to initiation of ASP2215 treatment at Cycle 1 Day -1 and at 
Day 15 of Cycle 1.  This DDI sub-study (Schedule 2E) will be conducted in the United States only. 
Subjects who have severe allergies to penicillins or cephalosporins cannot participate in this sub-study 
cohort.
Safety Information: Summary safety tables from the Dose Escalation Cohort (Cohort 1) meetings will 
be shared with all investigators participating in both cohorts (escalation and expansion). These tables 


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include severe and non-severe AEs.
Intra-subject dose escalation for Cohorts 1 and 2: 
In the dose escalation cohort  (Cohort 1), if the subjects on 20 mg and 40 mg dose levels do not 
achieve a composite CR (CRc), defined as either of CR, CRp or CRi, after one cycle of treatment and 
did not have DLT, they may dose escalate to the next dose level. 
In the dose expansion cohort (Cohort 2), subjects who do not achieve a CRc may dose escalate to the 
next dose level, if the next dose level has opened up for expansion (i.e., a decision has been made to 
escalate to next higher dosing level). 
Subjects who dose escalate will revert to more frequent safety evaluations [Section 5.1.2].
Continuation of Subjects in open label roll over study:
Should the Sponsor make the decision to end the study after primary analysis, all subjects receiving 
ASP2215 may be enrolled in an ASP2215 rollover study (2215-CL-0109).  Subjects must not meet 
any discontinuation criteria for this study and must meet the entry criteria for the rollover study prior 
to being enrolled.  
Subjects who choose not to participate or are not eligible for Study 2215-CL-0109 will complete their 
participation in Study 2215-CL-0101 by completing the End of Treatment follow up visit upon 
activation of Study 2215-CL-0109 at the institution.
Subjects, who are being followed for Long-term Follow-up at the time of study closure, will be 
discontinued.    
Figure 1:  Optimal Dose Escalation and Expansion


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Figure 2:  Optimal Efficacy Expansion of Cohort 2
Inclusion/Exclusion Criteria:  
Waivers to the inclusion criteria will NOT be allowed.
Inclusion:
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., HIPAA Authorization 
for U.S. 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 ≥18 years of age at the time of obtaining informed consent.
3.
Subject is defined as morphologically documented primary or secondary AML by the World 
Health Organization (WHO) criteria (2008) 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 has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
5.
Subject’s interval from prior treatment to time of study drug administration is at least 2 weeks for 
cytotoxic agents (except hydroxyurea given for controlling blast cells), or at least 5 half-lives for 
prior experimental agents or noncytotoxic agents.
6.
Subject must meet the following criteria as indicated on the clinical laboratory tests*:

Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 
institutional upper limit normal (ULN)

Total serum bilirubin ≤ 1.5 institutional ULN

Serum creatinine ≤ 1.5 institutional ULN or an estimated glomerular filtration rate 
(eGFR) of > 50 ml/min as calculated by the Modification of Diet in Renal Disease (MDRD) 


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equation.
7.
Subject is suitable for oral administration of study drug.
8.
Female subject must be either:

Of non child bearing potential:
post-menopausal (defined as at least 1 year without any menses) prior to Screening, 
or
documented surgically sterile or status post hysterectomy (at least 1 month prior to 
Screening)

Or, if of childbearing potential, 
must have a negative urine pregnancy test at Screening*, and 
must use two forms of birth control** (at least one of which must be a barrier 
method) starting at Screening and throughout the study period and for 180 days after 
the final study drug administration.
9.
Female subject must not be breastfeeding at Screening or during the study period, and for 60 
days after the final study drug administration.
10. Female subject must not donate ova starting at Screening and throughout the study period, and for 
180 days after the final study drug administration.
11. Male subject and their female spouse/partners who are of childbearing potential must be using 
highly effective contraception consisting of two forms of birth control** (one of which must be a 
barrier method) starting at Screening and continue throughout the study period and for 120 days 
after the final study drug administration.
12. Male subject must not donate sperm starting at Screening and throughout the study period and for 
120 days after the final study drug administration.
13. Subject agrees not to participate in another interventional study while on treatment.
MATE1 Sub-study (Schedule 2E) Subjects Only:
14. Subject has documented FLT3 mutation positive AML (ITD and/or activating point mutations)
*Screening labs and diagnostic tests may be performed by local laboratories to determine 
eligibility; however, samples will also be submitted for central read. 
**  Acceptable forms of birth control include:
Established use of oral, injected or implanted hormonal methods of contraception.
Placement of an intrauterine device (IUD) or intrauterine system (IUS).
Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/suppository.
Exclusion:
Waivers to the exclusion criteria will NOT be allowed.
Subject will be excluded from participation if any of the following apply:
1.
Subject was diagnosed as acute promyelocytic leukemia (APL).
2.
Subject has BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast crisis).
3.
Subject has active malignant tumors other than AML or Myelodysplastic Syndrome (MDS).
4.
Subject has persistent non-hematological toxicities of Grade 2 (CTC AE v4), with symptoms 
and objective findings, from prior AML treatment (including chemotherapy, kinase inhibitors, 
immunotherapy, experimental agents, radiation, or surgery).
5.
Subject has had hematopoietic stem cell transplant (HSCT) and meets any of the following:

Is within 2 months of transplant from C1D1


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
Has clinically significant graft-versus-host disease requiring treatment

Has Grade 2 persistent non-hematological toxicity related to the transplant
Donor lymphocytes infusion (DLI) is not permitted ≤ 30 days prior to study registration or during 
the first cycle of treatment on the study in Cohort 1 and first two cycles of the treatment in 
Cohort 2.
6.
Subject has clinically active central nervous system leukemia.
7.
Subject has disseminated intravascular coagulation abnormality (DIC).*
8.
Subject has had major surgery within 4 weeks prior to the first study dose.
9.
Subject has had radiation therapy within 4 weeks prior to the first study dose. 
10. Subject has congestive heart failure NYHA class 3 or 4, or subject with a history of congestive 
heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram performed within 
3 months prior to study entry results in a left ventricular ejection fraction that is ≥ 45%.
11. Subject with mean Fridericia-corrected QT interval (QTcF) > 450 ms at Screening based on 
central reading.
12. Subject with Long corrected QT interval (QTc) Syndrome at Screening.
13. Subject with hypokalemia and hypomagnesemia at Screening (defined as values below lower 
limit of normal [LLN]).
14. Subject requires treatment with concomitant drugs that are strong inhibitors or inducers of 
CYP3A4 or of P-glycoprotein (P-gp) or substrates of multidrug and toxin extrusion 1 (MATE 1) 
with the exception of antibiotics, antifungals, and antivirals that are used as standard of care 
post-transplant or to prevent or treat infections and other such drugs that are considered absolutely 
essential for the care of the subject.
15. Subject requires treatment with concomitant drugs that target serotonin 5HT1R or 5HT2BR  
receptors or sigma nonspecific receptor with the exception of drugs that are considered absolutely 
essential for the care of the subject
16. Subject has an active uncontrolled infection.*
17. Subject is known to have human immunodeficiency virus infection.
18. Subject has active hepatitis B or C, or other active hepatic disorder.*
19. Subject has any condition which, in the investigator’s opinion, makes the subject unsuitable for 
study participation (e.g. ophthalmic conditions such as advanced cataracts, subject is unable to 
undergo a comprehensive ophthalmologic exam, inability to visualize the fundus).  
MATE1 Sub-study (Schedule 2E) Subjects Only:
20. Subject has known severe allergy to penicillins or cephalosporins.
21. Subject was previously treated with ASP2215.
*Screening labs and diagnostic tests may be performed at local laboratories to determine eligibility; 
however, samples will also be submitted for central read.
Investigational Product(s):
ASP2215 tablets containing 10 mg, 40 mg or 100 mg of active ingredient.


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Dose(s):  
ASP2215 will be administered once daily in the following dose levels. However, not all dose levels 
will enroll, as described in the Study Design Overview.
Table 1: Dose Levels
Dose Level
ASP2215 Dose
DL1
20 mg
DL2*
30 mg
DL3
40 mg
DL4*
60 mg
DL5
80 mg
DL6
120 mg
DL7
200 mg
DL8**
300 mg 
DL9
450 mg
DL10
600 mg
* These dose levels may be omitted as described in Section 2.2.1 Study Design.
** For patients being treated with 40 mg tablets, dose escalations to 280 mg will be permitted
Mode of Administration:
ASP2215 will be administered orally without food allowed for at least 2 hours before and 1 hour after 
dosing. Subjects will be instructed to take the daily dose with water as close to the same time each 
morning as possible.
Comparative Drug(s):
Not applicable.
Concomitant Medication Restrictions or Requirements:   
Treatment with concomitant drugs that are strong inducers of CYP3A are prohibited.  Treatment with 
concomitant drugs that are strong inihibitors or inducers of P-gp, and concomitant drugs that target 
serotonin 5HT2BR receptors or signma nonspecific receptor should 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 to prevent or treat infections.  If CYP3A inhibitors 
are used concomitantly, subjexts should be closely monitored for adverse events (AEs).
Precaution should be used in use of ASP2215 with concomitant drugs that are known to prolong QT 
or QTc intervals.
During the initial 15 days of treatment in expansion cohorts with DDI studies [
Table 2B Schedule of Assessments with CYP3A4 Inhibitor Voriconazole, Table 2D Schedule of 
Assessments for Expansion Phase with CYP3A4 Induction, and Table 2E Schedule of Assessments 
for Expansion Phase with MATE1 Substrate Study], moderate or strong CYP3A4 inhibitors are 
prohibited, unless required for treatment of active infections.  In addition, during the initial 15 days of 
treatment for subjects assigned to Schedule 2E, MATE1 substrates are prohibited. Any other 
treatments of AML (including but not limited to chemotherapy, radiotherapy, surgery, 
immunotherapy or cellular therapy) are prohibited during therapy with ASP2215 with the following 
exceptions:

Hydroxyurea up to 5 gm daily for up to 2 weeks to keep the absolute blast count below 50,000

Hematopoietic Stem Cell Transplants (HSCT) for patients with CRc or PR


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
Intrathecal Chemotherapy used as prophylaxis
Please see Section 5.1.4 for additional information on HSCT.
Duration of Treatment:  
One dose daily in 28 day cycles until a discontinuation criterion is metor until rollover into the 
2215-CL-0109 study.
Definition of DLT:
A DLT is defined as any of the following events that occur within 30 days starting with the first dose 
taken on Day -2, and including the first treatment cycle in dose escalation cohort (Cohort 1) and that 
is considered to be possibly, probably or definitely related to study drug. In Cohort 2, DLT 
observation period is the first treatment cycle (28 days).
Any Grade ≥ 3 non-hematologic or extramedullary toxicity.
The following exceptions are noted:
Alopecia, anorexia, or fatigue.
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.
Grade 3 fever with neutropenia, with or without infection.
Grade 3 infection.
Hematologic toxicity will not be considered as a DLT. However, prolonged myelosuppression 
defined as ANC <500 for more than 21 days off therapy in the absence of evidence of active leukemia 
in the marrow or blood will be considered as a DLT.
Discontinuation Criteria 
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 will be taken off treatment if there is no PR or CRc and the subject, in the opinion of the 
Investigator, is no longer deriving clinical benefit after 2 cycles of therapy.
ASP2215 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 an 
ASP2215 related adverse event.
Investigator/sub-investigator 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.
Death
The subject will be discontinued from the post-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 Visit.


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Death
Endpoints for Evaluation:  
Primary: 
Safety and Tolerability (Determine MTD and AEs)
Pharmacokinetics (ASP2215)
Secondary:
Efficacy of ASP2215 in AML 
o CR rate
o Composite CR rate (CR + CRp + CRi)
o Best response rate (CRc + partial remission [PR])
o Duration of response
o Overall survival
o Event free survival
o Leukemia free survival
Pharmacokinetics of ASP2215, effect of strong or moderate CYP3A4 inhibitors 
Pharmacokinetics of midazolam, potential induction of CYP3A4 by ASP2215 
Pharmacokinetics of cephalexin, MATE1 inhibition by ASP2215
Exploratory:
Statistical Methods: 
Sample Size Justification: 
The sample size is not based on statistical power calculation. It should provide adequate information 
for the objective of the study.
Bayesian Logistic Regression Modeling in Dose Escalation and Expansion Phases:
A modified 3+3 design with an accelerated titration is applied in the dose escalation cohort as 
described in the Study Design Overview section. A 2-parameter Bayesian logistic regression will be 
used to model the dose-toxicity relationship on DLT. Subjects in either dose escalation cohort or dose 
expansion cohorts will be included in the model-fitting process to provide the complete safety 
information. The estimated DLT rates based on the Bayesian logistic regression model for each dose 
level will be provided as references for dose escalation procedures in dose escalation cohort and 
safety monitoring in dose expansion cohort. If the DLT rate for an expanded dose level is equal or 
higher than 20% with a posterior probability of 80%, then the enrollment to the dose level will be 
paused and the safety will be reassessed.
Subject Assignment in Cohort 2 Dose Expansion Cohort:
As a dose level is decided to be expanded, up to 17 subjects will be enrolled for the dose level in the 
dose expansion cohort (to have a total of 20 subjects enrolled at a dose level including the subjects 
from dose escalation cohort). When more than one dose levels are expanded in the dose expansion 
cohort (2), the newly enrolled subjects will be randomized to one of the open expanded dose levels, 
based on the relative chance of (20 – n) in each dose level, where n is the number of subjects already 
enrolled in the dose level.


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If 10 subjects without FLT3 mutations (ITD or activating point mutations) are enrolled into an 
expanded dose level (including the subjects in the dose escalation cohort and dose expansion cohort), 
only subjects with FLT3 mutations can be enrolled to the dose level.
Any dose level in the dose expansion cohort will be stopped if no CRc is achieved in more than 
6 subjects who complete 2 treatment cycles or less than 2 CRcs in more than 12 subjects.
Subject Assignment in Cohort 2 MATE1 Sub-study Dose Expansion Cohort:
Approximately 20 FLT3 mutation positive patients will be enrolled in the Expansion Phase with 
MATE1 Substrate Study (Schedule 2E).  All patients will be assigned to ASP2215 200 mg dose level 
and 40 mg tablets will be used.
Further Expansion for Efficacy Evaluation
To improve guidance for Recommended Phase 2 Dose, dose levels at and above 120 mg will be 
further expanded (when found to be tolerable in Cohort 1) based on the efficacy results observed in 
escalation and expansion cohorts. Approximately 40 additional subjects will be enrolled at these dose 
levels to bring the total enrolled to approximately 60 patients at the dose level inclusive of Cohort 1 
subjects. A minimum of 42 evaluable (receive 2 cycles of treatment or discontinue for progressive 
disease) FLT3 mutated patients will be enrolled.
The increased patient numbers will enable us to more accurately estimate the actual response rate 
(CRc) for a dose level based on the observed response rate.  With approximately 42 evaluable FLT3 
mutated subjects, the 90% 1-sided Confidence Interval is about 10% below the observed response rate 
for each dose level. If the estimated response rate is 50%, we would be 90% sure that the real 
response rate is higher than 40%. Response rate will be continuously monitored for each dose level 
and the enrollment will be stopped if the response rate for that dose level is at 90% significance level, 
less than 45% based on Wald’s Sequential Probability Ratio Test with 25% as the unacceptable low 
response rate and 80% power. 
The following table will apply (e.g., if 7 or less subjects respond as 25 FLT3 mutated subjects 
complete 2 cycles of treatment in a dose level, the enrollment at the dose level will be stopped): 
Enrolled Subjects
Number of CRc
14
3
17
4
20
5
23
6
25
7
28
8
31
9
34
10
37
11
Safety Analyses:
Safety analyses will consist of data summaries of AEs, DLTs, and other safety parameters. The 
number and percent of subjects experiencing 1 or more AE(s) will be summarized by cohort and dose 
level. The relationship to study drug, time of onset, and severity of AE will also be summarized. AEs 
will be coded to system organ class and preferred term using Medical Dictionary for Regulatory 
Activities (MedDRA) terminology.
Laboratory parameters will be summarized by cohort and dose level using descriptive statistics shifts 
in change from baseline, and data listings of clinically significant abnormalities. Vital signs and ECG 
parameters and their changes from baseline will be summarized by cohort and dose level using 




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V.
FLOW CHART AND SCHEDULE OF ASSESSMENTS
Figure 1
Study Flow Chart  
Cohort 1 (Escalation Cohort)
Cohort 2 (Expansion Cohort)
Expansion cohorts will start with 1st CR or one above the dose level with target inhibition
≥ 18 years with AML 
in relapse or 
refractory to 
induction regimen
ASP2215 
QDx28 
1 cycle
C
O
N
S
E
N
T
ASP2215
QDx28 q28 until subject meets 
discontinuation criteria 
S
C
R
E
E
N
30-DAY 
FOLLOW UP 
ASSESSMENT
SURVIVAL AND 
SUBSEQUENT TREATMENT
FOLLOW-UP Q3 MONTHS
≥ 18 years with AML 
in relapse or 
refractory to 
induction regimen
C
O
N
S
E
N
T
S
C
R
E
E
N
DOSE ASSIGNMENT
ASSIGN TO SINGLE 
OPEN DOSE OR 
RANDOMIZE
ASP2215
QDx28 q28 until subject meets 
discontinuation criteria or until 
rollover into the 2215-CL-0109 
study
30-DAY 
FOLLOW UP 
ASSESSMENT
SURVIVAL AND 
SUBSEQUENT TREATMENT
FOLLOW-UP Q3 MONTHS
DLT Observation
30 days


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Table 2A
Schedule of Assessments for Dose Escalation Phase (Cohort 1)
Activity
Screening
(Day -14 
to -3)
Day
-2
Day
-1
Cycle 1
Cycle 2
Subsequent 
Cycles
D 1r
D 4±1
D 8±1
D 15
D 16
D 22+1
D 1 ±3 D 15 ±1
D 1±3
Signed ICF
X
Medical and Disease History
X
Physical Examination  (incl. height and weight) n
X n 
X a
X
X n
X
X
X
X
X n
X
X n
Vital Signs
X
X a
X
X
X
X
X
X
X
X
X
ECOG Performance
X
X
X
X
X
X
Prior and Concomitant Medications
X b
X
X
X
X
X
X
X
X
X
X
Pregnancy Test for WOCBP
X f
X
X
X
Coagulation Profile (PT/INR, D-Dimer, Fibrinogen)
X
Chest X-ray (or CT of chest)t
X
12-lead ECG d
X d
X d
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Ophthalmologic Assessment m
X
X
X
Xm
Clinical Laboratory Tests (chemistry, hematology, 
coagulation, urinalysis) p
Xo 
X a
X
X a
X a
X a
X a
X a
X a
X a
X a
Thyroid Function Tests
X
Xq
MUGA or ECHO c
X
FLT3, C-CBL, AXL Mutation Status j (bone marrow 
aspirate or whole blood)
X
Bone Marrow Aspiration and Biopsy
X g
X g
X g
AE/SAE Assessment
X
X
X
X
X
X
X
X
X
X
X
PK (whole blood samples for plasma PK)
X e
X e
X e
X e
X e
X e
X e
X e
X e
PIA (whole blood samples for plasma inhibitory assay)
X l
X l
X l
X l
X l
X l
Xl
PGxh
X
Phosphorylation of  FLT-3, S6 and AXLk  
(whole blood)
X
X
X
X
ASP2215 Dosing at the Clinic i
X
X
X
X
X
X
X
X
X
IRT Transaction Requireds
X
X
X
X
X
X
X
X
ASP2215 Dispensing for Subject Take Home
X
X
X
X
X
X
X
Footnotes appear on next page


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a.
Obtained predose.
b.
Includes medications taken within 28 days prior to screening.
c.
MUGA scans are to be performed at Screening for subjects with history of congestive heart failure NYHA Class 3 or 4 (unless MUGA scans performed either within 
3 months prior revealed LVEF ≥45%).
d.
Screening ECGs are required. ECG assessment will be evaluated at D-2 and C1D15 at pre-dose, 2, 4, 6, and 24 hours post. Pre-dose ECG assessment will also be evaluated on C1D1, 
C1D8, C1D22, and D1 of each subsequent cycle. 24 hr post-dose ECG assessment will be performed on D-1 and D16 respectively. All efforts should be made to conduct ECG 
monitoring in triplicate between 7:00 am and 3:00 pm at all assessment time points. Pre-dose assessments should be taken within 
0.5 hours before drug administration. In addition, 2, 4, 6, and 24 hour post-dose assessments should be performed within ± 0.5 hours of nominal time. 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. See Section 
5.4.5
e.
PK samples will be collected at D-2 and C1D15 at pre-dose, (0.5 hours before drug administration) 0.5 (±10 minutes), 1 (±10 minutes), 2 (±10 minutes), 4 (±20 minutes), 
6 (±20 minutes), and 24 hours (±90 minutes) post dose (the 24 hour sample must be collected on Day -1 and before the next dose of ASP2215 on Day 16). Samples will also be 
collected on C1D1, C1D8, and C1D22 pre-dose (0.5 hours before drug administration) and 2 hours (±10 minutes) post dose. Thereafter PK samples will be collected pre-dose 
(0.5 hours before drug administration) on Day 1 of each cycle. See Section 5.6.1
f.
WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of study treatment.
g.
Bone marrow samples are required during Screening, Cycle 2 Day 1 and Cycle 3 Day 1. Screening samples may be collected up to 21 days prior to C1D1. For subjects who do not 
achieve a complete remission (CR, CRp, or CRi), the bone marrow assessments will be repeated at Day 1 of every 2 subsequent cycles. For subjects who achieve a complete remission 
(CR, CRp, or CRi), bone marrow will be repeated on one month after the date of remission and every 3 subsequent cycles for up to 
1 year from Cycle 1 Day 1 and after that only if there is suspicion of relapse in the peripheral blood. Bone marrow samples are also required at the Early Termination/End-of Study 
Visit, and as clinically indicated. If bone marrow aspirate is unobtainable (i.e., dry tap), an additional EDTA tube of peripheral blood should be collected instead.
h.
Buccal swab collected at Screening for optional pharmacogenomic study.
i.
ASP2215 is taken daily without food at home except on clinic days when it will be taken at the clinic and Day -1 when no ASP2215 will be taken.  Subjects will be instructed to take 
the daily dose with water as close to the same time each morning as possible.
j.
FLT3, C-CBL and AXL mutation status will be assessed from bone marrow sample taken at the Screening Visit. If bone marrow sample is unavailable (i.e., dry tap), the whole blood 
sample taken at the Screening Visit will be used.  
k.
Predose and 2 hours (±10 minutes) post dose on Day -2. Predose Day -1 (no dose on this day), Day 8, and Day 15 for determination of phosphorylation of FLT3, 
S6 and AXL. Day -1 sample will be taken in proximity to 24 hour PK sample following Day -2 dose administration. 
l.
PIA samples will be collected at D-2 and C1D15 at pre-dose (0.5 hours before drug administration), 2 (±10 minutes), 6 (±20 minutes), and 24 hours (±90 minutes) 
post dose (the 24 hour sample must be collected on Day -1 and before the next dose of ASP2215 on D16). Samples will also be collected on C1D1, C1D8, and C2D1 pre-dose (0.5 
hours before drug administration) and 2 hours (±10 minutes) post dose.
m. Ophthalmologic assessment to be performed by visual acuity measurement, ophthalmoscopy, slit lamp biomicroscopy, visual fields and optical coherence tomography (OCT) at 
Screening (within 12 days prior to dosing), 15th Day of Cycle 1 (± 3 days), 1st Day of Cycle 2 (± 3 days), Cycle 3 (± 3 days), and every 2 cycles thereafter (± 3 days), at the end of 
treatment, and when clinically indicated. 
n.
Height measurement performed only at Screening. Weight measurement should be performed on D1 of each Cycle. 
o.
Subjects may be screened from local labs only. However, screening samples must also be submitted for central read.
p.
Additional laboratory tests should be performed according to institutional standard of care.
q.
Thyroids function tests will be repeated after every 2 cycles of therapy (C3D1, C5D1, C7D1 etc.).
r.
For scheduling and logistical purposes, up to 3 days are allowed between Day -1 and Cycle 1 Day 1.
s.
For the purposes of drug preparation and dispensing activities, IRT Transactions may be done prior to the visit and do not need to fall within the protocol visit windows.
t.
Chest X-ray (or CT of chest) does not need to be repeated if performed within 2 weeks prior to start of Screening.


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Version 12.0, Incorporating Substantial Amendment 11
Table 2B
Schedule of Assessments for Expansion Phase with CYP3A4 Inhibitor Voriconazole Study (Cohort 2, Starting Dose Level)
Activity
Screening
(Day -14 to -1)
Cycle 1
Cycle 2
Subsequent 
Cycles
D 1
D 4±1
D 8±1
D 15
D 16
D 22±1
D 1±2
D 2
D 15±1
D 1±3
Signed ICF
X
Medical and Disease History 
X
Physical Examination o
X o
X o a
X
X
X
X
X o
X
X o
Vital Signs
X
X a
X
X
X
X
X
X
X
ECOG Performance
X
X a
X
X
X
X
Prior and Concomitant Medications
X b
X
X
X
X
X
X
X
X
Pregnancy Test for WOCBP
X f
X
X
X
Coagulation Profile (PT/INR, D-Dimer, Fibrinogen)
X
Chest X-ray (or CT of chest) t
X
12-lead ECG d
X
X
X
X d
X
X
X d
X
X d
Ophthalmologic Assessment m
X 
X
X
Xm
Clinical Laboratory Tests (chemistry, hematology, 
coagulation, urinalysis) q
Xp
X a
X a
X a
X a
X a
X a
X a
X a
Thyroid Function Tests
X
Xr
MUGA or ECHO c
X
FLT3, C-CBL,AXL Mutation Status j (bone marrow 
aspiration or whole blood)
X
Bone Marrow Aspiration and Biopsy  
X g
X g
X g
AE/SAE Assessment
X
X
X
X
X
X
X
X
X
PK (whole blood samples for plasma PK) 
X e
X e
X e
X e
X e
X e
X e
X e
PIA (whole blood samples for plasma inhibitory assay)
X l
X l
X l
Xl
PGxh
X
Phosphorylation of  FLT-3, S6 and AXL k  ( whole blood )
X
X
X
ASP2215 Dosing at the Clinic i
X
X
X
X
X
X
X
X
X
IRT Transaction Requireds
X
X
X
X
X
X
X
X
ASP2215 Dispensing for Subject Take Home
X
X
X
X
X
X
X
Voriconazole (CYP3A4 Inhibitor) dosing 
Xn
Xn
Xn
Footnotes appear on next page


Sponsor: APGD
ISN/Protocol 2215-CL-0101
EudraCT number 2014-002217-31
- CONFIDENTIAL –
02 Jun 2017
Astellas
Page 31 of 133
Version 12.0, Incorporating Substantial Amendment 11
a.
Obtained predose.
b.
Includes medications taken within 28 days prior to screening.
c.
MUGA scans are to be performed at Screening for subjects with history of congestive heart failure NYHA Class 3 or 4 (unless MUGA scans performed either within 3 months prior 
revealed LVEF ≥45%).
d.
Screening ECG is required. ECG assessment will be evaluated at C1D15 and C2D1 at pre-dose, 2, 4, 6, and 24 hours post. 24 hr post-dose ECG assessment will be performed on D16 
and C2D2 respectively.  Pre-dose ECG assessment will also be evaluated on C1D1, C1D8, C1D22, and D1 of each subsequent cycle. All efforts should be made to conduct ECG 
monitoring in triplicate between 7:00 am and 3:00 pm at all assessment time points. Pre-dose assessments should be taken within 0.5 hours before drug administration. In addition, 2, 
4, 6, and 24hour post-dose assessments should be performed within ± 0.5 hours of nominal time. 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. See Section 5.4.5
e.
PK samples for ASP2215 will be collected at C1D15, and C2D1 at pre-dose (0.5 hours before drug administration), 0.5(±10 minutes), 1 (±10 minutes), 2 (±10 minutes), 
4 (±20 minutes), 
6 (±20 minutes), and 24 hours (±90 minutes) post dose. 24 hr post-dose PK assessment will be performed on D16 and C2D2 respectively. Predose (0.5 hours before drug 
administration) PK samples will also be collected on C1D1, C1D8, C1D22, and on Day 1 of each cycle starting at Cycle 3. A predose (0.5 hours before drug administration) PK 
sample for CYP3A4 inhibitor will be taken on C2D1. See Section 5.6.1
f.
WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of study treatment.
g.
Bone marrow samples are required during Screening, Cycle 2 Day 1 and Cycle 3 Day 1. Screening samples may be collected up to 21 days prior to C1D1. For subjects who do not 
achieve a complete remission (CR, CRp, or CRi), the bone marrow assessments will be repeated at Day 1 of every 2 subsequent cycles. For subjects who achieve a complete remission 
(CR, CRp, or CRi), bone marrow will be repeated on one month after the date of remission and every 3 subsequent cycles for up to 1 year from Cycle 1 Day 1 and after that only if 
there is suspicion of relapse in the peripheral blood. Bone marrow samples are also required at the Early Termination/End-of Study Visit, and as clinically indicated. If bone marrow 
aspirate is unobtainable (i.e., dry tap), an additional EDTA tube of peripheral blood should be collected instead.
h.
Buccal swab collected at Screening for optional pharmacogenomic study.
i.
ASP2215 is taken daily without food at home except for clinic days when it will be taken at the clinic. Subjects will be instructed to take the daily dose with water as close to the same 
time each morning as possible.
j.
FLT3 C-CBL and AXL mutation status will be assessed from bone marrow sample taken at the Screening Visit. If bone marrow sample is unavailable (e.g., dry tap), the whole blood 
sample taken at the Screening Visit will be used.  
k.
Predose and 2 hours (±10 minutes) post dose on Day 1. Pre dose on Day 8 and Day 15 for determination of phosphorylation of FLT3, S6 and AXL. 
l.
PIA samples will be collected at C1D1, C1D8, C1D15 and C2D1 at pre-dose (0.5 hours before drug administration) and 2 hours (±10 minutes) post dose.
m.
Ophthalmologic assessment to be performed by visual acuity measurement, ophthalmoscopy and slit lamp biomicroscopy, visual fields and optical coherence tomography (OCT) at 
Screening (within 12 days prior to dosing), 15th Day of Cycle 1(± 3 days), 1st Day of Cycle 2 (± 3 days), Cycle 3(± 3 days) and every 2 cycles thereafter (± 3 days), at the end of 
treatment, and when clinically indicated. 
n.
Voriconazole (CYP3A4 inhibitor) will be administered at 200 mg every 12 hours starting on C1D16 through C2D1.
o.
Height measurement performed only at Screening. Weight measurement should be performed on D1 of each Cycle. 
p.
Subjects may be screened from local labs only. However, samples must also be submitted for central read.
q.
Additional laboratory tests should be performed according to institutional standard of care.
r.
Thyroids function tests will be repeated after every 2 cycles of therapy (C3D1, C5D1, C7D1 etc.).
s.
For the purposes of drug preparation and dispensing activities, IRT Transactions may be done prior to the visit and do not need to fall within the protocol visit windows.
t.
Chest X-ray (or CT of chest) does not need to be repeated if performed within 2 weeks prior to start of Screening.  


Sponsor: APGD
ISN/Protocol 2215-CL-0101
EudraCT number 2014-002217-31
- CONFIDENTIAL –
02 Jun 2017
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Page 32 of 133
Version 12.0, Incorporating Substantial Amendment 11
Table 2C
Schedule of Assessments for Expansion Cohort without DDI Studies (Cohort 2, Intermediate Dose Levels)
Activity
Screening
(Day -14
to -1)
Cycle 1
Cycle 2
Subsequent 
Cycles
D 1
D 4±1
D 8±1
D 15±1
D 22±1
D 1 ±3
D 15 ±1
D 1±3
Signed ICF
X
Medical and Disease History 
X
Physical Examination n
X n
X n a
X
X
X
X
X n
X
X n
Vital Signs
X
X a
X
X
X
X
X
X
X
ECOG Performance
X
X a
X
X
X
X
Prior and Concomitant Medications
X b
X
X
X
X
X
X
X
X
Pregnancy Test for WOCBP
X f
X
X
X
Coagulation Profile (PT/INR, D-Dimer, Fibrinogen)
X
Chest X-ray (or CT of chest) s
X
12-lead ECG d
X
X d
X
X d
X
X d
X d
Ophthalmologic Assessment m
X
X
X
Xm
Clinical Laboratory Tests (chemistry, hematology, coagulation, 
urinalysis) p
X o
X a
X a
X a
X a
X a
X a
X a
X a
Thyroid function tests
X
Xq
MUGA or ECHO c
X
FLT3, C-CBL,AXL Mutation Status j (bone marrow aspirate or whole 
blood)
X
Bone Marrow Aspiration and Biopsy  
X g
X g
X g
AE/SAE Assessment
X
X
X
X
X
X
X
X
X
PK (whole blood samples for plasma PK) 
X e
X e
X e
X e
X e
X e
PIA (whole blood samples for plasma inhibitory assay)
X l
X l
X l
Xl
PGxh
X
Phosphorylation of  FLT-3, S6 and AXLk   (whole blood )
X
X
X
ASP2215 Dosing at the Clinic i
X
X
X
X
X
X
X
IRT Transaction Requiredr
X
X
X
X
X
X
X
X
ASP2215 Dispensing for Subject Take Home
X
X
X
X
X
X
X
Footnotes appear on next page


Sponsor: APGD
ISN/Protocol 2215-CL-0101
EudraCT number 2014-002217-31
- CONFIDENTIAL –
02 Jun 2017
Astellas
Page 33 of 133
Version 12.0, Incorporating Substantial Amendment 11
a.
Obtained predose.
b.
Includes medications taken within 28 days prior to screening. 
c.
MUGA scans are to be performed at Screening for subjects with history of congestive heart failure NYHA Class 3 or 4 (unless MUGA scans performed either within 
3 months prior revealed LVEF ≥45%).
d.
Screening ECG is required. ECG assessment will be evaluated at C1D1 and C1D15 at pre-dose, and 2 hours post. Pre-dose ECG assessment will also be evaluated on C1D8, 
C1D22 and D1 of each subsequent cycle.  All efforts should be made to conduct ECG monitoring in triplicate between 7:00 am and 3:00 pm at all assessment time points. 
Pre-dose assessments should be taken within 0.5 hours before drug administration. In addition, 2 hour post-dose assessment should be performed within 
± 0.5 hours of nominal time. 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. See Section 5.4.5
e.
PK samples for ASP2215 will be collected at C1D1 and C1D15 at pre-dose (0.5 hours before drug administration) and 2 hours (±10 minutes) post dose. ASP2215 predose 
(0.5 hours before drug administration) PK samples will also be collected on C1D8, C1D22 and on Day 1 of each cycle starting at Cycle 2. See Section 5.6.1
f.
WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of hCG) within 72 hours prior to the start of study treatment.
g.
Bone marrow samples are required during Screening, Cycle 2 Day 1 and Cycle 3 Day 1. Screening samples may be collected up to 21 days prior to C1D1. For subjects who 
do not achieve a complete remission (CR, CRp, or CRi), the bone marrow assessments will be repeated at Day 1 of every 2 subsequent cycles. For subjects who achieve a 
complete remission (CR, CRp, or CRi), bone marrow will be repeated on one month after the date of remission and every 3 subsequent cycles for up to 
1 year from Cycle 1 Day 1 and after that only if there is suspicion of relapse in the peripheral blood. Bone marrow samples are also required at the Early Termination/ End-of 
Study Visit, and as clinically indicated. If bone marrow aspirate is unobtainable (i.e., dry tap), an additional EDTA tube of peripheral blood should be collected instead.  For 
France and Germany Only:  Bone marrow aspirate is required. Collection of both the bone marrow aspirate and bone marrow biopsy is preferred, but biopsy samples are only 
required in case of inadequate aspirate.
h.
Buccal swab collected at Screening for optional pharmacogenomic study.
i.
ASP2215 is taken daily at home except for clinic days when it will be taken at the clinic.
j.
FLT3 and C-CBL and AXL mutation status will be assessed from bone marrow sample taken at the Screening Visit. If bone marrow sample is unavailable (i.e., dry tap), the 
whole blood sample taken at the Screening Visit will be used.  
k.
Predose and 2 hours (±10 minutes) post dose on Day 1. Pre dose on Day 8 and Day 15 for determination of phosphorylation of FLT3, S6 and AXL.
l.
PIA samples will be collected at C1D1, C1D8, C1D15, and C2D1 at pre-dose (0.5 hours before drug administration) and 2 hours (±10 minutes) post dose.
m.
Ophthalmologic assessment to be performed by visual acuity measurement, ophthalmoscopy and slit lamp biomicroscopy, visual fields and optical coherence tomography 
(OCT) at Screening (within 12 days prior to dosing), 15th Day of Cycle 1 (± 3 days), 1st Day of Cycle 2 (± 3 days), Cycle 3(± 3 days), and every 2 cycles thereafter (± 3 
days), at the end of treatment, and when clinically indicated.  
n.
Height measurement performed only at Screening. Weight measurement should be performed on D1 of each Cycle.
o.
Subjects may be screened from local labs only. However, samples must also be submitted for central read.
p.
Additional laboratory tests should be performed according to institutional standard of care.
q.
Thyroids function tests will be repeated after every 2 cycles of therapy (C3D1, C5D1, C7D1 etc.).
r.
For the purposes of drug preparation and dispensing activities, IRT Transactions may be done prior to the visit and do not need to fall within the protocol visit windows.
s.
Chest X-ray (or CT of chest) does not need to be repeated if performed within 2 weeks prior to start of Screening.


Sponsor: APGD
ISN/Protocol 2215-CL-0101
EudraCT number 2014-002217-31
- CONFIDENTIAL –
02 Jun 2017
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Page 34 of 133
Version 12.0, Incorporating Substantial Amendment 11
Table 2D
Schedule of Assessments for Expansion Phase with CYP3A4 Induction Study (Cohort 2, MTD Level)
Activity
Screening
(Day -14 to -2)
D-1
Cycle 1
Cycle 2
Subsequent 
Cycles
D 1
D4±1
D8±1
D 15
D 16
D 22+1
D 1 ±3
D 15 ±1
D 1±3
Signed ICF
X
Medical and Disease History 
X
Physical Examination n
X n
X
X n a
X n
X
X
X
X n
X
X n
Vital Signs
X
X
X a
X
X
X
X
X
X
X
ECOG Performance
X
X
X a
X
X
X
X
Prior and Concomitant Medications
X b
X
X
X
X
X
X
X
X
X
Pregnancy Test for WOCBP
X f
X
X
X
Coagulation Profile (PT/INR, D-Dimer, Fibrinogen)
X
Chest X-ray (or CT of Chest) s
X
12-lead ECG d
X
X d
X
X d
X
X
X
X
X d
Ophthalmologic Assessment m
X m
X
X
Xm
Clinical Laboratory Tests (chemistry, hematology, 
coagulation, urinalysis) p
Xo
X a
X a
X a
X a
X a
X a
X a
X a
X a
Thyroid Function Tests
X
Xq
MUGA or ECHO c
X
FLT3, C-CBL, AXL  Mutation Status j (bone marrow 
aspirate or whole blood)
X
Bone Marrow Aspiration and Biopsy  
X g
X g
X g
AE/SAE Assessment
X
X
X
X
X
X
X
X
X
X
PK (Whole blood Samples for plasma PK) 
X e
X e
X e
X e
X e
X e
X e
X e
PIA (whole blood samples for plasma inhibitory assay)
X l
X l
X l
Xl
PGxh
X
Phosphorylation of  FLT-3,S6 and AXLk
(whole blood )
X
X
X
ASP2215 Dosing at the Clinic i
X
X
X
X
X
X
X
X
IRT Transaction Requiredr
X
X
X
X
X
X
X
X
ASP2215 Dispensing for Subject Take Home
X
X
X
X
X
X
X
Midazolam Dosing e
X e
X e
Footnotes appear on next page


Sponsor: APGD
ISN/Protocol 2215-CL-0101
EudraCT number 2014-002217-31
- CONFIDENTIAL –
02 Jun 2017
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Page 35 of 133
Version 12.0, Incorporating Substantial Amendment 11
a.
Obtained predose.
b.
Includes medications taken within 28 days prior to screening.
c.
MUGA scans are to be performed at Screening for subjects with history of congestive heart failure NYHA Class 3 or 4 (unless MUGA scans performed either within 3 months prior 
revealed LVEF ≥45%).
d.
Screening ECGs are required. ECG assessment will be evaluated at D-1 and C1D15 at pre-dose, 2, 4, 6, and 24 hours post. 24 hr post-dose ECG assessment will be performed on 
C1D1 and C1D16 respectively. Pre-dose ECG assessment will also be evaluated on C1D1, C1D8, C1D22 and D1 of each subsequent cycle. All efforts should be made to conduct 
ECG monitoring in triplicate between 7:00 am and 3:00 pm at all assessment time points. Pre-dose assessments should be taken within 0.5 hours before drug administration. In 
addition, 2, 4, 6, and 24hour post-dose assessments should be performed within ± 0.5 hours of nominal time. 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. See Section 5.4.5
e.
Midazolam (2 mg of syrup (1.0 ml) by mouth) will be administered as a single dose on Days -1 and C1D15. For all Midazolam PK timepoints, Vital Signs including respiratory rate 
are to be done.  Midazolam PK samples will be collected at D-1 and C1D15 at pre-dose (0.5 hours before drug administration), 0.5 (±10 minutes), 1 (±10 minutes), 2 (±10 minutes), 
4 (±20 minutes), 6 (±20 minutes), and 24 hours (±90 minutes) post dose (the 24 hour sample must be collected before the dose of ASP2215). 24 hr post-Midazolam dose assessment 
will be performed on C1D1 and D16 respectively. PK samples for ASP2215 will be collected at C1D1, C1D8, C1D15, and C1D22 at pre-dose (0.5 hours before drug administration) 
and 2 hours (±10 minutes) post dose. ASP2215 predose (0.5 hours before drug administration) PK samples will also be collected on Day 1 of each cycle starting at Cycle 2. See 
Section 5.6.1
f.
WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of hCG) within 72 hours prior to the start of study treatment.
g.
Bone marrow samples are required during Screening, Cycle 2 Day 1 and Cycle 3 Day 1. Screening samples may be collected up to 21 days prior to C1D1. For subjects who do not 
achieve a complete remission (CR, CRp, or CRi), the bone marrow assessments will be repeated at Day 1 of every 2 subsequent cycles. For subjects who achieve a complete remission 
(CR, CRp, or CRi), bone marrow will be repeated on one month after the date of remission and every 3 subsequent cycles for up to 1 year from Cycle 1 Day 1 and after that only if 
there is suspicion of relapse in the peripheral blood. Bone marrow samples are also required at the Early Termination/End-of Study Visit, and as clinically indicated. If bone marrow 
aspirate is unobtainable (i.e., dry tap), an additional EDTA tube of peripheral blood should be collected instead.
h.
Buccal swab collected at Screening for optional pharmacogenomic study.
i.
ASP2215 is taken daily without food at home except for clinic days when it will be taken at the clinic.  Subjects will be instructed to take the daily dose with water as close to the same 
time each morning as possible.
j.
FLT3 C-CBL and AXL mutation status will be assessed from bone marrow sample taken at the Screening Visit. If bone marrow sample is unavailable (e.g., dry tap), the whole blood 
sample taken at the Screening Visit will be used.  
k.
Predose and 2 hours (±10 minutes) post dose on C1D1. Pre dose on C1D8, and C1D15 for determination of phosphorylation of FLT3, S6 and AXL. 
l.
PIA samples will be collected at C1D1, C1D8, C1D15 and C2D1 pre-dose (0.5 hours before drug administration) and 2 hours (±10 minutes) post dose.
m.
Ophthalmologic assessment to be performed by visual acuity measurement, ophthalmoscopy and slit lamp biomicroscopy, visual fields and optical coherence tomography (OCT) at 
Screening (within 12 days prior to dosing), 15th Day of Cycle 1 (± 3 days), 1st Day of Cycle 2 (± 3 days), Cycle 3 (± 3 days), and every 2 cycles thereafter (± 3 days), at the end of 
treatment, and when clinically indicated. 
n.
Height measurement performed only at Screening. Weight measurement should be performed on D1 of each Cycle.
o.
Subjects may be screened from local labs only. However, samples must also be submitted for central read.
p.
Additional laboratory tests should be performed according to institutional standard of care.
q.
Thyroids function tests will be repeated after every 2 cycles of therapy (C3D1, C5D1, C7D1 etc.).
r.
For the purposes of drug preparation and dispensing activities, IRT Transactions may be done prior to the visit and do not need to fall within the protocol visit windows.
s.
Chest X-ray (or CT of chest) does not need to be repeated if performed within 2 weeks prior to start of Screening.  


