Clinical trial NCT02561455
Conditions: Advanced Solid Tumors Acute Myeloid Leukemia
Keywords: Advanced solid tumors Acute myeloid leukemia gilteritinib ASP2215
Sponsor: Astellas Pharma Global Development, Inc.
Start date: 2016-05-03; Completion date: 2020-07-28
Enrollment: 9 participants; Allocation: NA; Intervention model: PARALLEL

Brief summary:
The purpose of the study was to provide access to continued treatment for those who participated in other Astellas sponsored ASP2215 trials that completed the primary analysis and, had the potential to continue to derive clinical benefit from the treatment with ASP2215, and who did not meet any of the study discontinuation criteria in the present study.

Detailed description:

Arms: arm 1: Participants received gilteritinib 40 milligrams (mg) dose (one tablet of 40 mg) orally once a day in continuous 28-day cycles at least 2 hours after or 1 hour before food. Gilteritinib treatment continued until participants no longer received clinical benefit from therapy, or unacceptable toxicity occured, or met one of the treatment discontinuation criteria. arm 2: Participants received gilteritinib 80 mg dose (two tablets of 40 mg) orally once a day in continuous 28-day cycles at least 2 hours after or 1 hour before food. Gilteritinib treatment continued until participants no longer received clinical benefit from therapy, or unacceptable toxicity occured, or met one of the treatment discontinuation criteria. arm 3: Participants received gilteritinib 120 mg dose (three tablets of 40 mg) orally once a day in continuous 28-day cycles at least 2 hours after or 1 hour before food. Gilteritinib treatment continued until participants no longer received clinical benefit from therapy, or unacceptable toxicity occured, or met one of the treatment discontinuation criteria. arm 4: Participants received gilteritinib 200 mg dose (five tablets of 40 mg) orally once a day in continuous 28-day cycles at least 2 hours after or 1 hour before food. Gilteritinib treatment continued until participants no longer received clinical benefit from therapy, or unacceptable toxicity occured, or met one of the treatment discontinuation criteria.
Interventions: intervention 1: Gilteritinib
Intervention descriptions: intervention 1: oral tablet

Protocol documents:
Prot_000.pdf: 
Sponsor: APGD
ISN/Protocol 2215-CL-0109
- CONFIDENTIAL -
19 Jul 2018
Astellas
Page 1 of 70
Version 2.1 Incorporating Non-Substantial Amendment 1
A Phase 1/2 Open-label Rollover Study for Subjects Who Have 
Participated in an Astellas Sponsored ASP2215 Trial
Protocol for Phase 1/2 Study of ASP2215
ISN/Protocol 2215-CL-0109
Version 2.1
Incorporating Non-Substantial Amendment 1 [See Attachment 1]
19 July 2018
IND 117,548
Sponsor:
Astellas Pharma Global Development, Inc. (APGD)
1 Astellas Way
Northbrook, IL 60062
Protocol History:
Version 1.0 [22Jun2015]
Version 2.0 [17May2018] Incorporating Substantial Amendment 1
Investigator:  Investigator information is on file at Astellas
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.
NCT02561455


Sponsor: APGD
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Table of Contents
I.
SIGNATURES ······················································································ 7
II.
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL····························· 9
III.
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS ··················10
IV.
SYNOPSIS··························································································13
V.
SCHEDULE OF ASSESSMENTS ·····························································17
1
INTRODUCTION·················································································18
1.1
Background ····················································································18
1.2
Nonclinical and Clinical Data ·······························································19
1.2.1
Nonclinical Data·········································································19
1.2.2
Clinical Data ·············································································20
1.2.2.1
Studies Using Human Biomaterials ·············································20
1.2.2.2
Clinical Pharmacokinetics and Pharmacodynamics ···························20
1.2.2.3
Clinical Efficacy ···································································21
1.3
Summary of Key Safety Information for Study Drugs ···································21
1.3.1
Nonclinical Data·········································································21
1.3.2
ASP2215 Clinical Data ·································································23
1.4
Risk-Benefit Assessment·····································································24
2
STUDY OBJECTIVES, DESIGN AND ENDPOINTS·····································25
2.1
Study Objectives ··············································································25
2.2
Study Design and Dose Rationale···························································25
2.2.1
Study Design·············································································25
2.2.2
Dose Rationale···········································································25
2.2.2.1
ASP2215············································································25
2.3
Endpoints·······················································································25
2.3.1
Primary Endpoint········································································25
3
STUDY POPULATION··········································································25
3.1
Selection of Study Population ·······························································25
3.2
Inclusion Criteria··············································································26
3.3
Exclusion Criteria ·············································································27
4
TREATMENT(S)··················································································27
4.1
Identification of Investigational Products ··················································27


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4.1.1
Test Drug·················································································27
4.2
Packaging and Labeling ······································································28
4.3
Study Drug Handling ·········································································28
4.4
Blinding ························································································29
4.5
Assignment and Allocation ··································································29
5
TREATMENTS AND EVALUATION························································30
5.1
Dosing and Administration of Study Drugs and Other Medications····················30
5.1.1
Dose/Dose Regimen and Administration Period ····································30
5.1.2
Escalation or Reduction in Dose of the Study Drug·································30
5.1.3
Previous and Concomitant Treatment (Medication and Non-medication 
Therapy) ··················································································31
5.1.4
Treatment Compliance··································································32
5.2
Demographics and Baseline Characteristics ···············································32
5.2.1
Demographics············································································32
5.2.2
Medical History··········································································32
5.2.3
Diagnosis of the Target Disease, Severity and Duration of Disease ··············32
5.2.4
Performance Status······································································32
5.3
Efficacy Assessment··········································································33
5.4
Safety Assessment ············································································33
5.4.1
Vital Signs················································································33
5.4.2
Adverse Events ··········································································33
5.4.2.1
Adverse Events of Possible Hepatic Origin ····································33
5.4.3
Laboratory Assessments································································34
5.4.4
Physical Examination···································································35
5.5
Adverse Events and Other Safety Aspects ·················································35
5.5.1
Definition of Adverse Events ··························································35
5.5.2
Definition of Serious Adverse Events·················································36
5.5.3
Criteria for Causal Relationship to the Study Drug ·································37
5.5.4
Criteria for Defining the Severity of an Adverse Event ····························37
5.5.5
Reporting of Serious Adverse Events·················································37
5.5.6
Follow-up of Adverse Events··························································39
5.5.7
Monitoring of Common Serious Adverse Events ···································39
5.5.8
Procedure in Case of Pregnancy·······················································39
5.5.9
Emergency Procedures and Management of Overdose ·····························40


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5.5.10
Supply of New Information Affecting the Conduct of the Study··················40
5.5.11
Deviations from the Protocol and Other Actions Taken to Avoid Life-
threatening Risks to Subjects (Specific to sites in Japan Only)····················41
5.6
Test Drug Concentration ·····································································41
5.7
Other Measurements, Assessments or Methods ···········································41
5.8
Total Amount of Blood·······································································41
6
DISCONTINUATION············································································42
6.1
Discontinuation of Individual Subject(s)···················································42
6.2
Discontinuation of the Site···································································42
6.3
Discontinuation of the Study·································································42
7
STATISTICAL METHODOLOGY ···························································43
7.1
Sample Size····················································································43
7.2
Analysis Sets···················································································43
7.2.1
Full Analysis Set ········································································43
7.2.2
Per Protocol Set··········································································43
7.2.3
Safety Analysis Set······································································43
7.2.4
Pharmacokinetic Analysis Set ·························································43
7.3
Demographics and Other Baseline Characteristics········································43
7.3.1
Demographics············································································43
7.3.2
Medical History··········································································44
7.3.3
Disease History ··········································································44
7.3.4
Previous and Concomitant Medications ··············································44
7.3.5
Subject Disposition······································································44
7.3.6
Treatment Compliance··································································44
7.3.7
Extent of Exposure ······································································44
7.4
Analysis of Efficacy ··········································································44
7.5
Analysis of Safety·············································································44
7.5.1
Adverse Events ··········································································45
7.5.2
Laboratory Assessments································································45
7.5.3
Vital Signs················································································45
7.5.4
Physical Examination···································································45
7.5.5
Ophthalmologic Assessment···························································45
7.5.6
ECOG Performance Scores ····························································45
7.5.7
Pregnancy Test···········································································46


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7.6
Analysis of Pharmacokinetics ·······························································46
7.7
Protocol Deviations ···········································································46
7.8
Interim Analysis (and Early Discontinuation of the Clinical Study)····················46
7.9
Handling of Missing Data, Outliers, Visit Windows and Other Information ··········46
8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS ····················46
8.1
Procedure for Clinical Study Quality Control ·············································46
8.1.1
Data Collection ··········································································46
8.1.2
Specification of Source Documents···················································47
8.1.3
Clinical Study Monitoring······························································47
8.1.4
Direct Access to Source Data/Documents············································47
8.1.5
Data Management ·······································································48
8.1.6
Protocol Deviations ·····································································48
8.1.7
End of Trial in All Participating Countries···········································48
8.2
Ethics and Protection of Subject Confidentiality··········································49
8.2.1
Institutional Review Board/Independent Ethics Committee/Competent 
Authorities················································································49
8.2.2
Ethical Conduct of the Study···························································49
8.2.3
Informed Consent of Subjects ·························································49
8.2.3.1
Subject Information and Consent················································49
8.2.3.2
Supply of New and Important Information Influencing the Subject’s 
Consent and Revision of the Written Information ·····························50
8.2.4
Subject Confidentiality ·································································50
8.3
Administrative Matters ·······································································51
8.3.1
Arrangement for Use of Information and Publication of the Clinical Study ·····51
8.3.2
Documents and Records Related to the Clinical Study ·····························51
8.3.3
Protocol Amendment and/or Revision················································53
8.3.4
Insurance of Subjects and Others······················································54
8.3.5
Signatory Investigator for Clinical Study Report····································54
9
QUALITY ASSURANCE········································································55
10
STUDY ORGANIZATION······································································55
10.1
Independent Data Monitoring Committee··················································55
10.2
Other Study Organization ····································································55
10.3
Registration of Subjects (Specific to Japan) ···············································55
11
REFERENCES ····················································································56


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12
APPENDICES ·····················································································57
12.1
List of Excluded and Cautionary Concomitant Medications·····························57
12.2
Liver Safety Monitoring and Assessment ··················································62
12.3
Common Serious Adverse Events···························································65
13
ATTACHMENT 1:   NON-SUBSTANTIAL AMENDMENT 1··························68
14
SPONSOR’S SIGNATURES····································································70
List of Tables
Table 1
Schedule of Assessments·····································································17
Table 2
Test Drug (ASP2215 Tablets 40 mg) ·······················································28
Table 3
Dose Levels····················································································30
Table 4
Guidelines for ASP2215 Dose Reduction Event ··········································31
Table 5
ECOG Performance Status···································································33


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I.
SIGNATURES
1. SPONSOR’S SIGNATURE
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.
Specific to Japan:
AGREEMENT BETWEEN THE SPONSOR’S RESPONSIBLE PERSON AND THE 
INVESTIGATOR
This clinical study will be conducted in adherence to GCP, ICH Guidelines and applicable 
laws and regulatory requirements, as well as this study protocol. As the evidence of the 
agreement, the investigator (CHIKEN SEKININ ISHI) and responsible person of the Sponsor 
(CHIKEN IRAI SEKININSHA) inscribe in the bipartite agreement.


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2. INVESTIGATOR’S SIGNATURE
A Phase 1/2 Open-label Rollover Study for Subjects Who Have Participated in 
an Astellas Sponsored ASP2215 Trial
ISN/Protocol 2215-CL-0109 
Version 2.1 Incorporating Non-Substantial Amendment 1
19 Jul 2018
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
5HT1R
5-hydroxytryptamine receptor 1
5HT2BR
5-hydroxytryptamine receptor 2B
ΔQTcF
Fridericia-corrected QT interval corrected relative to baseline
AE
Adverse event
ALK
Anaplastic lymphoma kinase
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AML
Acute myeloid leukemia
APGD
Astellas Pharma Global Development, Inc.
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
AUST
Astellas United States Technologies
AXL
AXL tyrosine kinase
BCRP
Breast cancer resistance protein
Ca+2
Calcium
CK
Creatine kinase
CR
Complete remission
CRc
Composite complete remission
CRF
Case report form
CRi
Complete remission with incomplete hematologic recovery
CRO
Contract Research Organization
CRp
Complete remission with incomplete platelet recovery
CTCAE
Common Terminology Criterion for Adverse Events
Ctrough
Observed trough concentration
CYP
Cytochrome P450
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EGFR
Epidermal growth factor receptor
FLT3
FMS-like tyrosine kinase
GCP
Good Clinical Practice
HIPAA
Health Insurance Portability and Accountability Act
IC50
Half maximal inhibitory concentration
ICF
Informed Consent Form


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Abbreviations
Description of Abbreviations
ICH
International Conference on Harmonisation 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
ITD
Internal tandem duplication
LA-CRF
Liver Abnormality-Case Report Form
LFT
Liver function test
LTK
Leukocyte receptor tyrosine kinase
MATE1
Multidrug and toxin extrusion protein 1
NCI
National Cancer Institute
NDA
New Drug Application
NOAEL
No observed adverse effect level
OATP
Organic anion transporting polypeptide
PD
Protocol deviation
P-gp
P-glycoprotein
PR
Partial remission
PT
Preferred term
SAE
Serious adverse event
SAF
Safety Analysis Set
SAP
Statistical Analysis Plan
SOP
Standard Operating Procedure
TBL
Total bilirubin
TEAE
Treatment-emergent adverse event
TLFs
Tables, listings and figures
ULN
Upper limit of normal
WHO
World Health Organization


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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 and 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.
Screen failure
Potential subject who signed consent but did not meet 1 or more criteria 
required for participation in a trial and did not randomize to the trial.
Screening
A process of active consideration of potential subjects for enrollment in a trial.
Screening period
Period of time before entering the investigational period, usually from the time 
of starting a subject signing consent until just before the registration.
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:
19 Jul 2018, Version 2.1
Sponsor:
Astellas Pharma Global Development Inc. (APGD)
Protocol Number:
2215-CL-0109
Name of Study Drug:
ASP2215
Phase of Development:
Phase 1/2
Title of Study:
A Phase 1/2 Open-label Rollover Study for Subjects Who Have Participated in an Astellas Sponsored 
ASP2215 Trial
Planned Study Period:
From 3Q2015 to 3Q2023
Study period implies the period from the first screened subject at the first site until the last scheduled 
visit of the last subject in the study.
Study Objective(s):
The purpose of the study is to provide access to continued treatment for subjects who participated in 
other Astellas sponsored ASP2215 (single agent) trials and for whom the Investigator feels the subject 
may benefit from continued treatment.
Planned Total Number of Study Centers and Location(s):
Sites that currently have subjects actively participating in an Astellas sponsored ASP2215 trial.
North America, Europe, Asia
Study Population:
Subjects who are actively participating in an Astellas sponsored ASP2215 trial that has completed the 
primary analysis, whom the investigator feels may have potential to continue to derive clinical benefit 
from the treatment with ASP2215, and who did not meet any of the study discontinuation criteria in 
the present study.
Number of Subjects to be Enrolled / Randomized:
Dependent on the number of subjects enrolled in the protocols rolling over into this trial.
Study Design Overview:
This is a multi-center, open-label, rollover protocol for Astellas sponsored, single agent ASP2215 
trials in AML and advanced solid tumors.  Subjects must have completed the protocol requirements of 
the previous ASP2215 trial and be actively participating in the previous ASP2215 trial.  In addition, 
subjects must be continuing to derive clinical benefit from treatment with ASP2215 without any 
persistent intolerable toxicity from ASP2215, in the opinion of the investigator and must meet the 
entry criteria for this rollover study prior to being enrolled.
Subjects should sign the informed consent at their cycle 1 day 1 visit.  The assessments from the last 
treatment visit from the parent study can be utilized for the cycle 1 day 1 visit.  The subject will then 
receive ASP2215 study drug for the rollover study and return all ASP2215 study drug from the parent 
study.


