A Phase 2, Multicenter, Open-Label Study of DS-8201a, an Anti-HER2-Antibody Drug Conjugate (ADC) for HER2-Positive, Unresectable and/or Metastatic Breast Cancer Subjects Previously Treated With T-DM1 (DESTINY-Breast01)
Phase: PHASE2
Conditions: Breast Cancer
Sponsor: Daiichi Sankyo

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CLINICAL STUDY PROTOCOL 
 
A PHASE 2, MULTICENTER, OPEN-LABEL STUDY OF 
DS-8201A, AN ANTI-HER2-ANTIBODY DRUG 
CONJUGATE (ADC) FOR HER2-POSITIVE, 
UNRESECTABLE AND/OR METASTATIC BREAST 
CANCER SUBJECTS PREVIOUSLY TREATED WITH T-
DM1  
 
DS8201-A-U201 
 
IND/EudraCT NUMBERS: 127,553/2016-004986-18 
 
VERSION 5.0, 26 APR 2019 
VERSION 4.0, 27 JUL 2018 
VERSION 3.0, 22 JAN 2018 
VERSION 2.0, 19 OCT 2017 
VERSION 1.0, 15 MAY 2017 
 
DAIICHI SANKYO  
 
 
CONFIDENTIALITY STATEMENT 
Information contained in this document is proprietary to Daiichi Sankyo.  The information is 
provided to you in confidence which is requested under an agreed upon and signed 
Confidentiality and Disclosure Agreement.  Do not give this document or any copy of it or reveal 
any proprietary information contained in it to any third party (other than those in your 
organization who are assisting you in this work and are bound by the Confidentiality and 
Disclosure Agreement) without the prior written permission of an authorized representative of 
Daiichi Sankyo. 

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CRITICAL STUDY CONTACT LIST 
Sponsor (United States) 
Daiichi Sankyo Inc. 
211 Mt Airy Rd 
Basking Ridge, NJ 07920 
USA 
Sponsor (Japan) 
Daiichi Sankyo Company, Limited  
3-5-1, Nihonbashi-honcho, Chuo-ku, Tokyo 
103-8426, Japan 
  

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SUMMARY OF CHANGES 
DESCRIPTION OF EACH CHANGE AND RATIONALE 
Table 5.2 
Section 9.3.1.2 
Clarified that interstitial lung disease (ILD) biomarkers (i.e., KL-6, SP-D) will 
not be used for diagnosis or monitoring of drug-induced ILD.  
Table 5.2 
Section 9.3.1.2 
Table 6.2 (footnote) 
Specified that blood samples will be collected at the time of ILD event, if 
feasible, for PK and future exploratory analysis of biomarkers. 
Table 5.2 
Section 9.3.1.2 
Table 6.2 (footnote) 
Amended ILD monitoring plan to include that pulmonary function tests 
(PFTs) and pulse oximetry should be conducted, and arterial blood gas (ABG) 
exams should be conducted as clinically indicated, when evaluating potential 
ILD events. 
Table 5.2 
Reworded ILD dose modification language so it was clear that study drug 
should be interrupted for any ILD event regardless of CTCAE grade, and 
should be permanently discontinued in subjects demonstrating Grade 2, 3, or 4 
toxicity. 
Table 5.2 
Section 9.3.1.2 
Added statement to clarify that ILD events regardless of severity or 
seriousness will be followed until resolution even after drug discontinuation. 

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PROTOCOL SYNOPSIS 
EudraCT: 
2016-004986-18 
IND Number: 
127553 
Protocol Number: 
DS8201-A-U201 
Investigational Product: 
DS-8201a 
Active Ingredient(s)/INN: 
DS-8201a consists of an antibody component, MAAL-9001, covalently 
conjugated via a maleimide tetrapeptide linker, to a drug component 
MAAA-1181a. 
Study Title: 
A Phase 2, Multicenter, Open-Label Study of DS-8201a, an Anti-HER2-
Antibody Drug Conjugate (ADC) for HER2-Positive, Unresectable 
and/or Metastatic Breast Cancer Subjects Previously Treated with T-
DM1. 
Study Phase: 
Phase 2 
Indication Under Investigation: Unresectable/metastatic breast cancer with HER2 positive expression 
Study Objectives: 
Primary Objectives: 
 
To determine the objective response rate (ORR) of DS-8201a in 
HER2-positive, unresectable and/or metastatic breast cancer subjects 
who are resistant or refractory to T-DM1 
Secondary Objectives: 
 
To evaluate duration of response, best percent change in the sum of 
the longest diameters (SLD) of measurable tumors, disease control 
rate (DCR), clinical benefit rate (CBR), progression-free survival 
(PFS), and overall survival (OS) 
 
To further evaluate the safety of DS-8201a 
 
To determine the pharmacokinetics (PK) of DS-8201a 
 
To determine the recommended Phase 2 dose (RP2D) 
Exploratory Objectives 
 
To evaluate duration of stable disease, and time to response 
 
To evaluate potential biomarkers of response, such as serum HER2-
extracellular domain (ECD) 
 
To evaluate exposure-response relationships for efficacy and safety 
endpoints 
 

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Study Design: 
Phase 2, open-label, 2-part, global, multicenter trial.   
Study Design Schema of DS8201-A-U201 
 
Study Duration: 
Enrollment is planned to occur over approximately 12 months 
Treatment and follow-up projected to be completed within 
approximately 10 months thereafter.  
Anticipated duration of the study is at least 22 months.  
Study Centers and Location: 
Approximately 110 sites possibly including but not limited to: North 
America, Europe, Japan and other Asian countries.  Other countries may 
also be also considered. 
Subject Eligibility Criteria: 
Key Inclusion Criteria: 
 