Sponsor: APGD
ISN/Protocol 2215-CL-0101
EudraCT number 2014-002217-31
- CONFIDENTIAL –
02 Jun 2017
Astellas
Page 36 of 133
Version 12.0, Incorporating Substantial Amendment 11
Table 2E
Schedule of Assessments for Expansion Phase with MATE1 Substrate Study (Cohort 2, MATE1 Sub-study)
Activity
Screening
(Day -14 to -2)
D -1
Cycle 1
Cycle 2
Subsequent 
Cycles
D 1
D 4±1
D 8±1
D 9
D 15
D 16
D 22+1
D 1 ±3
D 15 ±1
D 1±3
Signed ICF
X
Medical and Disease History 
X
Physical Examination l
X l
X
X l a
X
X
X
X
X l
X
X l
Vital Signs
X
X
X a
X
X
X
X
X
X
X
ECOG Performance
X
X
X a
X
X
X
X
Prior and Concomitant Medications
X b
X
X
X
X
X
X
X
X
X
Pregnancy Test for WOCBP
X f
X
X
X
Coagulation Profile (PT/INR, D-Dimer, Fibrinogen)
X
Chest X-ray (or CT of Chest) q
X
12-lead ECG d
X
X
X
X
X s
X
X
X
X
X
Ophthalmologic Assessment k
X k
X
X
Xk
Clinical Laboratory Tests (chemistry, hematology, 
coagulation, urinalysis) n
Xm
X a
X a
X a
X a
X a
X a
X a
X a
X a
Thyroid Function Tests
X
Xo
MUGA or ECHO c
X
FLT3, C-CBL, AXL  Mutation Status j (bone 
marrow aspirate or whole blood)
X
Bone Marrow Aspiration and Biopsy  
X g
X g
X g
AE/SAE Assessment
X
X
X
X
X
X
X
X
X
X
ASP2215 PK (Whole blood Samples) 
X e
X e
X e
X e
X e
X e
X e
PGxh
X
ASP2215 Dosing at the Clinic i
X
X
X
X
X
X
X
X
Cephalexin Dosing and PK Collection r
X r
X
X r
X
IRT Transaction Requiredp
X
X
X
X
X
X
X
X
X
ASP2215 Dispensing for Subject Take Home
X
X
X
X
X
X
X
a. Obtained predose.
b. Includes medications taken within 28 days prior to screening.
Footnotes continued on next page


Sponsor: APGD
ISN/Protocol 2215-CL-0101
EudraCT number 2014-002217-31
- CONFIDENTIAL –
02 Jun 2017
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Version 12.0, Incorporating Substantial Amendment 11
c. MUGA scans are to be performed at Screening for subjects with history of congestive heart failure NYHA Class 3 or 4 (unless MUGA scans performed either within 
3 months prior revealed LVEF ≥45%).
d. Screening ECGs are required. ECG assessment will be evaluated at D-1 and C1D15 at pre-dose, 2 hours post, and 24 hours post dose. 24 hr post-dose ECG assessment will be performed 
on C1D1 and C1D16 respectively. Pre-dose ECG assessment will also be evaluated on C1D1, C1D8, C1D22 and D1 of each subsequent cycle. All efforts should be made to conduct 
ECG monitoring in triplicate between 7:00 am and 3:00 pm at all assessment time points. Pre-dose assessments should be taken within 0.5 hours before drug administration. In addition, 
2 and 24 hour post-dose assessments should be performed within ± 0.5 hours of nominal time. 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. See Section 5.4.5  If the QTcF for a subject from Day 1 to Day 8 has increased 
> 30 ms with no other known etiology, a confirmatory ECG should be performed on Day 9 and a dose reduction considered. See Section 5.1.2 and footnote s. The mean QTcF of the 
triplicate ECG tracings based on central reading will be used for all treatment decisions.
e. Pre-dose (0.5 hours before drug administration) PK samples will be collected at C1D1, C1D8, C1D16, C1D22 and on Day 1 of each cycle starting at Cycle 2. See Section 5.6.1  PK 
samples for ASP2215 will be collected on C1D15 at pre-dose (0.5 hours before drug administration), 1 (±10 minutes), 2 (±10 minutes), 4 (±20 minutes), 6 (±20 minutes).
f. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of hCG) within 72 hours prior to the start of study treatment.
g. Bone marrow samples are required during Screening, Cycle 2 Day 1 and Cycle 3 Day 1. Screening samples may be collected up to 21 days prior to C1D1. For subjects who do not 
achieve a complete remission (CR, CRp, or CRi), the bone marrow assessments will be repeated at Day 1 of every 2 subsequent cycles. For subjects who achieve a complete remission 
(CR, CRp, or CRi), bone marrow will be repeated on one month after the date of remission and every 3 subsequent cycles for up to 1 year from Cycle 1 Day 1 and after that only if there 
is suspicion of relapse in the peripheral blood. Bone marrow samples are also required at the Early Termination/ End-of Study Visit, and as clinically indicated. If bone marrow aspirate is 
unobtainable (i.e., dry tap), an additional EDTA tube of peripheral blood should be collected instead.
h. Buccal swab collected at Screening for optional pharmacogenomic study.
i. ASP2215 is taken daily without food at home except for clinic days when it will be taken at the clinic. Subjects will be instructed to take the daily dose with water as close to the same 
time each morning as possible.
j. FLT3, C-CBL and AXL mutation status will be assessed from bone marrow sample taken at the Screening Visit. If bone marrow sample is unavailable (i.e., dry tap), the whole blood 
sample taken at the Screening Visit will be used.  
k. Ophthalmologic assessment to be performed by visual acuity measurement, ophthalmoscopy and slit lamp biomicroscopy, visual fields and optical coherence tomography (OCT) at 
Screening (within 12 days prior to dosing), 15th Day of Cycle 1 (± 3 days), 1st Day of Cycle 2 (± 3 days), Cycle 3 (± 3 days), and every 2 cycles thereafter (± 3 days), at the end of 
treatment, and when clinically indicated. 
l. Height measurement performed only at Screening. Weight measurement should be performed on D1 of each Cycle.
m. Subjects may be screened from local labs only. However, samples must also be submitted for central read.
n. Additional laboratory tests should be performed according to institutional standard of care.
o. Thyroids function tests will be repeated after every 2 cycles of therapy (C3D1, C5D1, C7D1 etc.).
p. For the purposes of drug preparation and dispensing activities, IRT Transactions may be done prior to the visit and do not need to fall within the protocol visit windows.
q.Chest X-ray (or CT of chest) does not need to be repeated if performed within 2 weeks prior to start of Screening.
r. Cephalexin (Total daily dose 500 mg via oral tablet or capsule) will be administered as a single dose on Days -1 and C1D15. Cephalexin plasma PK samples will be collected at D-1 
and C1D15 at pre-dose (0.5 hours before drug administration), 0.5 (±10 minutes), 1 (±10 minutes), 1.5 (±10 minutes), 2 (±10 minutes), 3 (±10 minutes), 4 (±20 minutes), 6 (±20 minutes), 
and 24 hours (±90 minutes) post dose (the 24 hour sample must be collected before the dose of ASP2215). 24 hr post-Cephalexin dose assessment will be performed on C1D1 and D16 
respectively. Urine samples for cephalexin PK will be collected on Day -1 and C1D15 at 0-3 hours, 3-6 hours and 6-24 hours post dose with urine volume recorded and a sample from 
each timepoint collected.
s. A Cycle 1 Day 8 ECG will be taken and the central read results will be provided to the site 24 hours after receipt of the tracing. A confirmatory ECG should be performed on 
Cycle 1 Day 9 if the mean QTcF from the central read ECG for Cycle 1 Day 1 to Cycle 1 Day 8 has increased > 30 ms with no other known etiology. On Cycle 1 Day 8, it is 
recommended that the ECG is taken as early as possible in the morning and transmitted immediately. In addition, it is recommended that the Cycle 1 Day 9 visit is scheduled later in the 
day in order to allow for receipt and assessment of the Cycle 1 Day 8 central read ECG. This also allows for a subject to be contacted if the Cycle 1 Day 9 ECG is no longer required. If 
the Cycle 1 Day 9 ECG is still required, the result of the central read ECG will be received on Cycle 1 Day 10, in which the investigator should assess if the ASP2215 dose modification 
should occur as per the dose interruption or reduction guideline in Section 5.1.2


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Table 2F
Post-Treatment Schedule of Assessments
Activity
End of 
Treatment Visit a
30-Day
Follow-Up i
Long-term 
Follow-Up j
Physical Examination
X b
Vital Signs
X b
ECOG Performance
X b
Concomitant Medications
X
Pregnancy Test for WOCBP
X
12-lead ECG
X c
Ophthalmologic Assessment 
X b
Clinical Laboratory Tests  (chemistry, hematology, coagulation, urinalysis)
X b
Bone Marrow Aspiration and Biopsy 
X h
FLT3, AXL and C-CBL Mutationsg (bone marrow aspirate or whole blood)
X
AE/SAE Assessment
Xd
X e 
IRT Transaction Required
X
Survival and Subsequent Anti-leukemic Treatments and Their Outcomes
X e
X f
a. End of Treatment Visit is to be performed within 7 days of last dose.
b. Does not need to be repeated if collected at a regularly scheduled visit within 3 days of the End of Treatment Visit.
c. ECG monitoring should be between 7:00 am and 3:00 pm, if possible.  
d. If the subject undergoes HSCT and does not resume ASP2215, SAE data will only be collected for 7 days after End of Treatment Visit
e. Telephone contact with the subject is sufficient unless any assessment must be repeated for resolution of treatment-related AEs. 
f. Telephone contact every 3 months after the 30-Day follow up.
g. FLT3, AXL and C-CBL mutation analysis will be performed for relapsed subjects.
h. Does not need to be repeated if collected within 2 weeks of the End of Treatment Visit.  
i.
The 30-day follow-up visit and long term follow-up visits will not be performed if subject is enrolled into the roll-over study (2215-CL-0109).
j. Long-term Follow-up will be discontinued upon termination of the study by the Sponsor


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1
INTRODUCTION
1.1
Background
AML accounts for approximately 80% of acute leukemias diagnosed in adults. The median 
age at diagnosis is 66 years. It is estimated that 13,780 people (7,350 men and 6,430 women) 
will be diagnosed with AML, and 10,200 will die from the disease in 2012 in the United 
States. [Howlader, 2011]. While 60% to 80% of younger patients achieve a complete 
remission with standard therapy, only about 20% to 30% of the overall patient population has 
long-term disease-free survival. Outcomes are worse for patients aged 60 years or over, with 
complete remission rates in the range of 40% to 55% and poor long-term survival rates.
Along with age, remission rates and overall survival depend on a number of other factors, 
including cytogenetics, previous bone marrow disorders (such as myelodysplastic syndromes) 
and co-morbidities. Currently, there is no effective cure for the disease.
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 over 
expressed in the majority of AML cases. In addition, activated FLT3 with internal tandem 
duplication (ITD) at juxtamembrane domain and tyrosine kinase domain (TKD) mutations at 
around D835 in the activation loop are present in 25% to 30% and 5% to 10% of AML cases, 
respectively [Schlenk, 2009]. These activated mutations in FLT3 are oncogenic, and show 
transforming activity in cells [Yamamoto, 2001]. Furthermore, patients with these activated 
FLT3 show poor prognosis [Yanada, 2005].
Axl is a member of TAM family (Tyro-3, Axl, and Mer) receptor tyrosine kinases and is 
normally expressed in cells of mesenchymal origin, such as osteoblasts, fibroblasts, and blood 
cells.  Axl has been reported to be overexpressed or activated in many cancers, including acute 
myeloid leukemia (AML) [Linger 2008]. Axl overexpression in AML confers drug resistance 
[Hong 2008] and is associated with adverse prognosis [Rochlitz 1999 and Ben-Batalla 2013]. 
Axl inhibition suppresses the growth of human FLT3-positive AML in vivo [Park 2013]. 
Finally, Axl inhibition is also active in FLT3-negative (but Axl expressing) AML in vivo 
[Ben-Batalla 2013].
ASP2215 hemifumarate is a new chemical entity (NCE) discovered by Astellas Pharma Inc. 
in collaboration with 
 ASP2215 has an inhibitory effect on 
tyrosine kinases, mainly FLT3, Axl and ALK. ASP2215 demonstrated favorable efficacy in a 
non-clinical AML model, which means complete regression of tumors in the xenograft model 
mice transplanted with MV4-11, human AML cell line expressing FLT3-ITD, by repeated 
oral doses. In addition, ASP2215 inhibited the growth of cells expressing either wild type 
FLT3, FLT3-ITD, FLT3-D835Y, or FLT3-ITD-D835Y.


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1.2
Non-clinical and Clinical Data
1.2.1
Non-clinical Studies
1.2.1.1
Nonclinical Pharmacology
Primary Pharmacodynamic Studies
Inhibitory activity of ASP2215 on various tyrosine kinases [2215-PH-0006]
The inhibitory activity of ASP2215 against 79 tyrosine kinases and the IC50 values against 
FLT3 and KIT kinases were evaluated.
Among 79 tyrosine kinases tested, ASP2215 inhibited activities of FLT3, NPM-ALK, LTK, 
ALK and AXL kinases at 1 nmol/L, and TRKA, ROS, RET and MER kinases at 5 nmol/L by 
over 50% [Table 1]. IC50 values against FLT3 and KIT kinase activities were 0.291 and 
229 nmol/L, respectively.  
Table 1
Inhibitory Effect of ASP2215 on Various Tyrosine Kinases
Kinase
% Inhibition
ASP2215 (nmol/L)
1
5
FLT3 
86.8
96.4
NPM1-ALK 
82.2
99.5
LTK 
81.8
97.5
ALK 
76.1
97.6
AXL 
54.3
85.5
TRKA 
38.3
74.9
ROS 
35.0
71.7
RET 
26.0
65.5
MER 
21.5
55.7
Affinity of ASP2215 to various receptors, ion channels, transporters and effect of ASP2215 
on enzyme reactions [2215-PH-0007]
The affinity of ASP2215 to 20 receptors, 3 ion channels, 2 transporters and the inhibitory 
effect of ASP2215 on 3 enzyme reactions were evaluated. ASP2215 at 10 mcmol/L showed 
> 50% inhibition against each radioligand binding to Serotonin 5HT2B (human) receptor, 
Sigma (non-selective, guinea pig) receptor, Serotonin 5HT1 (non-selective, rat) receptor, and 
Adenosine A1 (rat) receptor, with respective IC50 values of 0.190, 0.615, 4.90 and 
4.57 mcmol/L. Each radioligand binding to all other receptors, ion channels, and tested 
enzyme reactions were not inhibited by >50% by ASP2215 at 10 mcmol/L [Table 2 and 
Table 3].  


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Table 2
Inhibition Effect of ASP2215 on Radioligand Binding to Various Receptors, 
Ion Channels and Transporters
Assay name
Inhibition (%) 
ASP2215
Positive substance 
K Channel KATP (Rat) 
4.79 
99.15 (Glybenclamide) 
K Channel SkCa (Rat) 
20.31 
99.17 (Apamin) 
Leukotriene B4 (Guinea pig) 
0.00 
98.35 (Leukotriene B4) 
Leukotriene D4 (Guinea pig) 
30.22 
100.00 (Leukotriene D4) 
Melatonin MT1 (Human) 
6.53 
99.86 (Melatonin) 
Muscarinic (Non-selective) (Rat) 
11.73 
100.00 (Atropine) 
Muscarinic M1 (Human) 
31.45 
100.00 (Atropine) 
Muscarinic M2 (Human) 
3.94 
100.00 (Atropine) 
Na Channel Site 2 (Rat) 
35.38 
100.00 (Dibucaine) 
Neurokinin NK1 (Human) 
40.97 
99.59 (L-703,606) 
Neurokinin NK2 (Human) 
18.52 
100.00 (Neurokinin A) 
Neurokinin NK3 (Human) 
16.62 
99.23 (Senktide) 
Norepinephrine Transporter (Human) 
1.86 
100.00 (Desipramine) 
Nicotinic (Neuronal) (Rat) 
25.87 
100.00 ([±]-Nicotine) 
Opiate (Non-selective) (Rat) 
23.44 
100.00 (Naloxone) 
Opiate μ (Human) 
6.49 
96.41 (DAMGO) 
Oxytocin (Rat) 
2.95 
99.95 (Oxytocin) 
PAF (Rabbit) 
3.17 
98.07 (PAF) 
Serotonin 5HT1 (Non-selective) (Rat) 
54.61 
97.91 (Serotonin) 
Serotonin 5HT2B (Human) 
100.00 
99.98 (Serotonin) 
Serotonin Transporter (Human) 
0.35 
100.00 (Imipramine) 
Sigma (Non-selective) (Guinea pig) 
92.39 
100.00 (Haloperidol) 
Testosterone (Human) 
0.00 
99.60 (Testosterone) 
Vasopressin V1 (Rat) 
3.09 
96.95 ([Arg8]-Vasopressin) 
VIP 1 (Human) 
0.00 
99.88 (VIP) 
DAMGO: Dermorphin, endomorphin, morphiceptin, nociceptin, and octreotide; PAF: platelet-activating factor 
Test substance concentration: 10 mcmol/L, Positive substance concentration: 1 mcmol/L for leukotriene B4, 
leukotriene D4 and VIP, or 10 mcmol/L for the others. Data are expressed as the mean values of duplicate 
samples. 
Table 3
Inhibition Effect of ASP2215 on Various Enzymes
Assay name
Inhibition (%) 
ASP2215
Positive substance
Acetylcholinesterase (Human) 
0.00 
99.28 (Eserine) 
MAO-A (Rat) 
11.36 
97.18 (Clorgyline) 
MAO-B (Rat) 
0.00 
93.14 (Ro 16-6491) 
MAO-A: monoamine oxidase A; MAO-B: monoamine oxidase B Test substance concentration: 10 mcmol/L, 
Positive substance concentration: 100 mcmol/L for Ro 16-6491, or 10 mcmol/L for the others. Data are 
expressed as the mean values of duplicate samples. 
Effect of ASP2215 on the growth of Ba/F3 cells expressing FLT3 (wt, ITD, D835Y, and 
ITD-D835Y) [2215-PH-0009] 
The inhibitory effect of ASP2215 on proliferation of Ba/F3 cells expressing either FLT3-wt, 
FLT3-ITD, FLT3-D835Y, or FLT3-ITD-D835Y was evaluated.  Inhibition of cell growth 
was assessed by a luminescent cell viability assay (CellTiter-Glo™), where Ba/F3 cells were 


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exposed to ASP2215 for 2 days. ASP2215 inhibited the cell growth of Ba/F3 cells expressing 
FLT3-wt, FLT3ITD, FLT3-D835Y, and FLT3-ITD-D835Y with IC50 values of 0.92, 1.8, 1.6, 
and 2.1 nmol/L, respectively.
Effect of ASP2215 on the growth of MV4-11 cells [2215-PH0008]
The inhibitory effect of ASP2215 on proliferation of MV4-11 cells, AML cells endogenously 
expressing FLT3-ITD, was evaluated. Inhibition of cell growth was assessed by a 
luminescent cell viability assay (CellTiter-Glo™), where MV4-11 cells were exposed to 
ASP2215 for 5 days. 
ASP2215 inhibited the growth of MV4-11 cells with an IC50 value of 0.92 nmol/L.
Inhibitory effect of ASP2215 on phosphorylation of FLT3 in MV4-11 cells [2215-PH-0010]
The inhibitory effect of ASP2215 on phosphorylation of FLT3 in MV4-11 cells was 
evaluated.  ASP2215 was added to the wells containing MV4-11 cells to achieve final 
concentrations of 0, 0.1, 1, and 10 nmol/L. At 2 hours after addition of ASP2215, the amount 
of phosphorylated FLT3 was analyzed by immunoprecipitation and western-blotting. Signals 
for FLT3 and phosphorylated FLT3 were detected using a CCD camera and quantified using 
ImageQuant TL software. The signals for phosphorylated FLT3 were normalized using those 
for FLT3. The mean percentage of phosphorylated FLT3 relative to control was calculated.
In MV4-11 cells, ASP2215 at 0, 0.1, 1, and 10 nmol/L resulted in FLT3 phosphorylation of 
100%, 86%, 19%, and 7%, respectively [Figure 2].  
Figure 2
Inhibitory Effect of ASP2215 on FLT3 Phosphorylation in MV4-11 Cells
p-FLT3: phosphorylated FLT3 
Antitumor activity of once-daily oral administration of ASP2215 in an MV4-11 xenograft 
model [2215-PH-0011]
The antitumor effect of ASP2215 at 1 to 10 mg/kg per day for 28 days in mice xenografted 
with human AML derived MV4-11 cells was evaluated. Nude mice were subcutaneously 
inoculated with MV4-11 cells. Mice were orally treated with either vehicle (0.5% 
methylcellulose solution; Control group) or ASP2215 at 1, 3, 6, or 10 mg/kg/day, once daily 
for 28 days. Antitumor activity was expressed as percent inhibition of tumor growth and 
percent regression of tumor. Tumor volume and body weight on Day 28 in ASP2215 treated 
groups were compared with those in the control group. 
ASP2215 induced significant growth inhibition of MV4-11 tumors and tumor regression
[Figure 3]. Further, ASP2215 at 6 and 10 mg/kg/day induced complete tumor regression for 


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4 and 6 out of 6 mice, respectively [Table 4]. Body weight of the mice treated with ASP2215 
was not affected at any tested doses. 
Figure 3
Antitumor Effect of ASP2215 in an MV4-11 Xenograft Model
Mice were treated with ASP2215 from Days 0 to 27. Each point represents the mean ± SEM (N=6). Data on 
Day −1 were utilized as those on Day 0. Statistical analysis was performed for the values on Day 28. *: P<0.05, 
**: P<0.01 and ***: P<0.001 compared with the control group (Dunnett’s test). 
Table 4
Effect of Once-daily Oral Administration of ASP2215 on Tumor Growth and 
Regression in an MV4-11 Xenograft Model
Percent inhibition of 
tumor growth (%)
Percent 
regression of 
tumor (%)
Animal number with 
complete regression
ASP2215
1 mg/kg
63
--
--
3 mg/kg
80
--
--
6 mg/kg
>100
93
4/6
10 mg/kg
>100
100
6/6
Nonclinical Safety Pharmacology Studies 
In vitro Effects on hERG Current [2215-PT-0001] 
ASP2215 hemifumarate showed a concentration-dependent suppression effect on the hERG
current in hERG transfected HEK293 cells at concentrations of 3×10−6, 1×10−5, and
3×10−5 mol/L with compensated suppression rates of 18.1%, 32.8%, and 70.7%, respectively,
and did not at 1×10−6 mol/L. The IC50 was 1.6×10−5 mol/L.
In vivo Effects on Central Nervous System in Rats [2215-PT-0003]
ASP2215 hemifumarate showed no effects on the central nervous system in rats at 10 mg/kg. 
At 30 mg/kg and higher, decreased urination was noted. In addition, at 100 mg/kg, decreased 
defecation was noted.


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In vivo Effects on Central Nervous, Cardiovascular and Respiratory Systems in Dogs 
[2215-PT-0002]
ASP2215 hemifumarate did not show any effect on the cardiovascular or respiratory system 
in dogs up to 100 mg/kg, or on the central nervous system at 1 mg/kg. At 3 mg/kg and higher, 
the following signs were noted: retching at 3 mg/kg, vomiting and positive fecal occult blood 
at 10 mg/kg and higher, a decrease in the blood Ca concentration at 30 mg/kg, and salivation 
and an increase followed by a decrease in the blood Ca concentration at 100 mg/kg. All of the 
findings recovered.
1.2.1.2
Nonclinical Pharmacokinetics
In vitro metabolic activity of ASP2215 in recombinant human cytochrome P450 Enzymes 
[2215-ME-0001] 
In vitro metabolism studies using recombinant human CYP-expressing microsomes indicated 
that the main CYP isozyme involved in the metabolism of ASP2215 was estimated to be 
CYP3A4.
In vitro metabolic fingerprinting of ASP2215 [2215-ME-0002]
In vitro metabolic fingerprinting of ASP2215 in pooled liver microsomes and cryopreserved 
hepatocytes using [14C]ASP2215 hemifumarate indicated that all metabolite peaks of  
[14C]ASP2215-derived radioactivity detected in human liver microsomes and hepatocytes 
were also found in those of at least one other species, suggesting that no human-specific 
ASP2215 metabolites were formed by liver microsomes or hepatocytes.
In vitro plasma protein binding of ASP2215 in mice, rats, rabbits, dogs, monkeys, and 
humans [2215-ME-0010]
The plasma protein binding ratios of ASP2215 at concentrations of 0.1, 1, and 10 mcg/mL as 
free base of [14C]ASP2215 hemifumarate were 85.1% to 89.6% in normal mice; 75.4% to 
84.2% in pharmacological model mice; 77.7% to 79.2% in rats; 75.5% to 78.7% in rabbits; 
78.0% to 80.7% in dogs; 81.3% to 82.4% in monkeys; and 90.2% to 90.5% in humans. The
major binding protein in human plasma was human serum albumin.
Inhibitory effect of ASP2215 on the MDR1-mediated transport, and transcellular transport of 
ASP2215 in human MDR1 expressing cells [2215-ME-0011]
ASP2215 is a substrate for P-gp. Although ASP2215 has the potential of P-gp inhibition, its 
potential was not so strong and the IC50 was more than 30 mcmol/L.
Inhibitory effect of ASP2215 on the human MATE1- and MATE2-K-mediated transport 
[2215-ME-0020]
ASP2215 showed inhibitory effect on MATE1-mediated [14C] metformin transport and 
MATE2-K-mediated [14C]metformin transport in a concentration dependent manner. The 
IC50 values of ASP2215 were calculated to be 0.0543 μmol/L and 47.7 μmol/L, respectively.


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1.2.1.3
Nonclinical Toxicology
Single dose toxicity study [2215-TX-0001]
In the single oral dose toxicity study in rats, the approximate lethal dose level was 300 mg/kg
for males and females. The major change was a gastrointestinal hemorrhagic disorder at
100 and 300 mg/kg. Reversibility of the changes noted in the surviving animals was seen.
Repeated dose toxicity studies [2215-TX-3004, 2215-TX-0002, 2215-TX-0003]
In the 1-week oral repeated dose toxicity study in rats, interstitial pneumonia in the lung and
vacuolar change in the rod-cone layer of the retina were observed in a male at 30 mg/kg. In
the 13-week oral repeated dose toxicity study in rats, deaths occurred at 20 mg/kg/day in both
sexes. Target organ toxicity was identified in the gastrointestinal tract, immune system, bone
marrow, eye, lung, kidney, and liver. The no observed adverse effect level (NOAEL) was
lower than 2.5 mg/kg/day for males and females because low body weight was noted in
males and effects on the immune system (low lymphocytes and serum gamma-globulin ratio,
and low spleen weight) were noted in females. The changes noted during the dosing period
recovered or tended to recover during the 4-week recovery period. The severely toxic dose in
10% of the animals (STD10) in rats was considered to be 20 mg/kg/day. In the 4-week oral
repeated dose study in dogs, deaths or moribund sacrifices occurred in males at 10 mg/kg/day 
(1 out of 4 animals), 100 mg/kg/day (all 7 animals), and 1000 mg/kg/day (6 out of 7 animals). 
Target organ toxicity was identified in the gastrointestinal tract, immune system, bone 
marrow, eye, kidney, and liver. The NOAEL was 1 mg/kg/day for males and females since 
decreased body weight, increased aspartate aminotransferase (AST) and thymic atrophy in 
males, lymphocyte necrosis in the mesenteric lymph node in females, and a positive fecal 
occult blood reaction and increased alkaline phosphatase (ALP) in both sexes were observed 
at 2.5 mg/kg/day and higher. Reversibility of the test article-related changes was indicated at 
the end of the 4-week recovery period. The highest non-severely toxic dose (HNSTD) in 
dogs was considered to be 5 mg/kg/day.
Genotoxicity studies [2215-TX-3008, 2215-TX-3009, 2215-TX-3010, 2215-TX-3011, 
2215-TX-0004, 2215-TX-0005]
ASP2215 induced gene mutation in bacteria in the screening in vitro reversion test but the 
extent of the increase in the number of revertant colonies was marginal and the
dose-relationship was unclear. On the other hand, ASP2215 did not induce gene mutation in 
the definitive in vitro reversion test in bacteria. Therefore, it was concluded that ASP2215 
does not have a potential to induce gene mutation. Although ASP2215 induced micronuclei 
in the screening in vitro micronucleus test, it did not induce chromosomal aberrations in the 
definitive in vitro chromosomal aberration test in mammalian cells. The positive results in the 
screening test were obtained only at concentrations where evaluation could not be done due 
to cytotoxicity in the definitive study. It was concluded that ASP2215 does not have potential 
to induce chromosomal aberrations in vitro. The screening in vivo micronucleus test showed 
that ASP2215 has a potential to induce chromosomal aberrations in mice. Based on the 
results of the battery of genotoxicity studies above, it was concluded that ASP2215 has a 
potential to induce genotoxicity in vivo.


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Phototoxicity study [2215-TX-0006]
ASP2215 hemifumarate showed no potential to induce phototoxicity to cultured mammalian
cells (Balb/c 3T3 cells) under the conditions of this study.
1.3
Summary of Key Safety Information for Study Drugs
1.3.1
Pre-Clinical Data
ASP2215 hemifumarate showed a concentration-dependent suppression effect on the hERG 
current in HEK293 cells at concentrations of 3x10-6, 1x10-5, and 3x10-5 mol/L with 
compensated suppression rates of 18.1%, 32.8%, and 70.7%, respectively, and did not at 
1x10-6 mol/L. The IC50 was 1.6x10-5 mol/L.
ASP2215 hemifumarate showed no effects on the central nervous system in rats at 10 mg/kg. 
At 30 mg/kg and higher, decreased urination was noted. In addition, at 100 mg/kg, decreased 
defecation was noted.
ASP2215 hemifumarate did not show any effect on the cardiovascular or respiratory system 
in dogs up to 100 mg/kg, or on the central nervous system at 1 mg/kg. At 3 mg/kg and higher, 
the following signs were noted: retching at 3 mg/kg, vomiting and positive fecal occult blood 
at 10 mg/kg and higher, a decrease in the blood Ca+2 concentration at 30 mg/kg, and 
salivation and an increase followed by a decrease in the blood Ca+2 concentration at 
100 mg/kg. All of the findings recovered.
In the single oral dose toxicity study in rats, the approximate lethal dose level was 300 mg/kg 
for males and females. The major change was a gastrointestinal hemorrhagic disorder at 
100 and 300 mg/kg. Reversibility of the changes noted in the surviving animals was seen. No 
single oral dose toxicity study in dogs was conducted. In the 4-week toxicity study in dogs, a 
dose of 1000 mg/kg/day caused deaths and moribund sacrifices on Day 2. The cause of death 
and moribundity was considered to be deterioration of general condition caused by 
gastrointestinal hemorrhage. The MTD was 5 mg/kg/day.
In the 1-week oral repeated dose toxicity study in rats, interstitial pneumonia in the lung and 
vacuolar change in the rod-cone layer of the retina were observed in a male at 30 mg/kg. In 
the 13-week oral repeated dose toxicity study in rats, deaths occurred at 20 mg/kg/day in both 
sexes. Target organ toxicity was identified in the gastrointestinal tract, immune system, bone 
marrow, eye, lung, kidney, and liver. The NOAEL was lower than 2.5 mg/kg/day for males 
and females because low body weight was noted in males and effects on the immune system 
(low lymphocytes and serum gamma-globulin ratio, and low spleen weight) were noted in 
females. The changes noted during the dosing period recovered or tended to recover during 
the 4-week recovery period. STD10 in rats was considered to be 19 mg/kg/day. In the 4-week 
oral repeated dose study in dogs, deaths occurred at 10 mg/kg/day or more. Target organ 
toxicity was identified in the gastrointestinal tract, immune system, bone marrow, eye, 
kidney, and liver. The NOAEL was 1 mg/kg/day for males and females since decreased body 
weight, increased AST and thymic atrophy in males, lymphocyte necrosis in the mesenteric 
lymph node in females, and a positive fecal occult blood reaction and increased ALP in both 


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sexes were observed at 2.5 mg/kg/day or higher. Reversibility of the test article related 
changes was indicated at the end of the 4-week recovery period. The HNSTD in dogs was 
considered to be 5 mg/kg/day. The first human dose is 20 mg/day based on the STD10.
Ocular toxicities (lens opacity, inflammation in the uvea and conjunctiva, and vacuolation in 
the rod-cone layer in the retina in rats, and dark discoloration of the ocular fundus in dogs) 
were observed. The lens opacity and inflammatory changes were reversible. In addition, the 
changes were observed only at the highest dose level in each study which was MTD or 
beyond MTD with low incidence. Therefore, these changes would not indicate a significant 
risk in clinical studies. In dogs, at the highest dose level of 5 mg/kg/day, abnormal fundus 
finding and OCT change were observed in some animals without any histopathological 
changes in the eye and these findings were reversible after the 4-week withdrawal period.  
ASP2215 induced gene mutation in bacteria in the screening in vitro reversion test but the 
extent of the increase in the number of revertant colonies was marginal and the dose 
relationship was unclear. On the other hand, ASP2215 did not induce gene mutation in the 
definitive in vitro reversion test in bacteria. Therefore, it was concluded that ASP2215 does 
not have a potential to induce gene mutation. Although ASP2215 induced micronuclei in the 
screening in vitro micronucleus test, it did not induce chromosomal aberrations in the 
definitive in vitro chromosomal aberration test in mammalian cells. The positive results in the 
screening test were obtained only at concentrations where evaluation could not be done due 
to cytotoxicity in the definitive study. It was concluded that ASP2215 does not have a 
potential to induce chromosomal aberrations in vitro. The screening in vivo micronucleus test 
showed that ASP2215 has a potential to induce chromosomal aberrations in mice. Based on 
the results of the battery of genotoxicity studies above, it was concluded that ASP2215 has a 
potential to induce genotoxicity in vivo.
ASP2215 hemifumarate showed no potential to induce phototoxicity to cultured mammalian 
cells (Balb/c 3T3 cells) under the conditions of this study.
1.3.2
ASP2215 Clinical Data
Of the first 154 patients that received ASP2215, 147 (95.5%) developed at least one Treatment 
Emergent Adverse Event (TEAE) during the study.  Overall, the most frequently reported 
TEAEs (occurring in at least 10% of patients) include febrile neutropenia (34.4%), anemia 
(27.9%), fatigue (26.6%), diarrhea (26.0%), peripheral edema (20.8%), increased AST (19.5%), 
dyspnea (18.2%), dizziness (16.9%), epistaxis (16.2%), constipation (15.6%), pyrexia, 
increased ALT and cough (14.9% each), nausea, sepsis and hypotension (14.3% each), 
vomiting (13.6%), increased blood creatinine and hypokalemia (13.0% each), decreased 
platelet count and hypocalcemia (12.3% each), hypomagnesemia (11.7%), hyponatremia 
(11.0%), thrombocytopenia, pneumonia and increased blood alkaline phosphatase (10.4% 
each).  A total of 102 (66.2%) patients experienced at least 1 TEAE considered by the 
Investigator to be at least possibly related to study drug. Common drug-related TEAEs 
(occurring in at least 5% of patients) include fatigue (13.6%), diarrhea (10.4%), anemia, 
constipation (9.1% each), increased AST (8.4%), nausea, peripheral edema, decreased platelet 


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count (7.8% each), dizziness (7.1%), thrombocytopenia, vomiting (6.5% each) and increased 
ALT (5.8%). 
A total of 112 (72.7%) of the patients developed at least one serious TEAE. The most 
commonly reported serious TEAE (occurring in at least 5% of patients) include febrile 
neutropenia (27.3%), sepsis (13.0%), AML (9.7%), pneumonia (6.5%), hypotension (5.8%), 
and diarrhea (5.2%). Of the serious TEAEs, 31 (20.1%) patients had serious TEAEs that were 
considered by the Investigators to be at least possibly related to ASP2215. Drug-related 
serious TEAEs that occurred in 2 more patients include febrile neutropenia (1.9%), diarrhea 
and abnormal liver function test (1.3% each).  The most commonly reported drug-related 
serious TEAEs occurred in the MedDRA System Organ Class of Infections and infestations 
(bacteraemia, diverticulitis, sepsis, and urosepsis) and Blood and lymphatic system disorders 
(anemia, febrile neutropenia, hemolytic anemia).
After the data cutoff, 1 patient in the 200 mg dose group developed altered mental status and 
1 episode of seizure with MRI results consistent with posterior reversible encephalopathy 
syndrome (PRES). ASP2215 was discontinued and the patient’s symptoms resolved.  
Additionally, 1 case of rhabdomyolysis with associated CK elevations was reported in a patient 
in the 300 mg dose group. Both SAEs were considered DLTs.
At doses of 120 mg/day and higher, moderate increases (grade 2) in creatinine kinase were 
seen in 10 of 59 patients (17%). One patient (1.6%) had severe (grade 3) elevation in creatinine 
kinase. For CK, 21 (13.6%) of patients experienced a shift of 2 grades or higher, and these 
shifts appeared to increase with increasing dose.  For ALT, 19 (12.3%) patients experienced a 
shift of 2 grades or higher.  For AST, 19 (12.3%) patients experienced a shift of 2 grades or 
higher.
1.4
Risk-Benefit Assessment
Approximately 30% of adult AML patients are refractory to induction therapy. Furthermore, 
of those who achieve CR, approximately 75% will relapse. Generally, there is no established 
standard for these patients and less than 20% will achieve CR with subsequent treatment.  
The response duration for patients who achieve CR with subsequent treatment is limited and 
most of the patients relapse. Patients who are in 2nd relapse or refractory to 1st salvage have 
an extremely poor prognosis, with survival measured in weeks. 
Some of the issues with other FLT3 inhibitor compounds are their short duration of disease 
control due to point mutations, prolonged myelosupression and corrected QT interval (QTc) 
prolongation. 
ASP2215 inhibits FLT3-ITD and FLT3 point mutations (D835). FLT3 is over-expressed in 
the majority of AML cases. There are activating FLT3 mutations in approximately 35% of 
AML cases. These mutations increase the transforming activity and decrease the prognosis 
for AML patients. 
ASP2215 showed no significant findings in the safety pharmacology studies. In the repeated 
dose toxicity studies with rats and dogs, mortality was shown and all major findings were 


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reversible and monitorable. ASP2215 has the potential to induce chromosomal aberrations in 
vivo. However, this potential will not interfere with human clinical studies recruiting AML 
patients, considering its potential benefit against the risk.
2
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS
2.1
Study Objectives
2.1.1
Primary Objectives
●
Assess the safety and tolerability, including determination of the maximum tolerated 
dose (MTD) of oral ASP2215 in subjects with relapsed or treatment-refractory AML.
●
Determine the pharmacokinetic (PK) parameters of ASP2215. 
2.1.2
Secondary Objectives
●
Investigate the anti-leukemic activity of various doses of ASP2215 in subjects with AML. 
●
Evaluate the effect of strong or moderate cytochrome P450-isozyme3A4 (CYP3A4) 
inhibitors on the PK of ASP2215.
●
Evaluate the potential induction of CYP3A4 by ASP2215 by assessment of midazolam PK.
●
Evaluate the effect of ASP2215 on MATE1 substrates by assessment of cephalexin PK.
2.2
Study Design and Dose Rationale
2.2.1
Study Design
This study is an open-label, dose escalation, first-in-human study in subjects with relapsed or 
refractory AML, with concomitant expansion cohort for multiple doses. One cycle is defined 
as 28 days and the subject will receive oral ASP2215 daily. The study treatment will continue 
until one of the discontinuation criteria is met or until rollover into the 2215-CL-0109 study. 
The starting dose level of ASP2215 is 20 mg daily and the decision to dose escalate to the next 
dose level will be made based on the assessment of safety variables including occurrence of 
grade 2 adverse events (AE) or DLTs.  
This study will have two cohorts of subjects [Figure 4 and Figure 5]:
●
Cohort 1: Dose escalation cohort
●
Cohort 2: Dose expansion cohort
Cohort 1 
Cohort 1 will comprise the initial dose escalation cohort with up to 10 dose levels [Table 5]. 
This cohort will be run at approximately 5 centers which will only participate in the dose 
expansion cohort (Cohort 2) if the enrollment in the dose escalation cohort (Cohort 1) is on a 
pause (i.e., dose level being tested at the time is fully enrolled and the one higher dose level 
has not yet been opened) . Subjects will be treated daily in 28 day cycles (with the exception 
of Cycle 1 where subjects will receive 29 doses). The DLT observation period is 30 days 
starting with the first dose taken on Day -2, and including the first 28 day treatment cycle. 