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Inclusion/Exclusion Criteria:
Inclusion:
1.
Institutional Review Board (IRB)-/Independent Ethics Committee (IEC)-approved written 
Informed Consent and privacy language as per national regulations [e.g., Health Insurance 
Portability and Accountability Act (HIPAA) Authorization for US sites] must be obtained from 
the subject or legally authorized representative prior to any study-related procedures (including 
withdrawal of prohibited medication, if applicable).
2.
Subject must currently be participating in an Astellas sponsored ASP2215 trial, receiving 
ASP2215 and have not met any discontinuation criteria of the parent study and can enroll 
into this rollover study without interruption of study drug, or with no more than 2 weeks 
interruption in study drug.
3.
Subject must be deriving benefit from continued treatment without any persistent intolerable 
toxicity from continued treatment of ASP2215, as determined by the investigator.
4.
Female subject must either:
Be of non-childbearing potential:
post-menopausal (defined as at least 1 year without any menses) prior to Screening, or 
documented surgically sterile or post-hysterectomy  (at least one 1 month prior to 
Screening)
Or, if of childbearing potential, 
Agree not to try to become pregnant during the study and for 180 days after the final
study drug administration
And have a negative urine pregnancy test at screening
And, if heterosexually active, agree to consistently use two forms of highly effective 
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.
5.
Female subject must agree not to breastfeed starting at Screening and throughout the study 
period, and for 60 days after the final study drug administration.
6.
Female subject must not donate ova starting at Screening and throughout the study period, 
and for 180 days after the final study drug administration.
7.
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* (at least 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.
8.
Male subject must not donate sperm starting at Screening and throughout the study period and, 
for 120 days after the final study drug administration.
9.
Subject agrees not to participate in another interventional study while on treatment.
*Highly effective forms of birth control include:

Consistent and correct usage of established oral contraception.

Established 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 (for regions where spermicidal 
foam/gel/film/cream/suppository is not available e.g., Japan)

Calendar-based contraceptive methods (Knaus-Ogino or rhythm method applicable to 
subjects enrolled at sites in Japan).


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Waivers to the inclusion criteria will NOT be allowed.
Exclusion:
1.
Subject requires treatment with concomitant drugs that are strong inducers of cytochrome 
P450 (CYP)3A.
2.
Subject requires treatment with concomitant drugs that target serotonin 5-hydroxytryptamine 
receptor 1 (5HT1R) or 5-hydroxytryptamine receptor 2B (5HT2BR) or sigma nonspecific receptor 
with the exception of drugs that are considered absolutely essential for the care of the subject. 
3.
Subject requires treatment with concomitant drugs that are strong inhibitors or inducers of 
P-glycoprotein (P-gp) with the exception of drugs that are considered absolutely essential for the 
care of the subject.
Waivers to the exclusion criteria will NOT be allowed.
Investigational Product(s):
ASP2215 tablets containing 40 mg of active ingredient.
Dose(s):
Subject will continue dosing at the dose received in original study with ASP2215, dose not to exceed 
280 mg. If the original subject dose is over 280 mg, the subject will begin dosing in this protocol at 
280 mg.
Mode of Administration:
ASP2215 will be administered orally.
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 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 that are considered absolutely essential for the care of the subject. Treatment with concomitant 
drugs that are strong inhibitors of CYP3A should be avoided with the exception of antibiotics, 
antifungals and antivirals that are used as standard of care to prevent or treat infections. If CYP3A
inhibitors are used concomitantly, subjects should be closely monitored for AEs.
Precaution should be used in treatment of ASP2215 with concomitant drugs that are known to prolong 
QT or QTc intervals.
Duration of Treatment:
Subject may continue on study drug until any of the criteria for study drug discontinuation have been 
met.
Discontinuation Criteria:
Subject declines further study participation (i.e. withdrawal of consent).
Subject develops an intolerable or unacceptable toxicity.
Investigator/sub-Investigator determines the subject is no longer receiving clinical benefit from 
study treatment.
Investigator/sub-Investigator determines that the continuation of the study treatment will be 
detrimental to the subject.




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V.
SCHEDULE OF ASSESSMENTS
Table 1
Schedule of Assessments
Assessments
Screening a
(Day -28 to 1)
Treatment 
Cycle 1 Day 1 a
Day 1 of Treatment Cycle 3 
and Every Other Cycle (i.e., 
Cycles 5, 7, 9, etc.) b
(+/- 5 days)
End of 
Treatment c
Informed Consent
X
Verify Inclusion/Exclusion 
X
X
Subject Enrollment
X
Demographics d
X
Medical History e
X
Physical Examination
X
X
Vital Signs
X
X
ECOG Performance Status
X
X
Clinical Laboratory Tests (chemistry, hematology, coagulation, urinalysis)
X
X
X
Pregnancy Test for Women of Childbearing Potential (WOCBP)
X
X
X
Prior and Concomitant Medications
Adverse Event Assessment g
ASP2215 Administration h
Daily
ECOG: Eastern Cooperative Oncology Group
a. Subject should sign the informed consent at the final visit of the original study they enrolled in. The Screening and Treatment Cycle 1 Day 1 visits may be combined. A subject’s 
procedures performed during their final visit for the original study will be used for Treatment Cycle 1 Day 1 if the final visit occurred within 7 days prior to visit.
b. Each treatment cycle is 28 days. Subject to be seen on Day 1 of every 2 treatment periods (every 8 weeks).
c. End of treatment visit to be conducted within 30 days of last dose, prior to starting a new anticancer therapy or upon marketing authorization and commercial availability of 
ASP2215 in the country of residence. Subjects discontinuing due to commercial availability will be notified by the site and an end of treatment visit scheduled within 3 months.
d. Demographic data will be obtained from the original study.
e. Medical history will be obtained from the original study.
f. Adverse events from the original study that are ongoing at the time of Screening will continue to be followed as adverse events during this protocol and should not be captured 
as medical history. Adverse events will be captured until the End of Treatment visit, 30 days after last dose, or until start of a new anticancer therapy, whichever is sooner.
g. Subject will continue dosing at the dose received in original study with ASP2215 dose not to exceed 280 mg.  If the original subject dose is over 280 mg, the subject will 
begin dosing in this protocol at 280 mg.


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1
INTRODUCTION
1.1
Background
ASP2215 hemifumarate (gilteritinib), is a new chemical entity discovered by Astellas Pharma 
Inc. in collaboration with Kotobuki Pharmaceutical Co., Ltd.  It is a FMS-like tyrosine kinase 
3 (FLT3) inhibitor under development for the treatment of acute myeloid leukemia (AML).  
ASP2215 also has inhibitory activities for AXL tyrosine kinase (AXL), leukocyte receptor 
tyrosine kinase (LTK) and anaplastic lymphoma kinase (ALK).
FLT3 is a member of the class III receptor tyrosine kinase family that is normally expressed 
on the surface of hematopoietic progenitor cells. FLT3 and its ligand play an important role in
proliferation, survival and differentiation of multipotent stem cells.  FLT3 is overexpressed in 
the majority of AML cases. In addition, activated FLT3 with an internal tandem duplication
(ITD) in and around the juxtamembrane domain and tyrosine kinase domain (TKD) mutations
at around D835 in the activation loop are present in 28% to 34% and 11% to 14% of AML 
cases, respectively [Schlenk & Döhner, 2009].  These activated mutations in FLT3 are 
oncogenic and show transforming activity in cells [Yamamoto et al, 2001].  Furthermore, 
patients with activated FLT3 show poor prognosis, with a higher relapse rate, more rapid 
relapse, reduced disease-free survival and overall survival [Patel et al, 2012; Gale et al, 2008; 
Yanada et al, 2005; Moreno et al, 2003].
ALK is another receptor tyrosine kinase; this molecule appears to play a role in the
development of the nervous system, although the mechanisms remain poorly understood 
[Camidge & Doebele, 2012].  Non-small cell lung cancer (NSCLC) with ALK gene 
arrangements represents approximately 4% to 5% of all NSCLC patients in both Caucasians 
and Asians. In absence of treatment with a targeted agent, ALK gene arrangements are 
associated with a poorer clinical outcome [Chia et al, 2014].  Over 20 ALK fusion partners 
have been identified in NSCLC. The most common ALK fusion is echinoderm microtubule 
associated protein like 4 (EML4)-ALK, representing 29% to 33% of gene fusions identified 
[Chia et al, 2014].  EML4-ALK demonstrated transforming activities in vitro and in vivo, 
confirming its oncogenic properties [Soda et al, 2007].
Nonclinical data suggest that AXL overexpression mediates resistance to epidermal growth 
factor receptor (EGFR) tyrosine kinase inhibitors in NSCLC with an EGFR activating 
mutation and that AXL inhibition can restore sensitivity to EGFR tyrosine kinase inhibitors.  
Nonclinical data also suggest that in some cases, overexpression of growth arrest-specific 
6 (GAS6; the ligand for AXL) can promote AXL activation in the setting of acquired 
resistance in the absence of AXL overexpression [Zhang et al, 2012]. The incidence of AXL 
or GAS6 overexpression in advanced NSCLC has not been extensively characterized.  In 
35 matched EGFR-mutant NSCLC specimens obtained from patients both before treatment 
with erlotinib or gefitinib and after the development of resistance, increased (2-fold or 
greater) expression of AXL was observed in 7 of 35 (20%) specimens and GAS6 in 7 of 28 
(25%) specimens [Zhang et al, 2012].


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1.2
Nonclinical and Clinical Data
Nonclinical and clinical data for ASP2215 available as of the writing of this protocol are 
summarized below. Please refer to the most current version of the ASP2215 Investigator 
Brochure.
1.2.1
Nonclinical Data
ASP2215 inhibited activities of FLT3, nucleophosmin-1 gene-ALK, LTK, ALK and AXL 
kinases at 1 and 5 nmol/L and tropomyosin receptor kinase A, ROS, RET and MER kinases 
at 5 nmol/L by over 50%. ASP2215 inhibited FLT3, echinoderm microtubule-associated 
protein-like 4-ALK variant 1 and KIT kinase activities with the half maximal inhibitory 
concentration (IC50) values of 0.291, 1.2 and 229 nmol/L, respectively.
ASP2215 inhibited each radioligand binding to adenosine A1 receptor (rat), serotonin 
5-hydroxytryptamine receptor 1 (5HT1R) (nonselective, rat), serotonin 5-hydroxytryptamine 
receptor 2B (5HT2BR) (human) and sigma receptor (nonselective, guinea pig) with IC50
values of 4.57, 4.90, 0.190 and 0.615 μmol/L, respectively.
ASP2215 inhibited human 5HT2BR function in a cell function assay with an IC50 value of 
5.82 μmol/L without showing agonistic activity.
ASP2215 inhibited the cell growth of Ba/F3 cells expressing FLT3-ITD, FLT3-D835Y and 
FLT3-ITD-D835Y with IC50 values of 1.8, 1.6 and 2.1 nmol/L, respectively. ASP2215 
inhibited the growth of MV4-11 cells with IC50 value of 0.92 nmol/L. In MV4-11 cells, 
treatment of ASP2215 at 0, 0.1, 1 and 10 nmol/L resulted in FLT3 phosphorylation of 100%, 
86%, 19% and 7%, respectively.
ASP2215 induced significant growth inhibition of MV4-11 tumors and tumor regression in 
vivo.  Further, ASP2215 at 6 and 10 mg/kg per day induced complete tumor regression for 
4 and 6 out of 6 mice, respectively. Body weight of the mice treated with ASP2215 was not 
affected at any tested doses.
These results indicate ASP2215 should show the antitumor efficacy against AML subjects 
with FLT3-ITD and FLT3 mutation at D835.
The IC50 value of ASP2215 against FLT3 kinase was about 800-fold lower than that against 
KIT kinase, and neutropenia was not observed in the toxicity studies in rats and dogs.
In Caco-2 cells, the permeability of ASP2215 was between that of known low and high 
permeability markers. ASP2215 was a substrate for P-glycoprotein (P-gp), but not a substrate 
for breast cancer resistance protein (BCRP), organic anion transporting polypeptide 
(OATP)1B1, OATP1B3 or organic cation transporter (OCT) 1. ASP2215 demonstrated a 
potential to inhibit BCRP and MATE1 at clinically relevant concentrations of ASP2215.
No major human-specific ASP2215 metabolites were formed by liver microsomes or 
hepatocytes. The main enzyme involved in the metabolism of ASP2215 was estimated to be 
cytochrome P450 (CYP) 3A4. ASP2215 has a potential to induce CYP enzyme activities 
(CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP3A4/5) and mRNA levels 