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Subjects in Cycle 1 will have PK sampling performed prior to start of the first cycle and after 
receiving a single dose of the study drug on Day -2. 
This study will follow an accelerated titration design. Dose levels are set at around 50% 
increments. One subject will be treated at the starting dose level of 20 mg. If no DLT is 
identified, the next subject will be enrolled at double the dose level, i.e., dose level 3 (40 mg 
see Table 5). This dose escalation approach will continue wherein only odd numbered dose 
levels (1, 3, 5) are tested until the first instance of a DLT or second instance (observed in two 
subjects at any of these dose levels) of a grade 2 AE judged related (e.g., possibly, probably, or 
definitely) by the investigator to be related to study drug (except for hematologic toxicities) 
occur.  
When a DLT or second instance (observed in two subjects) of grade 2 AE related to study drug 
is observed in a subject, the dose escalation schedule will stop the double-dose level method 
and follow the next consecutive dose level in Table 5 utilizing the modified 3+3 design. 
Modified 3+3 design testing each consecutive dose level may also be followed if recommended 
by dose escalation committee based on the review of pharmacokinetics data.  After dose level 5 
(80 mg), each subsequent dose level (6-10) will be tested using the 3+3 design. In this phase, 3 
subjects will be treated at each dose level. If no DLTs are observed, the subsequent subjects 
will be treated at the next dose level. If one DLT is observed in a dose level, 3 more subjects 
will be enrolled at that dose level. If the 3 additional subjects do not experience a DLT, the 
next dose level will be initiated. If 2 or more DLTs occur in a dose level, DLT will be 
established. The next lower dose level will be declared the maximum tolerated dose (MTD).
Subject replacement in the dose escalation cohort (Cohort 1)
A subject that receives less than 80% of the intended dose during Cycle 1 (e.g., misses 
6 daily doses or leaves the study for reasons other than a DLT), will not be evaluable for 
DLT and will be replaced by another subject in the dose level. In addition, if after enrollment 
any subject is found not to fulfill any inclusion/exclusion criteria that would adversely affect 
safety or efficacy evaluation of that subject, they may be replaced after discussion between 
the Principal Investigator and Medical Monitor.
Cohort 2
Cohort 2 is the dose expansion cohort. This cohort will be conducted at approximately 
35 additional centers that will not participate in the dose escalation cohort (Cohort 1). 
However, those centers participating in Cohort 1 may participate in Cohort 2 after the 
completion of the dose escalation phase (Cohort 1). Cohort 1 centers may also enroll patients 
in Cohort 2 if the enrollment in Cohort 1 is on a pause (i.e., dose level being tested at the time 
is fully enrolled and the one higher dose level has not yet been opened). Subjects will be 
treated daily in 28 day cycles. The DLT observation period is based on one completed 
cycle starting with the first dose taken on C1D1. 


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In the dose expansion phase (Cohort 2), a dose level may be expanded as follows: 
●
If one subject in the dose escalation cohort (Cohort 1) at any dose level achieves complete 
remission (CR), complete remission with low platelets (CRp) or complete remission with 
incomplete hematologic recovery (CRi) then this dose level will continue to enroll a 
minimum of 3 subjects. After the decision is made to escalate to the next dose level (0/3 or 
1/6 DLTs observed), the dose level will be expanded to enroll up to 17 additional subjects. 
All subsequent dose levels will also be expanded following a dose escalation decision for 
the dose level in the dose escalation cohort (Cohort 1). When more than one dose levels are 
expanded in the dose expansion cohort (Cohort 2), the newly enrolled patients will be 
randomized to all open expanded dose levels).
●
In the absence of a CRc, if the median decrease of FMS-like tyrosine kinase (FLT3) 
phosphorylation in plasma inhibitory assay (PIA) is equal or greater than 90% in a dose 
level with at least 3 subjects, then this dose level and the subsequent levels will be 
expanded following a dose escalation decision for the dose level (0/3 or 1/6 DLTs 
observed) in the dose escalation cohort (Cohort 1).
Subjects will be assigned in the dose escalation cohort (Cohort 1) or randomized in the dose 
expansion cohort (Cohort 2) to one of the open dose levels as defined in the statistical 
methodology section [Section 7]. At least 10 subjects with FLT3 mutations (ITD or 
activating point mutations) will be enrolled to each expanded dose level (including the 
subjects in the dose escalation cohort). Dose levels at and above 120 mg will be further 
expanded (when found to be tolerable in Cohort 1) based on the efficacy results observed in 
escalation and expansion cohorts as described in the Statistical section. At least 42 evaluable 
subjects with FLT3 mutations will be enrolled in dose levels selected for further expansion 
[Figure 5].  The safety in the dose expansion cohort (Cohort 2) will be monitored using 
Bayesian logistic regression modeling, as described in Section 7, based on the DLT rate 
observed in subjects from both the dose escalation and expansion cohorts. In the dose 
expansion cohort (Cohort 2), and for the first dose level only, the effect of CYP3A4 
inhibition for strong inhibitor voriconazole (Schedule 2B) will be evaluated in all subjects in 
the dose level. In the dose expansion cohort (Cohort 2), and at the highest dose level of 
ASP2215 (MTD or one level below MTD), the effect of ASP2215 on midazolam 
pharmacokinetics (Schedule 2D) will be evaluated. After completion of the CYP3A4 
inhibition expansion (Schedule 2B) and until MTD is determined, Cohort 2 subjects will 
participate without the DDI component (Schedule 2C). DDI studies (Schedules 2B, 2D and 
2E) will be conducted in the United States only.  European sites whose patients are 
randomized to the DDI arms of the study will follow Schedule 2C and will not administer 
their patients these medications. In addition, US sites approved by the sponsor to join the trial 
who cannot conduct the DDI portion of the trial will also be allowed to follow Schedule 2C 
even if patients are randomized to Schedule 2B or 2D.
Patients who have a contraindication to voriconazole or midazolam can participate in the trial 
without the DDI component (Schedule 2C) after discussion with the medical monitor. 


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If the first dose level closes prior to 12 patients completing the DDI component with 
voriconazole, the next lowest dose level open for enrollment will participate according to 
Schedule 2B to evaluate the effect of CYP3A4 inhibition for strong inhibitor voriconazole.
To further evaluate drug-drug interaction (DDI), a sub-study with a MATE1 substrate will be 
conducted [Table 2E].  This cohort will have approximately 20 subjects and will be enrolled 
at 200 mg.  The goal of this sub-study is to evaluate the effect of ASP2215 on the MATE1 
transporter.  The pharmacokinetics of 500 mg cephalexin will be investigated prior to 
initiation of ASP2215 treatment at Cycle 1 Day -1 and at Day 15 of Cycle 1.  This DDI sub-
study (Schedule 2E) will be conducted in the United States only.  Subjects who have severe 
allergies to penicillins or cephalosporins cannot participate in this sub-study cohort.
Safety Information: Summary safety tables from the Dose escalation cohort (Cohort 1) 
meetings will be shared with all investigators participating in both cohorts (escalation and 
expansion). These tables include severe and non-severe AEs.  
Intra-subject dose escalation for Cohorts 1 and 2:  
In the dose escalation cohort (Cohort 1), if the subjects on 20 mg and 40 mg dose levels do 
not achieve a composite CR (CRc), defined as either of CR, CRp or CRi, after 1 cycle of 
treatment and did not have DLT, they may dose escalate to the next dose level. 
In the dose expansion cohort (Cohort 2), subjects who do not achieve a CRc may dose 
escalate to the next dose level, if the next dose level has opened up for expansion (i.e., a 
decision has been made to escalate to next higher dosing level). 
Subjects who dose escalate will revert to more frequent safety evaluations [Section 5.1.2].
Continuation of Subjects in open label roll over study:
Should the Sponsor make the decision to end the study after primary analysis, all subjects 
receiving ASP2215 may be enrolled in an ASP2215 rollover study (2215-CL-0109).  
Subjects must not meet any discontinuation criteria for this study and must meet the entry 
criteria for the rollover study prior to being enrolled. 
Subjects who choose not to participate or are not eligible for Study 2215-CL-0109 will 
complete their participation in Study 2215-CL-0101 by completing the End of Treatment 
follow up visit upon activation of Study 2215-CL-0109 at the institution.
Subjects, who are being followed for Long-term Follow-up at the time of study closure, will 
be discontinued.    


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Figure 4
Optimal Dose Escalation and Expansion


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Figure 5
Optimal Efficacy Expansion of Cohort 2
Table 5
Dose Levels
Dose Level
ASP2215 Dose
DL1
20 mg
DL2*
30 mg
DL3
40 mg
DL4*
60 mg
DL5
80 mg
DL6
120 mg
DL7
200 mg
DL8**
300 mg
DL9
450 mg
DL10
600 mg
* These dose levels may be omitted as described in Section 2.2.1 Study Design.
** For patients being treated with 40 mg tablets, dose escalations to 280 mg will be permitted


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2.2.2
Dose Rationale
ASP2215 has been tested in numerous pre-clinical studies. In the repeated dose toxicity 
studies, deaths due to deteriorated general conditions occurred at 20 and 10 mg/kg/day in rats 
and dogs, respectively. Target organs were the gastrointestinal tract, immune system, eye, liver, 
kidney, lung and/or bone marrow in rats and dogs at ASP2215 doses at 2.5 mg/kg/day or more. 
All major findings were reversible and monitorable. STD10 and HNSTD were 20 and 
5 mg/kg/day in rats and dogs, respectively. Human equivalent doses based on body surface 
area conversion (factor: 0.162 for rat, 0.541 for dog) of the STD10 in rats and the HNSTD in 
dogs are 3.2 mg/kg and 2.7 mg/kg, respectively. One tenth of the rat STD10 is 19 mg for a 
person of 60 kg body weight (3.2 mg/kg x 1/10 x 60 kg) and one sixth of the dog HNSTD is 
27 mg for a person of 60 kg body weight (2.7 mg/kg × 1/6 × 60 kg). The first human dose is 
20 mg/day based on the rat STD10.
2.3
Endpoints
2.3.1
Primary Endpoints
●
Safety and Tolerability (Determine MTD)
●
Pharmacokinetics (ASP2215)
2.3.1.1
Definition of DLT
A DLT is defined as any of the following events that occur within 30 days starting with the 
first dose taken on Day -2, and including the first treatment cycle in dose escalation cohort 
(Cohort 1) and that is considered to be possibly or probably related to study drug. In 
Cohort 2, DLT observation period is the first treatment cycle (28 days).
Any Grade ≥ 3 non-hematologic or extramedullary toxicity. The following exceptions are 
noted:
●
Alopecia, anorexia, or fatigue.
●
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.
●
Grade 3 fever with neutropenia, with or without infection.
●
Grade 3 infection.
Hematologic toxicity will not be considered as a DLT. However, prolonged myelosuppression 
defined as ANC <500 for more than 21 days off therapy in the absence of evidence of active 
leukemia in the marrow or blood will be considered as a DLT.
2.3.2
Secondary Endpoints
●
Efficacy of ASP2215 in AML 
o
CR rate
o
CRc rate (CR + CRp + CRi)
o
Best response rate (CRc + partial remission [PR])
o
Duration of response


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o
Overall survival
o
Event free survival
o
Leukemia free survival
●
Pharmacokinetics of ASP2215, effect of strong or moderate CYP3A4 inhibitors 
●
Pharmacokinetics of midazolam, potential induction of CYP3A4 by ASP2215 
●
Pharmacokinetics of cephalexin, MATE1 inhibition by ASP2215
2.3.3
Exploratory Endpoints
 
3
STUDY POPULATION
3.1
Selection of Study Population 
Subjects with AML who relapsed after or are refractory to induction or salvage treatment will 
be selected for this study. Re-Screening is allowed, with a limit of two re-screenings for 
any potential subject. 
Re-Enrollment into the trial will be permissible for subjects who discontinue treatment for 
reasons other than toxicity or disease progression as long as they fulfill all Inclusion and 
Exclusion Criteria. All subjects that re-enroll will enroll into Cohort 2 and will follow the 
assigned Schedule of Assessments as if they are a new subject.
3.2
Inclusion Criteria
Waivers to the inclusion criteria will NOT be allowed.
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., HIPAA 
Authorization for U.S. 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 ≥ 18 years of age at the time of obtaining informed consent.


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3.
Subject is defined as morphologically documented primary or secondary AML by the 
World Health Organization (WHO) criteria (2008) 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 has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
5.
Subject’s interval from prior treatment to time of study drug administration is at least 
2 weeks for cytotoxic agents (except hydroxyurea given for controlling blast cells), or at 
least 5 half-lives for prior experimental agents or noncytotoxic agents. 
6.
Subject must meet the following criteria as indicated on the clinical laboratory tests*:
●
Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
≤2.5 institutional upper limit normal (ULN)
●
Total serum bilirubin ≤ 1.5 institutional ULN
●
Serum creatinine ≤ 1.5 institutional ULN or an estimated glomerular filtration 
rate (eGFR) of > 50 ml/min as calculated by the Modification of Diet in Renal 
Disease (MDRD) equation.
7.
Subject is suitable for oral administration of study drug.
8.
Female subject must be either:
●Of non child bearing potential:
●post-menopausal (defined as at least 1 year without any menses) prior to 
Screening, or
●documented surgically sterile or status post hysterectomy (at least 1 month 
prior to Screening)
●Or, if of childbearing potential, 
●must have a negative urine pregnancy test at Screening*, and 
●must use two forms of birth control** (at least one of which must be a barrier 
method) starting at Screening and throughout the study period and for 180
days after the final study drug administration.
9.
Female subject must not be breastfeeding at Screening or during the study period, and 
for 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 180 days after the final study drug administration.
11. Male subject and their female spouse/partners who are of childbearing potential must be 
using highly effective contraception consisting of two forms of birth control** (one of 
which must be a barrier method) starting at Screening and continue throughout the study 
period and for 120 days after the final study drug administration.
12. Male subject must not donate sperm starting at Screening and throughout the study 
period and for 120 days after the final study drug administration.
13. Subject agrees not to participate in another interventional study while on treatment.


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MATE1 Sub-study (Schedule 2E) Subjects Only:
14. Subject has documented FLT3 mutation positive AML (ITD and/or activating point 
mutations)
*Screening labs and diagnostic tests may be performed at local laboratories to determine 
eligibility. However, samples will also be submitted for central read.
**Acceptable forms of birth control include:
●Established use of oral, injected or implanted hormonal methods of contraception.
●Placement of an intrauterine device (IUD) or intrauterine system (IUS).
●Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/suppository
3.3
Exclusion Criteria
Waivers to the exclusion criteria will NOT be allowed.
Subject will be excluded from participation if any of the following apply:
1.
Subject was diagnosed as acute promyelocytic leukemia (APL).
2.
Subject has BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast crisis).
3.
Subject has active malignant tumors other than AML or Myelodysplastic syndrome 
(MDS).
4.
Subject has persistent nonhematological toxicities of ≥ Grade 2 (CTC AE v4), with 
symptoms and objective findings, from prior AML treatment (including chemotherapy, 
kinase inhibitors, immunotherapy, experimental agents, radiation, or surgery).
5.
Subject has had hematopoietic stem cell transplant (HSCT) and meets any of the 
following:
●
Is within 2 months of transplant from C1D1
●
Has clinically significant graft-versus-host disease requiring treatment
●
Has ≥ Grade 2 persistent non-hematological toxicity related to the transplant
Donor lymphocytes infusion (DLI) is not permitted ≤ 30 days prior to study registration 
or during the first cycle of treatment on the study in Cohort 1 and first two cycles of the 
treatment in Cohort 2.
6.
Subject has clinically active central nervous system leukemia.
7.
Subject has disseminated intravascular coagulation abnormality (DIC)*.
8.
Subject has had major surgery within 4 weeks prior to the first study dose.
9.
Subject has had radiation therapy within 4 weeks prior to the first study dose.
10. Subject has congestive heart failure NYHA class 3 or 4, or subject with a history of congestive 
heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram performed 
within 3 months prior to study entry results in a left ventricular ejection fraction that is ≥ 45%*.


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11. Subject with mean Fridericia-corrected QT interval (QTcF) > 450 ms at Screening based 
on central reading.
12. Subject with Long QTc Syndrome at Screening.
13. Subject with hypokalemia and hypomagnesemia at Screening (defined as values below 
lower limit of normal [LLN]).
14. Subject requires treatment with concomitant drugs that are strong inhibitors or inducers 
of CYP3A4 or of P-glycoprotein (P-gp) or substrates of multidrug and toxin extrusion 
1 (MATE 1) with the exception of antibiotics, antifungals, and antivirals that are used as 
standard of care post-transplant or to prevent or treat infections and other such drugs that 
are considered absolutely essential for the care of the subject.
15. Subject required treatment with concomitant drugs that target serotonin 5HT1R or 
5HT2BR receptors or sigma nonspecific receptor with the exception of drugs that are 
considered absolutely essential for the care of the subject.
16. Subject has an active uncontrolled infection*.
17. Subject is known to have human immunodeficiency virus infection. 
18. Subject has active hepatitis B or C, or other active hepatic disorder*.
19. Subject has any condition which, in the investigator’s opinion, makes the subject 
unsuitable for study participation (e.g., ophthalmic conditions such as advanced 
cataracts, subject is unable to undergo a comprehensive ophthalmologic exam, inability 
to visualize the fundus).  
MATE1 Sub-study (Schedule 2E) Subjects Only:
20. Subject has known severe allergy to penicillins or cephalosporins.
21. Subject was previously treated with ASP2215.
*Screening labs and diagnostic tests may be performed at local laboratories to determine 
eligibility. However, samples will also be submitted for central read.
4
TREATMENT(S)
4.1
Identification of Investigational Product(s)
4.1.1
Test Drug(s)
ASP2215 is an oral tablet that is available in a 10 mg tablet or a 100 mg tablet. The tablets 
are contained within blister cards. 
There will be a total of 140 tablets per carton (10 cards per carton and 14 tablets per card). The 
study site personnel will fill out the sub carton dispensing label to indicate the subject's 
ASP2215 dose and the corresponding number of tablets that need to be taken each day. 


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ASP2215 is also available in a 10 mg tablet, 40 mg tablet, and 100 mg tablet. The tablets are 
contained within 30 count bottles. 
4.2
Packaging and Labeling
All medication used in this study will be prepared, 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 Standard Operating Procedures (SOPs), Good 
Manufacturing Practice (GMP) guidelines, ICH GCP guidelines, and applicable local 
laws/regulations.
Each blister pack and bottle will bear a label conforming to regulatory guidelines, GMP and 
local laws and regulations which identifies the contents as investigational drug.
The study centers will be provided cartons containing 10- 2x7 blisters cards. Blistered 
ASP2215 should be stored between (2◦C to 8◦C) and protected from light, with excursions in 
the temperature permitted from (0◦C to 15◦C).  Temperature logs are to be maintained by the 
site with the storage temperatures recorded daily (at minimum).
Study centers will be provided bottles containing 30 tablets of ASP2215 10 mg, 40 mg or 
100 mg. Bottled ASP2215 should be stored at room temperature between 20°C and 25°C 
(68°F and 77°F) and protected from light in a tight container, with excursions in temperature 
permitted between 15°C and 30°C (59°F and 86°F).  
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,
●
that study drug is handled and stored according to labeled storage conditions,
●
that study drug with appropriate expiry/retest and is only dispensed to study subjects in 
accordance with the protocol, and
●
that any unused study drug is returned to the Sponsor or destroyed according to 
Institutional SOPs.
Drug inventory and accountability records for the study drugs 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 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 test 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.


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●
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 medication. 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 must return study drug to the Sponsor or designee at the end of the study or 
upon expiration or destroyed according to Institutional SOPs.
4.4
Blinding
This section is not applicable as this is an open label study. 
4.5
Assignment and Allocation
Patient assignment will be performed manually until the availability of the Interactive 
Response Technology (IRT) during the Escalation phase (Cohort 1). Prior to the initiation of 
the study treatment, the site staff will complete and forward the subject registration form to 
the Astellas designee to receive the assigned treatment. Specific procedures for assignment 
are contained in the Regulatory Binder. After the IRT system becomes available, patients will 
be registered, enrolled and assigned treatment through IRT interactions. Specific procedures 
for randomization through the IRT are contained in the IWRS Manual in the Regulatory 
Binder.
Randomization will be performed via Interactive Response Technology (IRT) during 
Expansion phase (Cohort 2). Prior to the initiation of the study treatment, the site staff will 
contact the IRT in order to determine the randomized treatment. Specific procedures for 
randomization through the IRT are contained in the IWRS Manual in the Regulatory Binder.
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
ASP2215 is an oral tablet that subjects will take once daily without food allowed for at least 
2 hours before and 1 hour after dosing for continuous 28 day cycles. Subjects will be instructed 
to take the daily dose with water as close to the same time each morning as possible. ASP2215 
will be self administered at home when subjects are not scheduled for clinic visits.
If a subject forgets to take a dose in the morning and it is before 1:00 p.m., they should be 
instructed to take their dose.  If the subject forgets to take their daily dose and it is after 
1:00 p.m., 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.






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See [Table 2D]:  Schedule of Assessments for Expansion Phase with CYP3A4 Induction 
Study (Cohort 2, MTD Level)
5.1.1.2.4
Expansion Cohort with MATE1 Substrate Study (Cohort 2 – MATE1 
Sub-study) (Evaluation of the effect of steady state ASP2215 on Cephalexin)
Cephalexin (500 mg oral tablet or capsule) will be administered as a single oral dose on 
Day -1 and Day 15 of Cycle 1.  ASP2215 200 mg will be administered QD starting on Day 1 
of Cycle 1. Cephalexin for use in this trial will not be provided by Astellas.
See [Table 2E]:  Schedule of Assessments for Expansion Phase with MATE1 Substrate Study 
(Cohort 2, MATE1 Sub-study)
All subjects will be assessed for toxicities before being allowed to continue to subsequent 
cycles.
5.1.2
Increase or Reduction in Dose of the Study Drug(s)
Guidelines for ASP2215 dose reduction are provided in Table 6  
The ASP2215 dose may be reduced for subjects after Cycle 1 in the dose escalation phase 
(Cohort 1), and at any cycle in the dose expansion phase (Cohort 2). Dose reduction during 
Cycle 1 in the dose escalation phase (Cohort 1) is only allowed if the subject has already 
experienced clinical benefit and after discussion with the medical monitor. Note that dose 
reductions should occur in a step-wise manner, following the dose levels outlined in Table 5  
After the initial dose reduction, additional dose reductions may occur unless stated otherwise. 
If no further dose reductions are available, study treatment will be discontinued. 


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Table 6
Guidelines for ASP2215 Dose Reduction Event
ASP2215 Dosing Instructions
Event
QTc Prolongation
If the mean QTcF from Cycle 1 Day 1 to Cycle 1 Day 8 has increased 
> 30 ms based on central read ECG without any other etiology, a 
confirmatory ECG will be performed on Day 9. If the Cycle 1 Day 9 
central read ECG is confirmatory, a dose reduction should be considered. 
QTcF values based on central reading from triplicate ECGs should be 
used for this determination (i.e., Day 8 mean QTcF from triplicate ECGs 
at predose minus the Day 1 mean QTcF from triplicate ECGs at predose).
Retinopathy 
Grade 2 
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 3/4 
Treatment will be discontinued. 
Non-hematological Events 
Grade 3 related to 
ASP2215
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 due to study 
drug
Treatment will be discontinued
Myelosuppression
CRp or CRi
Dose may be reduced without interruption if the following criteria are met:

Subject has received a minimum of 2 cycles of ASP2215

Platelets < 25 x 109/L and/or ANC ≤ 0.5 x 109/L;

Marrow blasts < 5%;

No evidence of extramedullary disease;
Further stepwise dose reduction is permitted if dosing 1 full cycle at the 
reduced dose has not resulted in the desired hematologic recovery.
Guidelines for dose escalation are provided in Table 7
In the dose escalation cohort (Cohort 1), if the subjects on 20 mg and 40 mg dose levels do 
not achieve a composite CR (CRc), defined as either of CR, CRp or CRi, after 1 cycle of 
treatment and did not have DLT, they may dose escalate to the next dose level. Only one 
dose escalation is allowed for lack of response.
In the dose expansion cohort (Cohort 2), subjects who do not achieve a CRc may dose escalate 
to the next dose level, if the next dose level has opened up for expansion (i.e., a decision has 
been made to escalate to next higher dosing level). After the initial dose escalation, additional 
dose escalations may occur following the dose levels in Table 5 if the next dose level has 
opened up for expansion (i.e., a decision has been made to escalate to next higher dosing level).


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Table 7
Guidelines for ASP2215 Dose Escalation Event
Cohort 1 (Dose escalation cohort)
No CRc (CR. CRp or CRi) after Cycle 1
Patients on 20 mg, 30 mg or 40 mg can 
escalate one dose level
Patients on 60-600 mg cannot escalate dose
Cohort 2 (Dose expansion cohort)
No CRc (CR. CRp or CRi) after Cycle 1
Can dose escalate in a step wise manner 
following the dose levels in Table 5
If dose escalated as per Table 8, the patients will revert to more frequent safety evaluations.  
The following tests will need to be done weekly (+/- 1 day) for one cycle. Resume regular 
monthly evaluation schedule as described in the Schedule of Assessments after the completion 
of the escalation cycle.  
Weekly Assessments
Cohort 1 (Dose Escalation)
Cohort 2 (Dose Expansion)
Physical Exam
Vital Signs
ECG
Clinical Laboratory Tests
AE/SAE Evaluation
In-Clinic Dosing
Pre-Dose PK
Serial PKs at Day of Escalation and 2 weeks post 
escalation 

Pre-dose, (0.5 hours before drug administration) 0.5 
(±10 minutes), 1 (±10 minutes), 2 (±10 minutes), 4 
(±20 minutes), 6 (±20 minutes), and 24 hours (±90 
minutes) post dose
Serial ECGs at Day of Escalation and 2 weeks post 
escalation 

Pre-dose, 2, 4, 6, and 24 hours post
Physical Exam
Vital Signs
ECG
Clinical Laboratory Tests
AE/SAE Evaluation
In-Clinic Dosing
Pre-Dose PK
5.1.3
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 end of treatment visit must be recorded in the CRF. Documentation will include 
the medication name, indication, dose and dates of administration. 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 
5HT1R or 5HT2BR or sigma nonspecific receptor are to be avoided with the exception of drugs 


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that are considered absolutely essential for the care of the subject. Treatment with concomitant 
drugs that are strong inhibotrs of CYP3A whould be avoided with with the exception of 
antibiotics, antifungals, and antivirals that are used as standard of care post-transplant or to 
prevent or treat infections. If CYP3A inhibitors are used comcomitantly, subjects should be 
closely monitored for AEs.
Precaution should be used in treatment of ASP2215 with concomitant drugs that are substrates 
of BCRP, since thetransporter has been shown to be inhibited by A2215 in in vitro studies.
Common CYP3A inhibitors, CYP3A inducers, drugs targeting the serotonin receptor P-gp 
inhibitors or inducers and drugs known to prolong QT or QTc intervals are listed 
[Appendix 12.1]. 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 ASP2215 with the exception of hydroxyurea up to 5 g daily for up to 2 weeks to 
keep the absolute blast count below 50 x 109/L, prophylactic intrathecal chemotherapy or 
cranial irradiation. Participation in another interventional study while on treatment is 
prohibited.
Refer to [Appendix 12.1, List of Excluded and Cautionary Concomitant Medications
During the initial 15 days of treatment in expansion cohorts with DDI studies [Table 2B
Schedule of Assessments with CYP3A4 Inhibitor Voriconazole, Table 2D Schedule of 
Assessments for Expansion Phase with CYP3A4 Induction, and Table 2E Schedule of 
Assessments for Expansion Phase with MATE1 Substrate Study], moderate or strong CYP3A 
inhibitors are prohibited, unless required for treatment of active infections. Common CYP3A 
Inhibitors and CYP3A Inducers are listed in Appendix 12.1  In addition, during the initial 
15 days of treatment for subjects assigned to Schedule 2E MATE1 substrates are prohibited.  
Any other treatments of AML (including but not limited to chemotherapy, radiotherapy, 
surgery, immunotherapy or cellular therapy) are prohibited during therapy with ASP2215 with 
the the following exceptions: 
●
hydroxyurea up to 5 gm daily for up to 2 weeks to keep the absolute blast count below 50,000.
●
HSCT for patients with CRc or PR
●
Intrathecal Chemotherapy used as prophylaxis.
Please see Section 5.1.4 for additional information on HSCT.
5.1.4
Resumption of treatment after Hematopoietic Stem Cell Transplantation 
(HSCT)
Subjects who achieve a CRc or PR can undergo HSCT without leaving the study. However, 
ASP2215 should be stopped and an End of Treatment visit should be performed prior to 
starting the conditioning regimen for HSCT. ASP2215 can be resumed after stem cell 
transplantation if the following conditions are met:


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●
Subject is between 30 – 60 days post HSCT
●
Subject has had successful engraftment as demonstrated by ANC ≥ 500/mm3 and 
platelets ≥ 20,000/mm3 without transfusions.
●
Subject does not have Grade ≥ 2 acute GVHD
●
Subject is in CRc
For subjects resuming treatment, subjects will follow the procedures listed under Subsequent 
Cycles Day 1 in the Schedule of Assessments. 
5.1.5
Treatment Compliance
The dose and schedule of ASP2215 and CYP3A4 inhibitor administered to each subject will
be recorded on the appropriate form at every cycle. Reasons for dose delay, reduction or 
omission will also be recorded. This information, plus tablet accountability for ASP2215 at 
every cycle will be used to assess compliance with the treatment. 
Treatment compliance should be monitored closely and deviations 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).
Any subjects that have been off treatment for more than 15 days other than for HSCT or 
study drug related AE, can only resume treatment after discussion with the medical monitor.
5.2
Demographics and Baseline Characteristics
5.2.1
Demographics
Demographic information will be collected for all subjects and will include initials, date of 
birth, 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 on the Medical History eCRF.  Details that will be collected include the onset date 
and recovery date and CTC grade, if applicable for ongoing conditions.
5.2.3
Diagnosis of the Target Disease, Severity, and Duration of Disease
AML diagnosis and studies related to AML subtype classification will be collected and will 
include date and method of diagnosis, bone marrow evaluations, histopathology, cytogenetics, 
immunophenotyping and cytochemistry, FLT3 mutation status performed using institutional 
assay,  lumbar puncture results if performed (RBC, WBC and differential, cytospin results), 
and related genetic syndromes. Dates for diagnostic procedures will be collected.
5.2.4
Performance Status
The ECOG Scale [Oken, 1982] will be used to assess performance status. 
Table 8
COG Performance Status
Grade
Description


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Grade
Description
0
Fully active, able to carry on all pre-disease 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
5.3
Efficacy | Pharmacodynamics | Pharmacokinetics | Immunogenicity 
Assessment
5.3.1
Response Definitions
Response to treatment will be defined per modified Cheson criteria [2003] as outlined below.
5.3.1.1
Composite Complete Remission Rate (CRc)
Defined as the confirmed remission rate of all complete and incomplete CRs (i.e., CR+ CRp + Cri).
5.3.1.2 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 x 109/L and platelet count ≥ 100 x 109/L, and normal marrow 
differential with < 5% blasts, and they will 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.
5.3.1.3 Complete Remission with Incomplete Platelet Recovery (CRp)
For subjects to be classified as being in CRp, they must achieve CR except for incomplete 
platelet recovery (< 100 109/L).
5.3.1.4
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.
5.3.1.5
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 with the total marrow blasts between 5% and 25%.


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5.3.1.6
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 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 to > 25% not 
attributable to any other cause or reappearance or new appearance of extramedullary leukemia.
5.3.1.7
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 End of Treatment 
Visit will be defined. 
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. All vital sign measures 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 Adverse Event page of the CRF. 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
Adverse Events
Adverse event collection will begin from time of informed consent and continue through the 
30 Day Follow-Up visit. Adverse events will be documented at each clinic visit, but can be 
collected at any time. Any adverse event that meets the definition of an SAE will also be 
reported on a separate form to the Sponsor. See Section 5.5 Adverse Events and Other Safety 
Aspects for information regarding adverse event collection and data handling.
5.4.2.1
Adverse Events during HSCT
Adverse event collection will continue during HSCT for subjects who remain on study.  
5.4.2.2
Adverse Events of Possible Hepatic Origin 
See Appendix 12.2 Liver Safety Monitoring and Assessment for detailed information on liver 
abnormalities, monitoring and assessment, if the AE for a subject enrolled in a study and 
receiving study drug is accompanied by increases in liver function testing (LFT, e.g., AST, 
ALT, bilirubin, etc.) or is suspected to be due to hepatic dysfunction. 


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Subjects with AEs of hepatic origin accompanied by Liver Function Test (LFT) abnormalities 
should be carefully monitored.
5.4.3
Laboratory Assessments
Below is a table of the laboratory tests that will be performed centrally during the conduct of 
the study. Refer to the Schedule of Assessments for study visit collection dates. 
Additional laboratory tests should be performed according to institutional standard of care. 
Clinical significance of out-of-range laboratory findings is to be determined and documented 
by the investigator/or delegated sub-investigator who is a qualified physician.


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Panel/Assessment
Matrix/Collecting Tube
Parameters to be Analyzed
Hematology
3 mL into 
ethylenediaminetetraacetic 
acid (EDTA) tube
White Blood Cell Count (WBC)*
WBC Differential*
Red Blood Cell Count (RBC)
Hemoglobin (Hgb)*
Hematocrit (Hct)*
Mean Corpuscular Volume
Platelet Count*
MCHC
MCH
Chemistry
10 mL into Serum tube
Sodium (Na)
Potassium (K)
Chloride (Cl)
Bicarbonate (HCO3)
Blood Urea Nitrogen (BUN)
Creatinine (Cr)
Glucose (Gl)
Calcium (Ca)
Phosphate (Pi)
Magnesium (Mg)
Albumin (Alb)
Total Protein (T Prot)
Alkaline Phosphatase (AlkP)
Lactate Dehydrogenase (LDH)
Creatine Phosphokinase (CK)
Aldolase
Triglycerides (Trig)
Total Cholesterol (T Chol)
Phospholipid
Globulin
Chemistry
10 mL into Serum tube
Liver Function Tests including:

Bilirubin Total (TBL)

Alanine Aminotransferase (ALT)

Aspartate Aminotransferase (AST)
Thyroid function tests including:

TSH

Free T4
Serum Pregnancy Test
1 mL Serum or urine**
HCG
Coagulation Profile 
(PT/INR, D-Dimer, 
Fibrinogen) 
2.5 mL into Na Citrate 
tube
INR (with PT if reported)
aPTT
Fibrinogen (Screening Only)
D-Dimer (Screening Only)
Table continued on next page


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Panel/Assessment
Matrix/Collecting Tube
Parameters to be Analyzed
Urinalysis
Dipstick
Color
Appearance
Specific Gravity
pH
Bilirubin
Blood 
Glucose
Ketones
Leukocyte esterase
Nitrite
Protein
Urobilinogen
Bone Marrow
Aspirate 3 mL EDTA, 2-3 
bedside smear slides, and 
biopsy (or peripheral blood 
in the event of a dry tap)
Blast count and cell counts*
Flowcytometry for blasts
FLT3 mutation status
C-CBL mutation status
AXL mutation status
PK
4 mL into K2 EDTA
ASP2215
Cephalexin (MATE1 cohort)
PIA (except for 
Schedule 2E)
4 mL of heparinized 
plasma
FLT3 inhibition (PIA)
Phosphorylation of FLT3,
S6 and AXL (except for 
Schedule 2E)
10 mL of heparinized 
whole blood
Phosphorylation of FLT3
Phosphorylation of AXL
Phosphorylation of S6
*In addition to the central read of these values, local results will also be collected and entered into the eCRF.
**Please refer to Schedule of Assessments. 
5.4.4
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 exam 
are to be performed only if clinically indicated. Physical examinations will be conducted at 
visits as outlined in the Schedule of Assessments. Each physical examination will include the 
observation and review of body system, weight at Screening and on D1 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 Adverse-Event page 
of the CRF. 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.  


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5.4.5
Electrocardiogram (ECG) 
ECGs will be conducted at visits as outlined in the Schedule of Assessments. Pre-dose 
assessments should be taken within 0.5 hours before drug administration. In addition, 2, 4, 
6 and 24 hour post dose assessments should be taken within ± 0.5 hours of nominal time. The 
12-lead ECGs will be recorded in triplicate (3 separate ECGs at least 5 minutes apart per 
timepoint) and transmitted electronically for central reading. 
ECGs should be obtained after the subject has rested quietly and is awake in a fully supine 
position (or semi-recumbent, if supine not tolerated) for 10 minutes before the first ECG from 
a triplicate. Whenever a study procedure coincides with the scheduled timepoint for an ECG 
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 can be changed if required in order to accommodate PK time 
points and is not mandatory.
The mean QTcF of the triplicate ECG tracings based on central reading will be used for all 
treatment decisions.  A Cycle 1 Day 8 ECG will be taken and the central read results will be 
provided to the site 24 hours after receipt of the tracing.  A confirmatory ECG should be 
performed on Cycle 1 Day 9 if the mean QTcF from Cycle 1 Day 1 to Cycle 1 Day 8 has 
increased > 30 ms with no other known etiology, based on the central read ECG.  On Cycle 1 
Day 8, it is recommended that the ECG is taken as early as possible in the morning and 
transmitted immediately.  In addition, it is recommended that the Cycle 1 Day 9 visit is 
scheduled later in the day in order to allow for receipt and assessment of the Cycle 1 Day 8 
central read ECG.  This also allows for a subject to be contacted if the Cycle 1 Day 9 ECG is 
no longer required.  If the Cycle 1 Day 9 ECG is still required, the central read ECG will be 
received on Day 10, in which the investigator should assess if the ASP2215 dose modification 
should occur as per the dose interruption or reduction guideline in Section 5.1.2
5.4.6
Ophthalmologic Exam
Ophthalmologic examinations will be conducted at visits as outlined in the Schedule of 
Assessments. The following tests and exams are required at every visit:
●
Visual Acuity (VA): Best-corrected visual acuity (BCVA) as per ETDRS or Snellen charts
●
Slit lamp examination
●
Ophthalmoscopy
●
Visual fields: Automated threshold visual fields, Humphrey 24-2. SITA Fast or Standard
●
Optical coherence tomography (OCT) 


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5.5
Adverse Events and Other Safety Aspects
5.5.1
Definition of Adverse Events (AEs)
An AE is defined as any untoward medical occurrence in a subject administered a study drug 
or has undergone study procedures and which does not necessarily have a causal relationship 
with this treatment.  An AE can therefore be any unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product. 
An abnormality identified during a medical test (e.g., laboratory parameter, vital sign, ECG 
data, physical exam) should be defined as an AE only if the abnormality meets one of the 
following criteria:
●
Induces clinical signs or symptoms
●
Requires active intervention
●
Requires interruption or discontinuation of study medication
●
The abnormality or investigational value is clinically significant in the opinion of the 
investigator.
Some countries may have additional local requirements for events that are required to be 
reported as AEs or in an expedited manner similar to an SAE. In these cases, it is the 
investigator’s responsibility to ensure these AEs or other reporting requirements are followed 
and the information is appropriately recorded in the (e)CRF accordingly.
5.5.2
Definition of Serious Adverse Events (SAEs)
An adverse event 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 adverse event 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 adverse event 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 or leads to prolongation of hospitalization 
(hospitalization for treatment/observation/examination caused by AE is to be considered 
as serious) 
●
Other medically important events
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, 


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should also usually be 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. 
Safety events of interest on the medicinal products administered to the subject as part of the 
study (e.g., study drug, comparator, background therapy) that may require expedited 
reporting and/or safety evaluation include, but are not limited to:
●
Overdose of the medicinal product(s)
●
Suspected abuse/misuse of the medicinal product(s)
●
Inadvertent or accidental exposure to the medicinal product(s)
●
Medication error involving the medicinal product(s) (with or without subject/patient 
exposure to the Sponsor medicinal product, e.g., name confusion)
All of the events of interest noted above should be recorded on the (e)CRF. Any situation 
involving these events of interest that also meets the criteria for an SAE should be recorded 
on the AE page of the (e)CRF and marked ‘serious’ and the SAE worksheet.
The Sponsor has a list of events that they classify as “always serious” events.  If an adverse 
event is reported that is considered to be an event per this classification as “always serious”, 
additional information on the event may be requested.  
5.5.3
Criteria for Causal Relationship to the Study Drug
Adverse events that fall under either "Possible" or "Probable" should be defined as "adverse 
events whose relationship to the study drugs could not be ruled out".
Causal relationship to 
the study drug
Criteria for causal relationship
Not Related
A clinical event, including laboratory test abnormality, with a temporal 
relationship to drug administration which makes a causal relationship 
improbable, and/or in  which other drugs, chemicals or underlying disease 
provide plausible explanations.
Possible
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the drug, but which could also be 
explained by concurrent disease or other drugs or chemicals. Information 
on drug withdrawal may be lacking or unclear.
Probable
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the drug, unlikely to be attributed to 
concurrent disease or  other drugs or chemicals, and which follows a 
clinically reasonable response on re- administration (rechallenge) or 
withdrawal (dechallenge).


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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 (NCI)-Common Terminology Criteria for Adverse Event (CTCAE) guidelines 
(Version 4.03). The items that are not stipulated in the NCI-CTCAE Version 4.03 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)
SAE collection will begin from time of informed consent through 30 after last dose of study 
medication. In the case of a serious adverse event (SAE), the investigator must contact the 
Sponsor by telephone or fax immediately (within 24 hours of awareness).
The investigator should complete and submit an SAE Worksheet containing all information 
that is required by the Regulatory Authorities to the Sponsor/delegated CRO by fax 
immediately (within 24 hours of awareness). If the faxing of an SAE Worksheet is not 
possible or is not possible within 24 hours, the local drug safety contact should be informed 
by phone.
For contact details, see Section II Contact Details of Key Sponsor's Personnel. Please fax or 
e-mail the SAE Worksheet to:
Astellas Pharma Global Development 
Global Pharmacovigilance
North American Fax number: 888-396-3750
(North America Alternate Fax: 847-317-1241)
International Fax number: +44 800 471 5263
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/Expert 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 and on the (e)CRF.


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The following minimum information is required:  
●
ISN/Study number, 
●
Subject number, sex and age,
●
The date of report,
●
A description of the SAE (event, seriousness of the event), and
●
Causal relationship to the study drug.
The Sponsor or Sponsor's designee will submit expedited safety reports (i.e., IND Safety 
Reports) to the regulatory agencies (i.e., FDA) as necessary, and will inform the investigators 
of such regulatory reports. Investigators must submit safety reports as required by their 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) within timelines set 
by regional regulations (i.e., EU, (e)CTD, FDA). Documentation of the submission to and 
receipt by the IRB/IEC of expedited safety reports should be retained by the site.
The Sponsor/delegated CRO will notify all investigators responsible for ongoing clinical 
studies with the study drug of all SAEs which require submission per local requirements of 
the IRB.  
The heads of the study sites/investigators should provide written documentation of IRB 
notification for each report to the Sponsor.
The investigators should provide written documentation of IRB notification for each report to 
the Sponsor.
You may contact the Sponsor's Medical Monitor/Expert 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. 
If during AE follow-up, the adverse event progresses to an "SAE", or if a subject experiences 
a new SAE, the investigator must immediately report the information to the Sponsor. 
Please refer to Appendix 12.2 Liver Safety Monitoring and Assessment for detailed 
instructions on Drug Induced Liver Injury (DILI).
5.5.7
Monitoring of Common Serious Adverse Events
Common serious adverse events are SAEs commonly anticipated to occur in the study 
population independent of drug exposure. SAEs classified as “common” are provided in 
Appendix 12.3 Common Serious Adverse Events for your reference. The list does NOT 
change your reporting obligations 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 you that some events reported 
as SAEs may not require expedited reporting to the regulatory authorities based on the 
classification of “common serious adverse events” as specified in Appendix 12.3 Common 
Serious Adverse Events. The Sponsor will monitor these events throughout the course of the 


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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
Procedure in Case of Pregnancy
If a female subject or partner of a male subject becomes pregnant during the study dosing 
period or within 120 days from the discontinuation of dosing, the investigator should report the 
information to the Sponsor/delegated CRO as if it is an SAE. 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.
The investigator will follow the medical status of the mother, as well as the fetus, as if the 
pregnancy is an SAE and will report the outcome to the Sponsor.
When the outcome of the pregnancy falls under the criteria for SAEs [spontaneous abortion, 
induced abortion, stillbirth, death of newborn, congenital anomaly (including anomaly in a 
miscarried fetus)], the investigator should respond in accordance with the report procedure 
for SAEs. Additional information regarding the outcome of a pregnancy (which is 
categorized as an SAE) is mentioned below.
●
"Spontaneous abortion" includes miscarriage, abortion and missed abortion
●
Death of an infant within 1 month after birth should be reported as an SAE regardless of 
its relationship with the study drug
●
If an infant dies more than 1 month after the birth, it should be reported if a relationship 
between the death and intrauterine exposure to the study drug is judged as "possible" by 
the investigator
●
In the case of a delivery of a living newborn, the "normality" of the infant is evaluated at 
the birth
●
Unless a congenital anomaly are identified prior to spontaneous abortion or miscarriage, 
the embryo or fetus should be assessed for congenital defects by visual examination
If during the conduct of a clinical trial, a male subject makes his partner pregnant, the subject 
should report the pregnancy to the investigator. The investigator will report the pregnancy to 
the Sponsor as an SAE.
5.5.9
Emergency Procedures and Management of Overdose
In the event of suspected ASP2215 overdose, the subject should receive supportive care and 
monitoring. The Medical Monitor/Expert should be contacted as applicable.
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. 


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5.6
Test Drug Concentration
5.6.1
Pharmacokinetics
Plasma concentrations of ASP2215 will be evaluated for the escalation and expansion phases 
as outlined in Schedule of Assessments. For each sample 4 mL of blood will be collected and 
processed. For the expansion phase with CYP3A4 inhibitor (Cohort 2 initial starting dose 
level) plasma concentration of CYP3A4 inhibitor will be evaluated as outlined in the schedule 
of assessments (single 4 mL blood sample, predose Cycle 2 Day 1). For the expansion phase 
with Midazolam (Cohort 2 MTD) plasma concentration of Midazolam and 1-hydroxy 
midazolam (metabolite, if possible) will be evaluated as outlined in the Schedule of 
Assessments (4 mL blood sample collected at each time point).  For the expansion phase with 
MATE1 substrate, plasma and urine concentration of cephalexin will be evaluated as outlined 
in the Schedule of Assessments [Table 2E] (4 mL blood sample and 6 mL urine sample 
collected at each time point).
Plasma samples may also be used for metabolite profiling of ASP2215. The reports for the 
metabolite profiling and identification will not be incorporated to the clinical study report. 
Blood sampling, processing, storage and shipment instructions will be provided in the Lab 
manual. Samples will be shipped to and analyzed by a Sponsor designated analytical laboratory. 
Please refer to the Lab Manual for more detailed information on this topic.
Dose Escalation Phase (Cohort 1)
ASP2215
Cycle 1:  Days -2, -and 15 
Pre-dose (0.5 hours before drug administration)
0.50, 1 and 2 hours post dose (±10 minutes) 4 and 
6 hours post dose (±20 minutes) 24 hours 
(±90 minutes) post ASP2215 dosing 
Cycle 1: Days 1, 8 and 22
Pre-dose (0.5 hours before drug administration)
2 hours (±10 minutes) post ASP2215 dosing
Cycles 2 +: Day 1
Pre-dose (0.5 hours before drug administration)
Expansion Phase with CP3A4 Inhibitor Voriconazole Study (Cohort 2, Starting Dose Level)
ASP2215
Cycle 1:  Day 15 and Cycle 2: Day 1
Pre-dose (0.5 hours before drug administration)
0.50, 1and 2 hours post dose (±10 minutes), 4 and 
6 hours post dose (±20 minutes) 24 hours 
(±90 minutes) post ASP2215 dosing
Cycle 1: Days 1, 8 and 22
Pre-dose (0.5 hours before drug administration)
Cycles 3 +: Day 1
Pre-dose (0.5 hours before drug administration)
CYP3A4 Inhibitor Voriconazole
Cycle 2: Day 1
Pre-dose (0.5 hours before drug administration)
Table continued on next page


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Expansion Phase without DDI Studies (Cohort 2, Intermediate Dose Levels)
ASP2215
Cycle 1: Days 1 and 15
Pre-dose (0.5 hours before drug administration)
2 hours (±10 minutes) post ASP2215 dosing
Cycle 1: Days 8 and 22 and Cycle 2+: Day 1
Pre-dose (0.5 hours before drug administration)
Expansion Phase with CYP3A4 Induction Study (Cohort 2, MTD Level)
ASP2215
Cycle 1:  Days 1, 8, 15, and 22
Pre-dose (0.5 hours before drug administration)
2 hours (±10 minutes) post ASP2215 dosing
Cycles 2 +: Day 1
Pre-dose (0.5 hours before drug administration)
Midazolam
Cycle 1:  Day -1 and Day 15
Pre-dose (0.5 hours before drug administration)
0.50, 1 and, 2 hours post dose (±10 minutes) 
4 and 6 hours post dose (±20 minutes) and 
24 hours (±90 minutes) post midazolam dosing
Expansion Phase with MATE1 Substrate Study (Cohort 2, MATE1 Sub-study)
ASP2215
Cycle 1:  Day 15
Pre-dose (0.5 hours before drug administration) 1 
and 2 hours post dose (±10 minutes), 4 and 
6 hours post dose (±20 minutes)  24 hours 
(±90 minutes) post ASP2215 dosing
Cycle 1:  Days 1, 8 and 22
Pre-dose (0.5 hours before drug administration) 
Cycles 2 +: Day 1
Pre-dose (0.5 hours before drug administration)
Cephalexin
Cycle 1:  Day -1 and Day 15
Plasma PK:  Pre-dose (0.5 hours before drug 
administration) 0.5, 1, 1.5, 2 and 3 hours post 
dose (±10 minutes) 4 and 6 hours post dose 
(±20 minutes) and 24 hours (±90 minutes) post 
cephalexin dosing
Urine PK:  0-3 hours, 3-6 hours and 6-24 hours 
post dose.
5.7
Other Measurements, Assessments or Methods
5.7.1
Pharmacodynamics
Excluding Schedule 2E, phosphorylation of FLT3, AXL and S6 will be evaluated to assess 
the percent inhibition of phosphorylation with samples collected as described in the Schedule 
of Assessments in the escalation and expansion phases (4 mL blood for each sample).
Excluding Schedule 2E, plasma inhibition assay (PIA) will be conducted from blood samples 
as described in the Schedule of Assessments in the escalation and expansion phases (4 mL 
blood for each sample). 


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Blood sampling, processing, storage and shipment instructions will be provided in the lab 
manual. Samples will be shipped to and analyzed by a Sponsor designated analytical laboratory. 
Please refer to the Lab Manual for more detailed information on this topic.
5.7.2
Samples for Exploratory Analyses
 
 
 
 
 
 
 
 
 
 
5.7.3
Sample for the Pharmacogenomics Sub-study (Optional)
An optional PGx research sub- study will be conducted in the future to analyze or determine
genes of relevance to clinical response, pharmacokinetics, and toxicity/safety issues. Germline 
DNA isolated from buccal swabs will be collected at screening and evaluated for genetic 
mechanisms underlying treatment response, pharmacokinetics, and safety endpoints. A 
sponsor-designated laboratory will perform the analyses.
Samples will be shipped to a Sponsor designated banking CRO.
Labels should uniquely identify each sample and contain at least:
●
Protocol number 2215-CL-0101,
●
Subject number, and
●
Purpose and biological matrix (i.e., “biobanking”, “buccal swab”).
Details on sample collection, labeling, storage and shipment procedures will be provided in a 
separate laboratory manual.
See Appendix 12.4, Retrospective PGx Sub-study for further details on the banking procedures.


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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, for 
disease assessment, institutional monitoring for donor chimerism, and GVHD assessment, 
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, hematology, chemistry, coagulation, and pregnancy test at 
specific study defined time points, pharmacokinetics, and bioanalytical sampling. 
The maximum amount of blood collected for study specific assessments within 24 hours is 
during the Dose Escalation Phase (Cohort 1) between Day -2 and Day -1 when approximately
64 mL of blood will be drawn.
The maximum amount of blood collected that is in addition to standard of care over any one 
month period is from Screening through Cycle 1 where approximately 272 mL will be drawn. 
Total blood volumes (PK, pFLT+pAXL+pS6 and PIA) collected include:
●
Table 2A Dose Escalation : Cycle 1 = 272 mL; Cycle 2 = 41 mL; additional cycles 
19 mL/visit
●
Table 2B Expansion CYP3A4 Inhibitor: Cycle 1 = 174 mL; ; Cycle 2 = 69 mL; additional 
cycles 19 mL/visit
●
Table 2C Expansion without DDI: Cycle 1 = 158 mL; Cycle 2 = 41 mL; additional cycles 
19 mL/visit
●
Table 2D Expansion CYP3A4 Induction: Cycle 1 = 228 mL; Cycle 2 = 41 mL; additional 
cycles 19 mL/visit
●
Table 2E Expansion MATE1 Substrate: Cycle 1 = 196 mL; Cycle 2 = 33 mL; additional 
cycles 19 mL/visit
6
DISCONTINUATION
6.1
Discontinuation of Individual Subject(s) 
A discontinuation is a subject who enrolled in the study and for whom study treatment is 
permanently discontinued prematurely for any reason.  
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 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 adverse event or an unresolved 
laboratory result that is significantly outside of the reference range, the investigator will 


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attempt to provide follow-up until the condition stabilizes or no longer is clinically 
significant.
Discontinuation Criteria from Treatment for Individual Subjects:
●
Subject declines further study participation (i.e., withdrawal of consent).
●
Subject is non-compliant with the 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 will be taken off treatment if there is no PR or CRc and the subject, in the 
opinion of the Investigator, is no longer deriving clinical benefit after 2 cycles of therapy
●
ASP2215 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 an ASP2215 related adverse event.
●
Investigator/sub-investigator 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.
●
Death 
The subject will be discontinued from the post 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 Visit.
●
Death
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.


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7
STATISTICAL METHODOLOGY
The statistical analysis will be coordinated by the responsible biostatistician of APGD-US. 
The 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 detailed in the Clinical Study Report (CSR).
Prior to Database 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 lock.
In general, all data will be summarized with descriptive statistics (number of subjects, mean, 
standard deviation, minimum, median and maximum) for continuous endpoints, and 
frequency and percentage for categorical endpoints.
7.1
Sample Size
The sample size is not based on statistical power calculation. It should provide adequate 
information for the objective of the study.
Up to 40 subjects are planned to be enrolled into up to 10 dose levels in the dose escalation 
phase depending on the number of dose levels studied. The dose expansion phase will enroll up 
to 250 subjects in the expansion cohort depending on the number of dose levels expanded. The 
total number of subjects estimated for enrollment is between 2 and 270 subjects. This excludes 
consideration of the replacement of subjects in the Dose Escalation Cohort (Cohort 1) that 
meet the replacement criteria, in which case the sample size would increase based on the 
number of subjects replaced.
7.2
Analysis Set
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 will consist of all subjects who are enrolled and receive at least one dose 
of study drug and who have at least one post-treatment data point. This will be the primary 
analysis set for efficacy analyses.
7.2.2
Per Protocol Set (PPS)
The per protocol set 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 PPS will be a secondary analysis set for efficacy analyses. 


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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 one dose of study medication, and will be used 
for safety analyses.
7.2.4
Pharmacokinetic Analysis Set (PKAS)
The pharmacokinetic analysis set (PKAS) consists of the subset of the SAF population for 
which sufficient plasma concentration data is available to facilitate derivation of at least one 
PK parameter and for whom the time of dosing on the day of sampling is 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. 
7.2.5
Pharmacodynamic Analysis Set (PDAS) 
The pharmacodynamic analysis set (PDAS) will include the subjects from the SAF 
population for whom sufficient pharmacodynamic measurements were collected The PDAS 
will be used for all analyses of pharmacodynamic data.
7.3
Demographics and Other Baseline Characteristics 
7.3.1
Demographics
Demographics and other baseline characteristics will be summarized by cohort and dose 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
Medical History
A detailed medical history for each subject will be obtained during screening period and will 
be summarized by cohort and dose levels for the SAF.
7.3.3
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, FLT3, C-CBL, and AXL mutation status and allelic 
ratio.
7.3.4
Previous and Concomitant Medications
The frequency of concomitant medications (prescription, over-the-counter, and nutritional 
supplements) will be summarized by cohort, dose and preferred term 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.


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7.3.5
Subject Disposition
The number and percentage of all subjects during the study will be reported by cohort and dose 
for enrollment, study drug administration, subject completion, premature discontinuation, and 
major protocol violations.
7.3.6
Treatment Compliance
Treatment compliance is defined as the total number of study drug actually taken by the
subject divided by the number of study drug expected to be taken during the study multiplied 
by 100. Descriptive statistics for study drug compliance will be presented by cohort and dose 
for the entire study period for the SAF by cohort and dose.
7.3.7
Extent of Exposure
Exposure to treatment, measured by the duration of treatment in number of days will be 
summarized by treatment on SAF. Duration of exposure to a study drug is defined as: (the last 
date that subject took study drug – the first dose date + 1). Any duration of dose interruptions 
will be excluded from the exposure. The total dose administered, number of dose reductions, 
number of dose escalations, number and proportion of subjects with dose reduction and dose 
escalation will be tabulated.
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
Complete remission (CR) rate, composite complete remission rate, overall response rate, 
duration of confirmed response, disease-free survival (DFS), event free survival (EFS) and 
overall survival (OS), will be summarized using descriptive statistics. The survival curve and 
median for time-to-event variables will be estimated using the Kaplan-Meier method and will 
be reported along with the corresponding 95% confidence interval.
To explore the relationship between dose level and CR response a dose-response model 
(logistic regression) will be fitted to the binary CR response with ITD mutation status, the 
first and second order of logarithm transformed dose as independent covariates for all 
subjects from the Dose Escalation Cohort and Dose Expansion Cohort. The CR response rate 
for each dose level will be estimated with two-sided 95% CI from this model.
7.5
Analysis of Safety
Safety analyses will consist of data summaries of AEs, DLTs, and other safety parameters. 
Safety analyses will be performed on the SAF.


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7.5.1
Bayesian Logistic Regression Modeling in Dose Escalation and Expansion 
Phases
A modified 3+3 design with an accelerated titration is applied in the dose escalation cohort as 
described in the Study Design Overview section [Section 2]. A 2-parameter Bayesian logistic 
regression will be used to model the dose-toxicity relationship on DLT. Subjects in either 
dose escalation cohort or dose expansion cohorts who complete at least one treatment 
cycle 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 logistic 
regression model for each dose level will be provided as references for dose escalation 
procedures in dose escalation cohort and safety monitoring in dose expansion cohort. If the 
DLT rate for an expanded dose level is equal or higher than 20% with a posterior probability 
of 80%, then the enrollment to the dose level will be paused and the safety will be reassessed.
7.5.2
Subject Assignment in Cohort 2 Dose Expansion Cohort
As a dose level is decided to be expanded, up to 17 subjects will be enrolled for the dose 
level in the dose expansion phase (to have a total of 20 subjects enrolled at a dose level 
including the subjects from dose escalation cohort). When more than one dose levels are 
expanded in the dose expansion cohort (Cohort 2), the newly enrolled subjects will be 
randomized to one of the open expanded dose levels, based on the relative chance of (20 – n) 
in each dose level, where n is the number of subjects already enrolled in the dose level, 
including both the dose escalation and expansion phases. 
If 10 subjects without FLT3 mutations (ITD or activating point mutations) are enrolled into 
an expanded dose level (including the subjects in the dose escalation cohort and dose 
expansion cohort), only subjects with FLT3 mutations can be enrolled to the dose level.
Any dose level in the dose expansion cohort will be stopped if no CRc is achieved in more 
than 6 subjects who complete 2 treatment cycles or less than 2 CRcs in more than 12 subjects 
are achieved.
Further Expansion for Efficacy Evaluation
To improve guidance for Recommended Phase 2 Dose, dose levels at and above 120 mg will 
be further expanded (when found to be tolerable in Cohort 1) based on the efficacy results 
observed in escalation and expansion cohorts. Approximately 40 additional Cohort 2 subjects 
will be enrolled at these dose levels to bring the total enrolled to approximately 60 patients at 
the dose level inclusive of Cohort 1 subjects. A minimum of 42 evaluable (receive 2 cycles of 
treatment or discontinue for progressive disease) FLT3 mutated patients will be enrolled.
The increased patient numbers will enable us to more accurately estimate the actual response 
rate (CRc) for a dose level based on the observed response rate. With approximately 
42 evaluable FLT3 mutated subjects, the 90% 1-sided Confidence Interval is about 10% below 
the observed response rate for each dose level. If the estimated response rate is 50%, we would 
be 90% sure that the real response rate is higher than 40%. Response rate will be continuously 
monitored for each dose level and the enrollment will be stopped if the response rate for that 
dose level is at 90% significance level, less than 45% based on Wald’s Sequential Probability 


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Ratio Test with 25% as the unacceptable low response rate and 80% power. The following 
table will apply (e.g., if 7 or less subjects respond as 25 FLT3 mutated subjects complete 
2 cycles of treatment in a dose level, the enrollment at the dose level will be stopped): 
Enrolled Subjects
Number of CRc
14
3
17
4
20
5
23
6
25
7
28
8
31
9
34
10
37
11
Subject Assignment in Cohort 2 MATE1 Sub-study Dose Expansion Cohort:
Approximately 20 FLT3 mutation positive patients will be enrolled in the Expansion Phase 
with MATE1 Substrate Study (Schedule 2E). All patients will be assigned to ASP2215 
200 mg dose level and 40 mg tablets will be used.
7.5.3
Determination of DLT and MTD
DLT review for dose escalation decisions and declaration of DLT and MTD will be 
performed for each dose level throughout the trial. Dose escalation decisions will be rule 
based as description in Study Design section 2.2.1  DLT will be summarized by cohort and 
dose for SAF. 
7.5.4
Adverse Events 
All adverse events recorded on treatment including within 30 days from the last study 
treatment will be summarized. AEs will be coded to system organ class (SOC) and preferred 
term (PT) using Medical Dictionary for Regulatory Activities (MedDRA) dictionary 
(Version 14.1) and will be graded according to the National Cancer Institute (NCI) Common 
Toxicity Criteria for Adverse Events (CTCAE) version 4.03.
The number and percent of subjects experiencing 1 or more AE(s) will be summarized by 
cohort, dose, SOC, and PT. The number and percentage of subjects with at least one Grade 3 or 
higher AE will be summarized by dose, SOC, and PT. 
Distribution of the maximum severity (grade) and treatment-related AEs will be summarized 
by cohort, dose, SOC, and PT. Distribution of serious adverse events (SAEs), 
discontinuations due to AE, and deaths on study will be presented for each treatment. 
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 treatment-emergent events unless otherwise stated. 
Listings of AEs, SAEs, deaths, and withdrawals due to adverse events will be presented.


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AEs and SAEs reported during HSCT while off ASP2215 as well as before resumption of 
ASP2215 will be summarized and listed separately.  
7.5.5
Laboratory Assessments 
Clinical laboratory evaluations (including hematology, urinalysis, serum chemistry, and 
coagulation) and their changes from baseline will be summarized by treatment 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 selected 
variables using the NCI-CTCAE grade and lab reference range indicator. Frequency of subjects 
with laboratory values outside normal range will be generated in addition to tabulation of worst 
toxicity grade.
7.5.6
Vital Signs 
Descriptive statistics will be used to summarize vital sign results and changes from baseline 
by cohort and dose and time. 
7.5.7
Physical Examination 
Physical examinations will be listed by treatment group. All clinically significant abnormal 
findings will be recorded as medical history, baseline conditions, or adverse events and graded 
using NCI-CTCAE guidelines.
7.5.8
ECGs 
The 12-lead ECG results will be summarized by treatment group 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 not clinically significant, and abnormal 
clinically significant) will be provided. ECG parameters and their change from baseline will be 
summarized by cohort and dose using descriptive statistics.
7.5.9
Ophthalmologic Assessment
Ophthalmologic variables will be summarized by dose level at each visit for each eye.
7.6
Analysis of Pharmacokinetics
Plasma concentrations and PK parameters will be summarized by cohort using descriptive 
statistics, including number of subjects, mean, standard deviation, minimum, median, 
maximum, geometric mean, and coefficient of variation (CV) of the mean and geometric 
mean). Time-course of drug concentrations will be plotted as appropriate.
7.6.1
Estimation of Pharmacokinetic Parameters 
Subjects with sufficient PK samples will have PK parameter estimates for ASP2215 
including calculation of AUC24, Cmax, Ctrough and tmax using standard NCA.
For subjects in the midazolam expansion cohort, those subjects with sufficient PK samples 
will have PK parameter estimates for midazolam (pre and post ASP2215 administration) and 


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1-hydroxy midazolam (metabolite, if possible) including calculation of AUC24, Cmax, Ctrough
and tmax using standard NCA. 
For subjects in CYP3A4 inhibitor expansion group, the PK parameters for ASP2215 will be 
summarized by pre and post CYP3A4 inhibitor administration.
For subjects in the MATE1 expansion cohort, those subjects with sufficient PK samples will 
have PK parameter estimates for cephalexin (pre and post ASP2215 administration) including 
calculation of AUC, Cmax, Ctrough and tmax using standard NCA. In addition, urinary PK 
parameters of amount of drug excreted in urine (Ae), fraction of drug excreted into urine in 
% (Ae[%]) and renal clearance (CLR) of cephalexin will be calculated.
7.6.2
Concentration-Response Relationship Analysis
Pharmacokinetic dose proportionality will be assessed.
7.7
Analysis of Pharmacodynamics 
Percent inhibition of phosphorylation of FLT3, S6 and AXL as compared to baseline 
sampling will be summarized at each time point by cohort (except for Schedule 2E).
Plasma inhibitory assay as compared to baseline sampling will be summarized at each time 
point by cohort (except for Schedule 2E).
 
 
 
 
 
 
 
 
 


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7.8
Protocol Deviations and Other Analyses 
Protocol deviations as defined in Section 8.1.6   Protocol Deviations will be summarized for 
all randomized subjects by treatment group and total as well as by site. 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. 
7.9
Interim Analysis (and Early Discontinuation of the Clinical Study)
No formal interim analysis is planned.
7.10
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.
7.11
Analysis of Re-Enrolled Subjects
The statistical handling of Re-Enrolled subjects will be defined in the Statistical Analysis Plan.  
Safety and efficacy information of the Re-Enrolled subjects will be summarized separately. 
8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS
8.1
Procedure for Clinical Study Quality Control
8.1.1
Data Collection
The investigator or site designee will enter data collected using an Electronic Data Capture 
(EDC) 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 10 days after the subject 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.


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Laboratory tests are performed at central laboratories. Laboratory data will be transferred 
electronically to the Sponsor or designee at predefined intervals during the study. The 
laboratory will provide the Sponsor or designee with a complete and clean copy of the data. 
ECG results are performed at a central ECG reading, ERT. 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.
For Screen failures the demographic data, reason for failing, informed consent, inclusion and 
exclusion criteria and Adverse Events will be collected in the eCRF.
8.1.2
Specification of 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 following information should be included in the source medical records:
●
Demographic data (age, sex, race, ethnicity, height and body weight)
●
Inclusion and exclusion criteria details
●
Participation in study and original signed and dated informed consent forms 
●
Visit dates
●
Medical history and physical examination details
●
Key efficacy and safety data, if applicable (as specified in the protocol)
●
Adverse events and concomitant medication 
●
Results of relevant examinations (e.g., ECG charts, X-ray films etc.)
●
Laboratory printouts (if applicable)
●
Dispensing and return of study drug details
●
Reason for premature discontinuation (if applicable)
●
Randomization number (if applicable) 
8.1.3
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/sub-investigator 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.  
8.1.4
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, such as source documents 


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[Section 8.1.2] 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.
8.1.5
Data Management
Data Management will be coordinated by the Global Data Science of the Sponsor in 
accordance with the standard operating procedures (SOPs) for data management. All study 
specific processes and definitions will be documented by Data Management. (e)CRF 
completion will be described in the (e)CRF instructions. Coding of medical terms and 
medications will be performed using MedDRA and World Health Organization (WHO) Drug 
Dictionary respectively.
8.1.6
Protocol Deviations 
A 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 trial 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.
For the purposes of this protocol, deviations requiring notification to Sponsor are defined as 
any subject who: 
●
Entered into the study even though they did not satisfy entry criteria. 
●
Developed withdrawal criteria during the study and not withdrawn
●
Received wrong treatment or incorrect dose. 
●
Received excluded concomitant treatment. 
When a 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 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 (TMF).  


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NOTE:  Other deviations outside of the categories defined above that are required to be 
reported by the IRB/IEC in accordance with local requirements will be reported, as 
applicable. 
8.1.7
End of Trial in All Participating Countries
The end of trial in all participating countries is defined as the Last Subject’s Last Visit.
8.2
Ethics and Protection of Subject Confidentiality 
8.2.1
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) / 
Competent Authorities (CA)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol amendments, 
the Investigator’s Brochure, the informed consent 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 IEC/IRB.  The IEC/IRB will review the ethical, scientific and 
medical appropriateness of the study before it is conducted.  IEC/IRB approval of the 
protocol, informed consent 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 IEC/IRB approval prior to 
implementation of the changes made to the study design at the site.  The investigator will be 
required to submit, maintain and archive study essential documents according to ICH GCP.
Any serious adverse events that meet reporting criteria, as dictated by local regulations, will 
be reported to both responsible Ethics Committees and Regulatory Agencies, as required. 
During the conduct of the study, the investigator should promptly provide written reports 
(e.g., ICH Expedited Reports, and any additional reports required by local regulations) to the 
IEC/IRB of any changes that affect the conduct of the study and/or increase the risk to 
subjects. Written documentation of the submission to the IEC/IRB should also be provided to 
Sponsor.
If required by local regulations, the investigator shall make accurate and adequate written 
progress reports to the IEC/IRB at appropriate intervals, not exceeding one year. The 
investigator shall make an accurate and adequate final report to the IRB/IEC within 90 days 
after the close-out visit for APGD-sponsored studies, or for APEB/APEL-sponsored studies 
within one year after last subject out (LSO) or termination of the study.
8.2.2
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. 


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8.2.3
Informed Consent of Subjects
8.2.3.1
Subject Information and Consent
The investigator or his/her representative will explain the nature of the study to the subject or 
his/her guardian or 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 informed consent form 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.
8.2.3.2
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 adverse drug reaction). The communication must be 
documented in the subject’s medical records and must document whether the subject is 
willing to remain in the study or not.
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 informed consent 
form A copy of the signed informed consent form 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.
8.2.4
Subject Confidentiality
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited. Such medical information may be 
given only after approval of the subject to the subject's physician 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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The Sponsor affirms the subject's right to protection against invasion of privacy. Only a 
subject identification number and/or initials 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 will ensure that the use and disclosure of protected health information (PHI) 
obtained during a research study complies with the federal and/or regional legislation related 
to the privacy and protection of personal information (i.e., HIPAA). 
8.3
Administrative Matters
8.3.1
Arrangement for Use of Information and Publication of the Clinical Study
Information concerning the study drug, patent applications, processes, unpublished scientific 
data, the Investigator's Brochure 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.
8.3.2
Documents and Records Related to the Clinical Study
The investigator will archive all study data (e.g., Subject Identification Code List, source 
data, CRFs, 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, two years 
after approval of the NDA or discontinuation of the IND). The Sponsor will notify the 
site/investigator if the NDA is approved or if the IND is discontinued. 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. All data will be entered on the CRFs supplied 
for each subject. 
The investigator and sponsor will mutually agree upon the storage format for the retention of 
electronic data.
8.3.3
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. 


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Depending on the nature of the amendment, either IRB/IEC, Competent Authority approval 
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 Informed Consent, written verification of IRB/IEC approval must 
be forwarded to the Sponsor. An approved copy of the new Informed Consent must also be 
forwarded to the Sponsor.
8.3.4
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.
9
QUALITY ASSURANCE
The Sponsor is implementing and maintaining quality assurance and quality control systems 
with written SOPs to ensure that trials are conducted and data are generated, documented, 
recorded, and reported in compliance with the protocol, GCP, and applicable regulatory 
requirement(s).
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.
10
STUDY ORGANIZATION
10.1
Independent Data-Monitoring Committee (IDMC) | Data and Safety 
Monitoring Board (DSMB) | Monitoring Committee | Other 
Evaluation Committee(s)
Not applicable.


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10.2
Other Study Organization-  Dose Escalation Committee
The Dose Escalation Committee will be responsible for the review of safety data at specified 
time points in order to provide an assessment of whether dose escalation or reduction should 
occur within the next cohort and/or to determine when maximum tolerated dose has been 
reached in a given dose level. At each meeting, individual subject data will be reviewed for 
dose escalation decisions. Additional details regarding responsibilities and membership 
requirements will be included in the Subject Enrollment and Dose Escalation Plan.


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11
REFERENCES 
Ben-Batalla I, Schultze A, Wroblewski M, Erdmann R, Heuser M, Waizenegger JS, et al. Axl, a 
prognostic and therapeutic target in acute myeloid leukemia mediates paracrine crosstalk of 
leukemia cells with bone marrow stroma. Blood. 2013 Oct 3;122(14):2443-52.
Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, 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):4642-4649.
Hong CC, Lay JD, Huang JS, Cheng AL, Tang JL, Lin MT, et al. Receptor tyrosine kinase AXL is 
induced by chemotherapy drugs and overexpression of AXL confers drug resistance in acute 
myeloid leukemia. Cancer Lett. 2008 Sep 18;268(2):314-24.
Howlader N, Noone AM, Krapcho M, Neyman N, Aminou R, Altekruse SF, et al (eds). SEER Cancer 
Statistics Review, 1975-2009 (Vintage 2009 Populations), National Cancer Institute. Bethesda, 
MD, http://seer.cancer.gov/csr/1975_2009_pops09/, based on November 2011 SEER data 
submission, posted to the SEER web site, April 2012.
Linger RM, Keating AK, Earp HS, Graham DK. TAM receptor tyrosine kinases: biologic functions, 
signaling, and potential therapeutic targeting in human cancer. Adv Cancer Res. 2008;100:35-83.
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 of Clin Oncol 1982; 5:649-655.
Park IK, Mishra A, Chandler J, Whitman SP, Marcucci G, Caligiuri MA. Inhibition of the receptor 
tyrosine kinase Axl impedes activation of the FLT3 internal tandem duplication in human acute 
myeloid leukemia: implications for Axl as a potential therapeutic target. Blood. 2013 Mar 
14;121(11):2064-73.
Rochlitz C, Lohri A, Bacchi M, Schmidt M, Nagel S, Fopp M, et al. Axl expression is associated with 
adverse prognosis and with expression of Bcl-2 and CD34 in de novo acute myeloid leukemia 
(AML): results from a multicenter trial of the Swiss Group for Clinical Cancer Research (SAKK). 
Leukemia. 1999 Sep;13(9):1352-8.
Schlenk RF and Döhner K. Impact of new prognostic markers in treatment decisions in acute myeloid 
leukemia. Curr Opin Hematol 2009;16(2):98-104.
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(8):2434-9.
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(8):1345-9.
Yonezawa & Inui, 2011, Importance of the multidrug and toxin extrusion MATE/SLC47A family to 
pharmacokinetics, pharmacodynamics/toxicodynamics and pharmacogenomics. Br J Pharmacol. 
2011 Dec; 164(7): 1817–1825.


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12
APPENDICES
12.1
List of Excluded Concomitant Medications
The following lists describe medications and foods which are common inhibitors of CYP3A. 
This list should not be considered all inclusive. Consult individual drug labels for specific 
information on a compound’s propensity to inhibit CYP3A.
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
The following lists describe medications and foods which 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.
CYP3A Inducers
Drug Type
Generic Drug Name
Antiepileptic, Anticonvulsant
Carbamazepine
Phenytoin
Antibiotic
Rifampicin
Food/Juice Supplement
St. John’s Wort
The following lists describe medications which 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.


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Drugs Targeting Serotonin Receptor 
Drug Type
Generic Drug Name
Affinity or function to 5HT2BR
Eletriptan Hydrobromide
Affinity or function to 5HT1R
Drugs
Almotriptan Malate
Aripiprazole
Avitriptan
Buspirone Hydrochloride
Dihydroergotamine Mesylate
Droperidol
Eletriptan Hydrobromide
Ergoloid Mesylates
Ergonovine Maleate
Ergotamine Tartrate
Frovatriptan Succinate
Haloperidol
Decanoate
Lesopitron
Methylergonovine Maleate
Methylergotamine
Methysergide Maleate
Naratriptan Hydrochloride
Pizotifen
Quetiapine Fumarate
Rizatriptan Benzoate
Sumatriptan Succinate
Tegaserod Maleate
Thioridazine
Hydrochloride
Ziprasidone Hydrochloride
Ziprasidone Mesylate
Zolmitriptan
Zotepine


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The following lists describe medications and foods which are common inhibitors or inducers 
of P-gp. This list should not be considered all inclusive. Consult individual drug labels for 
specific information on a compound’s propensity to inhibit or induce P-gp.
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 
Source: Table 12 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/uc
m093664.htm#major
The following list describes substrates of MATE1. This list should not be considered all 
inclusive. Consult individual drug labels for specific information on whether a compound is a 
substrate of MATE1.  
MATE1 Substrate
Transporter 
Substrate
MATE1
cephalexin
cephradine
fexofenadine
MATE1: multidrug and toxin extrusion 1
Source: Yonezawa & Inui, 2011
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
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
Table continued on next page


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Drug Type
Generic Drug Name
Azole antifungals 
Ketoconazole
Fluconazole
Itraconazole
Posaconazole
Voriconazole
Antimalarials
Amodiaquine
Atovaquone
Chloroquine
Doxycycline
Halofantrine
Mefloquine 
Proguanil
Primaquine
Pyrimethamine
Quinine
Sulphadoxine
Antiprotozoals
Pentamidine
Antiemetics
Droperidol
Dolasetron
Granisetron
Ondansetron
Antiestrogens
Tamoxifen
Immunosuppressants
Tacrolimus


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12.2
Liver Safety Monitoring and Assessment 
Any subject enrolled in a clinical study with active drug therapy and reveals an increase of 
serum aminotransferases (AT) to > 3 × ULN (to > 5 × ULN in subjects with liver metastases), 
or bilirubin > 2 × ULN, should undergo detailed testing for liver enzymes (including at least 
ALT, AST, ALP, and TBL). Testing should be repeated within 48-72 hours of notification of 
the test results. For studies for which a central laboratory is used, alerts will be generated by 
the central lab regarding moderate and severe liver abnormality to inform the investigator, 
study monitor 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
Total Bilirubin
Moderate
> 3 x ULN (in patients without liver 
metastases), > 5 x ULN (in patients with liver 
metastases)
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 × ULN
●
ALT or AST > 5 × ULN for more than 2 weeks (in the absence of liver metastases)
●
ALT or AST > 3 × ULN and INR > 1.5 (If INR testing is applicable/evaluated).
●
ALT or AST > 3 × 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 should complete the Liver Abnormality Case Report 
Form (LA-CRF) that has been developed globally and can be activated for any study or 
appropriate document. Subjects with confirmed abnormal liver function testing should be 
followed as described below. 
Confirmed moderately abnormal LFTs should be repeated 2-3 times weekly then weekly or 
less if abnormalities stabilize or the study drug has been discontinued and the subject is 
asymptomatic.  


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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 Serious Adverse 
Event (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.
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 should be recorded as ‘adverse events’ on the AE page of 
(e)CRF. Illnesses and conditions such as hypotensive events, and decompensated cardiac 
disease that may lead to secondary liver abnormalities should be noted. Non-alcoholic 
steatohepatitis (NASH) is seen in obese hyperlipoproteinemic, and/or diabetic patients 
and may be associated with fluctuating aminotransferase levels. The investigator should 
ensure that the medical history form captures any illness that pre-dates study enrollment 
that may be relevant in assessing hepatic function.
●
Obtain a history of concomitant drug use (including non-prescription medication, 
complementary and alternative medications), alcohol use, recreational drug use, and 
special diets. Medications, including dose, should be entered on the concomitant 
medication page of 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: 
o
acute viral hepatitis (A, B, C, D, E or other infectious agents). 
o
ultrasound or other imaging to assess biliary tract disease
o
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 Discontinuation
In the absence of an explanation for increased LFT’s, such as viral hepatitis, pre-existing or 
acute liver disease, presence of liver metastases, or exposure to other agents associated with 
liver injury, the subject may be discontinued from the study. The investigator may determine 
that it is not in the subject’s best interest to continue study enrollment. Discontinuation of 
treatment should be considered if:
●
ALT or AST > 8 × ULN
●
ALT or AST > 5 × ULN for more than 2 weeks (in subjects without liver metastases
●
ALT or AST > 3 × ULN and TBL > 2 × ULN or INR > 1.5 (If INR testing is 
applicable/evaluated)
●
ALT or AST > 5 × ULN and (TBL > 2 × ULN in patients with liver metastases)
●
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%). 


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In addition, if close monitoring for a subject with moderate or severe hepatic laboratory tests 
is not possible, drug 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 10–50% mortality (or 
transplant).” The two “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 times the upper limit of normal (“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 alkaline phosphatase) or Gilbert’s syndrome. 
References
Guidance for Industry titled “Drug-Induced Liver Injury: Premarketing Clinical Evaluation” issued by 
FDA on July 2009.
Temple R. Hy's law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug Saf. 2006:15:241-3.  


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12.3
Common Serious Adverse Events
The following is a list of serious adverse events 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 adverse event meeting the definition of an SAE as detailed in 
Section 5.5.2 Definition of Serious Adverse Event (SAE). The purpose of this list is to alert 
you that some events reported as SAEs may not require expedited reporting to the regulatory 
authorities based on the classification of “common serious adverse events”. You are required to 
follow the requirements detailed in Section 5.5.5 Reporting of Serious Adverse Events (SAE).
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
Table continued on next page


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Serious Adverse Events Caused by AML
Grades usually
observed with AML
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
Libido decreased
0-2
Meningismus
0-5
Seizure
0-5
Somnolence
0-5
Syncope
3
OTHER AE
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
Multi-organ 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


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12.4
Retrospective PGx Sub-Study 
INTRODUCTION
PGx research aims to provide information regarding how naturally occurring changes in a 
subject’s gene and/or expression 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 
(GWAS), the relationship between gene profiles and a drug’s kinetics, efficacy or toxicity may 
be better understood. As many diseases may be influenced by one 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 buccal swab samples is 
exploratory. The objective of this research will be to analyze or determine genes of relevance 
to clinical response, pharmacokinetics, and 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. As part of this sub-study, subjects must provide separate written consent prior 
to providing any buccal swab samples that may be used at a later time for genetic analysis.
SAMPLE COLLECTION AND STORAGE
Subjects who consent to participate in this sub-study will provide a buccal swab per vendor 
preparation instructions. Each sample will be identified by the unique subject number (first 
code). Samples will be shipped to a designated banking CRO either directly from site or via a 
central laboratory as directed by Astellas.
BANKING CRO STORAGE AND SAMPLE CODING 
Once received at the banking CRO, the samples will be assigned a unique sample code 
(second code) and stored frozen. A table linking the subject number (first code) with the 
newly-assigned sample code (second code) will be kept by the banking CRO. PGx analysis 
will be conducted using the second code only.
PGx ANALYSIS
Details on the potential PGx analysis cannot be established yet. Astellas may initiate the PGx 
analysis in case evidence suggests that genetic variants may be influencing the drug’s 
kinetics, efficacy and / or safety. Prior to initiating any analysis on the banked samples, the 
Astellas ethical committee (AREC) must approve the analysis plan.


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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.
INFORMATION DISCLOSURE TO THE SUBJECTS
Exploratory PGx analysis may be conducted following the conclusion of the clinical study, if 
applicable. The results of the genetic 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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13
ATTACHMENT 1:  SUBSTANTIAL AMENDMENT 11
I.  The purpose of this amendment is:
Substantial Changes
1.
Revise Study Design
DESCRIPTION OF CHANGE:
Subjects who are receiving ASP2215 treatment and have not met any 2215-CL-0101 
discontinuation criteria may be eligible to continue to receive ASP2215 treatment in a 
rollover study, 2215-CL-0109.  
Subjects who choose not to participate or are not eligible for Study 2215-CL-0109 will 
complete their participation in Study 2215-CL-0101 by completing the End of Treatment 
follow-up visit upon activation of Study 2215-CL-0109 at the institution.
Subjects in Study 2215-CL-0101 who are being followed for Long-term Follow-up at the 
time of study closure will be discontinued from any further follow-up.
RATIONALE:
The primary database lock and analyses for the 2215-CL-0101 study occurred on 17 June 
2016 including data up to the cut-point of 24 November 2015.
Astellas will close Study 2215-CL-0101 upon activation of Study 2215-CL-0109 at all 
participating institutions.  Study 2215-CL-0109 provides access for eligible subjects to 
continue to receive ASP2215 treatment.
2.
Update Concomitant Medication Guidelines
DESCRIPTION OF CHANGE:
Update concomitant drugs that strong inducers of cytochrome P450 (CYP) 3A, strong 
inhibitors or inducers of P-gp and drugs that target 5HT1R and 5HT2BR receptors are 
excluded.  Drugs known to prolong QT or QTc intervals should be used with caution. 
Update list of excluded concomitant medications.
RATIONALE:
Text is revised based on data available from nonclinical (in vitro) studies and 
pharmacokinetic data from clinical studies of ASP2215, and for alignment with the current 
guidance to the investigator in the Investigator’s Brochure.
Non-Substantial Changes
1.
Update Contact Details of Key Sponsor’s Personnel
DESCRIPTION OF CHANGE:
Update personnel changes.