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(CYP2B6, CYP2C8, CYP2C9 and CYP3A4).  However, these results should be interpreted 
with caution because these effects were not uniformly observed in all donor samples and the 
concentration-dependency of these effects could not be evaluated.  For CYP1A2, CYP2B6, 
CYP2C8, CYP2C9 and CYP2D6 inhibition, IC50 values were > 100 μmol/L. Very weak 
direct inhibition of CYP2C19 and CYP3A was observed.  Overall, ASP2215 showed 
minimal direct inhibition of CYP enzymes at clinically relevant concentrations.
1.2.2
Clinical Data
1.2.2.1 Studies Using Human Biomaterials
No human-specific ASP2215 metabolites were formed by liver microsomes or hepatocytes, 
with the exception of 1 minor metabolite detected in human hepatocytes. ASP2215 is a 
substrate for CYP3A4 and P-gp but not a substrate for human BCRP, OATP1B1, OATP1B3 
or OCT1. The IC50 values of inhibition to drug transport by P-gp, BCRP, OATP1B1, OCT1, 
OCT2, MATE1 and MATE2-K inhibition are > 30, 1.41, 29.4, 2.92, 34.9, 0.0543 and 
47.7 μmol/L, respectively.
1.2.2.2 Clinical Pharmacokinetics and Pharmacodynamics
The pharmacokinetic parameters of unchanged drug after single and multiple dosing of 
ASP2215 to AML subjects were investigated in the dose escalation cohort of 
Study 2215-CL-0101. Assessment of observed trough concentration (Ctrough) over time for 
individual subjects (both dose escalation and dose expansion cohorts) showed that in most 
subjects, the trough concentration of ASP2215 appeared to reach steady state by day 15 of 
multiple administrations of ASP2215 from 20 to 120 mg once daily.
Since ASP2215 is mainly metabolized by CYP3A4, the effect of a strong CYP3A4 inhibitor 
(voriconazole) on the pharmacokinetics of ASP2215 was investigated as a part of 
Study 2215-CL-0101. Since a substantial number of subjects in Study 2215-CL-0101 
required coadministration of strong (voriconazole and posaconazole) or moderate 
(fluconazole) CYP3A4 inhibitors during the course of treatment, Ctrough/dose values of these 
subjects were compared with subjects that did not receive CYP3A4 inhibitors. Overall, these 
data suggest a low probability for increased exposure of ASP2215 by strong or moderate 
CYP3A4 inhibitors.
Plasma inhibitory assay (PIA) from the samples collected predose and postdose on days 1, 8, 
15 and 29 demonstrated sustained inhibition of phospho-FLT3 at doses 80 mg and higher.
Evaluation of time matched ASP2215 plasma concentrations Fridericia-corrected QT interval 
corrected relative to baseline (ΔQTcF) was performed. Comparison of time matched 
ASP2215 plasma concentrations with ΔQTcF values showed no substantial relationship, 
although a positive trend was observed.  Overall these data indicate a low probability of a 
substantial increase in ΔQTcF over the range of ASP2215 plasma concentrations evaluated 
(20 to 300 mg).


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With increasing dose of ASP2215, increasing plasma concentrations of creatine kinase (CK) 
were observed. Comparison of day matched CK corrected relative to baseline with Ctrough 
ASP2215 values showed a correlation with a positive slope.  Similarly, comparison of the 
Common Terminology Criteria for Adverse Events (CTCAE) grade for CK elevations with 
ASP2215 Ctrough values showed increasing incidence of higher CTCAE grades with 
increasing drug exposure.  Overall, increasing CK plasma concentrations from baseline 
appeared to correlate with increasing ASP2215 plasma concentrations; the mechanism for 
this effect is unknown.
1.2.2.3 Clinical Efficacy
In Study 2215-CL-0101, as of 02Feb2015, 154 subjects were evaluable for response. The 
response assessments were done based on central laboratory evaluation of bone marrow 
samples supplemented with local results when the central results were not available (derived 
response).
Based on the derived response at end of treatment in the 154 subjects (both FLT3-mutation 
positive and negative) who received at least 1 dose of ASP2215, 41 (26.6%) subjects achieved 
composite complete remission (CRc), and the best overall response rate (CRc + PR) was 35.7%.
Nearly all subjects that achieved a derived response of partial remission (PR) or CRc at the 
end of treatment were FLT3-mutation positive. Based on the derived response in the 98 
FLT3-mutation positive subjects at the end of treatment, 36 (36.7%) subjects achieved CRc, 
and the best overall response rate was 49.0%. Five (5.1%) subjects achieved complete 
remission (CR), 3 (3.1%) subjects achieved complete remission with incomplete platelet
recovery (CRp), 28 (28.6%) subjects achieved complete remission with incomplete
hematologic recovery (CRi) and 12 (12.2%) subjects achieved PR.
CRc rates for 80, 120 and 200 mg dose groups were 41.7%, 48.6% and 45.8% respectively.   
Among the 77 FLT3-mutation positive subjects in the 80 mg, 120 mg, 200 mg, 300 mg and 
450 mg dose groups, 34 (44.2%) had achieved CRc as the derived response at the end of 
treatment and the overall response rate was 55.8%. Four (5.2%) subjects achieved CR, 
3 (3.9%) subjects achieved CRp, 27 (35.1%) subjects achieved CRi and 9 (11.7%) subjects 
achieved PR
Based on the derived response in the 47 FLT3-mutation negative subjects at the end of 
treatment, 2 (4.3%) subjects achieved CRc, and the best overall response rate was 8.5%.  
Two (4.3%) subjects each achieved CRi and PR.
1.3
Summary of Key Safety Information for Study Drugs
1.3.1
Nonclinical Data
ASP2215 showed a concentration-dependent suppression effect on the human ether-a-go-go-
related gene current in 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; no suppression 
was observed at 1 × 10−6 mol/L. The IC50 was 1.6 × 10-5 mol/L.


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ASP2215 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.  The changes in urination and defecation resolved in the recovery period.
ASP2215 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 calcium (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 definitive single oral dose toxicity study in dogs was conducted. In the 4-week toxicity 
study in dogs, a dose of 1000 mg/kg per 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.  
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 per 
day.  In the 13-week oral repeated dose toxicity study in rats, deaths occurred at 20 mg/kg per 
day in both sexes. Target organ toxicity was identified in the gastrointestinal tract, immune 
system, hematopoietic system, eye, lung, kidney and liver. The no observed adverse effect 
level (NOAEL) was lower than 2.5 mg/kg per day for males and females. The changes noted 
during the dosing period recovered or tended to recover during the 4-week recovery period.  
In the 4-week oral repeated dose study in dogs, mortality occurred at 10 mg/kg per day or 
more.  Target organ toxicity was identified in the gastrointestinal tract, immune system, 
hematopoietic system, eye, kidney and liver. The NOAEL was 1 mg/kg per day for males and 
females. Reversibility of most of the test article related changes was indicated by the end of 
the 4-week recovery period. In the 13-week oral repeated dose study in dogs, mortality 
occurred at 5 mg/kg per day. Target organ toxicity was identified in the lung, lacrimal gland, 
urinary bladder, epithelial tissue, gastrointestinal tract, immune system, hematopoietic 
system, eye, kidney and liver. The NOAEL was 1 mg/kg per day for males and females.  
Reversibility of most of the test article-related changes was indicated by the end of the 
4-week recovery period.
ASP2215 did not induce gene mutation in the definitive in vitro reversion test in bacteria.  
Similarly, ASP2215 did not induce chromosomal aberrations in the definitive in vitro 
chromosomal aberration test in mammalian cells. The definitive in vivo micronucleus test 
showed that ASP2215 has a potential to induce micronuclei 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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ASP2215 showed teratogenic potential and embryo-fetal deaths in the embryo-fetal development 
study in rats. The NOAEL of ASP2215 for dams and embryo-fetal development was 10 mg/kg 
per day.
ASP2215 showed no potential to induce phototoxicity to cultured mammalian cells.
1.3.2
ASP2215 Clinical Data
Of the first 154 subjects 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 subjects) include febrile neutropenia (34.4%), 
anemia (27.9%), fatigue (26.6%), diarrhea (26.0%), peripheral edema (20.8%), increased 
aspartate aminotransferase (AST) (19.5%), dyspnea (18.2%), dizziness (16.9%), epistaxis 
(16.2%), constipation (15.6%), pyrexia, increased alanine aminotransferase (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%) 
subjects 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 subjects) 
include fatigue (13.6%), diarrhea (10.4%), anemia, constipation (9.1% each), increased AST 
(8.4%), nausea, peripheral edema, decreased platelet 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 subjects developed at least one serious TEAE. The most 
commonly reported serious TEAE (occurring in at least 5% of subjects) 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%) subjects 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 subjects include febrile neutropenia (1.9%), diarrhea 
and abnormal liver function test (1.3% each).
Forty subjects experienced a TEAE that resulted in death. One event of intracranial 
hemorrhage, 1 event of septic shock, and the event of hemoptysis were considered possibly 
related to ASP2215 by the Investigator. One event of respiratory failure and the event of febrile 
neutropenia were considered probably related to ASP2215 by the Investigator. One event of 
bacteremia was recorded as grade 3 with a fatal outcome and was considered possibly related 
to ASP2215 by the Investigator.
The majority of patients (92 [79.3%]) experienced at least 1 grade 3 or higher TEAE. Common 
grade 3 or higher TEAEs (occurring in at least 2% of patients) include febrile neutropenia 
(30.2%), anemia (21.6%), pneumonia and sepsis (10.3%), decreased platelet count (9.5%), 
disease progression (7.8%) thrombocytopenia and hypoxia (6.9%), bacteremia, acute renal 
failure and hypotension (5.2%), leukocytosis, decreased neutrophil count and respiratory 
failure (4.3%), asthenia, multi-organ failure and acute myeloid leukemia (3.4%), fatigue, 


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pyrexia, cellulitis, septic shock, urinary tract infection, hypokalemia, hypophosphatemia, 
intracranial hemorrhage, dyspnea and epistaxis (2.6%).
After the data cutoff, 1 subject 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 subject’s symptoms resolved. 
Additionally, 1 case of rhabdomyolysis with associated CK elevations was reported in a 
subject in the 300 mg dose group. Both SAEs were considered DLTs.
For CK, 21 (13.7%) subjects experienced a shift of 2 grades or higher, and these shifts 
appeared to increase with increasing dose. For ALT, 19 (12.4%) subjects experienced a shift 
of 2 grades or higher. For AST, 19 (12.4%) subjects experienced a shift of 2 grades or higher.
Sixteen subjects experienced dose-limiting toxicities (DLTs); 14 subjects in the dose 
expansion cohort (1 in 20 mg dose group, 1 in 40 mg dose group, 2 in 80 mg dose group, 3 in 
120 mg dose group, 4 in 200 mg dose group, and 3 in the 300 mg dose group) and 2 subjects 
in the dose escalation cohort (both in the 450 mg dose group). None of the doses below 
450 mg met the criteria for pausing enrollment. Thus, the maximum tolerated dose (MTD) in 
Study 2215-CL-0101 is considered to be 300 mg.
1.4
Risk-Benefit Assessment
In Study 2215-CL-0101, ASP2215 has resulted in CRc in over 40% of subjects receiving 
80 mg or higher dose. The median survival was over 7 months in the 120 mg dose level. The 
majority of subjects in the trial received multiple treatments prior to receiving ASP2215. 
In summary, major findings in the safety pharmacology studies were vomiting, positive fecal 
occult blood and increased/decreased blood Ca+2 in dogs and decreased urination and 
defecation in rats. In the oral 13-week repeated dose toxicity study in rats and the 4- and 
13-week repeated dose toxicity studies in dogs, mortality occurred at 20, 10 and 5 mg/kg per 
day, respectively. With respect to other major target organ toxicities, effects on the lacrimal 
gland, urinary bladder, epithelial tissue, gastrointestinal tract, immune system, hematopoietic 
system, eye, liver, kidney and/or lung were observed in rats and dogs at 2.5 mg/kg per day or 
more. All major findings were reversible and monitorable.
ASP2215 has a potential to induce genotoxicity in vivo. ASP2215 showed teratogenic 
potential and embryo-fetal deaths in the embryo-fetal development toxicity study in rats.
This study is designed to only include subjects who are currently enrolled in an ASP2215 
trial and is intended to provide continued access to ASP2215 for subjects who have derived 
benefit in the opinion of the Investigator from their administered treatment on the original 
study in which they are currently participating.


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2
STUDY OBJECTIVES, DESIGN AND ENDPOINTS
2.1
Study Objectives
The objective of the study is to provide access to continued treatment for subjects who 
participated in other previous Astellas sponsored ASP2215 (single agent) trials and for whom 
the Investigator feels the subject may benefit from continued treatment.
2.2
Study Design and Dose Rationale
2.2.1
Study Design
This is a multi-center, open-label, rollover protocol for Astellas sponsored, single agent 
ASP2215 trials in AML and advanced solid tumors. Subjects must have completed the 
protocol requirements of the previous ASP2215 trial and be actively participating in the 
previous ASP2215 trial to be eligible for participation in this study. The number of subjects 
and number of centers will be dependent on the number of subjects and centers that enroll 
into the protocols rolling over into this trial. Centers in North America, Europe and Asia may 
rollover subjects into this trial. It is estimated that up to approximately 130 subjects across 
40 centers will enroll into this trial. Subjects will be eligible to continue receiving treatment 
in this study until they meet a discontinuation criterion as outlined in Section 6.1 or upon 
marketing authorization and commercial availability of ASP2215 in the country of residence.
2.2.2
Dose Rationale
2.2.2.1 ASP2215
Subjects will continue ASP2215 at the dose they were on at the time of their end of study 
visit in the previous ASP2215 study.
2.3
Endpoints
2.3.1
Primary Endpoint
Safety, as measured by adverse events (AEs) and safety laboratory evaluations.
3
STUDY POPULATION
3.1
Selection of Study Population 
Subjects who are actively participating in an Astellas sponsored ASP2215 trial that has 
completed the primary analysis, whom the investigator feels may have potential to continue 
to derive clinical benefit from the treatment with ASP2215, and who did not meet any of the 
study discontinuation criteria in the present study.