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RATIONALE:
Update the contact details based on changes to sponsor personnel.
2.
Updated Planned Study Period
DESCRIPTION OF CHANGE:
Update the study period to current planned end date of 2017.
RATIONALE:
To reflect the most current information.
3.
Update Pregnancy and Contraception Inclusion Criteria
DESCRIPTION OF CHANGE:
For female subjects the period after study participation during which the subject cannot 
become pregnant or donate ova is lengthened from 45 days to 180 days and for breastfeeding 
is lengthened from 45 days to 60 days.  
For male subjects the period after study participation during which the subject must use 
contraception and not donate sperm is lengthened from 105 days to 120 days.
For female subjects and female partners of male subjects, pregnancy reporting is lengthened 
from 90 to 180 days from the discontinuation of dosing.
RATIONALE:
Increased reproductive restrictions to ensure maximum protection against potential 
embryofetal toxicity.  Reporting period increased to clarify situation where female subject or 
partner of a male subject will be considered of non-child bearing potential.
No new patients will be enrolled under this version of the protocol; however, patients are still 
receiving treatment with ASP2215 under the study. Therefore, post discontinuation 
requirements are provided.
4.
Minor Administrative-type Changes
DESCRIPTION OF CHANGE: 
Include minor administrative-type changes, e.g., typos, format, numbering, consistency 
throughout the protocol.  
RATIONALE:
To provide clarifications to the protocol and to ensure complete understanding of study 
procedures.




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IV Synopsis – Study Design Overview and 2.2.1 Study Design
WAS:
This study is an open-label, dose escalation, first-in-human study in subjects with relapsed 
or refractory AML, with concomitant expansion cohort for multiple doses. One cycle is 
defined as 28 days and the subject will receive oral ASP2215 daily. The study treatment 
will continue until one of the discontinuation criteria is met. 
IS AMENDED TO:
This study is an open-label, dose escalation, first-in-human study in subjects with relapsed 
or refractory AML, with concomitant expansion cohort for multiple doses. One cycle is 
defined as 28 days and the subject will receive oral ASP2215 daily. The study treatment 
will continue until one of the discontinuation criteria is met or until rollover into the 
2215-CL-0109 study.
ADDED:
Continuation of Subjects in open label roll over study:
Should the Sponsor make the decision to end the study after primary analysis, all 
subjects receiving ASP2215 may be enrolled in an ASP2215 rollover study (2215-CL-
0109).  Subjects must not meet any discontinuation criteria for this study and must 
meet the entry criteria for the rollover study prior to being enrolled.  
Subjects who choose not to participate or are not eligible for Study 2215-CL-0109 will 
complete their participation in Study 2215-CL-0101 by completing the End of 
Treatment follow-up visit upon activation of Study 2215-CL-0109 at the institution.
Subjects, who are being followed for Long-term Follow-up at the time of study 
closure, will be discontinued.    
IV Synopsis - Inclusion Criteria and 3.2 Inclusion Criteria
WAS:
8. Female subject must be either:

Of non child bearing potential:
post-menopausal (defined as at least 1 year without any menses) prior to 
Screening, or
documented surgically sterile or status post hysterectomy (at least 1 month 
prior to Screening)

Or, if of childbearing potential, 
must have a negative urine pregnancy test at Screening*, and 
must use two forms of birth control** (at least one of which must be a 
barrier method) starting at Screening and throughout the study period and 
for 45 days after the final study drug administration.
9. Female subject must not be breastfeeding at Screening or during the study period, and 
for 45 days after the final study drug administration.
10. Female subject must not donate ova starting at Screening and throughout the study 


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period, and for 45 days after the final study drug administration.
11. Male subject and their female spouse/partners who are of childbearing potential must 
be using highly effective contraception consisting of two forms of birth control** (one 
of which must be a barrier method) starting at Screening and continue throughout the 
study period and for 105 days after the final study drug administration.
12. Male subject must not donate sperm starting at Screening and throughout the study 
period and for 105 days after the final study drug administration. 
IS AMENDED TO:
8. Female subject must be either:

Of non child bearing potential:
post-menopausal (defined as at least 1 year without any menses) prior to 
Screening, or
documented surgically sterile or status post hysterectomy (at least 1 month 
prior to Screening)

Or, if of childbearing potential, 
must have a negative urine pregnancy test at Screening*, and 
must use two forms of birth control** (at least one of which must be a 
barrier method) starting at Screening and throughout the study period and 
for 18045 days after the final study drug administration.
9. Female subject must not be breastfeeding at Screening or during the study period, and 
for 6045 days after the final study drug administration.
10. Female subject must not donate ova starting at Screening and throughout the study 
period, and for 18045 days after the final study drug administration.
11. Male subject and their female spouse/partners who are of childbearing potential must 
be using highly effective contraception consisting of two forms of birth control** (one 
of which must be a barrier method) starting at Screening and continue throughout the 
study period and for 120105 days after the final study drug administration.
12. Male subject must not donate sperm starting at Screening and throughout the study 
period and for 120105 days after the final study drug administration.
IV Synopsis – Concomitant Medication Restrictions or Requirements
WAS:
Treatment with concomitant drugs that are strong inhibitors or inducers of CYP3A4 or of 
P-glycoprotein (P-gp), or substrates of multidrug and toxin extrusion 1 (MATE 1) should 
be avoided with the exception of antibiotics, antifungals, and antivirals that are used as 
standard of care post-transplant or to prevent or treat infections and other such drugs that 
are considered absolutely essential for the care of the subject.
IS AMENDED TO:
Treatment with concomitant drugs that are strong inhibitors or inducers of CYP3A4 are 
prohibited.  Treatment with concomitant drugs that are strong inihibitors or inducers 
of or P glycoprotein (P-gp), and concomitant drugs that target serotonin 5HT2BR 


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receptors or signma nonspecific receptor or substrates of multidrug and toxin extrusion 
1 (MATE 1) should 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 post transplant or to 
prevent or treat infections and other such drugs that are considered absolutely essential for 
the care of the subject. If CYP3A inhibitors are used concomitantly, subjects should 
be closely monitored for adverse events (AEs).
Precaution should be used in use of ASP2215 with concomitant drugs that are known 
to prolong QT or QTc intervals.
IV Synopsis – Duration of Treatment
WAS:
One dose daily in 28 day cycles until a discontinuation criterion is met.
IS AMENDED TO:
One dose daily in 28 day cycles until a discontinuation criterion is met or until rollover 
into the 2215-CL-0109 study.


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V. FLOW CHART AND SCHEDULE OF ASSESSMENTS
WAS:
Figure 1
Study Flow Chart  
Cohort 1 (Escalation Cohort)
Cohort 2 (Expansion Cohort)
Expansion cohorts will start with 1st CR or one above the dose level with target inhibition
≥ 18 years with AML 
in relapse or 
refractory to 
induction regimen
ASP2215 
QDx28 
1 cycle
C
O
N
S
E
N
T
ASP2215
QDx28 q28 until subject meets 
discontinuation criteria 
S
C
R
E
E
N
30-DAY 
FOLLOW UP 
ASSESSMENT
SURVIVAL AND 
SUBSEQUENT TREATMENT
FOLLOW-UP Q3 MONTHS
≥ 18 years with AML 
in relapse or 
refractory to 
induction regimen
C
O
N
S
E
N
T
S
C
R
E
E
N
DOSE ASSIGNMENT
ASSIGN TO SINGLE 
OPEN DOSE OR 
RANDOMIZE
ASP2215
QDx28 q28 until subject meets 
discontinuation criteria 
30-DAY 
FOLLOW UP 
ASSESSMENT
SURVIVAL AND 
SUBSEQUENT TREATMENT
FOLLOW-UP Q3 MONTHS
DLT Observation
30 days


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IS AMENDED TO:
Figure 1
Study Flow Chart  
Cohort 1 (Escalation Cohort)
Cohort 2 (Expansion Cohort)
Expansion cohorts will start with 1st CR or one above the dose level with target inhibition
≥ 18 years with AML 
in relapse or 
refractory to 
induction regimen
ASP2215 
QDx28 
1 cycle
C
O
N
S
E
N
T
ASP2215
QDx28 q28 until subject meets 
discontinuation criteria 
S
C
R
E
E
N
30-DAY 
FOLLOW UP 
ASSESSMENT
SURVIVAL AND 
SUBSEQUENT TREATMENT
FOLLOW-UP Q3 MONTHS
≥ 18 years with AML 
in relapse or 
refractory to 
induction regimen
C
O
N
S
E
N
T
S
C
R
E
E
N
DOSE ASSIGNMENT
ASSIGN TO SINGLE 
OPEN DOSE OR 
RANDOMIZE
ASP2215
QDx28 q28 until subject meets 
discontinuation criteria or 
until rollover into the 
2215-CL-0109 study
30-DAY 
FOLLOW UP 
ASSESSMENT
SURVIVAL AND 
SUBSEQUENT TREATMENT
FOLLOW-UP Q3 MONTHS
DLT Observation
30 days


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Table 2F – Post-Treatment  Schedule of Assessments
WAS:
Activity
End of 
Treatment Visit a
30-Day
Follow-Up
Long-term 
Follow-Up
Physical Examination
X b
Vital Signs
X b
ECOG Performance
X b
Concomitant Medications
X
Pregnancy Test for WOCBP
X
12-lead ECG
X c
Ophthalmologic Assessment 
X b
Clinical Laboratory Tests  (chemistry, hematology, coagulation, urinalysis)
X b
Bone Marrow Aspiration and Biopsy 
X h
FLT3, AXL and C-CBL Mutationsg (bone marrow aspirate or whole blood)
X
AE/SAE Assessment
Xd
X e 
IRT Transaction Required
X
Survival and Subsequent Anti-leukemic Treatments and Their Outcomes
X e
X f
k. End of Treatment Visit is to be performed within 7 days of last dose.
l.
Does not need to be repeated if collected at a regularly scheduled visit within 3 days of the End of Treatment Visit.
m. ECG monitoring should be between 7:00 am and 3:00 pm, if possible.  
n. If the subject undergoes HSCT and does not resume ASP2215, SAE data will only be collected for 7 days after End of Treatment Visit
o. Telephone contact with the subject is sufficient unless any assessment must be repeated for resolution of treatment-related AEs. 
p. Telephone contact every 3 months after the 30-Day follow up.
q. FLT3, AXL and C-CBL mutation analysis will be performed for relapsed subjects.
r. Does not need to be repeated if collected within 2 weeks of the End of Treatment Visit.  


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IS AMENDED TO:
Activity
End of 
Treatment Visit a
30-Day
Follow-Up i
Long-term Follow-
Up j
Physical Examination
X b
Vital Signs
X b
ECOG Performance
X b
Concomitant Medications
X
Pregnancy Test for WOCBP
X
12-lead ECG
X c
Ophthalmologic Assessment 
X b
Clinical Laboratory Tests  (chemistry, hematology, coagulation, urinalysis)
X b
Bone Marrow Aspiration and Biopsy 
X h
FLT3, AXL and C-CBL Mutationsg (bone marrow aspirate or whole blood)
X
AE/SAE Assessment
Xd
X e 
IRT Transaction Required
X
Survival and Subsequent Anti-leukemic Treatments and Their Outcomes
X e
X f
a. End of Treatment Visit is to be performed within 7 days of last dose.
b. Does not need to be repeated if collected at a regularly scheduled visit within 3 days of the End of Treatment Visit.
c. ECG monitoring should be between 7:00 am and 3:00 pm, if possible.  
d. If the subject undergoes HSCT and does not resume ASP2215, SAE data will only be collected for 7 days after End of Treatment Visit
e. Telephone contact with the subject is sufficient unless any assessment must be repeated for resolution of treatment-related AEs. 
f. Telephone contact every 3 months after the 30-Day follow up.
g. FLT3, AXL and C-CBL mutation analysis will be performed for relapsed subjects.
h. Does not need to be repeated if collected within 2 weeks of the End of Treatment Visit.  
i.
The 30-day follow-up visit and long term follow-up visits will not be performed if subject is enrolled into the roll-over study (2215-CL-0109).
j. Long-term Follow-up will be discontinued upon termination of the study by the Sponsor.


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5.1.3 Previous and Concomitant Treatment (Medication and Non-Medication 
Therapy)
WAS:
All medications and concomitant treatments administered from 28 days prior to Cycle 1 
Day 1 must be recorded in the CRF. Documentation will include the medication name, 
indication, dose and dates of administration. Treatment with concomitant drugs that are 
strong inhibitors or inducers of CYP3A4 or P-glycoprotein (P-gp) or substrates of 
multidrug and toxin extrusion 1 (MATE 1) should be avoided with the exception of 
antibiotics, antifungals, and antivirals that are used as standard of care post-transplant or to 
prevent or treat infections and other such drugs that are considered absolutely essential for 
the care of the subject.
Precaution should be used in treatment of ASP2215 with concomitant drugs that are 
substrates of CYP1A2, 2B6, 2C9, and 3A4/5; P-gp, and BCRP, since these enzymes or 
transporters have been shown to be inhibited (CYP 2C19, CYP3A4/5, P-gp, and BCRP) or 
induced (CYP1A2, 2B6, 2C9, 2C19, and 3A4/5) by A2215 in in vitro studies.
During the initial 15 days of treatment in expansion cohorts with DDI studies [Table 2B
Schedule of Assessments with CYP3A4 Inhibitor Voriconazole, Table 2D Schedule of 
Assessments for Expansion Phase with CYP3A4 Induction, and Table 2E Schedule of 
Assessments for Expansion Phase with MATE1 Substrate Study], moderate or strong 
CYP3A4 inhibitors are prohibited, unless required for treatment of active infections. 
Common CYP3A4 Inhibitors and CYP3A4 Inducers are listed in Appendix 12.1. In 
addition, during the initial 15 days of treatment for subjects assigned to Schedule 2E 
MATE1 substrates are prohibited.  Any other treatments of AML (including but not limited 
to chemotherapy, radiotherapy, surgery, immunotherapy or cellular therapy) are prohibited 
during therapy with ASP2215 with the the following exceptions: 
●
hydroxyurea up to 5 gm daily for up to 2 weeks to keep the absolute blast count below 
50,000.
●
HSCT for patients with CRc or PR
●
Intrathecal Chemotherapy used as prophylaxis.
Please see Section 5.1.4 for additional information on HSCT.
IS AMENDED TO:
All medications and concomitant treatments administered from 28 days prior to Cycle 1 
Day 1 through the end of treatment visit must be recorded in the CRF. Documentation 
will include the medication name, indication, dose and dates of administration. Treatment 
with concomitant drugs that are strong inhibitors or inducers of CYP3A4 are prohibited. 
Treatment with concomitant drugs that are strong inhibitors or inducers of or P
glycoprotein (P-gp) or substrates of multidrug and toxin extrusion 1 (MATE 1) should be 
avoidedand concomitant drugs that target serotonin 5HT1R or 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 post-transplant or to 
prevent or treat infections and other such drugs that are considered absolutely essential for 


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the care of the subject. If CYP3A inhibitors are used comcomitantly, subjects should 
be closely monitored for AEs.
Precaution should be used in treatment of ASP2215 with concomitant drugs that are 
substrates of CYP1A2, 2B6, 2C9, and 3A4/5; P gp, and BCRP, since these enzymes or 
transporters have transporter has been shown to be inhibited (CYP 2C19, CYP3A4/5, P
gp, and BCRP) or induced (CYP1A2, 2B6, 2C9, 2C19, and 3A4/5) by A2215 in in vitro
studies.
Common CYP3A inhibitors, CYP3A inducers, drugs targeting the serotonin receptor 
P-gp inhibitors or inducers and drugs known to prolong QT or QTc intervals are 
listed [Appendix 12.1]. 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 
ASP2215 with the exception of hydroxyurea up to 5 g daily for up to 2 weeks to keep 
the absolute blast count below 50 x 109/L, prophylactic intrathecal chemotherapy or 
cranial irradiation. Participation in another interventional study while on treatment 
is prohibited.
Refer to [Appendix 12.1, List of Excluded and Cautionary Concomitant Medications].
During the initial 15 days of treatment in expansion cohorts with DDI studies [Table 2B
Schedule of Assessments with CYP3A4 Inhibitor Voriconazole, Table 2D Schedule of 
Assessments for Expansion Phase with CYP3A4 Induction, and Table 2E Schedule of 
Assessments for Expansion Phase with MATE1 Substrate Study], moderate or strong 
CYP3A4 inhibitors are prohibited, unless required for treatment of active infections. 
Common CYP3A4 Inhibitors and CYP3A4 Inducers are listed in Appendix 12.1. In 
addition, during the initial 15 days of treatment for subjects assigned to Schedule 2E 
MATE1 substrates are prohibited.  Any other treatments of AML (including but not limited 
to chemotherapy, radiotherapy, surgery, immunotherapy or cellular therapy) are prohibited 
during therapy with ASP2215 with the the following exceptions: 
●
hydroxyurea up to 5 gm daily for up to 2 weeks to keep the absolute blast count below 
50,000.
●
HSCT for patients with CRc or PR
●
Intrathecal Chemotherapy used as prophylaxis.
Please see Section 5.1.4 for additional information on HSCT.
5.5.8 Procedure in Case of Pregnancy
WAS:
If a female subject or partner of a male subject becomes pregnant during the study dosing 
period or within 90 days from the discontinuation of dosing, the investigator should report 
the information to the Sponsor/delegated CRO as if it is an SAE. 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 


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information.
IS AMENDED TO:
If a female subject or partner of a male subject becomes pregnant during the study dosing 
period or within 120 90 days from the discontinuation of dosing, the investigator should 
report the information to the Sponsor/delegated CRO as if it is an SAE. 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.
12.1  List of Excluded Concomitant Mediations
WAS:
The following lists describe medications and foods which are common inhibitors of 
CYP3A4. This list should not be considered all inclusive. Consult individual drug labels for 
specific information on a compound’s propensity to inhibit CYP3A4.
CYP3A4 Inhibitors
Drug Type
Generic Drug Name
Human Immunodeficiency Virus Protease 
Inhibitors
indinavir
nelfinavir
ritonavir
saquinavir
Food/Juice
grapefruit/ grapefruit juice
Seville oranges
Star Fruit
Others
amiodarone
cimetidine
clarithromycin
erythromycin
fluoxetine
fluvoxamine
itraconazole
ketoconazole
mibefradil
nefazodone
troleandomycin
verapamil
The following lists describe medications and foods which are common strong inducers of 
CYP3A4. This list should not be considered all inclusive. Consult individual drug labels for 
specific information on a compound’s propensity to induce CYP3A4.
CYP3A4 Inducers
Drug Type
Generic Drug Name
Anti-inflammatory
Dexamethasone
Antiepileptic, Anticonvulsant
Carbamazepine
Phenytoin


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Barbituate
Phenobarbital
Thiazolidinedione anti-hyperglycemic
Pioglitazone
Troglitazone
Antibiotic
Rifabutin
Rifampicin
Rifapentine
Food/Juice Supplement
St. John’s Wort
The following lists describe medications which 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 Receptor 
Drug Type
Generic Drug Name
Affinity or function to 5HT2BR
Eletriptan Hydrobromide
Affinity or function to 5HT1R
Drugs
Almotriptan Malate
Aripiprazole
Avitriptan
Buspirone Hydrochloride
Dihydroergotamine Mesylate
Droperidol
Eletriptan Hydrobromide
Ergoloid Mesylates
Ergonovine Maleate
Ergotamine Tartrate
Frovatriptan Succinate
Haloperidol
Decanoate
Lesopitron
Methylergonovine Maleate
Methylergotamine
Methysergide Maleate
Naratriptan Hydrochloride
Pizotifen
Quetiapine Fumarate
Rizatriptan Benzoate
Sumatriptan Succinate
Tegaserod Maleate
Thioridazine
Hydrochloride
Ziprasidone Hydrochloride


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Ziprasidone Mesylate
Zolmitriptan
Zotepine
The following lists describe medications and foods which are common inhibitors or inducers 
of P-gp. This list should not be considered all inclusive. Consult individual drug labels for 
specific information on a compound’s propensity to inhibit or induce P-gp.
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 
Source: Table 12 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/uc
m093664.htm#major
The following list describes substrates of MATE1. This list should not be considered all 
inclusive. Consult individual drug labels for specific information on whether a compound is a 
substrate of MATE1.  
MATE1 Substrate
Transporter 
Substrate
MATE1
cephalexin
cephradine
fexofenadine
MATE1: multidrug and toxin extrusion 1
Source: Yonezawa & Inui, 2011
Drugs targetting 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.
IS AMENDED TO:
The following lists describe medications and foods which are common inhibitors of 
CYP3A4. This list should not be considered all inclusive. Consult individual drug labels for 
specific information on a compound’s propensity to inhibit CYP3A4.


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CYP3A4 Inhibitors
Drug Type
Generic Drug Name
Human Immunodeficiency Virus Protease 
Inhibitors
Iindinavir
Nnelfinavir
Lopinavir/ritonavir
Rritonavir
Ssaquinavir
Food/Juice
grapefruit/ grapefruit juice
Seville oranges
Star Fruit
Others
amiodarone
cimetidine
Boceprevir
Cclarithromycin
erythromycin
fluoxetine
fluvoxamine
Iitraconazole
Kketoconazole
mibefradil
Nnefazodone
Posaconazole
Telaprevir
Telithromycin
Voriconazole
troleandomycin
verapamil
The following lists describe medications and foods which are common strong inducers of 
CYP3A4. This list should not be considered all inclusive. Consult individual drug labels for 
specific information on a compound’s propensity to induce CYP3A4.
CYP3A4 Inducers
Drug Type
Generic Drug Name
Anti inflammatory
Dexamethasone
Antiepileptic, Anticonvulsant
Carbamazepine
Phenytoin
Barbituate
Phenobarbital
Thiazolidinedione anti hyperglycemic
Pioglitazone
Troglitazone
Antibiotic
Rifabutin
Rifampicin
Rifapentine
Food/Juice Supplement
St. John’s Wort
The following lists describe medications which 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.


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Drugs Targeting Serotonin Receptor 
Drug Type
Generic Drug Name
Affinity or function to 5HT2BR
Eletriptan Hydrobromide
Affinity or function to 5HT1R
Drugs
Almotriptan Malate
Aripiprazole
Avitriptan
Buspirone Hydrochloride
Dihydroergotamine Mesylate
Droperidol
Eletriptan Hydrobromide
Ergoloid Mesylates
Ergonovine Maleate
Ergotamine Tartrate
Frovatriptan Succinate
Haloperidol
Decanoate
Lesopitron
Methylergonovine Maleate
Methylergotamine
Methysergide Maleate
Naratriptan Hydrochloride
Pizotifen
Quetiapine Fumarate
Rizatriptan Benzoate
Sumatriptan Succinate
Tegaserod Maleate
Thioridazine
Hydrochloride
Ziprasidone Hydrochloride
Ziprasidone Mesylate
Zolmitriptan
Zotepine
The following lists describe medications and foods which are common inhibitors or inducers 
of P-gp. This list should not be considered all inclusive. Consult individual drug labels for 
specific information on a compound’s propensity to inhibit or induce P-gp.
P-gp Inhibitors or Inducers
Transporter 
Gene 
Inhibitor 
Inducer 


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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 
Source: Table 12 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/uc
m093664.htm#major
The following list describes substrates of MATE1. This list should not be considered all 
inclusive. Consult individual drug labels for specific information on whether a compound is a 
substrate of MATE1.  
MATE1 Substrate
Transporter 
Substrate
MATE1
cephalexin
cephradine
fexofenadine
MATE1: multidrug and toxin extrusion 1
Source: Yonezawa & Inui, 2011
Drugs targetting 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.
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


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Dofetilide
Antipsychotics
Thioridazine
Mesoridazine
Chlorpromazine
Prochlorperazine
Trifluoperazine
Fluphenazine
Perphenazine
Pimozide
Risperidone
Ziprasadone
Lithium
Haloperidol
Table continued on next page
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
Antimalarials
Amodiaquine
Atovaquone
Chloroquine
Doxycycline
Halofantrine
Mefloquine 
Proguanil
Primaquine
Pyrimethamine
Quinine
Sulphadoxine
Antiprotozoals
Pentamidine


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Antiemetics
Droperidol
Dolasetron
Granisetron
Ondansetron
Antiestrogens
Tamoxifen
Immunosuppressants
Tacrolimus


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14
SPONSOR’S SIGNATURES


 
S-1 
ELECTRONIC SIGNATURE PAGE 
Document Type :  
Document Control Number :  
Amendment Number :  
International Study Number :  
Departmental Study Number :  
Actual Version Number :  
Document Version :  
Nonclinical Initial SD Approved Date (UTC) :  
Date (UTC) 
Signed by 
Sign Off Meaning 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
 
Full Name / Legal Name 
 
*UTC: Coordinated Universal Time 
06/09/2017 21:16:22
Clinical Study Protocol
Scientific Lead Approval
Study Manager Approval
Reissue v12.0, 02Jun2017
06/09/2017 20:25:11
Scientific Lead Approval
N/A
06/05/2017 20:49:08
N/A
MGC1700580
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2215-CL-0101
2.0
Scientific Lead Approval
N/A

SAP_001.pdf: 
A Phase 1/2 Open-Label, Dose Escalation Study 
Investigating the Safety, Tolerability, Pharmacokinetics, 
and Pharmacodynamics of ASP2215 in Patients with 
Relapsed or Refractory Acute Myeloid Leukemia
ISN/Protocol 2215-CL-0101
ClinicalTrials.gov Identifier: NCT02014558
Date of Statistical Analysis Plan Amendment 3:
20 Sep 2017
Sponsor: Astellas Pharma Global Development (APGD), Inc.
1 Astellas Way
Northbrook, IL 60062


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STATISTICAL ANALYSIS PLAN
Version 3 (Amendment 3), dated 20-Sep 2017
A Phase 1/2 Open-Label, Dose Escalation Study Investigating the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of ASP2215 in Patients with Relapsed or 
Refractory Acute Myeloid Leukemia
ISN/Protocol: 2215-CL-0101
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.


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Table of Contents
I.
LIST OF ABBREVIATIONS AND KEY TERMS··········································· 5
1
INTRODUCTION·················································································11
2
FLOW CHART AND VISIT SCHEDULE···················································12
3
STUDY OBJECTIVES AND DESIGN························································24
3.1
Study Objectives ··············································································24
3.1.1
Primary Objectives······································································24
3.1.2
Secondary Objectives···································································24
3.2
Study Design···················································································24
3.2.1
Study Design·············································································24
3.2.2
Dose/Dose Regimen and Administration Period ····································29
3.2.3
Increase or Reduction in Dose of the Study Drug(s)································32
3.3
Randomization·················································································34
4
SAMPLE SIZE ····················································································35
5
ANALYSIS SETS ·················································································35
5.1
Full Analysis Set (FAS) ······································································36
5.2
Per Protocol Set (PPS)········································································36
5.2.1
Reasons for Exclusion From PPS ·····················································36
5.3
Safety Analysis Set (SAF) ···································································36
5.4
Pharmacokinetics Analysis Set (PKAS)····················································37
5.5
Pharmacodynamic Analysis Set (PDAS)···················································37
5.6
Re-Enrolled Analysis Set·····································································37
5.7
Post-HSCT Analysis Set ·····································································37
6
ANALYSIS VARIABLES ·······································································37
6.1
Efficacy Endpoints············································································37
6.1.1
Response Definition·····································································37
6.1.2
Efficacy Variables·······································································39
6.2
Safety Variables···············································································43
6.2.1
Definition of DLT ·······································································43
6.2.2
Definition of MTD ······································································43
6.2.3
Other Safety Variables··································································43
6.3
Pharmacokinetics Variables ·································································47


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6.3.1
Pharmacokinetics for ASP2215························································47
6.3.2
Pharmacokinetics for Midazolam and Midazolam Metabolite·····················49
6.3.3
Pharmacokinetics for CYP3A4 Inhibitor Voriconazole ····························49
6.3.4
Pharmacokinetics for Cephalexin ·····················································49
6.4
Pharmacodynamics Variables ·······························································50
6.5
····························································50
6.6
Other Variables················································································50
7
STATISTICAL METHODOLOGY ···························································52
7.1
General Considerations·······································································52
7.2
Study Population ··············································································53
7.2.1
Disposition of Subjects ·································································53
7.2.2
Protocol Deviations ·····································································53
7.2.3
Demographic and Other Baseline Characteristics ···································54
7.2.4
Previous and Concomitant Medications ··············································55
7.2.5
Previous and Concomitant Transfusions ·············································55
7.2.6
Prior AML Chemotherapy ·····························································55
7.2.7
Non-Medication Therapy·······························································55
7.2.8
On-Study HSCT ·········································································56
7.3
Study Drugs····················································································56
7.3.1
Exposure··················································································56
7.3.2
Treatment Compliance··································································56
7.4
Analysis of Efficacy ··········································································57
7.5
Analysis of Safety·············································································59
7.5.1
Bayesian Logistic Regression Modeling in Dose Escalation and Expansion 
Phases·····················································································59
7.5.2
Subject Assignment in Dose Expansion Phase ······································60
7.5.3
Determination of DLT and MTD······················································60
7.5.4
Adverse Events ··········································································60
7.5.5
Clinical Laboratory Evaluation ························································62
7.5.6
Vital Signs················································································63
7.5.7
Electrocardiograms (ECGs)····························································63
7.5.8
Pregnancies···············································································64
7.5.9
Eastern Cooperative Oncology Group (ECOG) Performance Scores·············64
7.5.10
Ophthalmologic Assessment···························································65


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7.6
Analysis of PK·················································································65
7.6.1
Estimation of PK Parameters ··························································65
7.6.2
Statistical Analysis ······································································65
7.7
Analysis of PD·················································································67
7.7.1
%pFLT3, %pAXL, and pS6····························································67
7.7.2
PIA ························································································67
7.8
Subgroups of Interest ·········································································68
7.8.1
FLT3 Mutation Status···································································68
7.8.2
Demographic and Baseline Characteristics ··········································68
7.8.3
Subset Analysis for FLT3 Mutated Subjects in >=80mg Dose Levels············68
7.8.4
CYP3A4 Inhibitor Usage·······························································68
7.8.5
Baseline Hepatic and Renal Function·················································69
7.8.6
Drugs that Prolong QT with Known or Possible Risk of TdP ·····················69
7.8.7
Post-HSCT Safety and Efficacy ·······················································70
7.9
Other Analyses ················································································70
7.9.1
······················································70
7.9.2
PK-PD Analysis ·········································································70
7.10
Interim Analysis (and Early Discontinuation of the Clinical Study)····················70
7.11
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········70
7.11.1
Missing Data ·············································································70
7.11.2
Outliers ···················································································71
7.11.3
Visit Windows ···········································································71
8
DOCUMENT REVISION HISTORY·························································72
9
REFERENCES ····················································································77
10
APPENDICES ·····················································································78
10.1
Appendix 1: List of Medications that Prolong QT with Known or Possible Risk 
of TdP ··························································································78
10.2
Appendix 2: Study Communication Memo ················································87
10.3
Appendix 3: Key Contributors and Approvers ············································91


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I.
LIST OF ABBREVIATIONS AND KEY TERMS
List of Abbreviations
Abbreviations
Description of abbreviations
AE
Adverse Event
Alb
Albumin
ALP
Alkaline Phosphatase
ALT
Alanine Transaminase
AML
Acute Myeloid Leukemia
ANC
Absolute Neutrophil Count
APGD
Astellas Pharma Global Development
aPTT
Activated Partial Thromboplastin Time
ASCM
Analysis Set Classification Meeting 
ASP2215
Astellas Compound code for 2215
AST
Aspartate Transaminase
ATC
Anatomical Therapeutic Chemical classification system
AUC
Area Under the plasma concentration – time Curve
AUC24
Area under the concentration-time curve from the time of dosing to 24 hours 
after dosing
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 to the last 
measurable concentration (Clast) 
AUCtau
Area under the concentration-time curve from the time of dosing to the start of 
the next dosing interval 
BMI
Body Mass Index
BQL
Blow Quantification Limit
BUN
Blood Urea Nitrogen
Ca
Calcium
CI
Confidence Intervals
CK
Creatine Phosphokinase
Cl
Chloride
CL
Total systemic clearance after intravenous dosing
CL/F
Apparent total systemic clearance after single or multiple extra-vascular dosing 
Clast
Concentration corresponding to the time of the last measurable concentration


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Abbreviations
Description of abbreviations
Cmax
Maximum Concentration
Cr
Creatinine
CR
Complete Remission
CRc
Composite Complete Remission
CRi
Complete Remission with incomplete hematological recovery
CRp
Complete Remission with incomplete platelet recovery
CRF
Case Report Form
CS
Classification Specifications
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
Ctau
Concentration at time tau
Ctrough
Minimum Concentration
CV
Coefficient of Variation
CYP3A4
Cytochrome P450-isozyme3A4
DBP
Diastolic Blood Pressure
DDI
Drug-drug Interaction
DLT
Dose Limiting Toxicity
DN
Dose Normalized
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDTA
Ethylenediaminetetraacetic acid
EFS
Event-Free Survival
FAB
French-American-British 
FAS
Full Analysis Set
FLT3
FMS-like TyrosineKkinase
GD
Global Development
Gl
Glucose
H
High
hCG
Human Chorionic Gonadotropin
Hct
Hematocrit
HCO3
Bicarbonate
Hgb
Hemoglobin
HSCT
Hematopoietic Stem Cell Transplant
ICF
Informed Consent Form
ICH
International Conference on Harmonization


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Abbreviations
Description of abbreviations
IND
Investigational New Drug
INR
International Normalization Ratio
IRT
Interactive Response Technology
ISN
International Study Number
ITD
Internal Tandem Duplication
IU/L
International units/liter
IV
Intravenous
K
Potassium
KIT
Cell surface receptor tyrosine kinase that binds to stem cell factor
L
Liter
L
Low
LDH
Lactate Dehydrogenase
LFS
Leukemia-Free Survival
MCH
Mean Corpuscular Hemoglobin
MCHC
Mean Corpuscular Hemoglobin Concentration
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligrams
Mg
Magnesium
Min
Minute
mL
Milliliter
mmHg
millimeters of mercury
MRD
Minimum Residual Disease
msec
milliseconds
MTD
Maximum Tolerated Dose
MUGA
Multigated acquisition scan
N
Number
N
Normal
Na
Sodium
NCI
National Cancer Institute
NR
No Response
NYHA
New York Heart Association
OS
Overall Survival
pAXL
Phosphorylated AXL
pAXLn
Phosphorylated AXL Normalized to Total AXL
PD
Pharmacodynamic
PD
Protocol Deviation
PDAS
Pharmacodynamic Analysis Set


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Abbreviations
Description of abbreviations
pFLT3
Phosphorylated FLT3
pFLT3n
Phosphorylated FLT3 Normalized to Total FLT3
PGx
Pharmacogenomics
PK
Pharmacokinetic
Pi
Phosphate
PIA
Plasma Inhibitory Assay
PKAS
Pharmacokinetic Analysis Set
PPS
Per Protocol Set
PR
Partial Remission
pS6
Phosporylated S6
PT
Prothrombin Time
PT
Preferred Term
PTT
Partial Thromboplastin Time
QD
quaque die, a Latin phrase meaning “every day”
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate using Fridericia’s factor
RBC
Red Blood Cell
RR
Interval between 2 consecutive r waves on an ECG
SAE
Serious Adverse Event
SAF
Safety analysis set
SAP
Statistical Analysis Plan
SAS
Statistical Analysis System
SBP
Systolic Blood Pressure
SOC
System Organ Class
SOP
Standard Operating Procedure
T1/2
Half-life
tAXL
Total AXL
TBL
Total Bilirubin
T Chol
Total Cholesterol
TdP
Torsade de pointes
TEAE
Treatment Emergent Adverse Event
tFLT3
Total FLT3
TK
Tyrosine Kinase
TLF
Tables, Listings and Figures
Tmax
Time to observed Cmax
T Prot
Total Protein
Trig
Triglycerides


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Abbreviations
Description of abbreviations
TSH
Thyroid Stimulating Hormone
ULN
Upper limit of normal
Vz
Volume of distribution after intravenous dosing during the terminal elimination 
phase
Vz/F
Apparent volume of distribution during the terminal elimination phase after 
single extra-vascular dosing 
WBC
White Blood Cell
WHO
World Health Organization
WHO-DD
World Health Organization – Drug Dictionary
WOCBP
Women of childbearing potential


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List of Key Terms
Terms
Definition of terms
Baseline
Observed values/findings which are regarded as the starting point for 
comparison.
Enroll
To register or enter into a clinical trial. NOTE: Once a subject has been 
enrolled, the clinical trial protocol applies to the subject.
Intervention
The drug, 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, pharmacoeconomics). 
Investigational period
Period of time where major interests of protocol objectives are observed, 
and where the test drug or comparative drug (sometimes without 
randomization) 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 period
Period of time before entering the investigational period, usually from the 
time of starting a subject signing consent until just before the test drug or 
comparative drug (sometimes without randomization) is given to a subject. 
Randomization
The process of assigning trial subjects to treatment or control groups using 
an element of chance to determine assignments in order to reduce bias.
Screening
A process of active consideration of potential subjects for enrollment in a 
trial.
Screen failure
Potential subject who did not meet one or more criteria required for 
participation in a trial.
Study period
Period of time from the first site initiation date to the last site completing the 
study.
Variable
Any quantity 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 and secondary 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 and 
wherever possible, the SAP should be developed in parallel with protocol finalization. For 
Phase 2-4 studies the SAP should be developed and approved before First Subject In (FSI). If 
the expected interval between FSI and soft-lock is less than 12 weeks, then the SAP should 
be approved by 12 weeks prior to the planned date of soft-lock. 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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Table 1A
Schedule of Assessments for Dose Escalation Phase (Cohort 1)
Activity
Screening
(Day -14 to -3)
Day
-2
Day
-1
Cycle 1
Cycle 2
Subsequent 
Cycles
D 1r
D 4±1
D 8±1
D 15
D 16
D 22+1
D 1 ±3
D 15 ±1
D 1±3
Signed ICF
X
Medical and Disease History
X
Physical Examination  (incl. height and weight) n
X n
X a
X
X n
X
X
X
X
X n
X
X n
Vital Signs
X
X a
X
X
X
X
X
X
X
X
X
ECOG Performance
X
X
X
X
X
X
Prior and Concomitant Medications
X b
X
X
X
X
X
X
X
X
X
X
Pregnancy Test for WOCBP
X f
X
X
X
Coagulation Profile (PT/INR, D-Dimer, Fibrinogen)
X
Chest X-ray (or CT of chest)t
X
12-lead ECG d
X d
X d
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Ophthalmologic Assessment m
X
X
X
X
Clinical Laboratory Tests (chemistry, hematology, coagulation, urinalysis) p
Xo 
X a
X
X a
X a
X a
X a
Xa
X a
X a
X a
Thyroid Function Tests
X
Xq
MUGA or ECHO c
X
FLT3, C-CBL, AXL Mutation Status j (bone marrow aspirate or whole blood)
X
Bone Marrow Aspiration and Biopsy
X g
X g
X g
AE/SAE Assessment
X
X
X
X
X
X
X
X
X
X
X
PK (whole blood samples for plasma PK)
X e
X e
X e
X e
X e
X e
X e
X e
X e
PIA (whole blood samples for plasma inhibitory assay)
X l
X l
X l
X l
X l
X l
Xl
PGxh
X
Phosphorylation of  FLT-3, S6 and AXLk (whole blood)
X
X
X
X
ASP2215 Dosing at the Clinic i
X
X
X
X
X
X
X
X
X
IRT Transaction Required s
X
X
X
X
X
X
X
X
ASP2215 Dispensing for Subject Take Home
X
X
X
X
X
X
X
Table footnotes appear on next page


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a.
Obtained predose.
b.
Includes medications taken within 28 days prior to screening.
c.
MUGA scans are to be performed at Screening for subjects with history of congestive heart failure NYHA Class 3 or 4 (unless MUGA scans performed either within 3 months prior revealed LVEF 
≥45%).
d.
Screening ECGs are required. ECG assessment will be evaluated at D-2 and C1D15 at pre-dose, 2, 4, 6, and 24 hours post-dose. Pre-dose ECG assessment will also be evaluated on C1D1, C1D8, 
C1D22, and D1 of each subsequent cycle. 24 hr post-dose ECG assessment will be performed on D-1 and D16 respectively. All efforts should be made to conduct ECG monitoring in triplicate 
between 7:00 am and 3:00 pm at all assessment time points. Pre-dose assessments should be taken within 0.5 hours before drug administration. In addition, 2, 4, 6, and 24 hour post-dose assessments 
should be performed within ± 0.5 hours of nominal time. 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. See Section 5.4.5 of the protocol amendment 10.
e.
PK samples will be collected at D-2 and C1D15 at pre-dose (0.5 hours before drug administration), 0.5 (±10 minutes), 1 (±10 minutes), 2 (±10 minutes), 4 (±20 minutes), 6 (±20 minutes), and 
24 hours (±90 minutes) post dose (the 24 hour sample will be collected on Day -1 and before the next dose of ASP2215 on Day 16 respectively). Samples will also be collected on C1D1, C1D8, and 
C1D22 pre-dose (0.5 hours before drug administration) and 2 hours (±10 minutes) post dose. Thereafter PK samples will be collected pre-dose (0.5 hours before drug administration) on Day 1 of 
each cycle. See Section 5.6.1 of the protocol amendment 10.
f.
WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of study treatment.
g.
Bone marrow samples are required during Screening, Cycle 2 Day 1 and Cycle 3 Day 1. Screening samples may be collected up to 21 days prior to C1D1. For subjects who do not achieve a 
complete remission (CR, CRp, or CRi), the bone marrow assessments will be repeated at Day 1 of every 2 subsequent cycles. For subjects who achieve a complete remission (CR, CRp, or CRi), 
bone marrow will be repeated on one month after the date of remission and every 3 subsequent cycles for up to 1 year from Cycle 1 Day 1 and after that only if there is suspicion of relapse in the 
peripheral blood. Bone marrow samples are also required at the Early Termination/End-of Study Visit, and as clinically indicated. If bone marrow aspirate is unobtainable (i.e., dry tap), an additional 
EDTA tube of peripheral blood should be collected instead.
h.
Buccal swab collected at Screening for optional pharmacogenomic study.
i.
ASP2215 is taken daily without food at home except on clinic days when it will be taken at the clinic and Day -1 when no ASP2215 will be taken.  Subjects will be instructed to take the daily dose 
with water as close to the same time each morning as possible.
j.
FLT3, C-CBL and AXL mutation status will be assessed from bone marrow sample taken at the Screening Visit. If bone marrow sample is unavailable (e.g., dry tap), the whole blood sample taken 
at the Screening Visit will be used.  
k.
Predose and 2 hours (±10 minutes) post dose on Day -2. Predose Day -1 (no dose on this day), Day 8, and Day 15 for determination of phosphorylation of FLT3, S6 and AXL. Day -1 sample will be taken 
in proximity to 24 hour PK sample following Day -2 dose administration. 
l.
PIA samples will be collected at D-2 and C1D15 at pre-dose (0.5 hours before drug administration), 2 (±10 minutes), 6 (±20 minutes), and 24 hours (±90 minutes) post dose (the 24 hour sample must be 
collected on Day -1 and before the next dose of ASP2215 on D 16). Samples will also be collected on C1D1, C1D8, and C2D1 pre-dose (0.5 hours before drug administration) and 2 hours (±10 minutes) 
post dose.
m.
Ophthalmologic assessment to be performed by visual acuity measurement, ophthalmoscopy, slit lamp biomicroscopy, visual fields and optical coherence tomography (OCT) at Screening (within 
12 days prior to dosing), 15th Day of Cycle 1 (± 3 days), 1st Day of Cycle 2 (± 3 days), Cycle 3 (± 3 days), and every 2 cycles thereafter (± 3 days), at the end of treatment, and when clinically 
indicated. 
n.
Height measurement performed only at Screening. Weight measurement should be performed on D1 of each Cycle. 
o.
Subjects may be screened from local labs only. However, screening samples must be submitted for central read.
p.
Additional laboratory tests should be performed according to institutional standard of care.
q.
Thyroids function tests will be repeated after every 2 cycles of therapy (C3D1, C5D1, C7D1 etc.).
r.
For scheduling and logistical purposes, up to 3 days are allowed between Day -1 and Cycle 1 Day 1.
s.
For the purposes of drug preparation and dispensing activities, IRT Transactions may be done prior to the visit and do not need to fall within the protocol visit windows.
t.
Chest X-ray (or CT of chest) does not need to be repeated if performed within 2 weeks prior to start of Screening.