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3.2
Inclusion Criteria
Subject is eligible for the study if all of the following apply:
1.
Institutional Review Board (IRB)-/Independent Ethics Committee (IEC)-approved 
written Informed Consent and privacy language as per national regulations [e.g., Health 
Insurance Portability and Accountability Act (HIPAA) Authorization for US sites] must 
be obtained from the subject or legally authorized representative prior to any study-
related procedures (including withdrawal of prohibited medication, if applicable).
2.
Subject must currently be participating in an Astellas sponsored ASP2215 trial, receiving 
ASP2215 and is able to enroll into this rollover study without interruption of study drug, 
or with no more than 2 weeks interruption in study drug.
3.
Subject must be deriving benefit from continued treatment as determined by the 
Investigator.
4.
Female subject must either:
●Be of non-childbearing potential:
post-menopausal (defined as at least 1 year without any menses) prior to 
Screening, or 
documented surgically sterile or post-hysterectomy (at least one 1 month prior 
to Screening)
●Or, if of childbearing potential, 
Agree not to try to become pregnant during the study and for 180 days after the 
final study drug administration
And have a negative urine pregnancy test at screening
And, if heterosexually active, agree to consistently use two forms of highly 
effective 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.
5.
Female subject must agree not to breastfeed starting at Screening and throughout the 
study period, and for 60 days after the final study drug administration.
6.
Female subject must not donate ova starting at Screening and throughout the study 
period, and for 180 days after the final study drug administration.
7.
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* (at least 
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.
8.
Male subject must not donate sperm starting at Screening and throughout the study 
period and, for 120 days after the final study drug administration.
9.
Subject agrees not to participate in another interventional study while on treatment.


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*Highly effective forms of birth control include:
Consistent and correct usage of established oral contraception.
Established 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 (for regions 
where spermicidal foam/gel/film/cream/suppository is not available, e.g., Japan)
Calendar-based contraceptive methods (Knaus-Ogino or rhythm method applicable 
to subjects enrolled at sites in Japan).
Waivers to the inclusion criteria will NOT be allowed.
3.3
Exclusion Criteria
Subject will be excluded from participation if any of the following apply:
1.
Subject requires treatment with concomitant drugs that are strong inducers of 
cytochrome P450 (CYP)3A.
2.
Subject requires treatment with concomitant drugs that target serotonin 5-
hydroxytryptamine receptor 1 (5HT1R) or 5-hydroxytryptamine receptor 2B (5HT2BR) or 
sigma nonspecific receptor with the exception of drugs that are considered absolutely 
essential for the care of the subject.
3.
Subject requires treatment with concomitant drugs that are strong inhibitors or inducers 
of P-glycoprotein (P-gp) with the exception of drugs that are considered absolutely 
essential for the care of the subject.  
Waivers to the exclusion criteria will NOT be allowed.
4
TREATMENT(S)
4.1
Identification of Investigational Products
4.1.1
Test Drug
ASP2215 tablets contain 40 mg of active ingredient. The tablets are contained within the 
high-density polyethylene bottle.
There will be a total of 30 tablets per bottle. The study centers will be provided bottles of 
ASP2215 each containing 30 tablets. The study site personnel will fill out the label to indicate 
the dispensing date, subject's ASP2215 dose and the corresponding number of tablets that need 
to be taken each day. The ASP2215 40 mg tablet product information is listed in [Table 2].


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Table 2
Test Drug (ASP2215 Tablets 40 mg)
Test drug
ASP2215 Tablets 40 mg
Code name
ASP2215
Active ingredient
Chemical name: C29H44N8O3•1/2 C4H4O4
Composition and 
dosage form
One tablet contains 40 mg of ASP2215 in free form.
ASP2215 Tablets are round light-yellow film-coated tablets.
Lot No.
Described in separately prepared “Study Drug Handling Procedures”
Storage
Bottled ASP2215 should be stored at a 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). Store in original 
container.
4.2
Packaging and Labeling
ASP2215 used in this study will be prepared, packaged and labeled under the responsibility 
of qualified staff at Astellas Pharma Global Development, Inc. (APGD)-Astellas United 
States Technologies (AUST) or Sponsor’s designee in accordance with APGD-AUST or 
Sponsor’s designee Standard Operating Procedures (SOPs), Good Manufacturing Practice 
guidelines, International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP)
guidelines and applicable local laws/regulations.
Each bottle will bear a label conforming to regulatory guidelines, Good Manufacturing 
Practice and local laws and regulations which identifies the contents as investigational drug.
A qualified person of Astellas Pharma Europe B.V. or Sponsor’s designee will perform the 
final release of the medication according to Directive 2003/94/EC annex 13.
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 standard procedures for the 
alternative disposition of unused study drug are followed.
Drug inventory and accountability records for the study drugs will be kept by the investigator, 
head of study site (specific to Japan), or designee. Study drug accountability throughout the 
study must be documented and reconciled. 


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The following guidelines are therefore pertinent:
●
The investigator, or designee agrees not to supply study drug(s) to any persons except the 
eligible subjects in this study in accordance with the protocol.
●
The investigator, head of study site (specific to Japan) or designee will keep the study drugs 
in a pharmacy or other locked and secure storage facility under controlled storage conditions, 
accessible only to those authorized by the investigator to dispense these study drugs.
●
A study drug inventory will be maintained by the investigator or designee. The inventory 
will include details of material received and a clear record of when they were dispensed 
and to which subject.
●
At the conclusion or termination of this study, the investigator, head of study site 
(specific to Japan) 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 unused study drug ASP2215 supplied by Sponsor back to the 
Sponsor or designee at the end of the study or upon expiration.
Specific to Japan
In Japan, the head of the study site or the study drug storage manager should take 
accountability of the study drugs as follows:
●
The study drug storage manager should store and take accountability of the study drugs 
in conforming to the procedures for handling the study drugs written by the Sponsor.
●
The study drug storage manager should prepare and retain records of the study drug's 
receipt, the inventory at the study site, the use by each subject and the return to the 
Sponsor or alternative disposal of unused study drugs. These records should include 
dates, quantities, batch/serial numbers, expiration dates (if applicable) and the unique 
code numbers assigned to the study drugs and subjects.
●
The study drug storage manager should prepare and retain records that document 
adequately that the subjects were provided the doses specified by the protocol and 
reconcile all the study drugs supplied from the Sponsor.
4.4
Blinding
This section is not applicable as this is an open-label study.
4.5
Assignment and Allocation
Subject assignment will be performed via Interactive Response Technology (IRT).  Prior to 
the initiation of the study treatment, the site staff will contact the IRT in order to assign the 
subject to treatment.  Specific procedures for assignment and registration through the IRT are 
contained in the study procedures manual.


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5
TREATMENTS AND EVALUATION
5.1
Dosing and Administration of Study Drugs and Other Medications
5.1.1
Dose/Dose Regimen and Administration Period
ASP2215 is an oral tablet that subjects will take once daily without food in continuous 28-day 
cycles. Subjects will be instructed to take the assigned daily dose with water as close to the 
same time each morning as possible. ASP2215 can be taken at least 2 hours after or 1 hour 
before food. 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 within 6 hours of the planned 
dosing time, they should be instructed to take their dose. If the subject forgets to take their 
daily dose and more than 6 hours has passed the planned dosing time, they should be instructed 
to wait for the next morning to dose. If vomiting occurs after dosing, the subject should not 
receive another dose, but just wait until the next morning to dose.
ASP2215 will be given daily in continuous 28-day cycles. A subject will receive the 
corresponding number of bottles to cover 2 cycles of dosing (plus allowable window) at their 
dose level. For example, a subject taking 120 mg per day would be dispensed 7 bottles of 
ASP2215.  
Treatment should continue until the subject no longer receives clinical benefit from therapy 
in the opinion of the Investigator, until unacceptable toxicity occurs, or the subject meets a 
treatment discontinuation criterion.
5.1.2
Escalation or Reduction in Dose of the Study Drug
Guidelines for ASP2215 dose reduction for nonhematological events are provided in Table 4.
The Investigator may also dose reduce ASP2215 based on clinical assessment.
ASP2215 dose reduction is to follow a step-wise manner, as outlined in Table 3  After the 
initial dose reduction, one additional dose reduction may occur. If no further dose reductions 
are available, study treatment will be discontinued.
Table 3
Dose Levels
Subject Dose level
Dose Reduction Dose Level
280 mg
200 mg
200 mg
120 mg
120 mg
80 mg
80 mg
40 mg
40 mg
Study treatment discontinued


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Table 4
Guidelines for ASP2215 Dose Reduction Event
ASP2215 Dosing Instructions
Event
Action
Nonhematological Events
Grade 3 at least possibly 
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 related to ASP2215
Treatment will be discontinued.
AE: adverse event
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 electronic case report form (eCRF).
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 that are considered absolutely essential for the care 
of the subject. Treatment with concomitant drugs that are strong inhibitors of CYP3A should 
be avoided, with the exception of antibiotics, antifungals and antivirals that are used as 
standard of care to prevent or treat infections. If CYP3A inhibitors are used concomitantly, 
subjects should be closely monitored for AEs.
Precaution should be used in use of ASP2215 with concomitant drugs that are known to 
prolong QT or QTc intervals.
Precaution should be used in use of ASP2215 with concomitant drugs that are substrates of 
BCRP, since the transporter has been shown to be inhibited by ASP2215 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 in 
[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].


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5.1.4
Treatment Compliance
Study subjects should be counseled on the need to meet 100% compliance with study drug.  
Investigator or designee should ensure that study subjects meet this goal throughout the study 
period. Compliance will be verified by the accounting of study drug at each visit after 
baseline. When study drug is administered at the research facility, it will be administered 
under the supervision of study personnel.
Compliance of the study drug will be monitored by the accounting of unused medication 
returned by the subject at visits. Compliance will be documented.
The dose and schedule of ASP2215 administered to each subject will be recorded at every 
visit. Reasons for dose delay, reduction or omission will also be recorded. This information, 
plus tablet accountability for ASP2215 at every visit 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 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 for the subject will be obtained from the original study.
5.2.2
Medical History
Medical history data for the subject will be obtained from the original study.
5.2.3
Diagnosis of the Target Disease, Severity and Duration of Disease
Medical history of the target disease for the subject that was studied in the original protocol 
will be obtained from the original study.
5.2.4
Performance Status
The ECOG Scale [Oken et al, 1982] will be used to assess performance status [Table 5].


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Table 5
ECOG Performance Status
Grade
Description
0
Fully active, able to carry on all predisease performance without restriction.
1
Restricted in physically strenuous activity, but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, office work.
2
Ambulatory and capable of all self-care, but unable to carry out any work activities. Up 
and about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
5
Dead.
ECOG: Eastern Cooperative Oncology Group
5.3
Efficacy Assessment
Not applicable
5.4
Safety Assessment
5.4.1
Vital Signs
Vital signs, including systolic and diastolic blood pressures (mm Hg), 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 Treatment Cycle 1 Day 1 are noted, the 
changes will be documented as AEs on the AE 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
AE collection continues from the original study until the End of Treatment visit, 30 days after 
last dose or until start of a new anticancer therapy, whichever is sooner. AEs occurring during 
the original study will continued to be followed as AEs in the current study.  AEs will be 
documented at each clinic visit, but can be collected at any time. Any AE that meets the 
definition of a serious adverse event (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 AE collection and data handling.  
5.4.2.1 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 


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receiving study drug is accompanied by increases in liver function tests (LFTs) [e.g., AST, 
ALT, total bilirubin (TBL), etc.] or is suspected to be due to hepatic dysfunction.
Subjects with AEs of hepatic origin accompanied by LFT abnormalities should be carefully 
monitored.
5.4.3
Laboratory Assessments
The below table contains the laboratory tests that will be performed locally during the conduct 
of the study. Refer to the Schedule of Assessments for study visit collection days. 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.
Clinical significance of out-of-range laboratory findings is to be determined and documented 
by the Investigator/sub-Investigator who is a qualified physician.
Panel/ Assessment
Parameters to be Analyzed
Hematology
White Blood Cell Count
White Blood Cell Differential
Red Blood Cell Count
Hemoglobin
Hematocrit
Mean Corpuscular Volume
Platelet Count
Mean Corpuscular Hemoglobin 
Concentration
Mean Corpuscular Hemoglobin
Chemistry
Sodium
Potassium
Chloride
Bicarbonate
Blood Urea Nitrogen
Creatinine
Glucose
Calcium
Phosphate
Magnesium
Albumin
Total Protein
Alkaline Phosphatase
Lactate Dehydrogenase
Creatine Phosphokinase
Liver Function Tests including:
Total Bilirubin
Alanine Aminotransferase
Aspartate Aminotransferase
Serum Pregnancy Test
Human Chorionic Gonadotropin
Coagulation Profile 
(PT/INR) 
INR (with PT if reported)
aPTT
Table continued on next page


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Panel/ Assessment
Parameters to be Analyzed
Urinalysis
Color
Appearance
Specific Gravity
pH
Bilirubin
Blood
Glucose
Ketones
Leukocyte Esterase
Nitrite
Protein
Urobilinogen
aPTT: activated partial thromboplastin time; INR: international normalization ratio; PT: prothrombin time
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 exams 
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 and weight; height will be obtained from the original 
study. If clinically significant worsening of findings from Treatment Cycle 1 Day 1 is noted at 
any study visit, the changes will be documented as AEs on the AE page of the eCRF.  Clinical 
significance is defined as any variation in physical findings, which has medical relevance that 
could result in an alteration in medical care. The Investigator will continue to monitor the 
subject until the parameter returns to ≤ grade 1 or to the baseline (pretreatment) condition or 
until the Investigator determines that follow up is no longer medically necessary.
5.5
Adverse Events and Other Safety Aspects
5.5.1
Definition of Adverse Events
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. 
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 eCRF accordingly.
An abnormality identified during a medical test [e.g., laboratory parameter, vital sign, 
electrocardiogram (ECG) data, physical exam] should be defined as an AE only if the 
abnormality meets 1 of the following criteria:
●
Induces clinical signs or symptoms
●
Requires active intervention


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●
Requires interruption or discontinuation of study medication
●
The abnormality or investigational value is clinically significant in the opinion of the 
Investigator
5.5.2
Definition of Serious Adverse Events
An AE is considered “serious” if, in the view of either the Investigator or Sponsor, it results 
in any of the following outcomes:
●
Results in death
●
Is life threatening (an AE is considered “life-threatening” if, in the view of either the 
Investigator or Sponsor, its occurrence places the subject at immediate risk of death.  It 
does not include an AE that, had it occurred in a more severe form, might have caused 
death)
●
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions
●
Results in congenital anomaly or birth defect
●
Requires in-subject 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 1 of the other outcomes listed in the definition 
above.  These events, including those that may result in disability/incapacity, 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 and 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 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 AE is reported 
that is considered to be an event per this classification as “always serious,” additional information 
on the event may be requested.