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Table 1B
Schedule of Assessments for Expansion Phase with CYP3A4 Inhibitor Voriconazole Study (Cohort 2, Starting Dose Level)
Activity
Screening
(Day -14 to -1)
Cycle 1
Cycle 2
Subsequent 
Cycles
D 1
D 4±1
D 8±1
D 15
D 16
D 22+1
D 1 ±2
D 2
D 15 ±1
D 1±3
Signed ICF
X
Medical and Disease History 
X
Physical Examination o
X o
X o a
X
X
X
X
X o
X
X o
Vital Signs
X
X a
X
X
X
X
X
X
X
ECOG Performance
X
X a
X
X
X
X
Prior and Concomitant Medications
X b
X
X
X
X
X
X
X
X
Pregnancy Test for WOCBP
X f
X
X
X
Coagulation Profile (PT/INR, D-Dimer, Fibrinogen)
X
Chest X-ray (or CT of chest) t
X
12-lead ECG d
X
X
X
Xd
X
X
Xd
X
Xd
Ophthalmologic Assessment m
X
X
X
Xm
Clinical Laboratory Tests (chemistry, hematology, coagulation, urinalysis) q
Xp
X a
X a
X a
X a
X a
X a
X a
X a
Thyroid Function Tests
X
Xr
MUGA or ECHO c
X
FLT3, C-CBL,AXL Mutation Status j (bone marrow aspiration or whole blood)
X
Bone Marrow Aspiration and Biopsy  
X g
X g
X g
AE/SAE Assessment
X
X
X
X
X
X
X
X
X
PK (whole blood samples for plasma PK) 
X e
X e
X e
X e
X e
X e
X e
X e
PIA (whole blood samples for plasma inhibitory assay)
X l
X l
X l
Xl
PGxh
X
Phosphorylation of  FLT-3, S6 and AXLk  ( whole blood )
X
X
X
ASP2215 Dosing at the Clinic i
X
X
X
X
X
X
X
X
X
IRT Transaction Required s
X
X
X
X
X
X
X
X
ASP2215 Dispensing for Subject Take Home
X
X
X
X
X
X
X
Voriconazole (CYP3A4 Inhibitor) dosing
Xn
Xn
Xn
Table footnotes appear on next page


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a.
Obtained predose.
b.
Includes medications taken within 28 days prior to screening.
c.
MUGA scans are to be performed at Screening for subjects with history of congestive heart failure NYHA Class 3 or 4 (unless MUGA scans performed either within 3 months prior revealed LVEF 
≥45%).
d.
Screening ECG is required. ECG assessment will be evaluated at C1D15 and C2D1 at pre-dose, 2, 4, 6, and 24 hours post-dose. 24 hr post-dose ECG assessment will be performed on D16 and C2D2 
respectively.  Pre-dose ECG assessment will also be evaluated on C1D1, C1D8, C1D22, and D1 of each subsequent cycle. All efforts should be made to conduct ECG monitoring in triplicate 
between 7:00 am and 3:00 pm at all assessment time points. Pre-dose assessments should be taken within 0.5 hours before drug administration. In addition, 2, 4, 6, and 24 hour post-dose assessments 
should be performed within ± 0.5 hours of nominal time. 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. See Section 5.4.5 of the protocol amendment 10.
e.
PK samples for ASP2215 will be collected at C1D15, and C2D1 at pre-dose (0.5 hours before drug administration), 0.5(±10 minutes), 1 (±10 minutes), 2 (±10 minutes), 4 (±20 minutes), 6 (±20 
minutes), and 24 hours (±90 minutes) post dose. 24 hr post-dose PK assessment will be performed on D16 and C2D2 respectively. Predose (0.5 hours before drug administration) PK samples will 
also be collected on C1D1, C1D8, C1D22, and on Day 1 of each cycle starting at Cycle 3. A predose (0.5 hours before drug administration) PK sample for CYP3A4 inhibitor will be taken on C2D1. 
See Section 5.6.1 of the protocol amendment 10.
f.
WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of study treatment.
g.
Bone marrow samples are required during Screening, Cycle 2 Day 1 and Cycle 3 Day 1. Screening samples may be collected up to 21 days prior to C1D1. For subjects who do not achieve a 
complete remission (CR, CRp, or CRi), the bone marrow assessments will be repeated at Day 1 of every 2 subsequent cycles. For subjects who achieve a complete remission (CR, CRp, or CRi), 
bone marrow will be repeated on one month after the date of remission and every 3 subsequent cycles for up to 1 year from Cycle 1 Day 1 and after that onlyif there is suspicion of relapse in the 
peripheral blood. Bone marrow samples are also required at the Early Termination/End-of Study Visit, and as clinically indicated. If bone marrow aspirate is unobtainable (i.e., dry tap), an additional 
EDTA tube of peripheral blood should be collected instead.
h.
Buccal swab collected at Screening for optional pharmacogenomic study.
i.
ASP2215 is taken daily without food at home except for clinic days when it will be taken at the clinic. Subjects will be instructed to take the daily dose with water as close to the same time each 
morning as possible.
j.
FLT3, C-CBL and AXL mutation status will be assessed from bone marrow sample taken at the Screening Visit. If bone marrow sample is unavailable (e.g., dry tap), the whole blood sample taken at 
the Screening Visit will be used.  
k.
Predose and 2 hours (±10 minutes) post dose on Day 1, Day 8, and Day 15 for determination of phosphorylation of FLT3, S6 and AXL. 
l.
PIA samples will be collected at C1D1, C1D8, C1D15 and C2D1 at pre-dose (0.5 hours before drug administration) and 2 hours (±10 minutes) post dose.
m.
Ophthalmologic assessment to be performed by visual acuity measurement, ophthalmoscopy and slit lamp biomicroscopy, visual fields and optical coherence tomography (OCT) at Screening (within 
12 days prior to dosing), 15th Day of Cycle 1 (± 3 days), 1st Day of Cycle 2 (± 3 days), Cycle 3 (± 3 days), and every 2 cycles thereafter (± 3 days), at the end of treatment, and when clinically 
indicated. 
n.
Voriconazole (CYP3A4 inhibitor) will be administered at 200 mg every 12 hours starting on C1D16 through C2D1.
o.
Height measurement performed only at Screening. Weight measurement should be performed on D1 of each Cycle. 
p.
Subjects may be screened from local labs only. However, samples must be submitted for central read.
q.
Additional laboratory tests should be performed according to institutional standard of care.
r.
Thyroids function tests will be repeated after every 2 cycles of therapy (C3D1, C5D1, C7D1 etc.).
s.
For the purposes of drug preparation and dispensing activities, IRT Transactions may be done prior to the visit and do not need to fall within the protocol visit windows.
t.
Chest X-ray (or CT of chest) does not need to be repeated if performed within 2 weeks prior to start of Screening.


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Table 1C
Schedule of Assessments for Expansion Phase without DDI Studies (Cohort 2, Intermediate Dose Levels) 
Activity
Screening
(Day -14 to -1)
Cycle 1
Cycle 2
Subsequent 
Cycles
D 1
D 4±1
D 8±1
D 15±1
D 22+1
D 1 ±3
D 15 ±1
D 1±3
Signed ICF
X
Medical and Disease History 
X
Physical Examination n
X n
X n a
X
X
X
X
X n
X
X n
Vital Signs
X
X a
X
X
X
X
X
X
X
ECOG Performance
X
X a
X
X
X
X
Prior and Concomitant Medications
X b
X
X
X
X
X
X
X
X
Pregnancy Test for WOCBP
X f
X
X
X
Coagulation Profile (PT/INR, D-Dimer, Fibrinogen)
X
Chest X-ray (or CT of chest) s
X
12-lead ECG d
X 
Xd
X
Xd
X
Xd
Xd
Ophthalmologic Assessment m
X
X
X
X
Clinical Laboratory Tests (chemistry, hematology, coagulation, urinalysis) p
X o
X a
X a
X a
X a
X a
X a
X a
X a
Thyroid function tests
X
Xq
MUGA or ECHO c
X
FLT3, C-CBL,AXL Mutation Status j (bone marrow aspirate or whole blood)
X
Bone Marrow Aspiration and Biopsy  
X g
X g
X g
AE/SAE Assessment
X
X
X
X
X
X
X
X
X
PK (whole blood samples for plasma PK) 
X e
X e
X e
X e
X e
X e
PIA (whole blood samples for plasma inhibitory assay)
X l
X l
X l
Xl
PGxh
X
Phosphorylation of  FLT-3, S6 and AXLk   (whole blood )
X
X
X
ASP2215 Dosing at the Clinic i
X
X
X
X
X
X
X
IRT Transaction Required r
X
X
X
X
X
X
X
X
ASP2215 Dispensing for Subject Take Home
X
X
X
X
X
X
X
Table footnotes appear on next page


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a.
Obtained predose.
b.
Includes medications taken within 28 days prior to screening. 
c.
MUGA scans are to be performed at Screening for subjects with history of congestive heart failure NYHA Class 3 or 4 (unless MUGA scans performed either within 3 months prior 
revealed LVEF ≥45%).
d.
Screening ECG is required. ECG assessment will be evaluated at C1D1 and C1D15 at pre-dose, and 2 hours post-dose. Pre-dose ECG assessment will also be evaluated on C1D8, C1D22 
and D1 of each subsequent cycle. All efforts should be made to conduct ECG monitoring in triplicate between 7:00 am and 3:00 pm at all assessment time points. Pre-dose assessments 
should be taken within 0.5 hours before drug administration. In addition, 2 hour post-dose assessment should be performed within ± 0.5 hours of nominal time. 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. See Section 5.4.5
of the protocol amendment 10.
e.
PK samples for ASP2215 will be collected at C1D1 and C1D15 at pre-dose (0.5 hours before drug administration), 2, hours (±10 minutes) post dose. ASP2215 pre-dose (0.5 hours before 
drug administration) PK samples will also be collected on C1D8, C1D22 and on Day 1 of each cycle starting at Cycle 2. See Section 5.6.1 of the protocol amendment 10.
f.
WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of hCG) within 72 hours prior to the start of study treatment.
g.
Bone marrow samples are required during Screening, Cycle 2 Day 1 and Cycle 3 Day. Screening samples may be collected up to 21 days prior to C1D1. For subjects who do not achieve a 
complete remission (CR, CRp, or CRi), the bone marrow assessments will be repeated at Day 1 of every 2 subsequent cycles. For subjects who achieve a complete remission (CR, CRp, or 
CRi), bone marrow will be repeated on one month after the date of remission and every 3 subsequent cycles for up to 1 year from Cycle 1 Day 1 and after that only if there is suspicion of 
relapse in the peripheral blood. Bone marrow samples are also required at the Early Termination/End-of Study Visit, and as clinically indicated. If bone marrow aspirate is unobtainable 
(e.g., dry tap), an additional EDTA tube of peripheral blood should be collected instead. For France and Germany Only:  Bone marrow aspirate is required. Collection of both the bone 
marrow aspirate and bone marrow biopsy is preferred, but biopsy samples are only required in case of inadequate aspirate.
h.
Buccal swab collected at Screening for optional pharmacogenomic study.
i.
ASP2215 is taken daily at home except for clinic days when it will be taken at the clinic.
j.
FLT3 and C-CBL and AXL mutation status will be assessed from bone marrow sample taken at the Screening Visit. If bone marrow sample is unavailable (e.g., dry tap), the whole blood 
sample taken at the Screening Visit will be used.  
k.
Pre-dose and 2 hours (±10 minutes) post dose on Day 1. Pre-dose on Day 8 and Day 15 for determination of phosphorylation of FLT3, S6 and AXL.
l.
PIA samples will be collected at C1D1, C1D8, C1D15, and C2D1 at pre-dose (0.5 hours before drug administration) and 2 hours (±10 minutes) post dose.
m.
Ophthalmologic assessment to be performed by visual acuity measurement, ophthalmoscopy and slit lamp biomicroscopy, visual fields and optical coherence tomography (OCT) at 
Screening (within 12 days prior to dosing), 15th Day of Cycle 1 (± 3 days), 1st Day of Cycle 2 (± 3 days), Cycle 3 (± 3 days), and every 2 cycles thereafter (± 3 days), at the end of 
treatment, and when clinically indicated. 
n.
Height measurement performed only at Screening. Weight measurement should be performed on D1 of each Cycle.
o.
Subjects may be screened from local labs only. However, samples must be submitted for central read.
p.
Additional laboratory tests should be performed according to institutional standard of care.
q.
Thyroids function tests will be repeated after every 2 cycles of therapy (C3D1, C5D1, C7D1 etc.).
r.
For the purposes of drug preparation and dispensing activities, IRT Transactions may be done prior to the visit and do not need to fall within the protocol visit windows.
s.
Chest X-ray (or CT of chest) does not need to be repeated if performed within 2 weeks prior to start of Screening.


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Table 1D
Schedule of Assessments for Expansion Phase with CYP3A4 Induction Study (Cohort 2, MTD Level)
Activity
Screening
(Day -14 to -2)
D -1
Cycle 1
Cycle 2
Subsequent 
Cycles
D 1
D4±1
D8±1
D 15
D 16
D 22+1
D 1 ±3
D 15 ±1
D 1±3
Signed ICF
X
Medical and Disease History 
X
Physical Examination n
X n
X
X n a
X n
X
X
X
X n
X
X n
Vital Signs
X
X
X a
X
X
X
X
X
X
X
ECOG Performance
X
X
X a
X
X
X
X
Prior and Concomitant Medications
X b
X
X
X
X
X
X
X
X
X
Pregnancy Test for WOCBP
X f
X
X
X
Coagulation Profile (PT/INR, D-Dimer, Fibrinogen)
X
Chest X-ray (or CT of Chest) s
X
12-lead ECG d
X 
Xd
X
Xd
X
X
X
X
Xd
Ophthalmologic Assessment m
X m
X
X
Xm
Clinical Laboratory Tests (chemistry, hematology, coagulation, urinalysis) p
Xo
X a
X a
X a
X
X a
X a
X a
X a
X a
Thyroid Function Tests
X
Xq
MUGA or ECHO c
X
FLT3, C-CBL, AXL  Mutation Status j (bone marrow aspirate or whole blood)
X
Bone Marrow Aspiration and Biopsy  
X g
X g
X g
AE/SAE Assessment
X
X
X
X
X
X
X
X
X
X
PK (Whole blood Samples for plasma PK) 
X e
X e
X e
X e
X e
X e
X e
X e
PIA (whole blood samples for plasma inhibitory assay)
X l
X l
X l
Xl
PGxh
X
Phosphorylation of  FLT-3, S6 and AXL k
(whole blood )
X
X
X
ASP2215 Dosing at the Clinic i
X
X
X
X
X
X
X
X
IRT Transaction Required r
X
X
X
X
X
X
X
X
ASP2215 Dispensing for Subject Take Home
X
X
X
X
X
X
X
Midazolam Dosing e
X e
X e
Table footnotes appear on next page


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a.
Obtained predose.
b.
Includes medications taken within 28 days prior to screening.
c.
MUGA scans are to be performed at Screening for subjects with history of congestive heart failure NYHA Class 3 or 4 (unless MUGA scans performed either within 3 months prior revealed LVEF 
≥45%).
d.
Screening ECGs are required. ECG assessment will be evaluated at D-1 and C1D15 at pre-dose, 2, 4, 6, and 24 hours post-dose. 24 hr post-dose ECG assessment will be performed on C1D1 and 
C1D16 respectively. Pre-dose ECG assessment will also be evaluated on C1D1, C1D8, C1D22 and D1 of each subsequent cycle. All efforts should be made to conduct ECG monitoring in triplicate 
between 7:00 am and 3:00 pm at all assessment time points. Pre-dose assessments should be taken within 0.5 hours before drug administration. In addition, 2, 4, 6, and 24hour post-dose assessments 
should be performed within ± 0.5 hours of nominal time. 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. See Section 5.4.5 of the protocol amendment 10.
e.
Midazolam (2 mg of syrup (1.0 ml) by mouth) will be administered as a single dose on Days -1 and C1D15. For all Midazolam PK timepoints, Vital Signs including respiratory rate are to be done. 
Midazolam PK samples will be collected at D-1 and C1D15 at pre-dose (0.5 hours before drug administration), 0.5 (±10 minutes), 1 (±10 minutes), 2 (±10 minutes), 4 (±20 minutes), 6
(±20 minutes), and 24 hours (±90 minutes) post dose (the 24 hour sample must be collected before the dose of ASP2215). 24 hr post-Midazolam dose assessment will be performed on C1D1 and 
D16 respectively. PK samples for ASP2215 will be collected at C1D1, C1D8, C1D15, and C1D22 at pre-dose (0.5 hours before drug administration), and 2 hours (±10 minutes) post dose. ASP2215 
pre-dose (0.5 hours before drug administration) PK samples will also be collected on Day 1 of each cycle starting at Cycle 2. See protocol amendment 10 Sec 5.6.1.
f.
WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of hCG) within 72 hours prior to the start of study treatment.
g.
Bone marrow samples are required during Screening, Cycle 2 Day 1 and Cycle 3 Day 1. Screening samples may be collected up to 21 days prior to C1D1. For subjects who do not achieve a 
complete remission (CR, CRp, or CRi), the bone marrow assessments will be repeated at Day 1 of every 2 subsequent cycles. For subjects who achieve a complete remission (CR, CRp, or CRi), 
bone marrow will be repeated on one month after the date of remission and every 3 subsequent cycles for up to 1 year from Cycle 1 Day 1 and after that only if there is suspicion of relapse in the 
peripheral blood. Bone marrow samples are also required at the Early Termination/End-of Study Visit, and as clinically indicated. If bone marrow aspirate is unobtainable (e.g., dry tap), an 
additional EDTA tube of peripheral blood should be collected instead.
h.
Buccal swab collected at Screening for optional pharmacogenomic study.
i.
ASP2215 is taken daily without food at home except for clinic days when it will be taken at the clinic.  Subjects will be instructed to take the daily dose with water as close to the same time each 
morning as possible.
j.
FLT3, C-CBL and AXL mutation status will be assessed from bone marrow sample taken at the Screening Visit. If bone marrow sample is unavailable (e.g., dry tap), the whole blood sample taken at 
the Screening Visit will be used.  
k.
Predose and 2 hours (±10 minutes) post dose on C1D1. Pre dose on C1D8 and C1D15 for determination of phosphorylation of FLT3, S6 and AXL.
l.
PIA samples will be collected at C1D1, C1D8, C1D15 and C2D1 pre-dose (0.5 hours before drug administration) and 2 hours (±10 minutes) post dose.
m.
Ophthalmologic assessment to be performed by visual acuity measurement, ophthalmoscopy and slit lamp biomicroscopy, visual fields and optical coherence tomography (OCT) at Screening (within 
12 days prior to dosing), 15th Day of Cycle 1 (± 3 days), 1st Day of Cycle 2 (± 3 days), Cycle 3 (± 3 days), and every 2 cycles thereafter (± 3 days), at the end of treatment, and when clinically 
indicated. 
n.
Height measurement performed only at Screening. Weight measurement should be performed on D1 of each Cycle.
o.
Subjects may be screened from local labs only. However, samples must be submitted for central read.
p.
Additional laboratory tests should be performed according to institutional standard of care.
q.
Thyroids function tests will be repeated after every 2 cycles of therapy (C3D1, C5D1, C7D1 etc.).
r.
For the purposes of drug preparation and dispensing activities, IRT Transactions may be done prior to the visit and do not need to fall within the protocol visit windows.
s.
Chest X-ray (or CT of chest) does not need to be repeated if performed within 2 weeks prior to start of Screening. 


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Table 1E
Schedule of Assessments for Expansion Phase with MATE1 Substrate Study (Cohort 2, MATE1 Sub-study)
Activity
Screening
(Day -14 to -2)
D -1
Cycle 1
Cycle 2
Subsequent 
Cycles
D 1
D 4±1
D 8±1
D 9
D 15
D 16
D 22+1
D 1 ±3
D 15 ±1
D 1±3
Signed ICF
X
Medical and Disease History 
X
Physical Examination l
X l
X
X l a
X
X
X
X
X l
X
X l
Vital Signs
X
X
X a
X
X
X
X
X
X
X
ECOG Performance
X
X
X a
X
X
X
X
Prior and Concomitant Medications
X b
X
X
X
X
X
X
X
X
X
Pregnancy Test for WOCBP
X f
X
X
X
Coagulation Profile (PT/INR, D-Dimer, Fibrinogen)
X
Chest X-ray (or CT of Chest) q
X
12-lead ECG d
X
X
X
X
X s
X
X
X
X
X
Ophthalmologic Assessment k
X k
X
X
Xk
Clinical Laboratory Tests (chemistry, hematology, coagulation, 
urinalysis) n
Xm
X a
X a
X a
X a
X a
X a
X a
X a
X a
Thyroid Function Tests
X
Xo
MUGA or ECHO c
X
FLT3, C-CBL, AXL  Mutation Status j (bone marrow aspirate or whole 
blood)
X
Bone Marrow Aspiration and Biopsy  
X g
X g
X g
AE/SAE Assessment
X
X
X
X
X
X
X
X
X
X
ASP2215 PK (Whole blood Samples) 
X e
X e
X e
X e
X e
X e
X e
PGxh
X
ASP2215 Dosing at the Clinic i
X
X
X
X
X
X
X
X
Cephalexin Dosing and PK Collection r
X r
X
X r
X
IRT Transaction Requiredp
X
X
X
X
X
X
X
X
X
ASP2215 Dispensing for Subject Take Home
X
X
X
X
X
X
X
a.
Obtained predose.
b.
Includes medications taken within 28 days prior to screening.
c.
MUGA scans are to be performed at Screening for subjects with history of congestive heart failure NYHA Class 3 or 4 (unless MUGA scans performed either within 3 months prior revealed 
LVEF ≥45%).
Table footnotes continued on next page


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d.
Screening ECGs are required. ECG assessment will be evaluated at D-1 and C1D15 at pre-dose, 2 hours post, and 24 hours post dose. 24 hr post-dose ECG assessment will be performed on C1D1 
and C1D16 respectively. Pre-dose ECG assessment will also be evaluated on C1D1, C1D8, C1D22 and D1 of each subsequent cycle. All efforts should be made to conduct ECG monitoring in 
triplicate between 7:00 am and 3:00 pm at all assessment time points. Pre-dose assessments should be taken within 0.5 hours before drug administration. In addition, 2 and 24 hour post-dose 
assessments should be performed within ± 0.5 hours of nominal time. 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. See Section 5.4.5 of protocol amendment 10.  If the QTcF for a subject from Day 1 to Day 8 has increased > 30 ms with no 
other known etiology, a confirmatory ECG should be performed on Day 9 and a dose reduction considered.  See Section 5.1.2 of protocol amendment 10 and footnote s. The mean QTcF of the 
triplicate ECG tracings based on central reading will be used for all treatment decisions.
e.
Pre-dose (0.5 hours before drug administration) PK samples will be collected at C1D1, C1D8, C1D16, C1D22 and on Day 1 of each cycle starting at Cycle 2. See Section 5.6.1 of protocol 
amendment 10. PK samples for ASP2215 will be collected on C1D15 at pre-dose (0.5 hours before drug administration), 1 (±10 minutes), 2 (±10 minutes), 4 (±20 minutes), 6 (±20 minutes).
f.
WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of hCG) within 72 hours prior to the start of study treatment.
g.
Bone marrow samples are required during Screening, Cycle 2 Day 1 and Cycle 3 Day 1. Screening samples may be collected up to 21 days prior to C1D1. For subjects who do not achieve a 
complete remission (CR, CRp, or CRi), the bone marrow assessments will be repeated at Day 1 of every 2 subsequent cycles. For subjects who achieve a complete remission (CR, CRp, or CRi), 
bone marrow will be repeated on one month after the date of remission and every 3 subsequent cycles for up to 1 year from Cycle 1 Day 1 and after that only if there is suspicion of relapse in the 
peripheral blood. Bone marrow samples are also required at the Early Termination/ End-of Study Visit, and as clinically indicated. If bone marrow aspirate is unobtainable (i.e., dry tap), an 
additional EDTA tube of peripheral blood should be collected instead.
h.
Buccal swab collected at Screening for optional pharmacogenomic study.
i.
ASP2215 is taken daily without food at home except for clinic days when it will be taken at the clinic. Subjects will be instructed to take the daily dose with water as close to the same time each 
morning as possible.
j.
FLT3, C-CBL and AXL mutation status will be assessed from bone marrow sample taken at the Screening Visit. If bone marrow sample is unavailable (i.e., dry tap), the whole blood sample taken at 
the Screening Visit will be used.  
k.
Ophthalmologic assessment to be performed by visual acuity measurement, ophthalmoscopy and slit lamp biomicroscopy, visual fields and optical coherence tomography (OCT) at Screening (within 
12 days prior to dosing), 15th Day of Cycle 1 (± 3 days), 1st Day of Cycle 2 (± 3 days), Cycle 3 (± 3 days), and every 2 cycles thereafter (± 3 days), at the end of treatment, and when clinically 
indicated. 
l.
Height measurement performed only at Screening. Weight measurement should be performed on D1 of each Cycle.
m.
Subjects may be screened from local labs only. However, samples must also be submitted for central read.
n.
Additional laboratory tests should be performed according to institutional standard of care.
o.
Thyroids function tests will be repeated after every 2 cycles of therapy (C3D1, C5D1, C7D1 etc.).
p.
For the purposes of drug preparation and dispensing activities, IRT Transactions may be done prior to the visit and do not need to fall within the protocol visit windows.
q.
Chest X-ray (or CT of chest) does not need to be repeated if performed within 2 weeks prior to start of Screening.
r.
Cephalexin (Total daily dose 500 mg via oral tablet or capsule) will be administered as a single dose on Days -1 and C1D15. Cephalexin plasma PK samples will be collected at D-1 and C1D15 at 
pre-dose (0.5 hours before drug administration), 0.5 (±10 minutes), 1 (±10 minutes), 1.5 (±10 minutes), 2 (±10 minutes), 3 (±10 minutes), 4 (±20 minutes), 6 (±20 minutes), and 24 hours (±90 
minutes) post dose (the 24 hour sample must be collected before the dose of ASP2215). 24 hr post-Cephalexin dose assessment will be performed on C1D1 and D16 respectively. Urine samples for 
cephalexin PK will be collected on Day -1 and C1D15 at 0-3 hours, 3-6 hours and 6-24 hours post dose with urine volume recorded and a sample from each timepoint collected.
s.
A Cycle 1 Day 8 ECG will be taken and the central read results will be provided to the site 24 hours after receipt of the tracing. A confirmatory ECG should be performed on Cycle 1 Day 9 if the 
mean QTcF from the central read ECG for Cycle 1 Day 1 to Cycle 1 Day 8 has increased > 30 ms with no other known etiology. On Cycle 1 Day 8, it is recommended that the ECG is taken as early 
as possible in the morning and transmitted immediately. In addition, it is recommended that the Cycle 1 Day 9 visit is scheduled later in the day in order to allow for receipt and assessment of the 
Cycle 1 Day 8 central read ECG. This also allows for a subject to be contacted if the Cycle 1 Day 9 ECG is no longer required. If the Cycle 1 Day 9 ECG is still required, the result of the central 
read ECG will be received on Cycle 1 Day 10, in which the investigator should assess if the ASP2215 dose modification should occur as per the dose interruption or reduction guideline in 
Section 5.1.2 of protocol amendment 10.  


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Table 1F
Post-Treatment Schedule of Assessments
Activity
End of Treatment Visit a
30-Day Follow-Upi
Long-term Follow-Upj
Physical Examination
X b
Vital Signs
X b
ECOG Performance
X b
Concomitant Medications
X
Pregnancy Test for WOCBP
X
12-lead ECG
X c
Ophthalmologic Assessment 
X b
Clinical Laboratory Tests  (chemistry, hematology, coagulation, urinalysis)
X b
Bone Marrow Aspiration and Biopsy 
X h
FLT3 , AXL and C-CBL Mutations g (bone marrow aspirate or whole blood)
X
AE/SAE Assessment
X d
X e
IRT Transaction Required
X
Survival and Subsequent Anti-leukemic Treatments and Their Outcomes
X e
X f
a.
End of Treatment Visit is to be performed within 7 days of last dose.
b.
Does not need to be repeated if collected at a regularly scheduled visit within 3 days of the End of Treatment Visit.
c.
ECG monitoring should be between 7:00 am and 3:00 pm, if possible.  
d.
If the subject undergoes HSCT, SAE data will only be collected for 7 days after End of Treatment Visit.
e.
Telephone contact with the subject is sufficient unless any assessment must be repeated for resolution of treatment-related AEs. 
f.
Telephone contact every 3 months after the 30-Day follow up.
g.
FLT3, AXL and C-CBL mutation analysis will be performed for relapsed subjects.
h.
Does not need to be repeated if collected within 2 weeks of the End of Treatment Visit.
i.
The 30-day follow-up visit and long term follow-up visits will not be performed if subject is enrolled into the roll-over study (2215-CL-0109).
j.
Long-term follow-up will be discontinued upon termination of the study by the Sponsor.


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3
STUDY OBJECTIVES AND DESIGN
3.1
Study Objectives
3.1.1
Primary Objectives
●
Assess the safety and tolerability, including determination of the maximum tolerated 
dose (MTD) of oral ASP2215 in subjects with relapsed or treatment-refractory AML.
●
Determine the pharmacokinetic (PK) parameters of ASP2215. 
3.1.2
Secondary Objectives
●
Investigate the anti-leukemic activity of various doses of ASP2215 in subjects with AML.
●
Evaluate the effect of strong or moderate cytochrome P450-isozyme3A4 (CYP3A4)
inhibitors on the PK of ASP2215.
●
Evaluate the potential induction of CYP3A4 by ASP2215 by assessment of midazolam PK.
●
Evaluate the effect of ASP2215 on MATE1 substrates by assessment of cephalexin PK.
3.2
Study Design
3.2.1
Study Design
This study is an open-label, dose escalation, first-in-human study in subjects with relapsed or 
refractory AML, with concomitant expansion cohort for multiple doses. One cycle is defined 
as 28 days and the subject will receive oral ASP2215 daily. The study treatment will continue 
until one of the discontinuation criteria is met or until rollover into the 2215-CL-0109 study. 
The starting dose level of ASP2215 is 20 mg daily and the decision to dose escalate to the next 
dose level will be made based on the assessment of safety variables including occurrence of 
grade 2 adverse events (AE) or DLTs.
This study will have two cohorts of subjects (Figure 1 and Figure 2):
●
Cohort 1: Dose escalation cohort
●
Cohort 2: Dose expansion cohort
Cohort 1 
Cohort 1 will comprise the initial dose escalation cohort with up to 10 dose levels (Table 2). 
This cohort will be run at approximately 5 centers which will only participate in the dose 
expansion cohort (Cohort 2) if the enrollment in the dose escalation cohort (Cohort 1) is on a 
pause (i.e., dose level being tested at the time is fully enrolled and the one higher dose level 
has not yet been opened). Subjects will be treated daily in 28 day cycles (with the exception 
of Cycle 1 where subjects will receive 29 doses). The DLT observation period is 30 days 
starting with the first dose taken on Day -2, and including the first 28 day treatment cycle. 
Subjects in Cycle 1 will have PK sampling performed prior to start of the first cycle and after 
receiving a single dose of the study drug on Day -2.


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This study will follow an accelerated titration design. Dose levels are set at around 50% 
increments. One subject will be treated at the starting dose level of 20 mg. If no DLT is 
identified, the next subject will be enrolled at double the dose level, i.e. dose level 3 (40 mg
see Table 2). This dose escalation approach will continue wherein only odd numbered dose 
levels (1, 3, 5) are tested until the first instance of a DLT or second instance (observed in two 
subjects at any of these dose levels) of a grade 2 AE judged related (e.g., possibly, probably, 
or definitely) by the investigator to be related to study drug (except for hematologic 
toxicities) occur.  
When a DLT or second instance (observed in two subjects) of grade 2 AE related to study 
drug is observed in a subject, the dose escalation schedule will stop the double-dose level 
method and follow the next consecutive dose level in Table 2 utilizing the modified 3+3 
design. Modified 3+3 design testing each consecutive dose level may also be followed if 
recommended by dose escalation committee based on the review of pharmacokinetics data. 
After dose level 5 (80 mg), each subsequent dose level (6-10) will be tested using the 3+3 
design. In this phase, 3 subjects will be treated at each dose level. If no DLTs are observed, 
the subsequent subjects will be treated at the next dose level. If one DLT is observed in a 
dose level, 3 more subjects will be enrolled at that dose level. If the 3 additional subjects do 
not experience a DLT, the next dose level will be initiated. If 2 or more DLTs occur in a dose 
level, DLT will be established. The next lower dose level will be declared the maximum 
tolerated dose (MTD).
Subject replacement in the dose escalation cohort (Cohort 1)
A subject that receives less than 80% of the intended dose during Cycle 1 (e.g., misses 
6 daily doses or leaves the study for reasons other than a DLT), will not be evaluable for 
DLT and will be replaced by another subject in the dose level. In addition, if after enrollment 
any subject is found not to fulfill any inclusion/exclusion criteria that would adversely affect 
safety or efficacy evaluation of that subject, they may be replaced after discussion between 
the Principal Investigator and Medical Monitor.
Cohort 2
Cohort 2 is the dose expansion cohort. This cohort will be conducted at approximately 
35 additional centers that will not participate in the dose escalation cohort (Cohort 1). 
However, those centers participating in Cohort 1 may participate in Cohort 2 after the 
completion of the dose escalation phase (Cohort 1). Cohort 1 centers may also enroll patients
in Cohort 2 if the enrollment in Cohort 1 is on a pause (i.e. dose level being tested at the time 
is fully enrolled and the one higher dose level has not yet been opened). Subjects will be 
treated daily in 28 day cycles. The DLT observation period is based on one completed cycle 
starting with the first dose taken on C1D1.
In the dose expansion phase (Cohort 2), a dose level may be expanded as follows: 
●
If one subject in the dose escalation cohort (Cohort 1) at any dose level achieves complete 
remission (CR), complete remission with low platelets (CRp) or complete remission with 
incomplete hematologic recovery (CRi) then this dose level will continue to enroll a 


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minimum of 3 subjects. After the decision is made to escalate to the next dose level (0/3 or 
1/6 DLTs observed), the dose level will be expanded to enroll up to 17 additional subjects. 
All subsequent dose levels will also be expanded following a dose escalation decision for 
the dose level in the dose escalation cohort (Cohort 1). When more than one dose levels are 
expanded in the dose expansion cohort (Cohort 2), the newly enrolled patients will be 
randomized to all open expanded dose levels.
●
In the absence of a CRc, if the median decrease of FMS-like tyrosine kinase (FLT3) 
phosphorylation in plasma inhibitory assay (PIA) is equal or greater than 90% in a dose 
level with at least 3 subjects, then this dose level and the subsequent levels will be 
expanded following a dose escalation decision for the dose level (0/3 or 1/6 DLTs 
observed) in the dose escalation cohort (Cohort 1).
Subjects will be assigned in the dose escalation cohort (Cohort 1) or randomized in the dose 
expansion cohort (Cohort 2) to one of the open dose levels as defined in the statistical 
methodology section (Section 7). At least 10 subjects with FLT3 mutations (internal tandem 
duplication (ITD) or activating point mutations) will be enrolled to each expanded dose level 
(including the subjects in the dose escalation cohort).
Dose levels at and above 120 mg will be further expanded (when found to be tolerable in 
Cohort 1) based on the efficacy results observed in escalation and expansion cohorts as 
described in the Statistical section. At least 42 evaluable subjects (receive 2 cycles of 
treatment or discontinue for progressive disease) with FLT3 mutations will be enrolled in 
dose levels selected for further expansion (See Figure 2). The safety in the dose expansion 
cohort (Cohort 2) will be monitored using Bayesian logistic regression modeling, as 
described in Section 7, based on the DLT rate observed in subjects from both the dose 
escalation and expansion cohorts. In the dose expansion cohort (Cohort 2), and for the first 
dose level only, the effect of CYP3A4 inhibition for strong inhibitor voriconazole
(Schedule 1B) will be evaluated in all subjects in the dose level. In the dose expansion cohort 
(Cohort 2), and at the highest dose level of ASP2215 (MTD or one level below MTD), the 
effect of ASP2215 on midazolam pharmacokinetics (Schedule 1D) will be evaluated. After 
completion of the CYP3A4 inhibition expansion (Schedule 1B) and until MTD is 
determined, Cohort 2 subjects will participate without the DDI component (Schedule 1C).
DDI studies (Schedule 1B, 1D, and 1E) will be conducted in the United States only. 
European sites whose patients are randomized to the DDI arms of the study will follow 
Schedule 1C and will not administer their patients these medications. In addition, US sites 
approved by the sponsor to join the trial who cannot conduct the DDI portion of the trial will 
also be allowed to follow Schedule 1C even if patients are randomized to Schedule 1B or 1D. 
Patients who have a contraindication to voriconazole or midazolam can participate in the trial 
without the DDI component (Schedule 1C) after discussion with the medical monitor.
If the first dose level closes prior to 12 patients completing the DDI component with 
voriconazole, the next lowest dose level open for enrollment will participate according to 
Schedule 1B to evaluate the effect of CYP3A4 inhibition for strong inhibitor voriconazole.


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To further evaluate drug-drug interaction (DDI), a sub-study with a MATE1 substrate will be 
conducted [Table 1E].  This cohort will have approximately 20 subjects and will be enrolled 
at 200 mg.  The goal of this sub-study is to evaluate the effect of ASP2215 on the MATE1 
transporter.  The pharmacokinetics of 500 mg cephalexin will be investigated prior to 
initiation of ASP2215 treatment at Cycle 1 Day -1 and at Day 15 of Cycle 1. This DDI 
sub-study (Schedule 1E) will be conducted in the United States only.  Subjects who have 
severe allergies to penicillins or cephalosporins cannot participate in this sub-study cohort.
Safety Information: Summary safety tables from the Dose escalation cohort (Cohort 1) 
meetings will be shared with all investigators participating in both cohorts (escalation and 
expansion). These tables include severe and non-severe AEs.  
Re-Enrollment into the trial will be permissible for subjects who discontinue treatment for 
reasons other than toxicity or disease progression as long as they fulfill all Inclusion and 
Exclusion Criteria. All subjects that re-enroll will enroll into Cohort 2 and will follow the 
assigned Schedule of Assessments as if they are a new subject.
Intra-subject dose escalation for Cohorts 1 and 2:  
In the dose escalation cohort (Cohort 1), if the subjects on 20 mg and 40 mg dose levels do 
not achieve a composite CR (CRc), defined as either of CR, CRp or CRi, after 1 cycle of 
treatment and did not have DLT, they may dose escalate to the next dose level. 
In the dose expansion cohort (Cohort 2), subjects who do not achieve a CRc may dose 
escalate to the next dose level, if the next dose level has opened up for expansion (i.e.,
a decision has been made to escalate to next higher dosing level). 
Subjects who dose escalate will revert to more frequent safety evaluation (Refer to 
Section 3.2.3).
Table 2
Dose Levels
Dose Level
ASP2215 Dose
DL1
20 mg
DL2*
30 mg
DL3
40 mg
DL4*
60 mg
DL5
80 mg
DL6
120 mg
DL7
200 mg
DL8**
300 mg
DL9
450 mg
DL10
600 mg
* These dose levels may be omitted as described in Section 3.2.1 Study Design.
** For patients being treated with 40 mg tablets, dose escalations to 280 mg will be permitted


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Figure 1
Optimal Dose Escalation and Expansion


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Figure 2
Optimal Efficacy Expansion of Cohort 2
3.2.2
Dose/Dose Regimen and Administration Period
3.2.2.1 Dose Escalation Phase (Cohort 1)
ASP2215 will be administered on Day -2 to evaluate pharmacokinetics following a single 
dose through 48 hours. Starting on Day 1 of Cycle 1 ASP2215 will be administered QD for 
28 additional doses until disease progression or patient discontinuation.


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See [Table 1A]:  Schedule of Assessments for Dose Escalation Phase (Cohort 1)
3.2.2.2
Expansion Phase (Cohort 2)
During the initial 15 days of treatment in the expansion cohorts with DDI studies (Schedule 
1B, 1D and  1E), moderate or strong CYP3A4 inhibitors are prohibited, unless required for 
treatment of active infections. DDI studies (Schedule 1B, 1D and 1E) will be conducted in 
the United States only. European sites whose patients are randomized to the DDI arms of the 
study will follow schedule 1C and will not administer their patients these medications. In 
addition, US sites approved by the sponsor to join the trial who cannot conduct the DDI 
portion of the trial will also be allowed to follow schedule 1C even if patients are randomized 
to schedule 1B or 1D.
3.2.2.2.1
Expansion Cohort with CYP3A4 Inhibitor Study (Cohort 2 Starting Dose 
Level) (Evaluation of CYP3A4 inhibitor on ASP2215)
ASP2215 will be administered QD starting on Day 1 of Cycle 1. Starting on Day 16 a strong 
CYP3A4 inhibitor (voriconazole) will be administered daily at 200 mg every 12 hours through 
Day 1 of Cycle 2. Voriconazole for use in this trial will be provided by Astellas (15 day 
supply).
See [Table 1B]: Schedule of Assessments for Expansion Phase with CYP3A4 Inhibitor Study 
(Cohort 2, Starting Dose Level)


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3.2.2.2.2
Expansion Cohort without DDI Studies (Cohort 2 Intermediate Dose Levels)
ASP2215 will be administered QD starting on Day 1 of Cycle 1.
See [Table 1C]: Schedule of Assessments for Expansion cohort without DDI Studies 
(Cohort 2, Intermediate Dose Levels)
3.2.2.2.3
Expansion Cohort with Induction Study (Cohort 2- MTD Level) (Evaluation 
of the effect of steady state ASP2215 on Midazolam)
Midazolam (2 mg of syrup (1.0 ml) by mouth) will be administered as a single oral dose on 
Day -1 and Day 15 of Cycle 1.  ASP2215 will be administered QD starting on Day 1 of 
Cycle 1. Midazolam for use in this trial will be provided by Astellas.
See [Table 1D]:  Schedule of Assessments for Expansion Phase with CYP3A4 Induction 
Study (Cohort 2, MTD Level)
3.2.2.2.4
Expansion Cohort with MATE1 Substrate Study (Cohort 2 – MATE1 
Sub-study) (Evaluation of the effect of steady state ASP2215 on Cephalexin)
Cephalexin (500 mg oral tablet or capsule) will be administered as a single oral dose on 
Day -1 and Day 15 of Cycle 1.  ASP2215 200 mg will be administered QD starting on Day 1 
of Cycle 1. Cephalexin for use in this trial will not be provided by Astellas.