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5.5.3
Criteria for Causal Relationship to the Study Drug
AEs that fall under either "Possible" or "Probable" should be defined as "AE 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 readministration (rechallenge) or 
withdrawal (dechallenge).
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)-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 adverse event
5.5.5
Reporting of Serious Adverse Events
SAE collection will continue in the original study through the End of Treatment visit, 30 days 
after last dose of study medication, or until start of a new anticancer therapy, whichever is 
sooner. Any ongoing SAE will be captured in the 2215-CL-0109 study. In the case of an
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 Contract Research 
Organization (CRO) by fax immediately (within 24 hours of awareness). If the faxing of an 


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SAE Worksheet is not possible or is not possible within 24 hours, the local drug safety 
contact should be informed by phone.  
SPECIFIC to Investigational sites in Japan: 
In the case of a SAE, the Investigator or sub-Investigator must report to the head of the study 
site and must contact the Sponsor by telephone or fax immediately (within 24 hours of 
awareness).
The Investigator should complete and submit JUTOKUNA YUUGAIJISHOU HOUKOKUSHO 
containing all information that is required by the Regulatory Authorities to the Sponsor by 
fax immediately (within 24 hours of awareness) and to the head of the hospital. If the faxing 
of JUTOKUNA YUUGAIJISHOU HOUKOKUSHO is not possible or is not possible within 
24 hours, the Sponsor should be informed by phone.
For contact details, see Section II Contact Details of Key Sponsor's Personnel.  Please fax or 
email the SAE Worksheet to:
Astellas Pharma Global Development
Global Pharmacovigilance
North American Fax: 888-396-3750
(North America Alternate Fax: 847-317-1241)
International Fax: +44-800-471-5263
Email: safety-us@astellas.com
SPECIFIC to Investigational sites in Japan: 
JUTOKUNA YUUGAIJISHOU HOUKOKUSHO the SAE Worksheet to:
Astellas Pharma Inc.-Japan
APGD-JP Clinical Development,
Fax: +81-0-3243-5737
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 (see 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.
The following minimum information is required:
●
International study number/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.


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The Sponsor or Sponsor's designee will submit expedited safety reports (i.e., investigational 
new drug [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 IRB/IEC within timelines set by regional regulations (i.e., European 
Union, (e)Common Technical Document, 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 
IRB/IEC/head of the study site.
The heads of the study sites/Investigators should provide written documentation of IRB/IEC 
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 AE 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.
5.5.7
Monitoring of Common Serious Adverse Events
Common SAEs are SAEs commonly anticipated to occur in the study population independent 
of drug exposure. SAEs classified as “common” are provided in Appendix 12.3 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 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 180 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 


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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.
SPECIFIC to Investigational sites in Japan:
1.
When information is obtained regarding serious and unexpected adverse drug reactions 
(or other) that are specified in Article 273 of the Act on Securing Quality, Efficacy and 
Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy 
Products, Gene Therapy Products, and Cosmetics, in compliance with Article 80-2 
Paragraph 6 of the Pharmaceutical Affairs Law, the Sponsor should inform all the 
Investigators involved in the clinical study, the head of the study site and the regulatory 
authorities of such information. The head of the study site who receives such information 
will decide whether the clinical study should be continued after hearing the opinions of 


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the IRB. The Investigator will supply the new information to the subjects, in compliance 
with Section 8.2.3.2 Supply of New and Important Information Influencing the Subject’s 
Consent and Revision of Written Information.
2.
In addition to the above item (1), when the head of the study site receives the revisions of 
the Investigator’s Brochure, protocol or written information, information on the matters 
covering the quality of the study drug, efficacy and safety, information necessary for 
conducting the clinical study properly or documents to be examined by the IRB should 
be sent to the IRB.
5.5.11
Deviations from the Protocol and Other Actions Taken to Avoid Life-threatening
Risks to Subjects (Specific to sites in Japan Only)
The Investigator must not deviate from or amend the protocol, excluding an emergency case 
for avoiding risks to the subjects. When the Investigator does not follow the protocol in order 
to avoid urgent risks for subjects, the Investigator should take the following actions.
1.
Describe the contents of the deviation or amendment and the reasons for it in a written 
notice and immediately send the document stating the deviation or amendment and the 
reasons to the Sponsor and the head of the study site. Keep a copy of the notice.
2.
Consult with the Sponsor at the earliest possibility for cases in which it is necessary to 
amend the protocol. Obtain approval for a draft of the amended protocol from the IRB 
and the head of the study site as well as written approval from the Sponsor.
5.6
Test Drug Concentration
Not applicable.
5.7
Other Measurements, Assessments or Methods
Not applicable.
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. The amount of blood collected at each clinic visit is 
approximately 15 mL.
At any time during the study, if any laboratory abnormalities are found for a subject
additional blood may be drawn for monitoring.


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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 AE or an unresolved laboratory 
result that is significantly outside of the reference range, the Investigator will attempt to 
provide follow-up until the condition stabilizes or no longer is clinically significant.
Discontinuation Criteria from Treatment for Individual Subjects:
●
Subject declines further study participation (i.e., withdrawal of consent).
●
Subject develops an intolerable or unacceptable toxicity.
●
Investigator/sub-Investigator determines the subject is no longer receiving clinical 
benefit from study treatment.
●
Investigator/sub-Investigator determines that the continuation of the study treatment will 
be detrimental to the subject.
●
Female subject becomes pregnant.
●
Subject is lost to follow-up despite reasonable efforts by the Investigator to locate the 
subject.
●
Death.
6.2
Discontinuation of the Site
If an Investigator intends to discontinue participation in the study, the Investigator must
immediately inform the Sponsor (specific to sites in Japan: and the head of the Study site).
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-United 
States. A Statistical Analysis Plan (SAP) will be written to provide details of the analysis, 
along with specifications for tables, listings and figures (TLFs) to be produced. The SAP will 
be finalized before the database soft lock at the latest. Any changes from the analyses 
planned in SAP will be justified in the Clinical Study Report.
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 for this study is based on the number of subjects who are continuing to 
derive benefit from treatment with ASP2215 as assessed by their Investigator at the 
completion of the original study they enrolled under.
7.2
Analysis Sets
Detailed criteria for analysis sets will be laid out in Classification Specifications and the 
allocation of subjects to analysis sets will be determined prior to database hard-lock.
7.2.1
Full Analysis Set
No efficacy analysis is planned for this study.
7.2.2
Per Protocol Set
No efficacy analysis is planned for this study.
7.2.3
Safety Analysis Set
For the statistical summary of the safety data, the SAF will be used.  The SAF consists of all 
subjects who took at least 1 dose of study medication (ASP2215) and will be used for safety 
analyses.  
7.2.4
Pharmacokinetic Analysis Set
No pharmacokinetic analysis is planned for this study.
7.3
Demographics and Other Baseline Characteristics
7.3.1
Demographics
Descriptive summary statistics will be produced for all parameters.


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7.3.2
Medical History
A detailed medical history for each subject will be obtained during Screening of the prior 
study and will be summarized by treatment group for the SAF.
7.3.3
Disease History
Each subject’s complete cancer history will be listed.  
7.3.4
Previous and Concomitant Medications
The frequency of concomitant medications (prescription, over-the-counter and nutritional 
supplements) will be summarized by treatment group and preferred term (PT) for SAF.  
Medications will be coded using the World Health Organization (WHO) drug dictionary.  
Medications will be counted by the number of subjects who took each medication. A subject 
taking the same medication multiple times will only be counted once for that medication.  
Medications will be presented in decreasing order of frequency based on the total number of 
subjects who took each medication.
7.3.5
Subject Disposition
The number and percentage of all subjects during the study will be reported per treatment 
group, study drug administration, subject completion, premature discontinuation and major 
protocol violations.
7.3.6
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 dose for the 
entire study period for the SAF by treatment group.
7.3.7
Extent of Exposure
Exposure to treatment, measured by the duration of treatment in number of days will be 
summarized by treatment group 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 – number of days without 
drug administration in between). The total dose administered, number and proportion of 
subjects with dose reduction, dose escalation and dose interruption will be tabulated.
7.4
Analysis of Efficacy 
No efficacy analysis is planned for this study.
7.5
Analysis of Safety
The safety evaluation will be based on AEs and clinical laboratory assessments. Descriptive 
statistics will be used to summarize safety data. All safety data will be performed on the SAF.


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7.5.1
Adverse Events
All AEs recorded on treatment including within 30 days from the last study treatment will be 
summarized. AEs will be coded to SOC and PT using MedDRA and will be graded according 
to the NCI-CTCAE version 4.03.
The number and percent of subjects experiencing 1 or more AE(s) will be summarized by 
treatment group, SOC and PT. The number and percentage of subjects with at least 1 grade 3 
or higher AE will be summarized by treatment group, SOC and PT.
Distribution of the maximum severity (grade) and treatment-related AEs will be summarized 
by treatment group, SOC and PT. Distribution of SAEs, discontinuations due to AE and
deaths on study will be presented for each treatment group.
Additional summary tables will be generated for the following population subsets: subjects 
with SAEs including deaths, subjects who discontinue due to AEs and Investigator-attributed 
relationship to study drug for AEs and SAEs.
All summaries of AEs will include only treatment-emergent events unless otherwise stated.  
Listings of AEs, SAEs, deaths and withdrawals due to AEs will be presented.
7.5.2
Laboratory Assessments 
Clinical laboratory evaluations (including hematology, urinalysis, 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.
7.5.3
Vital Signs
Descriptive statistics will be used to summarize vital sign results and changes from baseline 
by treatment group and time.
7.5.4
Physical Examination 
Physical examination will be listed by treatment group. All clinically significant abnormal
findings will be recorded as medical history or AEs and graded using NCI-CTCAE 
guidelines.
7.5.5
Ophthalmologic Assessment
Ophthalmologic variables will be summarized by treatment group at the end of treatment for 
each eye.
7.5.6
ECOG Performance Scores
ECOG performance scores will be summarized by treatment group and visit.


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7.5.7
Pregnancy Test
Pregnancy test result for women of childbearing potential will be displayed in a listing.
7.6
Analysis of Pharmacokinetics
No pharmacokinetic analysis is planned for this study.
7.7
Protocol Deviations
Protocol deviations (PDs) as defined in Section 8.1.6 Protocol Deviations will be summarized 
for all registered subjects by treatment group and total as well as by site. A data listing will be 
provided by site and subject. 
The PD 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
7.8
Interim Analysis (and Early Discontinuation of the Clinical Study)
No formal interim analysis is planned.
7.9
Handling of Missing Data, Outliers, Visit Windows and Other 
Information
Imputation methods for missing data, if applicable, and the definitions for windows to be 
used for analyses by visit will be outlined in the SAP.
8
OPERATIONAL 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 
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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For screen failures, the minimum demographic data (i.e., sex, age, informed consent date) 
and reason for screen failure will be collected in the eCRF and screen failure log if 
applicable.
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 (ICFs)
●
Visit dates
●
Medical history and physical examination details
●
Key efficacy and safety data, if applicable (as specified in the protocol)
●
AEs 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 
(refer to Section 8.1.2 Specification of Source Documents) when they are requested by the 
Sponsor monitors and auditors, the IRB/IEC or regulatory authorities. The confidentiality of 
the subject's identities shall be well protected consistent with local and national regulations 
when the source documents are subject to direct access.


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8.1.5
Data Management
Data Management will be coordinated by the Global Data Science department of the Sponsor 
in accordance with the SOPs for data management. All study specific processes and 
definitions will be documented by Data Management. (e)CRF completion will be described 
in the (e)CRF instructions. Coding of medical terms and medications will be performed using 
MedDRA and WHO Drug Dictionary respectively.
8.1.6
Protocol Deviations
A PD 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.
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.


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8.2
Ethics and Protection of Subject Confidentiality
8.2.1
Institutional Review Board/Independent Ethics Committee/Competent 
Authorities
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 SAE 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 1 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 Astellas Pharma Europe 
B.V./Astellas Pharma Europe Ltd.-sponsored studies within 1 year after last subject out 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.  
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 (specific to sites in Japan, place a personal 
seal) 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 (specific to sites in Japan, or sealed) ICF will be given to the subject 
and the original will be placed in the subject’s medical record. An entry must also be made in 


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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.
3.
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 reconsent subjects with the updated ICF even if relevant 
information was provided orally. The Investigator or his/her representative who obtained 
the written informed consent and the subject should sign and date the ICF (specific to 
sites in Japan, place a personal seal). A copy of the signed (specific to sites in Japan, 
sealed) ICF will be given to the subject and the original will be placed in the subject’s 
medical record. An entry must be made in the subject’s records documenting the 
reconsent 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.
All individuals and organizations involved in the study must pay very careful attention to 
protect subjects’ privacy with appropriate measures, for example, by prohibiting the use of 
any private information that may identify a subject (e.g., name or address). These details shall 
be processed in accordance with the applicable local and regional laws.
Even though any individuals involved in the study, including the study monitors and auditors, 
may get to know matters related to subject's privacy due to direct access to source documents, 
or from other sources, they may not leak the content to third parties.
The Sponsor affirms the subject's right to protection against invasion of privacy. Only a 
subject identification number and/or initials will identify subject data retrieved by the 


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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 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 Sponsor will provide the investigator and/or institution with the following:
●
Study protocol (and amendments, where applicable)
●
Investigator’s Brochure (and amendments, where applicable)
●
CRFs 
●
JUTOKUNA YUUGAIJISHOU HOUKOKUSHO (specific to Investigational sites in 
Japan)
●
Study drug with all necessary documentation
●
Study contract
In order to start the study, the investigator and/or study site is required to provide the 
following documentation to the Sponsor: 
Financial disclosure in compliance with federal regulation 21CFR Part 54
●
Signed and dated FDA form 1572, if conducted under a U.S. IND
●
Signed Investigator's Statement in this protocol and CRF
●
Current Curricula Vitae of all investigators
●
List of sub-investigators and collaborators 
●
IRB approval of the protocol, protocol amendments (if applicable) including a 
membership list with names and qualification (COPY)
●
Instruction and decision of the head of the study site (specific to sites in Japan)


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●
Study contract
●
Laboratory normal reference ranges (if applicable, signed and dated by the responsible 
laboratory employee)
At the end of the study, the sponsor is responsible for the collection of:
●
Unused CRFs and other study documentation,
●
Unused study drug
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 United States sites, 2 years 
after approval of the New Drug Application (NDA) or discontinuation of the IND).  The 
Sponsor will notify the site/Investigator if the NDA/Marketing Authorisation Application/
J-NDA is approved or if the IND/Investigational Medicinal Product Dossier/CHIKEN 
TODOKE 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.
SPECIFIC to Investigational Sites in Japan:
The records to be retained at the study sites are the ones listed as essential documents in GCP.  
These records shall be retained by the head of the study site or the record keeper designated 
by the head until notice issued by the Sponsor on completion of the retention period is 
received. These documents are also subject to direct access and should be provided upon 
request from the Sponsor or regulatory authorities.
The head of the study site will retain the essential documents that should be stored at the 
study site in an appropriate manner according to the rules of the study site concerned until the 
date defined in 1. or 2. below, whichever comes later.
1.
Approval date of marketing of the test drug (if development of the drug is stopped, until 
3 years after the decision to discontinue development is notified)
2.
Until 3 years after discontinuation or termination of the study.
The following are the major documents to be retained at the study site.
1.
Source documents (clinical data, documents and records for preparing the CRF) hospital 
records, medical records, test records, memoranda, administration records, data recorded 
by automatic measuring instruments, reproductions or transcripts verified as precise 
copies, microfiche, negative films, microfilms/magnetic media, X-ray films, subject files 
and study-related records kept at either a pharmacy, a laboratory or medical technical 


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office, as well as subject registration forms, laboratory test slips including central 
measurement, worksheets specified by the Sponsor, records of clinical coordinators and 
records related to the clinical study selected from those verified in other departments or 
hospitals.
2.
Contracts, written ICFs, written information and other documents or their copies 
prepared by the study personnel.  A letter of request for clinical study (including a 
request for continuation/amendment), letter of request for review, notice of clinical study 
contract, clinical study contract, notification of discontinuation or completion of clinical 
study, written information for informed consent (including revisions), signed and dated 
written informed consent (including revisions), Curriculum Vitaes of Investigators, list 
of sub-Investigators, list of signatures and print of seals (copy) and CRFs (copy), etc.
3.
The protocol, documents obtained from the IRB related to the adequacy of conducting 
the clinical study by the head of the study sites (Article 32-1, MHW Ordinance No. 28), 
documents obtained from the IRB related to the adequacy of conducting a clinical study 
whose period exceeds 1 year or the adequacy of continuously conducting the clinical 
study from which information on adverse drug reactions is obtained and other documents 
obtained. An agreed-upon protocol (including revisions), Investigator's Brochure 
(including revisions), operational procedures for the Investigator, materials and 
information supplied by the Sponsor (e.g., AE report), matters reported by the 
Investigator (revisions of the protocol, AE reports, etc.), operational procedures for the 
IRB, the list of names of the IRB members, materials for IRB review (including 
continuous deliberation), IRB review records (including continuous deliberation) and the 
review result report of the IRB (including continuous deliberation), etc.
4.
Records of control for study drugs and other duties related to the clinical study.  
Procedure for controlling the study drugs, drug inventory and accountability record, 
vouchers for the receipt and return of the study drugs and the prescriptions for 
concomitant medications
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 nonsubstantial amendments.  
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)
followed by the approval of the head of the study site (specific to sites in Japan).  
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.


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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
Insurance of Subjects and Others
The Sponsor has covered this study by means of an insurance of the study according to 
national requirements. The name and address of the relevant insurance company, the 
certificate of insurance, the policy number and the sum insured are provided in the 
Investigator's File.
SPECIFIC to Investigational Sites in Japan:
If a subject suffers any study-related injury, the Sponsor will compensate appropriately 
according to the severity and duration of the damage. However, if it was caused intentionally 
or was due to gross negligence by the study site, the Sponsor will consult with the study site 
about handling the injury, based on the agreed study contract. Compensation for the 
study-related injury is provided by the following procedures:
1.
If a subject incurs an injury as a result of participation in the clinical study, the study site 
should provide medical treatment and other necessary measures. The Sponsor should be 
notified of the injury.
2.
When the subject claims compensation from the study site for the above study-related 
injury, or such compensation may be claimed, the study site should immediately 
communicate the fact to the Sponsor. Both parties should work together towards 
compensation settlement.
3.
The Sponsor shall pay compensation or indemnification and bear expenses necessary for 
the settlement as provided in the clinical contract.
4.
The Sponsor shall make an arranging for insurance and take measures necessary to 
ensure the compensation or indemnification mentioned above.
8.3.5
Signatory Investigator for Clinical Study Report
ICH E3 guidelines recommend and European Union Directive 2001/83/EC requires that a 
final study report which forms part of a Marketing Authorization Application be signed by 
the representative for the Coordinating Investigator(s) or the Principal Investigator(s).  The 
representative for the Coordinating Investigator (s) or the Principal Investigator(s) will have 
the responsibility to review the final study results to confirm to the best of his/her knowledge 
it accurately describes the conduct and results of the study.  The representative for
Coordinating Investigator(s) or the Principal Investigator(s) will be selected from the 
participating Investigators by the Sponsor prior to database lock.


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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, CRFs and source documents. Direct access to these documents will be required 
by the auditors. 
10
STUDY ORGANIZATION
10.1
Independent Data Monitoring Committee
Not applicable.
10.2
Other Study Organization
Not applicable.
10.3
Registration of Subjects (Specific to Japan)
The Investigator will fill in the subject registration forms to reconfirm whether the candidate 
subjects are eligible. The Sponsor should obtain the information on candidate subjects to be 
included in the clinical study from subject registration forms before administration to confirm 
their eligibility, and to inform the Investigator of the results. 
In the situation of rapidly proliferative disease which is acute or requires immediate-treatment, 
it is difficult for the Sponsor to confirm the eligibility of the candidate subjects prior to starting 
the study.  Confirmation should be made instantly for the eligibility of the candidates by 
referring to the subject’s registration forms obtained after the start of administration.
Prevention system in IRT will be constructed to check duplicative registration from minimum 
information (each birth date and gender of subjects).
In case IRT system points out a possibility as duplicative registration, clinical research 
monitor must check whether or not the registration is duplicative. 
Investigators and Clinical Research Coordinators in each site can check directly with subjects 
whether or not the registration is duplicative.


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11
REFERENCES 
Astellas Pharma, ASP2215 Investigator’s Brochure Global Edition 3; 24 February 2015.
Astellas Pharma, ASP2215 Investigator’s Brochure Global Edition 3; 24 February 2015 & Addendum 
to ASP2215 Investigator’s Brochure Global Edition 3, dated 20 Apr 2015.
Camidge DR, Doebele RC. Treating ALK-positive lung cancer--early successes and future 
challenges. Nat Rev Clin Oncol. 2012;9:268-77.
Chia PL, Mitchell P, Dobrovic A, John T. Prevalence and natural history of ALK positive 
non-small-cell lung cancer and the clinical impact of targeted therapy with ALK inhibitors. 
Clin Epidemiol. 2014;6:423-32.
Gale RE, Green C, Allen C, Mead AJ, Burnett AK, Hills RK, et al. The impact of FLT3 internal 
tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large 
cohort of young adult patients with acute myeloid leukemia. Blood. 2008;111:2776-84.
Moreno I, Martín G, Bolufer P, Barragán E, Rueda E, Román J, et al. Incidence and prognostic value 
of FLT3 internal tandem duplication and D835 mutations in acute myeloid leukemia.
Haematologica. 2003;88:19-24.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response 
criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-55.
Patel JP, Gönen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J, et al. Prognostic relevance of 
integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366:1079-89.
Schlenk RF, Döhner K. Impact of new prognostic markers in treatment decisions in acute myeloid 
leukemia. Curr Opin Hematol. 2009;16:98-104.
Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, et al. Identification of the 
transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448:561-6.
Yamamoto Y, Kiyoi H, Nakano Y, Suzuki R, Kodera Y, Miyawaki S, et al. Activating mutation of 
D835 within the activation loop of FLT3 in human hematologic malignancies. Blood. 
2001;97:2434-9.
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;19:1345-9.
Yonezawa A, Inui K. Importance of the multidrug and toxin extrusion MATE/SLC47A family to 
pharmacokinetics, pharmacodynamics/toxicodynamics and pharmacogenomics. Br J 
Pharmacol. 2011;164:1817-25.
Zhang Z, Lee JC, Lin L, Olivas V, Au V, LaFramboise T, et al. Activation of the AXL kinase causes 
resistance to EGFR-targeted therapy in lung cancer. Nat Genet. 2012;44:852-60.


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12
APPENDICES
12.1
List of Excluded and Cautionary Concomitant Medications
The following list describes medications and foods that are common strong inhibitors of 
CYP3A. This list should not be considered all inclusive. Consult individual drug labels for 
specific information on a compound’s propensity to inhibit CYP3A.
Strong CYP3A Inhibitors
Drug Type
Generic Drug Name
Human Immunodeficiency Virus Protease 
Inhibitors
Lopinavir
Indinavir
Nelfinavir
Ritonavir
Saquinavir
Food/Juice
grapefruit juice
Others
Boceprevir
Conivaptan
Posaconazole
Telaprevir
Telithromycin
VoriconazoleClarithromycin
Itraconazole
Ketoconazole
Nefazodone
Source: Table 3 in FDA Draft Guidance for Industry – Drug Interaction Studies – Study Design, Data Analysis, 
Implications for Dosing, and Recommendations (February 2012) 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm292362.pdf.
CYP: cytochrome P450.
Treatment with concomitant drugs that are strong inducers of CYP3A are prohibited. The 
following list describes medications and foods that are common strong inducers of CYP3A. 
This list should not be considered all inclusive. Consult individual drug labels for specific 
information on a compound’s propensity to induce CYP3A.
CYP3A Inducers
Drug Type
Generic Drug Name
Antiepileptic, Anticonvulsant
Carbamazepine
Phenytoin
Antibiotic
Rifabutin
Rifampicin
Rifapentine
Food/Juice Supplement
St. John’s wort
Source: Table 4 in FDA Draft Guidance for Industry – Drug Interaction Studies – Study Design, Data Analysis, 
Implications for Dosing, and Recommendations (February 2012) http://www.fda.gov/downloads/drugs/guidance
complianceregulatoryinformation/guidances/ucm292362.pdf.
CYP: cytochrome P450.


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The following list describes medications that target serotonin receptors.This list should not be 
considered all inclusive. Consult individual drug labels for specific information on whether a 
compound targets serotonin receptors.
Drugs Targeting Serotonin Receptors 
Drug Type
Generic Drug Name
Affinity or function to 5HT2BR
eletriptan hydrobromide
Affinity or function to 5HT1R
almotriptan malate 
aripiprazole 
avitriptan 
buspirone hydrochloride 
dihydroergotamine mesylate
droperidol 
eletriptan hydrobromide 
ergoloid mesylates 
ergonovine maleate 
ergotamine tartrate 
frovatriptan succinate 
haloperidol 
haloperidol decanoate
lesopitron 
methylergonovine maleate 
methylergotamine 
methysergide maleate 
naratriptan hydrochloride 
pizotifen 
quetiapine fumarate 
rizatriptan benzoate 
sumatriptan succinate 
tegaserod maleate 
thioridazine 
thioridazine hydrochloride 
ziprasidone hydrochloride 
ziprasidone mesylate 
zolmitriptan 
zotepine
5HT1R: 5-hydroxytryptamine receptor 1; 5HT2BR: 5-hydroxytryptamine receptor 2B
The following list describes medications and foods that are common inhibitors or inducers of 
P-gp. This list should not be considered all inclusive. Consult individual drug labels for 
specific information on a compound’s propensity to inhibit or induce P-gp.


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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,Carbamazep
ine, Phenytoin, 
Rifampin, 
St John’s wort, 
Tipranavir/ritonavir
P-gp: P-glycoprotein
Source: Table 12 in http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/
DrugInteractionsLabeling/ucm093664.htm#major
Drugs Targeting Sigma (nonspecific) Receptor (sigma R)
No list of drugs that target sigma nonspecific receptor is provided. Please consult individual 
drug labels for specific information on whether a compound targets sigma nonspecific 
receptors.
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
Table continued on next page


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Drug Type
Generic Drug Name
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
Azole antifungals 
Ketoconazole
Fluconazole
Itraconazole
Posaconazole
Voriconazole
Antimalarials
Amodiaquine
Atovaquone
Chloroquine
Doxycycline
Halofantrine
Mefloquine 
Proguanil
Primaquine
Pyrimethamine
Quinine
Sulphadoxine
Table continued on next page


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Drug Type
Generic Drug Name
Antiprotozoals
Pentamidine
Antiemetics
Droperidol
Dolasetron
Granisetron
Ondansetron
Antiestrogens
Tamoxifen
Immunosuppressants
Tacrolimus
Source: Yap 2003
Reference
Yap Y. Drug induced QT prolongation and torsades de pointes. Heart. 2003;89(11):1363-
1372.