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See [Table 1E]:  Schedule of Assessments for Expansion Phase with MATE1 Substrate Study 
(Cohort 2, MATE1 Sub-study)
3.2.3
Increase or Reduction in Dose of the Study Drug(s)
Guidelines for ASP2215 dose reduction are provided in Table 3
The ASP2215 dose may be reduced for subjects after Cycle 1 in the dose escalation phase 
(Cohort 1), and at any cycle in the dose expansion phase (Cohort 2). Dose reduction during 
Cycle 1 in the dose escalation phase (Cohort 1) is only allowed if the subject has already 
experienced clinical benefit and after discussion with the medical monitor. Note that dose 
reductions should occur in a step-wise manner, following the dose levels outlined in Table 2
After the initial dose reduction, additional dose reductions may occur unless stated otherwise. 
If no further dose reductions are available, study treatment will be discontinued. 
Table 3
Guidelines for ASP2215 Dose Reduction Event
ASP2215 Dosing Instructions
Event
QTc Prolongation
If the mean QTcF from Cycle 1 Day 1 to Cycle 1 Day 8 has increased > 30 ms 
based on central read ECG without any other etiology, a confirmatory ECG will be 
performed on Day 9. If the Cycle 1 Day 9 central read ECG is confirmatory, a 
dose reduction should be considered. QTcF values based on central reading from 
triplicate ECGs should be used for this determination (i.e., Day 8 mean QTcF from 
triplicate ECGs at predose minus the Day 1 mean QTcF from triplicate ECGs at 
predose).
Retinopathy 
Grade 2 
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 3/4 
Treatment will be discontinued. 
Table continued on next page


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Non-hematological Events 
Grade 3 related to 
ASP2215 
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 due to study drug
Treatment will be discontinued
Myelosuppression
CRp or CRi
Dose may be reduced without interruption if the following criteria are met:

Subject has received a minimum of 2 cycles of ASP2215

Platelets < 25 x 109/L and/or ANC ≤ 0.5 x 109/L;

Marrow blasts < 5%;

No evidence of extramedullary disease;
Further stepwise dose reduction is permitted if dosing 1 full cycle at the reduced 
dose has not resulted in the desired hematologic recovery.
Guidelines for dose escalation are provided in Table 4
In the dose escalation cohort (Cohort 1), if the subjects on 20 mg and 40 mg dose levels do 
not achieve a composite CR (CRc), defined as either of CR, CRp or CRi, after 1 cycle of 
treatment and did not have DLT, they may dose escalate to the next dose level. Only one 
dose escalation is allowed for lack of response.
In the dose expansion cohort (Cohort 2), subjects who do not achieve a CRc may dose escalate 
to the next dose level, if the next dose level has opened up for expansion (i.e., a decision has 
been made to escalate to next higher dosing level). After the initial dose escalation, additional 
dose escalations may occur following the dose levels in Table 2 if the next dose level has 
opened up for expansion (i.e., a decision has been made to escalate to next higher dosing 
level).
Table 4
Guidelines for ASP2215 Dose Escalation Event
Cohort 1 (Dose escalation cohort)
No CRc (CR, CRp or CRi) after Cycle 1
Patients on 20 mg, 30mg or 40 mg can escalate one 
dose level
Patients on 60-600 mg cannot escalate dose
Cohort 2 (Dose expansion cohort)
No CRc (CR. CRp or CRi) after Cycle 1
Can dose escalate in a step wise manner following the 
dose levels in Table 2
If the dose escalated as per Table 4, the patients will revert to more frequent safety 
evaluations. The following tests will need to be done weekly (+/- 1 day) for one cycle. 
Resume regular monthly evaluation schedule as described in the Schedule of Assessments 
after the completion of the escalation cycle.  


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Weekly Assessments
Cohort 1 (Dose Escalation)
Cohort 2 (Dose Expansion)
Physical Exam
Vital Signs
ECG
Clinical Laboratory Tests
AE/SAE Evaluation
In-Clinic Dosing
Pre-Dose PK
Serial PKs at Day of Escalation and 2 weeks post 
escalation 

Pre-dose (0.5 hours before drug 
administration), 0.5 (±10 minutes), 1 (±10 
minutes), 2 (±10 minutes), 4 (±20 minutes), 6 
(±20 minutes), and 24 hours (±90 minutes) 
post dose
Serial ECGs at Day of Escalation and 2 weeks post 
escalation 

Pre-dose, 2, 4, 6, and 24 hours post
Physical Exam
Vital Signs
ECG
Clinical Laboratory Tests
AE/SAE Evaluation
In-Clinic Dosing
Pre-Dose PK
3.3
Randomization
Patient assignment will be performed manually until the availability of the Interactive 
Response Technology (IRT) during the Escalation phase (Cohort 1). Prior to the initiation of 
the study treatment, the site staff will complete and forward the subject registration form to 
the Astellas designee to receive the assigned treatment. Specific procedures for assignment 
are contained in the Regulatory Binder. After the IRT system becomes available, patients will 
be registered, enrolled and assigned treatment through IRT interactions. Specific procedures 
for randomization through the IRT are contained in the IWRS Manual in the Regulatory 
Binder.
Randomization will be performed via Interactive Response Technology (IRT) during 
Expansion phase (Cohort 2). Prior to the initiation of the study treatment, the site staff will 
contact the IRT in order to determine the randomized treatment. Specific procedures for 
randomization through the IRT are contained in the IWRS Manual in the Regulatory Binder.
As a dose level is decided to be expanded, up to 17 subjects will be enrolled for the dose 
level in the dose expansion phase (to have a total of 20 subjects enrolled at a dose level 
including the subjects from dose escalation cohort). When more than one dose levels are 
expanded in the dose expansion phase (Cohort 2), the newly enrolled subjects will be 
randomized to one of the open expanded dose levels, based on the relative chance of (20 – n) 


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in each dose level, where n is the number of subjects already enrolled in the dose level, 
including both the dose escalation and expansion phases. 
If 10 subjects without FLT3 mutations (internal tandem duplication (ITD) or activating point 
mutations) are enrolled an expanded dose level (including the subjects in the dose escalation 
cohort and dose expansion cohort), only subjects with FLT3 mutations can be enrolled to the 
dose level.
Dose levels at and above 120 mg will be further expanded (when found to be tolerable in 
Cohort 1) based on the efficacy results observed in escalation and expansion cohorts. 
Approximately 40 additional subjects will be enrolled at these dose levels to bring the total 
enrolled to approximately 60 patients at the dose level inclusive of Cohort 1 subjects.
Approximately 20 FLT3 mutation positive patients will be enrolled in the Expansion Phase 
with MATE1 Substrate Study (Schedule 2E). All patients will be assigned to ASP2215 
200 mg dose level. 
4
SAMPLE SIZE
The sample size is not based on statistical power calculation. It should provide adequate 
information for the objective of the study.
Up to 40 subjects are planned to be enrolled into up to 10 dose levels in the dose escalation 
phase depending on the number of dose levels studied. The dose expansion phase will enroll up 
to 250 subjects in the expansion cohort depending on the number of dose levels expanded. The 
total number of subjects estimated for enrollment is between 2 and 270 subjects. This excludes 
consideration of the replacement of subjects in the Dose Escalation Cohort (Cohort 1) that
meet the replacement criteria, in which case the sample size would increase based on the 
number of subjects replaced.
5
ANALYSIS SETS
In accordance with International Conference on Harmonization (ICH) recommendations in 
guidelines E3 and E9, the following analysis sets will be used for the analyses.
Detailed criteria for analysis sets will be laid out in Classification Specifications (CS) and the 
allocation of subjects to analysis sets will be determined prior to database hard lock. 
Safety Analysis Set (SAF) will be used for the analyses of safety and biomarker variables. Full 
Analysis Set (FAS), Safety Analysis Set (SAF) and Per Protocol Set (PPS) will be used for 
efficacy analysis. Pharmacokinetic Analysis Set (PKAS) will be used for pharmacokinetic 
analyses. Pharmacodynamic Analysis Set (PDAS) will be used for the analyses of 
pharmacodynamic data. The data from all patients who were randomized or allocated to 
treatment will be included in the data listings. All allocated/randomized subjects are those who 
signed the informed consent form, had a randomization/registration date, received a 
randomization number (for subjects in expansion phase only) and received drug assignment 
through either the Astellas clinical study manager or the IRT system.


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5.1
Full Analysis Set (FAS)
The Full Analysis Set (FAS) consists of all subjects who were enrolled and received at least 
one dose of study drug and who have at least one post-treatment data point. Re-enrolled 
subjects will be excluded from FAS. All three subjects enrolled at site 
 will be 
excluded from FAS due to concerns with this site’s compliance to good clinical practice as 
explained in the attached study communication memo (Appendix 10.2).
Specifically, the following will lead to a subject’s exclusion from the FAS:
●
No study drug taken
●
No data post-treatment
●
Previous enrolled into the study and discontinued the treatment and re-enrolled into the 
study
●
Three subjects enrolled at site 
The selection of subjects for the FAS will be confirmed in the Analysis Set Classification 
Meeting (ASCM).
The FAS will be used for summaries of efficacy data, as well as selected demographic and 
baseline characteristics.
5.2
Per Protocol Set (PPS)
The Per-Protocol Set (PPS) includes all subjects of the FAS who do not meet criteria for 
exclusion from PPS listed in Section 5.2.1 of this SAP. 
Final judgments on exclusion of subjects from the PPS are to be made at the ASCM, held 
prior to database hard lock. 
The PPS will be used for sensitivity analyses of efficacy data. Also, selected demographic 
and baseline characteristics will be summarized for the PPS.
5.2.1
Reasons for Exclusion From PPS
The following reasons may lead to subject’s exclusion from PPS:
●
Entered into the study even though the subject violates the inclusion or exclusion criteria 
which may affect the assessment of the efficacy of the study drug
●
Received wrong treatment or incorrect dose
●
Administration of anti-leukemia treatment prohibited by protocol 
●
No post-baseline efficacy measurement
5.3
Safety Analysis Set (SAF)
The Safety Analysis Set (SAF) consists of all subjects who received at least one dose of 
study drug. Re-enrolled subjects will be excluded from SAF.
The SAF will be used for summaries of demographic and baseline characteristics and all 
safety and tolerability related variables. The SAF will also be used for sensitivity analyses of 
efficacy data.


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5.4
Pharmacokinetics Analysis Set (PKAS)
The Pharmacokinetics Analysis Set (PKAS) consists of the subset of the SAF for which 
sufficient plasma concentration data are available to facilitate derivation of at least one PK 
parameter and for whom the time of dosing on the day of sampling is 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 Classification Specifications.
The PKAS is used for all tables and graphical summaries of the PK data.
5.5
Pharmacodynamic Analysis Set (PDAS)
The Pharmacodynamic Analysis Set (PDAS) will include the subjects from the SAF for 
whom sufficient pharmacodynamic measurements were collected. Any formal definitions for 
exclusion of subjects from the PDAS will be documented in the Classification Specifications.
The PDAS will be used for all analyses of pharmacodynamic data.
5.6
Re-Enrolled Analysis Set
Re-Enrolled Analysis Set includes subjects who discontinued treatment for reasons other than 
toxicity or disease progression and were re-enrolled into expansion phase and received at 
least one dose of study drug after re-enrollment. 
5.7
Post-HSCT Analysis Set
Post-HSCT Analysis Set includes subjects who received at least one dose of study drug and
meet either of the following criteria:
●
Underwent on-study HSCT and resumed ASP2215 after HSCT
●
Discontinued the treatment for HSCT and were re-enrolled into the study and received at 
least one dose of study drug after re-enrollment
Post-HSCT Analysis Set will be used for selected safety and efficacy summaries.
6
ANALYSIS VARIABLES
6.1
Efficacy Endpoints
Efficacy endpoints of ASP2215 in AML are secondary endpoints of the study.
6.1.1
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 at a post-baseline visit, 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 x 109/L and platelet count 
≥ 100 x 109/L, and normal marrow differential with < 5% blasts, and they will be red blood 
cell (RBC) and platelet transfusion independent (defined as 1 weeks without RBC transfusion 


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and 1 week without platelet transfusion). There must be no presence of Auer rods. There 
should be no evidence of extramedullary leukemia. The blast counts in peripheral blood must be 
≤2%.
●
Complete Remission with Incomplete Platelet Recovery (CRp)
For subjects to be classified as being in CRp at a post-baseline visit, 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 at a post-baseline visit, 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.
●
Complete Remission with Partial Hematologic Recovery (CRh)
For subjects to be classified as being in CRh at a post-baseline visit, they cannot be classified 
as being in CR and must have bone marrow blasts < 5% and partial hematologic recovery 
ANC >= 0.5 x 109/L and platelets >= 50 x 109/L. There should be no evidence of 
extramedullary leukemia. 
●
Partial Remission (PR)
For subjects to be classified as being in PR at a post-baseline visit, 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 with the total marrow blasts between 5% and 
25%. A value of less or equal than 5% blasts is also considered a PR if Auer rods are present.
There should be no evidence of extramedullary leukemia.
●
Non-Responder (NR)/Not Evaluable (NE)
Subjects who do not achieve CR, or CRp, or CRi or PR will be considered non-responder. 
Except in the situation where no bone marrow assessments are formed and no blast from 
peripheral blood is observed (blast <= 2%), in which case a subject will be considered not 
evaluable.  
●
Relapse
Relapse after CR, CRh, CRp or CRi is defined as a reappearance of leukemic blasts in the 
peripheral blood (> 2%) or ≥5% blasts in the bone marrow aspirate not attributable to any 
other cause or reappearance or new appearance of extramedullary leukemia.  


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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 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 for all visits (in the order of CR, CRp,
CRi, and PR) post-treatment. Subjects who achieve the best response of CR, CRp, CRi or PR 
will be classified as responders. Subjects who do not achieve at least PR will be considered 
non-responders. 
Two best responses will be defined. Best response at the end of cycle 2 is defined as the best 
measured response (CR, CRp, CRi, PR) up to the end of 2 cycles of treatment. Best response 
at the end of treatment is defined as the best measured response (in the order of CR, CRp,
CRi, PR) up to the End of Treatment Visit.
6.1.2
Efficacy Variables
Efficacy variables include:
●
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, PR rate – Defined similarly as CR rate.
●
Composite complete remission (CRc) rate– Defined as the confirmed remission rate of 
all complete and incomplete CRs (i.e., CR+ CRp + CRi).
●
Complete remission and complete remission with partial hematologic recovery 
(CR/CRh) rate - Defined as the number of subjects who achieve either CR or CRh at any 
of the post-baseline visits divided by the number of subjects in the analysis population. 
●
Complete remission with partial hematologic recovery (CRh) rate – Defined as the 
number of subjects who achieve CRh at any of the post-baseline visits and do not 
achieve best response of CR divided by the number of subjects in the analysis 
population. 
●
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.
●
Overall survival (OS) – The time from the date of first dose of study drug until the date 
of death from any cause (death date – first dose date + 1). 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 – first dose date + 1).
The date of last contact is the latest date the subject is known to be alive.


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Subjects who discontinue the treatment and are re-enrolled into the study will be followed 
from first dose date before re-enrollment until the death or last contact after 
re-enrollment.
As sensitivity analysis, OS will be defined similarly as above, however, subject who 
undergo an allogeneic HSCT will be censored at the time of HSCT (HSCT date – first 
dose date +1).
●
Event-free survival (EFS) – The time from the date of first dose of study drug until the 
date of documented relapse, treatment failure or death from any cause, whichever occurs 
first (relapse date or treatment failure date or death date – first dose date + 1). For a 
subject with none of these events, EFS is censored at the date of last relapse-free disease 
assessment (last relapse-free disease assessment date – first dose date +1). Subject 
without post-treatment disease assessment will be censored at randomization date.
Treatment failure includes those subjects who discontinued the treatment due to 
“progressive disease” or “lack of efficacy” without a previous response of CR, CRp, CRi 
or PR.
Treatment failure date refers to the start of new anti-leukemia therapy or the last 
treatment evaluation date when new anti-leukemia therapy date is not available.
For subjects who are censored, last relapse-free disease assessment date refers to the 
subject’s last disease assessment date.
●
Leukemia-free survival (LFS) – The time from the date of first CRc until the date of 
documented relapse or death for subjects who achieve CRc (relapse date or death date –
first CRc disease assessment date + 1). For a subject who is not known to have relapsed 
or died, LFS is censored on the date of last relapse-free disease assessment date (last 
relapse-free disease assessment date – first CRc disease assessment date + 1).
●
Duration of remission – This includes duration of CRc (DCRc), duration of CR (DCR), 
duration of CRi (DCRi), duration of CRp (DCRp), duration of CR/CRh (DCRCRh), 
duration of CRh (DCRh), and duration of response (DR) (i.e., CRc + PR).
o
Duration of CRc – Duration of CRc is defined as the time from the date of first 
CRc until the date of documented relapse for subjects who achieved CRc 
(relapse date – first CRc disease assessment date + 1). Subjects who die 
without report of relapse are considered non-events and censored at their last 
relapse-free disease assessment date (last relapse-free disease assessment date –
first CRc disease assessment date + 1). Other subjects who do not relapse on 
study are considered non-events and censored at the last relapse-free disease 
assessment date.
o
Duration of CR is defined similarly as duration of CRc for subjects who 
achieved CR.
o
Duration of CRp is defined similarly as duration of CRc for subjects who 
achieved CRp.  


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o
Duration of CRi is defined similarly as duration of CRc for subjects who 
achieved CRi.
o
Duration of CR/CRh is defined similarly as duration of CRc for subjects who 
achived either CR or CRh. For subjects who achieve both CR and CRh, the  
first CR date or CRh date, whichever occurs first, will be used.
o
Duration of CRh is defined similarly as duration of CRc for subjects who 
achieved CRh but don’t have best response of CR.
o
Duration of response – 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 achieved CRc or PR (relapse date – first CRc or PR disease 
assessment date + 1). Subjects who die without report of relapse are considered 
non-events and censored at their last relapse-free disease assessment date (last 
relapse-free disease assessment date – first CRc or PR disease assessment date 
+ 1). Other subjects who do not relapse on study are considered non-events and 
censored at the last relapse-free assessment date.
●
Time to remission – This includes time to CRc (TTCRc), time to CR (TTCR), time to 
CRi (TTCRi), time to CRp (TTCRp), time to first CR/CRh (TTFCRCRh), time to best 
CR/CRh (TTBCRCRH), time to response (TTR), and time to best response (TTBR).
o
Time to CRc is defined as the time from the first dose of study drug until the 
date of first CRc (first CRc disease assessment date – first dose date +1). 
TTCRc will only be evaluated for subjects who achieved CRc.
o
Time to CR is defined similarly as time to CRc for subjects who achieved CR.
o
Time to CRp is defined similarly as time to CRc for subjects who achieved
CRp.
o
Time to CRi is defined similarly as time to CRc for subjects who achieved CRi.
o
Time to first CR/CRh is defined similarly as time to CRc for subjects who 
achieved either CR or CRh. For subjects who achieve both CR and CRh, the 
first CR date or CRh date, whichever occurs first, will be used. 
o
Time to best CR/CRh is defined similarly as time to CRc for subjects who 
achieved either CRor CRh. For subjects who achieve both CR and CRh, the 
first CR date will be used.
o
Time to response is defined as the time from the first dose of study drug until 
the date of either first CRc or PR (first CRc or PR disease assessment date –
first dose date +1). TTR will only be evaluated for subject who achieved CRc 
or PR.
o
Time to best response is defined as the time from the first dose of study drug 
until the first disease assessment date when subject achieved best response 
(first disease assessment date of best response – first dose date +1). TTR will 
only be evaluated in subjects who achieved best response of CR, or CRp, or 
CRi, or PR. 


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●
Transfusion status (dependent vs. independent)
For the purpose of defining transfusion conversion rate and transfusion maintenance rate, 
transfusion status (independent vs. dependent) at baseline period and post-baseline 
period are defined in the following for subjects who took at least one dose of study drug:
Baseline transfusion status:
o
Baseline period is defined as the period from 28 days prior to first dose until 
28 days after the first dose. For subjects who are on treatment <28 days, 
baseline period is from the 28 days prior to first dose until the end of
treatment.  
o
Subjects are considered baseline transfusion independent if there is no RBC or 
platelet transfusions within the baseline period; otherwise, the subject is 
baseline transfusion dependent. 
Post-baseline transfusion status:
o
Post-baseline period is defined as the period from 29 days after first dose date 
until last dose date. 
o
For subjects who are on treatment >=84 days, subjects are considered post-
baseline transfusion independent if there is one consecutive 56 days without 
any RBC or platelet transfusion within post-baseline period.
o
For subjects who are on treatment >28 days but <84 days, if there is no RBC 
or platelet transfusion within post-baseline period, post-baseline transfusion 
status is not evaluable. 
o
For subjects who are on treatment <=28 days, post-baseline transfusion status 
is not evaluable. 
o
Otherwise, the subject is considered post-baseline transfusion dependent.     
●
Transfusion conversion rate 
Transfusion conversion rate is defined for subjects who have evaluable post-baseline 
transfusion status. It is defined as the number of subjects who were transfusion 
dependent at baseline period but become transfusion independent at post-baseline period 
divided by the total number of subjects who are transfusion dependent at baseline period.
●
Transfusion maintenance rate
Transfusion maintenance rate is defined for subjects who have evaluable post-baseline 
transfusion status. It is defined as the number of subjects who were transfusion 
independent at baseline period and still maintain transfusion independent at post-baseline 
period divided by the total number of subjects who are transfusion independent at 
baseline period.


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6.2
Safety Variables
Safety and tolerability (determine MTD) are the primary endpoints of the study.
6.2.1
Definition of DLT 
A DLT is defined as any of the following events that occur within 30 days starting with the 
first dose taken on Day -2, and including the first treatment cycle in dose escalation cohort 
(Cohort 1) and that is considered to be possibly, probably or definitely related to study drug. 
In Cohort 2, DLT observation period is the first treatment cycle (28 days).
Any Grade ≥ 3 non-hematologic or extramedullary toxicity. The following exceptions are 
noted:
●
Alopecia, anorexia, or fatigue.
●
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.
●
Grade 3 fever with neutropenia, with or without infection.
●
Grade 3 infection.
Hematologic toxicity will not be considered as a DLT. However, prolonged myelosuppression 
defined as ANC <500 for more than 21 days off therapy in the absence of evidence of active 
leukemia in the marrow or blood will be considered as a DLT.
6.2.2
Definition of MTD
The MTD is defined as the highest dose associated with the occurrence of DLTs in less than 
33% of the subjects in dose escalation cohort. If ≥ 2 out of 6 subjects in dose escalation 
cohort experience a DLT in a dose level, the next lower dose level will be declared the 
maximum tolerated dose (MTD). Please see details in Section 3.2.1   
6.2.3
Other Safety Variables
Safety will be assessed by evaluation of the following variables:
●
Treatment-emergent adverse events (TEAEs; frequency, severity grade, seriousness, and
relationship to study drug)
o
TEAE is defined as an adverse event observed after starting administration of the 
study drug. If the adverse event occurs on Day -2 (dose escalation phase) or 
Cycle 1 Day 1 (dose expansion phase) and the onset check box is marked “Onset 
after first dose of study drug” or the onset check box is left blank, then the 
adverse event will be considered treatment emergent. If the adverse event occurs 
on Day -2 (dose escalation phase) or Cycle 1 Day 1 (dose expansion phase) and 
the onset check box is marked “Onset before first dose of study drug”, then the 
adverse event will not be considered treatment emergent. If a subject experiences 
an event both during the pre-investigational period and during the investigational 
period, the event will be considered as TEAE only if it has worsened in severity 


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(i.e., it is reported with a new start date). All adverse events collected that begin 
within 30 days after taking the last dose of study drug will also be counted as 
TEAE, except for subjects that undergo HSCT without leaving the study and plan 
to resume ASP2215 treatment after HSCT. For these subjects, TEAE is defined 
as adverse events observed after starting administration of the study treatment 
until the last dose before on study HSCT plus 30 days, and adverse events that 
begin after resumption of ASP2215 and within 30 days after the last dose of
ASP2215 will also be counted as TEAE. Any AEs with onset dates completely 
missing will be considered TEAEs in summaries. AEs with partially missing 
onset dates will be assumed TEAEs unless the available portion of the date 
indicates that the onset was strictly before start of study medication.
o
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.
o
Adverse event during HSCT period is defined as an adverse event observed on or 
after the on study HSCT  until the day before resumption of ASP2215.
●
Serious adverse events (SAEs) include adverse events that are flagged as serious by the 
investigator 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. Targeted medical events are identified using MedDRA preferred terms, 
MedDRA Queries (SMQs), and laboratory filters. Details are provided in the table 
below. 
Targeted Medical 
Event
Search Strategy (MedDRA Preferred Terms, MedDRA SMQ, and/or Lab 
Filter)
Gastrointestinal
(GI) hemorrhage
Gastrointestinal haemorrhage SMQ (narrow),
Gastrointestinal perforation SMQ (narrow),
Gastrointestinal ulceration SMQ (narrow) and
Gastrointestinal perforation, ulcer,
haemorrhage, obstruction non-specific
findings/procedures SMQ (narrow)
Hepatotoxicity
Drug-related hepatic disorders comprehensive search SMQ (broad and narrow)
Renal toxicity
Acute renal failure SMQ (broad and narrow) 
Ocular Toxicity
Retinal disorders SMQ (broad and narrow),
corneal disorders SMQ (broad and narrow),
conjunctival disorders SMQ (broad and narrow), 
lens disorder SMQ (broad and narrow), 
uveitis (PT)
Phospholipidosis
Beta-N-acetyl-Dglucosaminidase abnormal (PT), 
Beta-N-acetyl-D-glucosaminidase increased (PT), 
Niemann-Pick disease (PT)
Lipidosis (PT)
Eosinophilic pneumonia SMQ (broad and narrow)
Table continued on next page


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Targeted Medical 
Event
Search Strategy (MedDRA Preferred Terms, MedDRA SMQ, and/or Lab 
Filter)
Pulmonary
edema/hemorrhage
Acute pulmonary oedema (PT), 
bronchial oedema (PT), 
pulmonary oedema (PT), 
non-cardiogenic pulmonary oedema (PT), 
pleural effusion (PT), 
pulmonary haemorrhage (PT), 
bronchial haemorrhage (PT), 
pulmonary alveolar haemorrhage (PT),
respiratory tract haemorrhage (PT),
Haemoptysis (PT), 
Haemothorax (PT),
Pleural haemorrhage (PT), 
pulmonary haematoma (PT), 
thoracic haemorrhage (PT), 
Tracheal haemorrhage (PT)
Interstitial pneumonia
Eosinophilic pneumonia SMQ (broad and narrow)
Prolonged QT
interval
Torsade de Pointes/QTprolongation SMQ (broad and narrow), 
Death and Sudden death HLT
●
Clinical laboratory variables 
Hematology, chemistry including liver function test and thyroid function test, 
coagulation, urinalysis, and bone marrow will be collected during the conduct of the 
study as listed in the table below.
Panel/Assessment
Matrix/Collecting Tube
Parameters to be Analyzed
Hematology
3- mL into ethylenediamine-
tetraacetic acid  (EDTA) tube
White Blood Cell Count (WBC)*
WBC Differential*
Red Blood Cell Count (RBC)
Hemoglobin (Hgb)*
Hematocrit (Hct)*
Mean Corpuscular Volume
Platelet Count*
MCHC
MCH
Table continued on next page


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Panel/Assessment
Matrix/Collecting Tube
Parameters to be Analyzed
Chemistry
8.5 mL into Serum tube
Sodium (Na)
Potassium (K)
Chloride (Cl)
Bicarbonate (HCO3)
Blood Urea Nitrogen (BUN)
Creatinine (Cr)
Glucose (Gl)
Calcium (Ca)
Phosphate (Pi)
Magnesium (Mg)
Albumin (Alb)
Total Protein (T Prot)
Alkaline Phosphatase (AlkP)
Lactate Dehydrogenase (LDH)
Creatine Phosphokinase (CK)
Aldolase
Triglycerides (Trig)
Total Cholesterol (T Chol)
Phospholipid
Globulin
Liver Function Tests including:

Bilirubin Total (TBL)

Alanine Aminotransferase (ALT)

Aspartate Aminotransferase (AST)
Thyroid function tests including:

TSH

Free T4
Coagulation Profile 
(PT/INR, D-Dimer, 
Fibrinogen) 
2.5 mL into Na Citrate tube
INR (with PT if reported)
aPTT
Fibrinogen (Screening Only)
D-Dimer (Screening Only)
Urinalysis
Dipstick
Color
Appearance
Specific Gravity
pH
Bilirubin
Blood 
Glucose
Ketones
Leukocyte esterase
Nitrite
Protein
Urobilinogen
Table continued on next page


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Panel/Assessment
Matrix/Collecting Tube
Parameters to be Analyzed
Bone Marrow
Aspirate 3 mL EDTA, 2-3 
bedside smear slides, and biopsy 
(or peripheral blood in the event 
of a dry tap)
Blast count and cell counts*
Flowcytometry for blasts
FLT3 mutation status
C-CBL mutation status
AXL mutation status
*In addition to the central read of these values, local results will also be collected and entered into the eCRF.
●
Vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate and body 
temperature)
●
12-lead electrocardiogram (ECG)
●
Ophthalmologic assessment (visual acuity measurement, ophthalmoscopy, slit lamp 
biomicroscopy, visual fields and optical coherence tomography)
●
ECOG performance scores
6.3
Pharmacokinetics Variables
6.3.1
Pharmacokinetics for ASP2215 
Pharmacokinetics for ASP2215 is one of the primary endpoints of the study.
Plasma concentration data of ASP2215 will be used in noncompartmental pharmacokinetic 
analysis. Plasma concentration of ASP2215 will be evaluated for the dose escalation and dose 
expansion phases as outlined in Table 5 below. For the expansion phase with MATE1 substrate, 
plasma and urine concentration of cephalexin will be evaluated as outlined in Table 5 below.
Table 5
PK Sampling Schedule
Dose Escalation Phase (Cohort 1)
ASP2215
Cycle 1:  Days -2, -and 15 
Pre-dose (0.5 hours before drug administration)
0.50, 1 and 2 hours post dose (±10 minutes), 4 and 6 hours 
post dose (±20 minutes), and 24 hours (±90 minutes) post 
ASP2215 dosing 
Cycle 1: Days 1, 8 and 22
Pre-dose (0.5 hours before drug administration)
2 hours (±10 minutes) post ASP2215 dosing
Cycles 2 + : Day 1
Pre-dose (0.5 hours before drug administration)
Expansion Phase with CP3A4 Inhibitor Voriconazole Study  (Cohort 2, Starting Dose Level)
ASP2215
Cycle 1:  Day 15 and Cycle 2: Day 1
Pre-dose (0.5 hours before drug administration)
0.50, 1 and 2 hours post dose (±10 minutes), 4 and 6 hours 
post dose (±20 minutes), and 24 hours (±90 minutes) post 
ASP2215 dosing 
Cycle 1: Days 1, 8 and 22
Pre-dose (0.5 hours before drug administration)
Cycles 3 + : Day 1
Pre-dose (0.5 hours before drug administration)
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CYP3A4 Inhibitor Voriconazole
Cycle 2: Day 1
Pre-dose (0.5 hours before drug administration)
Expansion Phase without DDI Studies (Cohort 2, Intermediate Dose Levels)
ASP2215
Cycle 1: Days 1 and 15
Pre-dose (0.5 hours before drug administration)
2 hours (±10 minutes) post ASP2215 dosing
Cycle 1: Days 8 and 22 and Cycle 2+ : Day 1
Pre-dose (0.5 hours before drug administration)
Expansion Phase with CYP3A4 Induction Study (Cohort 2, MTD Level)
ASP2215
Cycle 1:  Days 1, 8, 15, and 22
Pre-dose (0.5 hours before drug administration)
2 hours (±10 minutes) post ASP2215 dosing
Cycles 2 + : Day 1
Pre-dose (0.5 hours before drug administration)
Midazolam
Cycle 1:  Day -1 and Day 15
Pre-dose (0.5 hours before drug administration)
0.50, 1 and 2 hours post dose (±10 minutes), 4 and 6 hours 
post dose (±20 minutes), and 24 hours (±90 minutes) post 
Midazolam dosing 
Expansion Phase with MATE1 Substrate Study (Cohort 2, MATE1 Sub-study)
ASP2215
Cycle 1:  Day 15
Pre-dose (0.5 hours before drug administration) 1 and 2 hours 
post dose (±10 minutes), 4 and 6 hours post dose (±20 
minutes)  24 hours (±90 minutes) post ASP2215 dosing
Cycle 1:  Days 1, 8 and 22
Pre-dose (0.5 hours before drug administration) 
Cycles 2 +: Day 1
Pre-dose (0.5 hours before drug administration)
Cephalexin
Cycle 1:  Day -1 and Day 15
Plasma PK:  Pre-dose (0.5 hours before drug administration) 
0.5, 1, 1.5, 2 and 3 hours post dose (±10 minutes) 4 and 6 
hours post dose (±20 minutes) and 24 hours (±90 minutes) post 
cephalexin dosing
Urine PK:  0-3 hours, 3-6 hours and 6-24 hours post dose.
In subjects with sufficient PK samples on Day -2 and Cycle 1 Day 15 of dose escalation phase, 
Cycle 1 Day 15 and Cycle 2 Day 1 of dose expansion phase with CYP3A4 inhibitor study, the 
following PK parameters will be determined for ASP2215:
Dose Escalation Phase
●
Day – 2: Cmax, tmax, AUClast, AUC24
●
Cycle 1 Day 15: Cmax, tmax, t1/2, AUClast, AUC24
●
Accumulation ratio: AUC24 Cycle 1 Day 15/AUC24 Day -2
t1/2 may be based on accumulation ratio if the interval for t1/2 using log-linear regression 
is shorter than the calculated t1/2 and linear pharmacokinetics are observed.


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Dose Expansion Phase with CYP3A4 Inhibitor Voriconazole Study (Cohort 2, Starting Dose 
Level)
●
Cycle 1 Day 15 and Cycle 2 Day 1:  Cmax, tmax, AUClast, AUC24, 
●
Ratio: AUC24 Cycle 2 Day 1/AUC24 Cycle 1 Day 15
Dose Expansion Phase with MATE1 Substrate Study (Cohort 2, MATE1 Sub-study)
●
Cycle 1 Day 15:  Cmax, tmax, AUClast, AUC24
WinNonlin calculates Ctau, based on the terminal rate constant and extrapolates or interpolates 
to the appropriate timepoint if Clast is not at the scheduled time (e.g., 24 hours) and bases 
AUC24 on this value.  If this calculation is not possible then AUClast may be reported.
In addition, dose normalized plasma concentration and dose normalized PK parameter (Cmax, 
AUC24, AUClast), will be derived as follows:
Dose normalized plasma concentration = plasma concentration / ASP2215 dose level taken at 
the corresponding timepoint.
Dose normalized PK parameter = PK parameter / ASP2215 dose level taken at the 
corresponding visit.
6.3.2
Pharmacokinetics for Midazolam and Midazolam Metabolite
Pharmacokinetics for Midazolam is secondary endpoint of the study.
Plasma concentration of Midazolam and 1-hydroxy Midazolam (Midazolam metabolite, if 
available) will be evaluated for the dose expansion phases as outlined in Table 5.
The following PK parameters will be determined for Midazolam and 1-hydroxy (if possible) 
in dose expansion phase with induction study.
●
Day -1 and Cycle 1 Day 15:  Cmax, tmax, AUClast, AUC24
WinNonlin calculates Ctau, based on the terminal rate constant and extrapolates or interpolates 
to the appropriate timepoint if Clast is not at the scheduled time (e.g., 24 hours) and bases 
AUC24 on this value.  If this calculation is not possible then AUClast may be reported for 
AUC24
6.3.3
Pharmacokinetics for CYP3A4 Inhibitor Voriconazole
Plasma concentration of CYP3A4 inhibitor Voriconazole will be evaluated for the dose 
expansion phases as outlined in Table 5.
6.3.4
Pharmacokinetics for Cephalexin
Pharmacokinetics for Cephalexin is secondary endpoint of the study.
Plasma concentration of Cephalexin will be evaluated for the dose expansion phases MATE1 
sub-study as outlined in Table 5.


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The following PK parameters and urinary PK parameters will be determined for Cephalexin 
in dose expansion phase MATE1 sub-study.
●
Day -1 and Cycle 1 Day 15:  Cmax, tmax, t1/2, , AUClast, AUCinf, CL/F, and Vz/F 
●
Day -1 and Cycle 1 Day 15 urinary PK parameters: Ae (amount of drug excreted in 
urine), %Ae (fraction of drug excreted into urine in %), CLR (renal clearance)
6.4
 
 
 
 
 
6.5
 
6.6
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.
●
Planned duration of exposure
Planned duration of exposure will be calculated in days, using the following formula:
Date of last dose of study drug – Date of first dose + 1, when first dose is on Cycle 1 
Day 1;
Date of last dose of study drug – Date of first dose, when first dose is on Day -2.
When the start or stop date is missing, then the exposure will be treated as missing.
●
Average daily dose
Defined as total dose administered divided by planned duration of exposure.


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●
Relative dose intensity
Average daily dose
----------------------------------------- x 100%
Intial dose level actually taken
●
Percent treatment compliance
Treatment compliance for ASP2215 is defined as:
Total amount of study drug actually consumed
--------------------------------------------------------------- x 100%
  Amount of study drug should have been taken
Where, the amount of study drug that should have been taken depends on the duration of 
exposure and the actual dose level as recorded on the study drug dosing CRF page. It 
will be calculated as:
Sum of [(stop date of study drug – start date of study drug + 1) * dose level]
The amount of study drug actually consumed will be calculated as:   
(total number of 10 mg tablets dispensed – total number of 10 mg tablets returned) * 
10 mg + (total number of 100mg tablets dispensed – total number of 100mg tablets 
returned) * 100 mg + (total number of 40 mg tablets dispensed – total number of 
40 mg tablets returned) * 40 mg
●
Duration of AML
Duration of AML will be calculated in days using the following formula:
(Registration/randomization 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 dose (inclusive) and the date of last dose (inclusive) of study drug.
●
Previous and concomitant transfusion
Previous transfusion is defined as transfusion received before the date of first dose of 
study drug, i.e., transfusion completed before the date of first dose.
Concomitant transfusion is defined as transfusion received between the date of first dose 
(inclusive) and the date of last dose (inclusive) of study drug.
●
CYP3A4 inhibitor types 
CYP3A4 inhibitor types are defined based on subject’s consumption of the following 
medications while on the study according to concomitant medication and drug exposure 
information:
Strong CYP3A4 inhibitor: voriconazole or posaconazole
Moderate CYP3A4 inhibitor: fluconazole
No CYP3A4 inhibitor: none of the above medication


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●
Baseline hepatic function group
Baseline hepatic function group is defined per the NCI-ODWG criteria based on total 
bilirubin and AST at the baseline from central lab as follows:
Normal: 
total bilirubin <= ULN and AST <= ULN
Mild HD: 
ULN < total bilirubin < = 1.5 x ULN or AST > ULN
Moderate HD: 1.5 x ULN < total bilirubin <= 3 x ULN, any AST
Severe HD: 
3 x ULN < total bilirubin <= 10 x ULN, any AST
●
Baseline rental function group
Baseline rental function group is defined using baseline eGFR (MDRD formula) as 
follows:
Normal:
eGFR >= 90
Mild:
60 <= eGFR < 90
Moderate:
30 <= eGFR < 60
Severe:
eGFR < 30
eGFR is estimated by MDRD formula as follows:
eGFR (mL/min/1.73 m2) = 175 x (serum creatinine)-1.154 x (Age)-0.203 x (0.742 if female) 
x (1.212 if African American)
Serum creatinine value from central lab need to be converted from micro moL/L to 
mg/dL (1 mg/dL = 88.4 micro mol/L)
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 plasma concentrations and continuous PK parameters, the coefficient of 
variation and 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).
Summaries based on FAS and PPS (e.g., disposition, baseline and efficacy data) will be 
presented by planned dose level, unless specifically stated otherwise. Safety analysis and 
other summaries based on SAF will be presented by actual dose level received.
Pharmacokinetic summaries based on PKAS and pharmacodynamic summaries based on 
PDAS will be presented by actual dose level received. For subjects with dose 
increase/decrease, actual dose level refers to the initial dose level received before dose 
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All statistical comparisons will be made using two sided tests at the α=0.05 significance level 
unless specifically stated otherwise.  All null hypotheses will be of no treatment difference,
all alternative hypotheses will be two-sided, unless specifically stated otherwise.
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 will be presented by cohort and dose level.
Efficacy endpoints will also be stratified by FLT3 mutation status as detailed in Section 7.8
For the definition of subgroups of interest please refer to Section 7.8.
Laboratory results, vital signs, ECG, ECOG, and ophthalmologic assessments collected after 
on-study HSCT will be labeled as post-HSCT visits sequentially.
Re-enrolled subjects will not be included in summary statistics unless specifically stated 
otherwise. Information collected after re-enrollment will be listed.
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/randomization, allocated to treatment/randomized (overall only);
●
Number and percentage of subjects allocated to treatment/randomized in each analysis 
set, by cohort, dose level and overall;
●
Number and percentage of subjects completed and discontinued treatment, by primary 
reason for treatment discontinuation for allocated/randomized subjects, by cohort and
dose level; 
●
Number and percentage of subjects completed and discontinued the study, by primary 
reason for study discontinuation for allocated/randomized subjects and by cohort and 
dose level; 
●
Number and percentage of subjects completed and discontinued the post-study period, 
by primary reason for post-study period discontinuation for allocated/randomized 
subjects and by cohort and dose level; and
●
Number and percentage of subjects excluded from PPS by reason for exclusion defined 
in Section 5.2.1, by cohort and dose level for FAS.
7.2.2
Protocol Deviations
Protocol deviations as defined in the study protocol (Section 8.1.6 Protocol Deviations) will 
be assessed for all subjects randomized or allocated to treatment. The number and percentage 
of subjects meeting any criteria will be summarized for each criterion and overall, by cohort, 
dose level, and total 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 


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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 by descriptive statistics.
Number and percentage of subjects allocated to treatment in each country and site will be 
presented by cohort and dose level for the SAF.
Descriptive statistics for age, weight, body mass index (BMI) and height at study entry will 
be presented. Frequency tabulations for sex, ethnicity, age group (defined in Section 7.8),  
race and baseline transfusion status will be presented. This will be done for the subjects not 
randomized/not allocated to treatment (screen failures), as well as for the SAF, FAS and PPS 
by cohort and dose level. Summary of demographic characteristics will be stratified by FLT3
mutation status from local assessment and central assessment.
Baseline hepatic function and renal function will be summarized using frequency tables by 
cohort and dose level for 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, local FLT3-ITD mutation status, local FLT3 point mutation status will be 
presented by cohort and dose level 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, by cohort and dose level 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.
Frequency tabulations for prior transplant including number of transplant received, graft type, 
donor relatedness, match type and outcome of transplant will be presented by cohort and dose 
level for the SAF.
Results from lumbar puncture and MUGA scan, if performed, will be provided in listing.
Demographic information, AML disease history, medical history and prior transplant for 
re-enrolled subjects will be provided in listings.