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Version 2.1 Incorporating Non-Substantial Amendment 1 
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 to > 3 × upper limit of normal (ULN) (to > 5 × ULN in subjects with 
liver metastases) or TBL > 2 × ULN, should undergo detailed testing for liver enzymes 
(including at least ALT, AST, alkaline phosphatase [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
TBL
Moderate
> 3 x ULN (in subjects without liver 
metastases), > 5 x ULN (in subjects 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 metasteses)
●
ALT or AST > 3 × ULN and International normalization ratio (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) 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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Version 2.1 Incorporating Non-Substantial Amendment 1 
Severe hepatic liver function abnormalities as defined above, in the absence of another etiology 
may be considered an important medical event and may be reported as a SAE. The Sponsor 
should be contacted and informed of all subjects for whom severe hepatic liver function 
abnormalities possibly attributable to study drug are observed.
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 ‘AEs’ 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.  Nonalcoholic 
steatohepatitis is seen in obese hyperlipoproteinemic and/or diabetic subjects and may be 
associated with fluctuating aminotransferase levels. The Investigator should ensure that 
the medical history form captures any illness that predates study enrollment that may be 
relevant in assessing hepatic function. 
●
Obtain a history of concomitant drug use (including nonprescription medication, 
complementary and alternative medications), alcohol use, recreational drug use and
special diets. Medications, 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 LFTs, such as viral hepatitis, preexisting 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 metasteses)
●
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 subjects with liver metasteses)
●
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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Version 2.1 Incorporating Non-Substantial Amendment 1 
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 2 “requirements” for Hy’s Law are the following:
1.
Evidence that a drug can cause hepatocellular-type injury, generally shown by an 
increase in transaminase elevations higher than 3 × ULN (2 × ULN elevations are too 
common in treated and untreated subjects to be discriminating)
2.
Cases of increased TBL (at least 2 × ULN) with concurrent transaminase elevations at 
least 3 × ULN and no evidence of intra- or extra-hepatic bilirubin obstruction (elevated 
ALP) or Gilbert’s syndrome
Source: Temple R. Hy's law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug Saf. 
2006;15:241-3.
Reference
FDA. Guidance for industry-drug-induced liver injury: premarketing clinical evaluation. 2009.


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Version 2.1 Incorporating Non-Substantial Amendment 1 
12.3
Common Serious Adverse Events
The following is a list of SAEs that the Sponsor considers to be associated with the disease 
state being studied. The list does NOT change your reporting obligations or prevent the 
need to report an AE meeting the definition of an SAE as detailed in Section 5.5.2
Definition of Serious Adverse Events. The purpose of this list is to alert 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.
For IND safety reporting, single occurrences of the following events may be excluded from 
expedited reporting to the regulatory agencies. If aggregate analysis of these events indicate
they occur more frequently with study drug, an expedited IND safety report may be 
submitted to the regulatory agencies.
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
Table continued on next page


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Version 2.1 Incorporating Non-Substantial Amendment 1 
Serious Adverse Events Caused by AML
Grades Usually 
Observed with AML
Tumor lysis syndrome
3 - 5
Vasculitis
0 - 5
Vomiting
0 - 2
Weight loss
0 - 2
AE: adverse event; AML: acute myeloid leukemia; GVHD: graft-versus-host disease; INR: International 
normalization ratio
Serious Adverse Events from Advanced Solid Tumors
Grades
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
Diarrhea
0-2
Dyspnea
0-5
Fatigue
0-3
Flushing
0-2
Gamma-glutamyltransferase increased
0-1
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
Pruritus
0-3
Tumor Lysis Syndrome
3-5
Vasculitis
0-5
Vomiting
0-2
Weight loss
0-2


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Version 2.1 Incorporating Non-Substantial Amendment 1
13
ATTACHMENT 1:   NON-SUBSTANTIAL AMENDMENT 1
I.  The purpose of this amendment is:
Non-Substantial Changes
1.
Extend Planned Study Period
DESCRIPTION OF CHANGE: 
The planned study period is extended to 3Q2023.  
RATIONALE:
This study is a rollover study. Timelines for rollover is contingent on feeder study completion.  
The study timeline is being extended to accommodate potential future feeder studies. 
2.
Update Laboratory Assessments
DESCRIPTION OF CHANGE: 
Five chemistry parameters are removed from the list of required laboratory assessments.
RATIONALE:
Aldolase, triglycerides, total cholesterol, phospholipid and globulin laboratory assessments 
are not routinely performed at local laboratories. Removal of these laboratory parameters will 
not compromise subject safety monitoring and will streamline laboratory assessments that 
sites are able to complete through their local laboratory. 
3.
Minor Administrative-type Changes
DESCRIPTION OF CHANGE: 
Include minor administrative-type changes (e.g., typos, format, numbering and consistency 
throughout the protocol).  
RATIONALE:
To provide clarifications to the protocol and to ensure complete understanding of study 
procedures.
II.  Amendment Summary of Changes:
IV Synopsis, Planned Study Period
WAS:
From 3Q2015 to 1Q2019
IS AMENDED TO:
From 3Q2015 to 1Q20193Q2023


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5 Treatments and Evaluation
5.4.3 Laboratory Assessments
WAS:
Panel/ Assessment
Parameters to be Analyzed
Chemistry
Sodium
Potassium
Chloride
Bicarbonate
Blood Urea Nitrogen
Creatinine
Glucose
Calcium
Phosphate
Magnesium
Albumin
Total Protein
Alkaline Phosphatase
Lactate Dehydrogenase
Creatine Phosphokinase
Aldolase
Triglycerides
Total Cholesterol
Phospholipid
Globulin
Liver Function Tests including:
Total Bilirubin
Alanine Aminotransferase
Aspartate Aminotransferase
IS AMENDED TO:
Panel/ Assessment
Parameters to be Analyzed
Chemistry
Sodium
Potassium
Chloride
Bicarbonate
Blood Urea Nitrogen
Creatinine
Glucose
Calcium
Phosphate
Magnesium
Albumin
Total Protein
Alkaline Phosphatase
Lactate Dehydrogenase
Creatine Phosphokinase
Aldolase
Triglycerides
Total Cholesterol
Phospholipid
Globulin
Liver Function Tests including:
Total Bilirubin
Alanine Aminotransferase
Aspartate Aminotransferase
III.  Non-Substantial Amendment Rationale:
Rationale for Non-Substantial Designation
All revisions made to the protocol are administrative in nature and do not impact the safety or 
scientific value of the clinical study.


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Version 2.1 Incorporating Non-Substantial Amendment 1 
[GPF v4.1]
14
SPONSOR’S SIGNATURES

SAP_001.pdf: 
Sponsor: Astellas Pharma Inc.
SAP Final Version 2.0
ISN/Protocol 2215-CL-0109
17-June 2020
Astellas
Page 1 of 20
STATISTICAL ANALYSIS PLAN
Final Version 2.0, dated 17-June-2020
A Phase 1/2 Open-label Rollover Study for Subjects Who Have 
Participated in an Astellas Sponsored ASP2215 Trial
Protocol for Phase 1/2 Study of ASP2215
ISN: 2215-CL-0109
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.
NCT02561455


Sponsor: Astellas Pharma Inc.
SAP Final Version 2.0
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Astellas
Page 2 of 20
Table of Contents
I.
LIST OF ABBREVIATIONS AND KEY TERMS··········································· 4
1
INTRODUCTION·················································································· 6
2
SCHEDULE OF ASSESSMENTS ······························································ 7
3
STUDY OBJECTIVE(S) AND DESIGN······················································· 8
3.1
Study Objective(s) ············································································· 8
3.2
Study Design···················································································· 8
3.3
Randomization·················································································· 8
4
SAMPLE SIZE······················································································ 8
5
ANALYSIS SETS ·················································································· 8
5.1
Safety Analysis Set (SAF) ···································································· 9
6
ANALYSIS VARIABLES ········································································ 9
6.1
Efficacy Endpoints············································································· 9
6.2
Safety Variables ················································································ 9
6.3
Pharmacokinetic Variables···································································10
6.4
Pharmacodynamic Variables·································································10
6.5
Other Variables················································································10
7
STATISTICAL METHODOLOGY ···························································10
7.1
General Considerations·······································································10
7.2
Study Population ··············································································11
7.2.1
Disposition of Subjects ·································································11
7.2.2
Protocol Deviations ·····································································11
7.2.3
Demographic and Other Baseline Characteristics ···································11
7.2.4
Previous and Concomitant Medications ··············································12
7.2.5
Non-Medication Therapy·······························································12
7.3
Study Drugs····················································································12
7.3.1
Exposure··················································································12
7.3.2
Treatment Compliance··································································13
7.4
Analysis of Efficacy ··········································································13
7.5
Analysis of Safety·············································································13
7.5.1
Adverse Events ··········································································13
7.5.2
Clinical Laboratory Evaluation ························································14


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7.5.3
Vital Signs················································································16
7.5.4
Electrocardiograms (ECGs)····························································16
7.5.5
Pregnancies···············································································16
7.5.6
Ophthalmologic Assessment ·························································16
7.5.7
Other Safety-Related Observations ···················································17
7.6
Analysis of Pharmacokinetics ·······························································17
7.7
Analysis of Pharmacodynamics ·····························································17
7.8
Subgroups of Interest ·········································································17
7.9
Other Analyses ················································································17
7.10
Interim Analysis (and Early Discontinuation of the Clinical Study)····················17
7.11
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········17
7.11.1
Missing Data ·············································································17
7.11.2
Outliers ···················································································17
7.11.3
Visit Windows ···········································································17
8
DOCUMENT REVISION HISTORY ·························································18
9
REFERENCES ····················································································18
10
APPENDICES ·····················································································19
10.1
Appendix 1: Key Contributors and Approvers ············································19


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I.
LIST OF ABBREVIATIONS AND KEY TERMS
List of Abbreviations
Abbreviations
Description of abbreviations
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AML
Acute myeloid leukemia
APGD
Astellas Pharma Global Development, Inc.
AST
Aspartate aminotransferase
CRF
Case report form
CTCAE
Common Terminology Criterion for Adverse Events
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
INR
International normalization ratio
LA-CRF
Liver Abnormality-Case Report Form
LFT
Liver function test
MedDRA
Medical Dictionary for Regulatory Activities
NCI
National Cancer Institute
NCI-CTCAE
National Cancer Institute-Common Terminology Criteria for Adverse Events
PD
Protocol deviation
PR
Partial remission
PT
Preferred term
SAE
Serious adverse event
SAF
Safety Analysis Set
SAP
Statistical Analysis Plan
SOC
System Organ Class
TBL
Total bilirubin
TEAE
Treatment-emergent adverse event
TLFs
Tables, listings and figures
ULN
Upper limit of normal
WHO
World Health Organization
WHO-DD
World Health Organization – Drug Dictionary


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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.
Screen failure
Potential subject who signed consent but did not meet 1 or more criteria 
required for participation in a trial and did not randomize to the trial.
Screening
A process of active consideration of potential subjects for enrollment in a 
trial.
Screening period
Period of time before entering the investigational period, usually from the 
time of starting a subject signing consent until just before the registration.
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 database hard lock. This statistical analysis is 
coordinated by the responsible biostatistician of APGD. 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 tables, listings and figures (TLFs)
meeting will be held to allow a review of the clinical trial data and to verify the data that will 
be used for analysis set classification. If required, consequences for the statistical analysis 
will be discussed and documented. A meeting to determine analysis set classifications may 
also be held prior to database hard lock.


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2
SCHEDULE OF ASSESSMENTS
Table 1
Schedule of Assessments
Assessments
Screening a
(Day -28 to 1)
Treatment Cycle 
1 Day 1 a
Day 1 of Treatment 
Cycle 3 and Every 
Other Cycle (i.e., Cycles 
5, 7, 9, etc.) b
(+/- 5 days)
End of Treatment c
Informed Consent
X
Verify Inclusion/Exclusion 
X
X
Subject Enrollment
X
Demographics d
X
Medical History e
X
Physical Examination
X
X
Vital Signs
X
X
ECOG Performance Status
X
X
Clinical Laboratory Tests (chemistry, hematology, coagulation, urinalysis)
X
X
X
Pregnancy Test for Women of Childbearing Potential (WOCBP)
X
X
X
Prior and Concomitant Medications
Adverse Event Assessment f
ASP2215 Administration g
Daily
ECOG: Eastern Cooperative Oncology Group
a.
Subject should sign the informed consent at the final visit of the original study they enrolled in. The Screening and Treatment Cycle 1 Day 1 visits may be combined. A subject’s 
procedures performed during their final visit for the original study will be used for Treatment Cycle 1 Day 1 if the final visit occurred within 7 days prior to visit.
b.
Each treatment cycle is 28 days. Subject to be seen on Day 1 of every 2 treatment periods (every 8 weeks).
c.
End of treatment visit to be conducted within 30 days of last dose, prior to starting a new anticancer therapy or upon marketing authorization and commercial availability of 
ASP2215 in the country of residence. Subjects discontinuing due to commercial availability will be notified by the site and an end of treatment visit scheduled within 3 months.
d.
Demographic data will be obtained from the original study.
e.
Medical history will be obtained from the original study.
f.
Adverse events from the original study that are ongoing at the time of Screening will continue to be followed as adverse events during this protocol and should not be captured as 
medical history. Adverse events will be captured until the End of Treatment visit, 30 days after last dose, or until start of a new anticancer therapy, whichever is sooner.
g.
Subject will continue dosing at the dose received in original study with ASP2215, dose not to exceed 280 mg. If the original subject dose is over 280 mg, the subject will begin 
dosing in this protocol at 280 mg. 


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3
STUDY OBJECTIVE(S) AND DESIGN
3.1
Study Objective(s)
The objective of the study is to provide access to continued treatment for subjects who 
participated in other previous Astellas sponsored ASP2215 (single agent) trials and for whom 
the Investigator feels the subject may benefit from continued treatment.
3.2
Study Design
This is a multi-center, open-label, rollover protocol for Astellas sponsored, single agent 
ASP2215 trials in Acute myeloid leukemia (AML) and advanced solid tumors. Subjects must 
have completed the protocol requirements of the previous ASP2215 trial and be actively 
participating in the previous ASP2215 trial. In addition, subjects must be continuing to derive 
clinical benefit from treatment with ASP2215 without any persistent intolerable toxicity from 
ASP2215, in the opinion of the investigator and must meet the entry criteria for this rollover 
study prior to being enrolled.
Subjects should sign the informed consent at their cycle 1 day 1 visit. The assessments from 
the last treatment visit from the parent study can be utilized for the cycle 1 day 1 visit. The 
subject will then receive ASP2215 study drug for the rollover study and return all ASP2215 
study drug from the parent study. 
The number of subjects and number of centers will be dependent on the number of subjects 
and centers that enroll into the protocols rolling over into this trial. Centers in North America, 
Europe and Asia may rollover subjects into this trial. It is estimated that up to approximately 
130 subjects across 40 centers will enroll into this trial. Subjects will be eligible to continue
receiving treatment in this study until they meet a discontinuation criterion as outlined in the 
protocol or upon marketing authorization and commercial availability of ASP2215 in the 
country of residence.
Subjects will continue ASP2215 at the dose they were on at the time of their end of study 
visit in the previous ASP2215 study.
3.3
Randomization
There was no randomization necessary.
4
SAMPLE SIZE
The sample size for this study is based on the number of subjects who are continuing to 
derive benefit from treatment with ASP2215 as assessed by their Investigator at the 
completion of the original study they enrolled under.
5
ANALYSIS SETS
In accordance with International Conference on Harmonisation (ICH) recommendations in 
guidelines E3 and E9, the following analysis sets will be used for the analyses.


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5.1
Safety Analysis Set (SAF)
The Safety Analysis Set (SAF) consists of all enrolled subjects who received at least one 
dose of study medication (ASP2215) and will be used for safety analyses.
6
ANALYSIS VARIABLES
6.1
Efficacy Endpoints
Not applicable.
6.2
Safety Variables
Safety will be assessed by evaluation of the following variables:
●
Treatment-emergent adverse events (TEAEs); frequency, severity, seriousness, and 
relationship to study drug.
●
Clinical laboratory variables (hematology, biochemistry including liver enzymes and 
total bilirubin, and urinalysis)
●
Vital signs (systolic and diastolic blood pressure and pulse rate)
●
Physical Examination
●
ECOG Performance Scores
All adverse events (AEs) recorded on treatment including within 30 days from the last study 
treatment or until start of a new anticancer therapy, whichever is sooner will be summarized. 
AEs will be coded to System Organ Class (SOC) and Preferred term (PT) using Medical 
Dictionary for Regulatory Activities (MedDRA) version 23.0 and will be graded according to 
the National Cancer Institute- Common Terminology Criteria for Adverse Events (NCI-
CTCAE) version 4.03. The adverse events recorded prior to the first dose of study medication 
will be considered as adverse events during the pre-investigational period.
TEAE is defined as an adverse event observed after starting administration of the test 
drug/comparative drug within 109 study. If the adverse event occurs on Day 1 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 1 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 (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. The ongoing adverse event from original 
protocol will not be considered as TEAE of this study.
A drug-related TEAE is defined as any TEAE with at least possible relationship to study 
treatment as assessed by the investigator or with missing assessment of the causal 
relationship. 


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6.3
Pharmacokinetic Variables
There were no pharmacokinetic variables in this study.    
6.4
Pharmacodynamic Variables
There were no pharmacodynamic variables in this study.
6.5
Other Variables
●
The duration of exposure
For each subject, the Length of Time on treatment 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.
Percent overall 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. 
Total number of study drug actually taken is calculated as total number of tablets
dispensed – total number of tablets returned
Number of study drug expected to be taken is calculated as (Date of last dose of study 
drug – Date of first dose + 1) x planned number of tablets per day (see table below)
Daily Dose (mg)
Number of Tablets per Day
40 
1
80
2
120
3
200
5
280
7
When the total number of tablets taken is missing, then the compliance will be treated as 
missing.
●
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.
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. 


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Safety analysis and other summaries based on SAF will be presented by actual treatment 
received. Baseline refers to Cycle 1 Day 1. If no data was collected on Cycle 1 Day 1 the last 
value or measurement taken prior to study drug administration will be utilized as baseline. 
All data processing, summarization, and analyses will be performed using SAS® Version 
9.1.3 or higher on Unix. Specifications for table, figures, and data listing formats can be 
found in the TLF specifications for this study.
For the definition of subgroups of interest please refer to section 7.8.
7.2
Study Population
7.2.1
Disposition of Subjects
The following subject data will be presented:
●
Number of subjects with informed consent, discontinued before study enrollment, 
registered by treatment arm;
●
Number and percentage of subjects completed and discontinued screening, treatment, or 
study by primary reason for treatment discontinuation for all dosed subjects by treatment 
arm; 
7.2.2
Protocol Deviations
Protocol deviations as defined in the study protocol (Section 8.1.6 Protocol Deviations) will 
be assessed for all dosed patients. The number and percentage of subjects meeting any 
criteria will be summarized for each criterion and overall, by treatment group 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 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 in each country and site will be presented by treatment 
group for the SAF.
Descriptive statistics for age, height, weight and BMI at study entry will be presented.  
Frequency tabulations for sex, ethnicity, age group (<65 years vs. >= 65 years) and race will 
be presented. This will be done for the SAF.


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Medical history is coded in MedDRA and will be summarized by System Organ Class (SOC) 
and Preferred Term (PT) as well as by PT alone, by treatment group for the SAF. 
Disease history will not be summarized.  Each subject’s complete cancer history will be 
listed.
7.2.4
Previous and Concomitant Medications
Previous medications are coded with World Health Organization – Drug Dictionary (WHO-
DD), and will be summarized by therapeutic subgroup (ATC 2nd level) and chemical 
subgroup (ATC 4th level) and preferred WHO name by treatment group for the SAF. 
As with previous medication, concomitant medication will be summarized for each treatment 
group 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.
7.2.5
Non-Medication Therapy
Frequency tabulations of subjects with non-medication therapy and reason for use will be 
presented by treatment group for SAF. Number of non-medication therapy received per 
subject will be summarized using descriptive statistics.
7.3
Study Drugs
7.3.1
Exposure
The following information on drug exposure will be presented for each treatment group for 
the SAF:
●
Number and percent of subject with dose increases, decreases or interruptions by 
treatment group.
Duration of exposure will be summarized in two ways.
●
Descriptive statistics will be presented by treatment group.
●
Exposure time will be categorized according to the following categories by treatment 
group:
○
less than 7 days
○
at least 7 days, less than 14 days 
○
at least 14 days, less than 28 days 
○
at least 28 days, less than 42 days
○
at least 42 days, less than 84 days
○
84 days or more
○
Unknown.
Counts and percentages of subjects in each of these categories will be summarized for each 
treatment group for the SAF.


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7.3.2
Treatment Compliance
Overall compliance with the 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 treatment group.
●
Percent compliance will be categorized according to the following categories by 
treatment group:
○
less than 50%
○
at least 50%, less or equal to 75%
○
greater than 75%, less or equal to 100%
○
greater than 100%
○
Unknown.
7.4
Analysis of Efficacy 
Not Applicable.
7.5
Analysis of Safety
All analysis of safety will be presented by treatment group for SAF.
7.5.1
Adverse Events
All adverse events will be evaluated by incidence including serious adverse events (SAEs), 
deaths, and discontinuation due to adverse events.  Severity, investigator-attributed 
relationship to study drug, duration, and outcome of the events will also be recorded.  These 
adverse events will be coded by to SOC and PT using a MedDRA dictionary (v23.0) and will 
be graded by NCI-CTCAE Grade (v4.03).
An overview table by treatment group will include the following details:
●
Number of TEAEs,
●
Number and percentage of subjects with TEAEs,
●
Number of drug related TEAEs,
●
Number and percentage of subjects with causally drug related TEAEs,
●
Number of serious TEAEs,
●
Number and percentage of subjects with serious TEAEs,
●
Number of serious drug related TEAEs,
●
Number and percentage of subjects with serious drug related TEAEs,
●
Number of drug related TEAEs leading to death
●
Number and percentage of subjects with drug related TEAEs leading to death
●
Number of TEAEs leading to permanent discontinuation of study drug,
●
Number and percentage of subjects with TEAEs leading to permanent discontinuation of 
study drug, and
●
Number of deaths.


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The number and percentage of subjects with TEAEs, as classified by SOC and PT will be 
summarized by treatment group. Summaries will be provided for:
●
TEAEs
●
Grade 3 or higher TEAEs
●
Drug related TEAEs, 
●
Serious TEAEs, 
●
Drug related serious TEAEs, 
●
TEAEs leading to permanent discontinuation of study drug, 
●
Drug related TEAEs leading to permanent discontinuation of study drug, 
The number and percentage of subjects with TEAEs will be also summarized for:
●
TEAEs by SOC, PT and relationship to study drug
●
Serious TEAEs by SOC, PT and relationship to study drug
●
TEAEs by SOC, PT and NCI CTCAE grade
●
Serious TEAEs by SOC, PT and NCI CTCAE grade
●
Drug related TEAEs by SOC, PT and NCI CTCAE grade
●
TEAEs by PT only
In the subject count, if a subject has multiple TEAEs with the same SOC or PT, but with 
differing NCI-CTCAE grade or relationship to study drug, then the subject will be counted 
only once with the maximum NCI-CTCAE grade or relationship to study drug, however, if 
any of the grade or relationship are missing then the subject will be counted only once with 
missing value.  In the adverse event count, the adverse events will be presented in each 
category they were classified to. Drug related TEAEs will be presented in a similar way by 
severity only.
If necessary, adverse events of special interest will be analyzed.
7.5.2
Clinical Laboratory Evaluation
Quantitative clinical laboratory variables, i.e. hematology, biochemistry, coagulation and 
urinalysis based on local assessment will be summarized using mean, standard deviation, 
minimum, maximum and median for each treatment group 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 library reference ranges. 
The number and percentage of subjects below and above reference range will be summarized 
for each treatment group at each visit.
Frequency tabulations of qualitative clinical laboratory variables (urinalysis) will be 
presented for each treatment group at each visit. 
For hematology and biochemistry, shift tables will be presented: 
●
Shift tables of reference range changes from baseline to the worst finding during the 
treatment period (low, normal, high), and


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●
Summary shifts of reference range changes from baseline to the worst finding during the 
treatment period (shift from normal or high to low, shift from normal or low to high, 
categorized increase [shift from low to normal or from normal to high], categorized no 
change [value stays in the same reference range], categorized decrease [shift from high 
to normal or from normal to low]).
Laboratory results will also be graded using NCI-CTCAE v4.03, 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. For hematology and biochemistry 
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 the 
worst post-baseline grade will also be presented.
Laboratory results will be used for summaries as described above. 
7.5.2.1 Liver Enzymes and Total Bilirubin 
The following potentially clinically significant criteria in liver function tests (LFTs) for 
Alkaline Phosphatase (ALP), Alanine Transaminase (ALT), total bilirubin (TBL), Aspartate 
Transaminase (AST) and their combination are defined. The subject’s highest value during 
the investigational period will be used. 
Parameter
Criteria
ALT
> 3xULN
> 5xULN
> 10xULN
> 20xULN
AST
> 3xULN
> 5xULN
> 10xULN
> 20xULN
ALT or AST
> 3xULN
> 5xULN
> 8xULN
> 10xULN
> 20xULN
Total Bilirubin
> 2xULN
ALP
> 1.5xULN


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Parameter
Criteria
ALT or AST or Total Bilirubin(*)
ALT or AST > 3xULN (in subjects 
without liver metastases), > 5 x ULN (in 
subjects with liver metastases) or 
(Total bilirubin > 2xULN)
ALT or AST AND Total Bilirubin(*)
ALT or AST > 3xULN and
Total bilirubin > 2xULN
ALT or AST AND INR(*)
ALT or AST > 3xULN and
INR > 1.5xULN
(*) 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 treatment 
group
7.5.3
Vital Signs
Vital signs (systolic blood pressure, diastolic blood pressure, and pulse rate) will be 
summarized using mean, standard deviation, minimum, maximum and median by treatment 
group and visit. Additionally, a within-subject change will be calculated per visit as the 
post-baseline measurement minus the baseline measurement and summarized by treatment 
group 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 treatment group.
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
7.5.4
Electrocardiograms (ECGs)
Not applicable. 
7.5.5
Pregnancies
A detailed listing of all pregnancies will be provided.
7.5.6
Ophthalmologic Assessment
A detailed listing of the Ophthalmologic variables for both eyes will be provided, if data are 
available.


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7.5.7
Other Safety-Related Observations
●
ECOG PS: A summary table by visit and grade will be produced. A detailed listing will 
be provided.
7.6
Analysis of Pharmacokinetics
Not applicable.
7.7
Analysis of Pharmacodynamics
Not applicable.
7.8
Subgroups of Interest 
No subgroup analysis is planned.
7.9
Other Analyses
No other analysis is planned.
7.10
Interim Analysis (and Early Discontinuation of the Clinical Study)
No formal interim analysis is planned in this study.  Clinical data might be reviewed on an 
ongoing basis.
7.11
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information
Refer to the specification document for TLFs in which more details are provided.
7.11.1
Missing Data
As a general principle, no imputation of missing data for other variables will be done. 
Exceptions are the start and stop dates of AEs and concomitant medication. The imputed dates 
will be used to allocate the concomitant medication and AEs to a treatment group, in addition 
to determining whether an AE is/is not treatment emergent. Listings of the AEs and 
concomitant medications will present the actual partial dates; imputed dates will not be shown.
For continuous variables (e.g., clinical laboratory measurement, vital signs), subjects with 
missing baseline variable will be excluded from the analysis of change from baseline.
Missing end of treatment information will be imputed by last observation carried forward. 
Visit-by-visit analyses of data will exclude subjects who did not provide data at the visit in 
question.
7.11.2
Outliers
All values will be included in the analyses.  
7.11.3
Visit Windows
Analyses will not exclude subject data due to the subject’s failure to comply with the visit 
schedule.


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All the assessments will be allocated to case report form (CRF) or visit based on the table 
below:
CRF visit
Visit Window
Screening
Not applicable
Study Visit
C1D1 to Last Dose Date
End of Treatment Visit
Last dose date + 30
The value which assessment day is the closest to the defined target day within these windows 
is used. If two values are equally close, the latter is used in the analysis.
8
DOCUMENT REVISION HISTORY 
Version
Date
Changes
Comment/rationale for change
1.00
19-NOV-2015
NA
Document finalized
2.00
17-JUN-2020
Many, abbreviations, 
dosing exposure, 
concomitant 
medications
Many discrepancies between protocol 
and SAP.   Protocol amended.
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)


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10
APPENDICES
10.1
Appendix 1: Key Contributors and Approvers
List of Key Contributors and Approvers
Key Contributors
The following contributed to or reviewed this Statistical Analysis Plan as relevant to their 
indicated discipline or role.
Primary author (s)
Principal Biostatistician, 
Contributors and Reviewers
APGD
GDO Management Global Data Science
PPD
PPD
PPD
PPD
PPD
PPD


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Author and Approver Signatories 
(E-signatures are attached at end of document)  
 was the study statistician for this study and the 
primary author of this Statistical Analysis Plan 
 
 was the global statistical lead (STATL) for 
this project and biostatistics peer reviewer of this Statistical Analysis Plan 
 
 
 
This Statistical Analysis Plan was approved by: 
 
 
 
 
 
 
PPD
PPD
PPD
PPD
PPD