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7.2.4
Previous and Concomitant Medications
Previous medications are coded with WHO-DD, and will be summarized by therapeutic 
subgroup (ATC 2nd level) and chemical subgroup (ATC 4th level) and preferred WHO name 
by cohort and dose level for the SAF.
As with previous medication, concomitant medication will be summarized for each cohort 
and dose level by therapeutic subgroup (ATC 2nd level) and 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 and investigational period. A medication which 
can be classified into several chemical and/or therapeutic subgroups is presented in all 
chemical and therapeutic subgroups.
Usage of concomitant medication and number of concomitant medication taken (grouped into 
categories as defined in Section 7.8) that prolong QT with known and possible risk of TdP 
will be summarized using frequency table by cohort and dose level for SAF. The list of 
medications are provided in Appendix 10.1
Previous and concomitant medications for re-enrolled subjects will be provided in listing.
7.2.5
Previous and Concomitant Transfusions
All transfusions received by subjects within 28 days prior to Day 1 of Cycle 1 through end of 
treatment will be recorded on the eCRF. Data will include the date, blood product, start and 
stop date, indication, and the number of units given.
Frequency tabulations of subjects received transfusions and blood product will be presented 
for previous transfusion and concomitant transfusion by cohort and dose level for SAF. 
Descriptive statistics will be presented for number of transfusion unit received per subject.
Previous and concomitant transfusions for re-enrolled subjects will be provided in listing.
7.2.6
Prior AML Chemotherapy
Frequency tabulations of subjects with prior AML chemotherapy, regimen, type of treatment, 
best response to prior AML therapy, lines of therapy received and subjects with prior TKI 
therapy will be presented by cohort and dose level for SAF. Descriptive statistics will be 
presented for duration of response to prior AML therapy. 
Prior AML chemotherapy for re-enrolled subjects will be provided in listing.
7.2.7
Non-Medication Therapy
Frequency tabulations of subjects with non-medication therapy and reason for use will be 
presented by cohort and dose level for SAF. Number of non-medication therapy received per 
subject will be summarized using descriptive statistics.
Non-medication therapy for re-enrolled subjects will be provided in listing.


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7.2.8
On-Study HSCT
For subjects undergo on-study HSCT, HSCT conditioning regimen and post-HSCT 
re-eligibility assessment for resuming study drug will be provided in listings. 
7.3
Study Drugs
7.3.1
Exposure
The following information on ASP2215 drug exposure will be presented by cohort and dose 
level for the SAF:
●
Descriptive statistics for cumulative amount of the drug subject was exposed to, average 
daily dose and relative dose intensity; and
●
Number and percent of subject with dose increases, decreases or interruptions.
Duration of exposure will be summarized in two ways.
●
Descriptive statistics will be presented by cohort and dose level.
●
Exposure time will be categorized according to the following categories by cohort and
dose level:
o
less than 14 days
o
at least 14 days, less than 28 days 
o
at least 28 days, less than 56 days 
o
at least 56 days, less than 84 days
o
84 days or more
o
Unknown.
Counts and percentages of subjects in each of these categories will be summarized by cohort 
and dose level for the SAF.
Listing of subjects with dose reduction and dose escalation will also be provided.
Descriptive statistics for duration of exposure, cumulative amount of the drug subject was 
exposed to, average daily dose, and relative dose intensity will be presented for CYP3A4 
inhibitor (Voriconazole), Midazolam, and Cephalexin by dose level for the SAF.
7.3.2
Treatment Compliance
Overall compliance with the ASP2215 dosing schedule 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 by cohort 
and dose level:
o
less than 50%
o
at least 50%, less or equal to 80%
o
greater than 80%
o
Unknown.


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Exposure and treatment compliance for re-enrolled subjects will be provided in listing.
7.4
Analysis of Efficacy 
All analyses involving response will be carried out in two ways.
1.
Derived response based on central assessment supplemented by local assessment:
response will be derived based on the definitions in Section 6.1.1 using centrally 
evaluated myeloblast counts from bone marrow aspirate or biopsy assessments
whichever is present (if both are present, both must qualify for the criteria) and 
centrally evaluated hematology results including ANC, platelet count and blast
count in peripheral blood. If neither central bone marrow aspirate nor biopsy is 
available, myeloblast will be imputed with locally evaluated bone marrow 
aspirate/biopsy assessments (if both are present, both must qualify for the criteria). 
Missing central hematology results will be imputed with local hematology results as 
collected on the eCRF.
2.
Investigator reported response: taken directly from the eCRF. 
Derived response will be considered as primary and investigator reported response will be 
considered as supportive. 
Efficacy analysis will be conducted on the FAS, SAF and PPS and stratified by FLT3 
mutation status from local assessment and central assessment. Efficacy for re-enrolled 
subjects will be provided in listing.
●
Response Variables
Best response after 2 cycles of treatment, and best response at the end of treatment will be 
summarized by dose level and FLT3 mutation status. The number and percentage of subjects 
in each category will be presented together with two-sided exact 95% CIs based on binomial 
distribution.
The number and percentage of subject with CRc, CRh, CR/CRh, and response (CRc + PR)
will also be summarized by dose level and FLT3 mutation status along with two-sided exact 
95% CI based on binomial distribution. 
To explore the relationship between dose level and CR response, a dose-response logistic 
regression model will be fitted to the binary CR response with FLT3 mutation status, the first 
and second order of logarithm transformed dose as independent covariates for all subjects 
from the dose escalation phase and dose expansion phase. The CR response rate for each 
dose level will be estimated with two-sided 95% CI from this model.
The example SAS code for logistic regression and estimating model fitted CR rate and 95% 
CI is shown below:
proc logistic data=response;
class flt3;
model cr (event="1")= flt3 lndose lndose2/lackfit covb;
output out=predcr p=phat_cr lower=lcl_cr upper=ucl_cr /alpha=0.05;
run;


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where response is the input dataset; cr, flt3, lndose, lndose2 are variables for response, FLT3 
mutation status, logarithm of dose and logarithm of dose square respectively; predcr is the 
output dataset, phat_cr, lcl_cr, ucl_cr are variables for predicted response rate, lower limit of 
confidence interval and upper limit of confidence interval respectively. 
●
Time-to-Event Variables
OS, EFS, LFS, and duration of remission will be summarized using descriptive statistics. The 
survival curve and the median will be estimated using the Kaplan-Meier method and will be 
reported along with the corresponding 95% CIs.
The example SAS code used to produce median from Kaplan-Meier estimates and 
corresponding 95% CI is shown below:
proc lifetest data=adtte plots=(s) outsurv=surv;
time survtime*censor(0);
strata trt;
run;
where adtte is the input dataset, surv is the output dataset, survtime, censor, trt are variables 
for survival time, censoring, and dose respectively. 
●
Transfusion Variables
Transfuion conversion rate and transfusion maintenance rate will be summarized by dose 
level and FLT3 mutation status. 
Shift table of transfusion status from baseline period to post-baseline period will be presented 
by dose level and FLT3 mutation status.
●
Further Expansion for Efficacy Evaluation and Stopping Rules
To improve guidance for recommended phase 2 dose, dose levels at and above 120 mg will 
be further expanded as described in Section 3.2.1 The increased patient numbers will enable 
us to more accurately estimate the actual response rate (CRc) for a dose level based on the 
observed response rate. With approximately 42 evaluable FLT3 mutated subjects, the 90% 
1-sided Confidence Interval is about 10% below the observed response rate for each dose 
level. If the estimated response rate is 50%, we would be 90% sure that the real response rate 
is higher than 40%. Response rate will be continuously monitored for each dose level and the 
enrollment will be stopped if the response rate for that dose level is at 90% significance level, 
less than 45% based on Wald’s Sequential Probability Ratio Test with 25% as the 
unacceptable low response rate and 80% power. The following table will apply (e.g., if 7 or 
less subjects respond as 25 FLT3 mutated subjects complete 2 cycles of treatment in a dose 
level, the enrollment at the dose level will be stopped):


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Enrolled Subjects
Number of CRc
14
3
17
4
20
5
23
6
25
7
28
8
31
9
Any dose level in the dose expansion cohort will be stopped if no CRc in more than 
6 subjects who complete 2 treatment cycles or less than 2 CRc’s in more than 12 subjects are 
achieved.
7.5
Analysis of Safety
All analysis of safety will be presented by cohort and dose level for SAF, unless specified 
otherwise.
7.5.1
Bayesian Logistic Regression Modeling in Dose Escalation and Expansion
Phases
A modified 3+3 design with an accelerated titration is applied in the dose escalation phase as 
described in the Study Design section (Section 2). A 2-parameter Bayesian logistic regression 
will be used to model the dose-toxicity relationship on DLT. The relationship between the 
dose levels and the rate of DLT event is modeled as the following Bayesian logistic 
regression
 	


1 −

 = log () + log ( 
 ∗)
Where 
 is the DLT rate at the i-th dose level, α and β are bivariately normally distributed 
with mean vector components µ1 and µ2 and variance-covariance matrix as shown below
	
 ~ 	 
!
 , # $ 
!
%$ $!
%$ $!
$!
! &'
The bivariate normal non-informative prior for the parameter (, ) is  = 2.27, ! =
0.26, $ = 1.98, $! = 0.40 and % = −0.16, and the 1200mg dose level is used as the 
reference dose level dose*.
Subjects in either dose escalation cohort or dose expansion cohort who complete at least one
treatment cycle 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 logistic 
regression model for each dose level will be provided as references for dose escalation 
procedure in dose escalation cohort and safety monitoring in dose expansion cohort. If the 
DLT rate for an expanded dose level is equal or higher than 20% with a posterior probability 
of 80%, then the enrollment to the dose level will be paused and the safety will be reassessed.


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7.5.2
Subject Assignment in Dose Expansion Phase
As a dose level is decided to be expanded, up to 17 subjects will be enrolled for the dose 
level in the dose expansion phase (to have a total of 20 subjects enrolled at a dose level 
including the subjects from dose escalation cohort). When more than one dose levels are 
expanded in the dose expansion phase (Cohort 2), the newly enrolled subjects will be 
randomized to one of the open expanded dose levels, based on the relative chance of (20 – n) 
in each dose level, where n is the number of subjects already enrolled in the dose level, 
including both the dose escalation and expansion phases. Randomization will be performed 
via Interactive Response Technology (IRT) during dose expansion phase (Cohort 2).
If 10 subjects without FLT3 mutations (internal tandem duplication (ITD) or activating point 
mutations) are enrolled an expanded dose level (including the subjects in the dose escalation 
cohort and dose expansion cohort), only subjects with FLT3 mutations can be enrolled to the 
dose level.
7.5.3
Determination of DLT and MTD
DLT review for dose escalation decisions and declaration of DLT and MTD will be 
performed for each dose level throughout the trial. Dose escalation decisions will be rule 
based as description in Study Design section (Section 3). The number and percentage of 
subjects with DLT, as classified by SOC and PT will be summarized for SAF.
7.5.4
Adverse Events
For the purpose of safety assessments in this study, events recorded during the 
pre-investigational period will be classified as Baseline Signs and Symptoms. All adverse 
event (AE) recorded on treatment including within 30 days from the last study treatment will 
be summarized. 
Summaries and listings of SAEs 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 coding dictionary for this study will be MedDRA. It will be used to summarize AEs by 
SOC and PT. AEs will be graded using National Cancer Institute’s Common Terminology 
Criteria for AEs (NCI-CTCAE). 
An overview table will include the following details by cohort and dose level:
●
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,


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●
Number and percentage of subjects with drug related TEAEs leading to permanent 
discontinuation of study drug, 
●
Number and percentage of subjects with grade 3 or higher TEAE, 
●
Number of deaths,
●
Number and percentage of subjects with AE during on-study HSCT period, and
●
Number and percentage of subjects with SAE during on-study HSCT period.
The number and percentage of subjects with TEAEs, as classified by SOC and PT will be 
summarized by 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,
●
AE during on study HSCT period, and
●
SAE during on study HSCT period. 
The number and percentage of subjects with TEAEs, as classified by PT only, will be 
summarized by cohort and dose level.
AE summary tables will include subject counts as opposed to AE counts. If a subject 
experiences more than one episode of a particular AE, that subject will be counted only once 
for that event. 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 body system, the subject will be counted only once in that body system.  
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.
The number and percentage of subjects with AESIs, as classified by PT, will be summarized 
by cohort and dose level.
The number and percentage of subjects with TEAEs, as classified by SOC and PT will be 
summarized by dose level for re-enrolled analysis set. 
All AEs, deaths, SAEs, withdrawals due to adverse events, and AEs for re-enrolled subjects
will be displayed in listings. 


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7.5.5
Clinical Laboratory Evaluation
The baseline visit is the last measurement taken prior to initial study drug administration.  
Quantitative clinical laboratory variables, i.e., hematology, biochemistry, coagulation and 
urinalysis will be summarized using mean, standard deviation, minimum, maximum and 
median by cohort and dose level at each visit. Additionally, a within-subject change will be 
calculated as the post-baseline measurement minus the baseline measurement 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 
for each cohort and dose level at each visit.
Frequency tabulations of qualitative clinical laboratory variables (urinalysis) will be 
presented by cohort and dose level at each visit. 
For hematology and biochemistry two types of shift tables will be presented:
●
Shift tables of reference range changes from baseline to each treatment visit (low, 
normal, high), and
●
Summary shifts of reference range changes from baseline to each treatment visit (shift 
from normal or high to low, shift from normal or low to high, categorized increase [shift 
from low to normal, low to high, or from normal to high], categorized no change [value 
stays in the same reference range], categorized decrease [shift from high to normal, high 
to low, or from normal to low]).
Laboratory results will also be graded using NCI-CTCAE, 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. The number and percentage of subjects with grade 3 or 4 laboratory test results
will be summarized by cohort and dose level and laboratory parameter (the name of the 
adverse event associated with the abnormal laboratory test result will 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. 
7.5.5.1 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 
investigational period will be used. 


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Parameter
Criteria
ALT
> 3xULN
> 5xULN
> 10xULN
> 20xULN
AST
> 3xULN
> 5xULN
> 10xULN
> 20xULN
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 during the investigational period will be presented by cohort and 
dose level.
7.5.6
Vital Signs
The baseline visit is the last measurement taken prior to initial study drug administration.  
Vital signs (systolic blood pressure, diastolic blood pressure, pulse rate, respiratory rate and 
body temperature) will be summarized using mean, standard deviation, minimum, maximum 
and median by cohort, dose level and visit. Additionally, a within-subject change will be 
calculated per visit as the post-baseline measurement minus the baseline measurement and 
summarized by cohort, dose level and visit.  
Tables for potentially clinically significant vital signs will be generated using baseline value 
and highest value obtained during treatment for each subject for each cohort and dose level.
The following potentially clinically significant criteria are defined for each parameter:
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
7.5.7
Electrocardiograms (ECGs)
12-lead ECGs will be recorded in triplicate at the scheduled time points. Each ECG tracing 
will be taken 5 minutes apart. ECGs will be read at the site for clinical decision making and 
transmitted to a central reviewer. Data from the central reviewer will be used in summary 
presentations. The three values of each ECG parameter within a time point from the central 
reviewer will be averaged to determine time-specific parameter for a subject, and used in 
summaries.


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ECG variables will be summarized using mean, standard deviation, minimum, maximum and 
median for each cohort and dose level at each treatment visit and time point, including 
changes from baseline. 
Number and percentage of subjects with normal and abnormal results as assessed by central 
review for the overall interpretation will be tabulated by cohort and dose level at each 
treatment visit and time point. 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 for each treatment visit and 
time point 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 for each treatment visit and time point.
Change from Baseline
Variable
Cumulative Category
Interval Category
QTc Interval (msec)
<0 
≥0
> 30
> 60 
<0 
≥0 to ≤30
> 30 to ≤60
> 60 
Number and percent of subjects with 12 lead ECG abnormalities as well as number and 
percent of subjects whose 12 lead ECG reading changed from normal at baseline to abnormal 
will be tabulated by cohort and dose level at each treatment visit and time point. 
7.5.8
Pregnancies
A detailed listing of all pregnancies will be provided.
7.5.9
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.


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ECOG will also be summarized using shift table from baseline to post-baseline score for each 
dose level by visit.
7.5.10
Ophthalmologic Assessment 
Frequency tabulations of qualitative ophthalmologic variables (ophthalmoscopy, 
biomicroscopy – conjunctiva, biomicroscopy – cornea, biomicroscopy – anterior chamber, 
biomicroscopy – lens pathology, and optical coherence tomography) will be presented by 
cohort and dose level at each visit for each eye.
Quantitative ophthalmologic variables (logmar score for visual acuity, mean deviation for 
visual field) will be summarized using mean, standard deviation, minimum, maximum and 
median by cohort and dose level at each visit for each eye.
7.6
Analysis of PK
PK analysis will be conducted on the PKAS. 
7.6.1
Estimation of PK Parameters
The PK parameter calculation will be performed using noncompartmental method in 
WinNonlin® (
 USA, version 6.3 or higher) software. For AUC 
determination, linear up and log down analysis will be used.
7.6.2
Statistical Analysis
7.6.2.1 Plasma Concentrations and PK Parameters
Plasma concentrations and PK parameters (including urinary PK parameters) will be 
summarized by cohort and dose level and where appropriate by nominal time points using 
descriptive statistics, including number of subjects, mean, standard deviation, minimum, 
median, maximum, geometric mean, and coefficient of variation (CV). Time-course of drug 
concentrations obtained from serial PK sampling will be plotted by cohort and dose level. For 
ASP2215, trough concentrations will also be plotted by cohort and dose level. To minimize 
the effect of dose modification on evaluation, ASP2215 plasma concentration data will be 
summarized and plotted by actual dose level excluding the data obtained at the visits within 
15 days after the day of dose modification, ASP2215 plasma concentration data will also be 
summarized by initial dose level excluding all data obtained after dose modification. 
Additional exploratory analyses may be performed after examination of the data.
7.6.2.2 Dose Proportionality
Dose proportionality over the dose range will be examined based on a combination of 
statistical analyses along with visual inspection of plots of parameters against doses. If 
non-proportionality is concluded or the results are inconclusive over the entire dose range, 
additional analyses may be performed on other dose ranges until a selected dose range is 
found for which dose proportionality is concluded.


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Power model regression
Dose proportionality can be evaluated statistically by using the power model. The power 
model has the form:
parameter = a × (dose)b × random error
where parameter is PK parameter, a and b are the coefficient and exponent, respectively, of 
the power equation. The power model can be linearized by taking logarithms:
ln(parameter) = ln(a) + b × ln(dose) + random error
Proportionality will be concluded if the 90% confidence interval for b is entirely within the 
interval
	1 + ln (0.5)
ln (2) , 1 + ln (2)
ln (2)
where r is the ratio of high dose to low dose.
7.6.2.3 Drug-Drug Interaction
●
Strong CYP3A4 Inhibitor (Voriconazole):
A drug-drug interaction for the effect of voriconazole on ASP2215 will be examined by 
obtaining the Geometric LS Mean Ratio and 90% CI for ASP2215 for the following ratios:
o
Cmax Cycle 2 Day 1 / Cmax Cycle 1 Day 15
o
AUC24 Cycle 2 Day 1 / AUC24 Cycle 1 Day 15
●
Induction by ASP2215
A drug-drug interaction for the effect of ASP2215 on Midazolam and 1-hydroxy Midazolam
will be examined by obtaining the Geometric LS Mean Ratio and 90% CI for Midazolam and 
1-hydroxy Midazolam for the following ratios:
o
Cmax Cycle 1 Day 15 / Cmax Cycle 1 Day -1
o
AUC24 Cycle 1 Day 15 / AUC24 Cycle 1 Day -1
●
Effect of ASP2215 on MATE1 substrate
A drug-drug interaction for the effect of ASP2215 on Cephalexin will be examined by 
obtaining the Geometric LS Mean Ratio and 90% CI for Cephalexin for the following ratios:
o
Cmax Cycle 1 Day 15 / Cmax Cycle 1 Day -1
o
AUClast Cycle 1 Day 15 / AUClast Cycle 1 Day -1
o
AUCinf Cycle 1 Day 15 / AUCinf Cycle 1 Day -1
o
Ae Cycle 1 Day 15 / Ae Cycle 1 Day -1 
o
CL/F Cycle 1 Day 15 / CL/F Cycle 1 Day -1 
o
CLr Cycle 1 Day 15 / CLr Cycle 1 Day -1 


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The example SAS code used to produce Geometric LS Mean Ratio and 90% CI is shown 
below:
proc mixed alpha=0.1;
class visit;
by tmt;
model logpk = visit / ddfm=KR;
lsmeans visit/ diff=control(‘C1D15’) CL alpha=0.1;
run;
where visit, tmt, logpk are variables for visit, dose, logarithm of PK parameter respectively. 
●
Potential of drug-drug interaction across cohorts
To explore the potential of drug-drug interaction with moderate or strong CYP3A4 inhibitors, 
dose-normalized PK parameters of ASP2215 (dose normalized Cmax, dose normalized
AUC24, dose normalized AUClast) will be summarized by cohort and CYP3A4 inhibitor type, 
and box-plot of these parameters will be presented, accordingly. In addition, the 
dose-normalized trough concentration will be summarized and plotted by CYP3A4 inhibitor
use (no CYP3A4 inhibitor, moderate CYP3A4 inhibitor, strong CYP3A4 inhibitor). If 
possible, it will be further stratified by the presence of dose modification. To minimize the 
effect of dose modification on evaluation, the data from the visit within 15 days after the day 
of dose modification will be excluded. Analysis focusing on the entire use of CYP3A4 
inhibitor (no CYP3A4 inhibitor use entirely, moderate CYP3A4 use entirely, strong CYP3A4 
inhibitor use entirely) up to Cycle 2 Day 1 will also be conducted.
7.7
Analysis of PD
7.7.1
%pFLT3, %pAXL, and pS6
Baseline corrected phosphorylation of FLT3 (%pFLT3), and baseline corrected 
phosphorylation of AXL (%pAXL) will be summarized descriptively using mean, standard 
deviation, minimum, maximum and median by cohort and dose level at each visit. 
Phosphorylation of S6 (pS6) will be listed only. 
Additional analysis may be conducted based on initial data assessment.
7.7.2
PIA
PIA will be summarized descriptively using mean, standard deviation, minimum, maximum 
and median by cohort and dose level at each visit.
Graphical assessment of percent inhibition vs. time will be evaluated.
Where time matched plasma concentration data are available, graphical assessment of 
percent inhibition vs. ASP2215 will be evaluated.
Additional analysis may be conducted based on initial data assessment.


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7.8
Subgroups of Interest 
7.8.1
FLT3 Mutation Status
Efficacy endpoints and demographics will be stratified by FLT3 mutation status (Positive, 
Negative, All Subjects) based on local assessment and central assessment. Demogrphics and 
response assessments will be further stratified by FLT3 mutations type (FLT3-ITD mutation 
vs. FLT3-Point mutation).
7.8.2
Demographic and Baseline Characteristics
Selected efficacy endpoints (response assessment, OS, EFS), safety endpoint (TEAE, 
drug-related TEAE, SAE, drug-related SAE) and demographics will be summarized for one 
or more subgroups defined on the basis of the categorized variables listed below:
Grouping variable
Subgroups
Age group 
< 65 years
>=65 years
Sex
Female
Male
Prior TKI usage
Yes
No
Prior HSCT status
Yes
No
Prior lines of AML therapy
1 line of prior AML therapy
2 lines of prior AML therapy
>=3 lines of prior AML therapy
7.8.3
Subset Analysis for FLT3 Mutated Subjects in >=80mg Dose Levels
Subset analysis will be conducted on FLT3 mutated subjects in >=80mg dose levels, 
including treatment discontinuation, demographics, study drug exposure, response 
assessment, overall survival, duration of remission, drug-related TEAE, SAE, drug-related 
SAE, grade 3 or higher TEAE, TEAE with special safety interest, TEAE by NCI CTCAE 
grade, lab assessments, ECG, and ophthalmologic assessments.  
The analyese will be based on local FLT3 mutation status, efficacy endpoints will also be 
analyzed using central FLT3 mutation status. 
7.8.4
CYP3A4 Inhibitor Usage
CYP3A4 inhibitor types were defined in Section 6.6
To explore the impact of CYP3A4 inhibitor usage on safety and efficacy, TEAE, drug-related 
TEAE, SAE, drug-related SAE, as classified by SOC and PT, as well as response assessment
will be summarized by cohort, dose level and subgroups defined below.


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Grouping variable
Subgroups
CYP3A4 inhibitor usage
Yes
No
CYP3A4 inhibitor type(*)
Strong CYP3A4 inhibitor
Moderate CYP3A4 inhibitor
No CYP3A4 inhibitor
(*) If a subject takes both strong CYP3A4 inhibitor and moderate CYP3A4 inhibitor, the subject isconsider as 
taking strong CYP3A4 inhibitor. 
To explore the impact of CYP3A4 inhibitor usage on PK/PD, dose normalized PK 
parameters of ASP2215 as well as dose normalized trough concentration will be summarized 
by CYP3A4 inhibitor type as described in Section 7.6.2.3
7.8.5
Baseline Hepatic and Renal Function
Baseline hepatic function groups (normal, mild HD, moderate HD, severe HD) and baseline 
renal function groups (normal, mild, moderate, severe) were defined in Section 6.6.
To explore the impact of baseline hepatic function and baseline rental function on safety, 
TEAE, drug-related TEAE, SAE, drug related SAE, as classified by SOC and PT will be 
summarized by dose level and baseline hepatic function groups, and by dose level and 
baseline rental function groups for SAF in 120mg and 200mg dose levels. 
Lab shift tables of NCI-CTCAE grade change from baseline to worst post-baseline grade will 
be summarized by baseline hepatic function groups and baseline rental function groups. 
7.8.6
Drugs that Prolong QT with Known or Possible Risk of TdP
The list of medications that prolong QT with known or possible risk of TdP are provided in 
Appendix 10.1
To explore the impact of concomitant usage of QT prolongation drug on safety, TEAE, drug-
related TEAE, SAE, drug related SAE as classified by SOC and PT will be summarized by 
cohort, dose level and subgroups defined below. QTcF interval will also be summarized by 
dose level and subgroups defined below.
Grouping variable
Subgroups
Usage of drug that prolong QT
Yes
No
Number of drug taken that prolong QT
0-1
2
>=3


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7.8.7
Post-HSCT Safety and Efficacy
Post HSCT safety and efficacy will be analyzed for subjects who undergo on-study HSCT 
and resume ASP2215 as well as subjects who come off treatment for HSCT and re-enroll into 
the study. TEAE, drug-related TEAE, SAE, drug-related SAE, and LFS within 2 months of
restarting ASP2215 post HSCT will be summarized.
7.9
Other Analyses
7.9.1
 
 
 
7.9.2
PK-PD Analysis
7.9.2.1 dQTcF Exposure Relationship
Assessment of dQTcF versus ASP2215 plasma concentrations will be assessed graphically 
(plot with line and 95% CI) and by linear mixed effect modeling with ASP2215 as 
covariates. Other analyses may be explored.
7.9.2.2
 
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 
In general, missing PK data should not be imputed if an appropriate method for imputation is 
not provided prospectively. Missing samples should not be assigned concentration values and 
consequently should not be included in the pharmacokinetic analysis. It should be carefully 
considered if the missing data affects the estimation of individual pharmacokinetic 
parameters before further analysis.
Concentrations below the lower limit of quantification (BQL) should be treated as missing 
when the terminal elimination rate constant is evaluated. Otherwise BQL should be treated as 
zero in the estimation of individual pharmacokinetic parameters.
Imputation methods for other missing data, if applicable, are described in individual sections.


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7.11.2
Outliers
Outliers of individual plasma concentrations can be identified by pharmacokinetic 
plausibility (e.g., concentration at pre-dose) or by appropriate statistical methods, and the 
dataset which excludes outliers can be used to calculate pharmacokinetic parameters for 
primary analysis. An additional analysis may be conducted as exploratory analysis using the 
original dataset before excluding the outliers may be performed and the differences between 
their results may be discussed if primary analysis is performed without outliers. A listing of 
outliers must be described in the pharmacokinetic analysis report along with the reasons for 
exclusion.
All values will be included in the non-PK 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.
CRF visit
Visit Window
Cycle 1 Day 4
C1D4 ± 1
Cycle 1 Day 8
C1D8 ± 1
Cycle 1 Day 22
C1D22 ± 1
Cycle 2 Day 1
C2D1 ± 3
Cycle 2 Day 15
C2D15 ± 1
Cycle X Day 1
CXD1 ± 3
End of Treatment Visit
Last dose date + 7
Scheduled visit will be calculated using number of days relative to the first dose date based 
on the fact that ASP2215 will be administered over continuous 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.  
In PK analysis, actual sampling times should be used in all calculations for individual 
pharmacokinetic parameters if an appropriate allowance of the deviation between actual and 
scheduled sampling times cannot be defined prospectively.
For ease of summarization, scheduled sampling times can be used to present results in tables, 
listings, and figures. Allowance of plasma concentrations for calculation of summary 
parameters will be based on sample time point:
●
Pre-dose – Within 30 minutes before drug administration
●
Post dose 0.5, 1, 1.5, 2 and 3 hours – Within ± 10 minutes of nominal time
●
Post dose 4 and 6 hours – Within ±20 minutes of nominal time
●
Post dose 24 hours – Within ±90 minutes of nominal time


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8
DOCUMENT REVISION HISTORY 
Version
Date
Changes
Comment/rationale for change
1.0
06-Nov-
2013
NA
Document finalized based on 
protocol amendment 1 dated 16-
Jul-2013
2.0 (Amendment 
1)
12-
Sept-
2014
Updated Schedule of Assessment
and footnote
Updated due to protocol 
amendment 2 dated 21-Jan-2013, 
amendment 4 dated 19-May-
2014, amendment 5 dated 07-Jul-
2014
Remove PD analysis from 
secondary objectives.
Updated due to protocol 
amendment 2 dated 21-Jan-2013
Updated Study Design section to
1.
allow changing to modified 
3+3 design and testing all dose 
levels based on 
recommendation of dose 
escalation committee; 
2.
add subject replacement 
guidance; 
3.
allow subjects that have 
contraindication to 
voricaonzole and/or 
midazolam to participate 
without the DDI component;
4.
allow voriconazole DDI study 
to be conducted at the next 
lowest dose level if the 
original dose level is closed 
before 12 subjects participated 
in the DDI study; 
5.
restrict DDI study 
participation to US only;
6.
further expand selected dose 
levels for efficacy evaluation;
7.
modification of re-screening 
language.
Updated due to protocol 
amendment 2 dated 21-Jan-2013, 
amendment 4 dated 19-May-
2014, amendment 5 dated 07-Jul-
2014
Updated Dose/Dose Regimen and 
Administration Period section to 
1.
clarify dose and route of 
voriconazole and midazolam;
2.
limit DDI study participation 
to US.
Updated due to protocol 
amendment 2 dated 21-Jan-2013, 
amendment 4 dated 19-May-
2014,
Updated Increase or Reduction in 
Dose of Study Drugs section to 
clarify required assessments and 
frequency of assessment after a 
subject dose escalation event.
Updated due to protocol 
amendment 2 dated 21-Jan-2013,
amendment 4 dated 19-May-
2014


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Version
Date
Changes
Comment/rationale for change
Updated Randomization section to 
1.
add instruction for use of IRT 
system;
2.
further expand selected dose 
levels for efficacy evaluation.
Updated due to protocol 
amendment 2 dated 21-Jan-2013, 
amendment 5 dated 07-Jul-2014
Incased sample size to 
approximately 170 subjects in the 
expansion cohort.
Updated due to protocol 
amendment 5 dated 07-Jul-2014
Clarified “All 
allocated/randomized subjects” in 
Analysis Sets section
To provide additional guidance 
for programming. 
Added definition for AESI in 
Other Safety Variables section and 
AESI analysis in Analysis of 
Safety section
AESI analysis was added to 
provide additional safety 
summaries for targeted medical 
events.
Updated laboratory assessment 
table in Other Safety Variables 
section
Updated due to protocol 
amendment 2 dated 21-Jan-2013
Add allowable collection windows 
for PK samples in 
Pharmacokinetic Variables section
Updated due to protocol 
amendment 2 dated 21-Jan-2013.
Clarified derivation of selected PK 
parameters and PK parameter 
symbols in Pharmacokinetic 
Variables section
Due to recent updates from 
pharmacokineticist
Changed PD parameters from 
Secondary endpoints to 
Exploratory endpoints.
Updated due to protocol 
amendment 2 dated 21-Jan-2013.
Added BMI derivation and 
clarified duration of exposure 
derivation in Other Variables 
section
To provide additional guidance 
for programming.
Added further expansion for 
efficacy evaluation and stopping 
rules in Analysis of Efficacy 
section
Updated due to protocol 
amendment 5 dated 07-Jul-2014
Added detailed formula for 
Bayesian logistic regression in 
Analysis of Safety section
To provide additional 
information for modeling. 
Updated power model regression 
in Dose Proportionality section
Due to recent updates from phase 
I statistics group
Moved PK data handling from 
Analysis of PK section to Handing 
of Missing Data, Outliers, Visit 
Windows, and Other Information 
section
Move the text to the appropriate 
SAP section
Add subgroup analysis to stratify 
all efficacy endpoints by FLT3 
mutation status. 
Due to increased interest in FLT3 
mutated subjects in protocol 
amendment 5. 


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Version
Date
Changes
Comment/rationale for change
Updated list of abbreviation
To add additional abbreviations 
for completeness
Update section 1 about timing of 
SAP development
Updated to comply with version 
3 SAP template dated 02-Jul-
2014
Updated Adverse Event section to 
include standard text relating to 
Always Serious AEs and clarify 
the summary for TEAE by 
severity grade and relationship
Updated to comply with version 
3 SAP template dated 02-Jul-
2014
Updated clinical important QTc 
interval criteria and change from 
baseline criteria in ECG section.
Updated to comply with version 
3 SAP template dated 02-Jul-
2014
Updated Appendix 10.1 Key 
contributors and approvers
Updated to comply with version 
3 SAP template dated 02-Jul-
2014
Added explanation of variables in 
example SAS code
To provide additional 
clarification for programming
Add peripheral blast <=2% 
criterion in section 6.1.1
To clarify the response definition
Clarified imputation of central 
bone marrow aspirate/biopsy in 
section 7.4
To provide additional 
clarification for programming
3.0 (Amendment 
2)
31-Aug-
2015
Updated Schedule of Assessment 
and footnote
Updated due to protocol 
amendment 8 dated 16-Apr-
2015, amendment 9 dated 26-
May-2015
Added secondary objective for 
MATE1 sub-study
Updated due to protocol 
amendment 9 dated 26-May-
2015
Updated study design (Section 
3.2) to allow for re-enrolled 
subjects and add MATE1 sub-
study
Updated due to protocol 
amendment 6 dated 23-Sep-2014, 
amendment 9 dated 26-May-
2015
Updated guidelines for dose 
reduction and dose escalation.
Updated due to protocol 
amendment 7 dated 15-Dec-
2014,
Amendment 10 dated 18-Aug-
2014.
Updated randomization (Section 
3.3) and sample size (3.4) to 
incorporate MATE1 sub-study
Updated due to protocol 
amendment 9 dated 26-May-
2015
Added Re-enrolled Analysis Set
Updated due to protocol 
amendment 6 dated 23-Sep-2014
In Section 6.1 (efficacy endpoint), 
clarified definitions for CRc, 
NR/NE, EFS. Added variable for 
time to remission.
To provide additional 
clarification for programming.
In Section 6.2 (safety variables), 
Updated due to protocol 


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Version
Date
Changes
Comment/rationale for change
updated TEAE to take into 
consideration of on-study HSCT 
and added definitions for AE and 
SAE during on-study HSCT 
period.
amendment 7 dated 15-Dec-2014
In Section 6.3 (PK variables), 
updated PK schedules and added 
PK variables related with MATE1 
sub-study
Updated due to protocol 
amendment 9 dated 26-May-
2015
Updated Section 7 (Statistical 
Methodology) to:
1.
Added analysis for re-enrolled 
subjects.
2.
Added analysis based on 
central FLT3 mutation 
assessment.
3.
Added analysis for AE/SAE 
during on-study HSCT period
4.
Added analysis for QTc based 
on interval categories.
5.
Added PK analysis for 
MATE1 sub-study.
Updated due to protocol 
amendment 6 dated 23-Sep-2014,
amendment 7 dated 15-Dec-
2014,
amendment 9 dated 26-May-
2015
17-Sep-
2015
Updated Section 7.8 (Subgroup of 
Interest) to:
1.
Add subset analysis for FLT3 
mutated subject in >=80mg 
dose level
2.
Add subgroup analysis for 
CYP3A4 inhibitor usage
3.
Add subgroup analysis for 
baseline hepatic and renal 
function
4.
Add subgroup analysis for QT 
prolongation drug usage
5.
Add subgroup analysis for 
post-HSCT safety and efficacy
Updated Section 6.6 to add 
definitions for the corresponding 
subgroups of interest.
Added Appendix 10.1 
Updated due to protocol 
amendment 6 dated 23-Sep-2014,
amendment 7 dated 15-Dec-
2014,
Added additional subgroup 
analysis due to new safety signals 
and address regulartory 
questions.
23-Sep-
2015
Update Section 6.3 and Section 
7.6 to add definitions and analyses 
for dose normalized plasma 
concentration and dose normalized 
PK parameters, add additional 
DDI analysis with strong or 
moderate CYP3A4 inhibitor.
Add dose normalized analyses to 
adjust for within subject dose 
modifications. 
23-Sep-
2015
Update Section 6.4 and Section 
7.7  to clarify the definition and 
analyses for baseline corrected 
To provide additional 
clarification for programming.


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Version
Date
Changes
Comment/rationale for change
phosphorylation of FLT3, AXL 
and S6.
14-Jan-
2016
Update Section 5 to add Post-
HSCT Analysis Set, and exclude 
subjects with legal findings from 
FAS
A new population was added to 
support the new subgroup 
analysis. FAS was updated to 
address the impact of subjects 
with legal findings on the 
analysis. 
14-Jan-
2016
Update Section 6.6 and 7.3 to add 
definition and analysis for relative 
dose intensity.
Added to better evaluate the 
exposure to study drug.
14-Jan-
2016
Remove Section 7.6.2.3 (PK 
analysis for gender difference). 
This is exploratory analysis, it 
will be conducted by PK group 
separately if needed.
08-Feb-
2016
Update Section 5.2.1 (reason for 
exclusion from PPS) to remove 
treatment compliance <80% 
criterion
Treatment compliance will be 
assessed for exclusion from PPS 
through ICH E3 criteria of 
incorrect treatment or wrong 
dose.
02-Mar-
2016
Update Section 6.3.1, 6.3.2, and 
6.3.4 to update PK parameters to 
be estimated.
Clarified PK parameters which 
will be reported.
02-Mar-
2016
Update Section 7.6.2.3 to remove 
the language of the criteria based 
on 90%CI.
The criteria was removed 
because formal sample size 
calculation was not conducted.
02-
May-
2016
Update Section 7.6.2.3 to update 
PK parameters for statistical 
analysis
Alignment of estimated PK 
parameters with statistical 
analysis of PK parameters for 
MATE1 cohort
4.0 (Amendment 
3)
15-Aug-
2017
Updated Flow chart and visit 
schedule, and Table 1F
Updated due to protocol 
amendment 11 dated 02-Jun-
2017
15-Aug-
2017
Updated Response Definition in 
Section 6.1.1 to add definition for 
CRh, update PR definition, and 
clarify visit level response vs. 
subject level best response
Added CRh endpoint to support 
AA submission, added 
clarification to response 
definition
15-Aug-
2017
Update Section 6.1.2 to add 
efficacy endpoint for CR/CRh 
rate, CRh rate, duration of 
CR/CRh, duration of CRh, time to 
CRh, time to first CR/CRh, time to 
best CR/CRh, transfusion status, 
transfusion conversion rate and 
transfusion maintenance rate.
Update Section 7.4 to add analyses 
for these endpoint.
Additional endpoint and analyses 
added to support AA submission. 
15-Aug-
2017
Update Section 7.5.5 to add 
analysis for grade 3 or 4 laboratory 
Additional endpoint and analyses 
added to support AA submission. 


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Version
Date
Changes
Comment/rationale for change
results. 
20-Sep-
2017
Update last relapse-free disease 
assessment definition in Section 
6.1.2 to include assessment with 
NE.
To be consistent with definitions 
in 2215-CL-0301
Update duration of remission 
definition in Section 6.1.2 not to 
censor subject at HSCT
To be consistent with definitions 
in 2215-CL-0301
Update Sections 6.5, 7.8.2, 7.9.1, 
to remove C-CBL mutation and 
AXL mutation.
3-gene analysis will be described 
in biomarker SAP
9
REFERENCES
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)
Skolnik JM, Barrett, JS, Jayaraman, B, et al. Shortening the Timeline of Pediatric Phase 1 Trials: The 
Rolling Six Design. J Clin Oncol 2008;26: 190-195
Cheson BD, Bennett JM, Willman CL, 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):4642-4649.
Sievers EL, Larson RA, Stadtmauer EA, et al. Efficacy and safety of Gemtuzumab Ozogamicin in 
Patients with CD33-Positive Acute Myeloid Leukemia in First Relapse. J Clin Oncol. 
2001;19:3244-3254. 
Karnofsky DA, Burchenal JH. “The Clinical Evaluation of Chemotherapeutic Agents in Cancer." In: 
MacLeod CM (Ed), Evaluation of Chemotherapeutic Agents. Columbia Univ Press. 1949;196.


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10
APPENDICES
10.1
Appendix 1: List of Medications that Prolong QT with Known or 
Possible Risk of TdP


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10.2
Appendix 2: Study Communication Memo












 
S-1 
ELECTRONIC SIGNATURE PAGE 
Document Type :  
Document Control Number :  
Amendment Number :  
International Study Number :  
Departmental Study Number :  
Actual Version Number :  
Document Version :  
Nonclinical Initial SD Approved Date (UTC) :  
Date (UTC) 
Signed by 
Sign Off Meaning 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
 
Full Name / Legal Name 
 
*UTC: Coordinated Universal Time 
09/28/2017 09:58:42
Statistical Analysis Plan
Scientific Lead Approval
Study Statistician Approval
Version 3.0
09/27/2017 19:34:26
Signature as Document Originator
N/A
09/27/2017 18:28:53
N/A
MGC1301668
09/28/2017 14:06:46
2215-CL-0101
6.0
Scientific Lead Approval
N/A