Men or women ≥ 20 years old in Japan and Korea, ≥ 18 years old in 
the United States (for other countries, please follow the reference1)  
 
Pathologically documented breast cancer that: 
 
is unresectable or metastatic 
 
has confirmed HER2 positive expression (estrogen receptor 
(ER)/progesterone receptor (PR) positive subjects may be 
enrolled if they are HER2 positive) as determined according to 
American Society of Clinical Oncology – College of 
American Pathologists (ASCO-CAP) guidelines evaluated at a 
Central Laboratory.  See Laboratory Manual for details 
 
Subjects must have an adequate tumor sample available for 
confirmation of HER2 status by Central Laboratory (based on most 
recent tumor tissue sample).   
 
Subject must have breast cancer which is resistant or refractory to T-
DM1 (all parts except Part 2b) 
 
For Part 2b, an exploratory portion of the study, subjects must 
have discontinued treatment with T-DM1 for reasons other 
than resistant or refractory disease 
 
Presence of at least one measurable lesion per Response Evaluation 
Criteria in Solid Tumors (RECIST) version 1.1 
                                                 
1 https://hrpo.wustl.edu/wp-content/uploads/2015/01/5-Determining-Legal-Age-to-Consent.pdf 

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Study Endpoints: 
Primary Endpoints: 
 ORR assessed by independent central imaging facility review 
based on RECIST version 1.1. 
Secondary Endpoints: 
 Efficacy Endpoints: 
 
Duration of response 
 
Best percent change in the SLD of measurable tumors 
 
DCR 
 
CBR 
 
PFS 
 
OS 
 
ORR assessed by the investigator based on RECIST version 
1.1 
 Safety Endpoints: 
 
Serious adverse events (SAEs)  
 
Treatment-emergent adverse events (TEAEs)  
 
TEAEs leading to discontinuations 
 
Adverse events of special interest 
 
Elevated troponin levels 
 
Physical examination findings (including Eastern Cooperative 
Oncology Group Performance Status (ECOG PS)  
 
Vital sign measurements 
 
Standard clinical laboratory parameters  
 
ECG parameters  
 
Echocardiogram (Echo)/ multigated acquisition (MUGA) 
findings  
 
Ophthalmologic findings, and; 
 
Anti-drug antibodies (ADA)  
 Pharmacokinetic Endpoints (DS-8201a, total anti-HER2 
antibody and MAAA-1181a): 
 
PK parameters (Cycle 1): maximum serum concentration 
(Cmax), time to Cmax (Tmax), area under the concentration-
time curve from dosing until the last quantifiable 
concentration (AUClast), AUC from the time of dosing until 
day 21 (AUC0-21d)and, if appropriate, AUC from 0 through 

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infinity (AUCinf), terminal elimination half-life (T1/2), 
clearance (CL) and volume of distribution at steady-state 
(Vss) 
 
Serum concentrations. 
Exploratory endpoints: 
 Efficacy endpoints 
 
Duration of stable disease 
 
Time to response 
 
Evaluate exposure-response relationships for efficacy and 
safety endpoints 
 Potential biomarkers of response, such as serum HER2ECD 
concentrations 
Planned Sample Size: 
The estimated total number of subjects planned is approximately 230.   
Statistical Analyses: 
A data cut-off date for the primary analysis will be identified during Part 
2.  
Efficacy analyses: 
The primary efficacy analysis will be performed for all subjects who 
initially received the RP2D of DS-8201a and had measurable tumors 
assessed by independent central imaging facility review at baseline.  The 
primary efficacy endpoint is ORR assessed by independent central 
imaging facility review based on RECIST version 1.1.  ORR will be 
summarized with its two-sided 95% exact confidence interval (CI). 
The secondary efficacy parameters include duration of response, best 
percent change in the SLD of measurable tumors, DCR, CBR, PFS, OS, 
and ORR assessed by the investigator based on RECIST version 1.1.  
DCR, CBR, ORR assessed by the investigator based on RECIST version 
1.1 will be analyzed for each part/dose group in the same manner as the 
primary ORR analysis.  Duration of response, PFS, and OS will be 
summarized with median event times and their 2-sided 95% CIs using 
the Brookmeyer and Crowley method. 
Safety analyses: 
Safety endpoints will include SAEs, treatment-emergent adverse events 
(TEAEs), physical examination findings, ECOG PS, vital sign 
measurements, standard clinical laboratory parameters, ECG parameters, 
Echo/MUGA findings, ADA and ophthalmologic findings.  TEAEs will 
be graded according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03.  Safety 
analyses in general will be descriptive and will be presented in tabular 
format with the appropriate summary statistics. 
Pharmacokinetic analyses: 
Serum concentrations for DS-8201a, total anti-HER2 antibody and 

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MAAA-1181a will be listed, plotted, and summarized using descriptive 
statistics by Part (and Stage)/dose level/study day at each time point.  PK 
parameters will be listed and summarized using descriptive statistics by 
Part (and Stage)/dose level. 
 

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TABLE OF CONTENTS 
CRITICAL STUDY CONTACT LIST ...........................................................................................2 
INVESTIGATOR AGREEMENT...................................................................................................3 
SUMMARY OF CHANGES ...........................................................................................................4 
PROTOCOL SYNOPSIS ................................................................................................................5 
TABLE OF CONTENTS ...............................................................................................................11 
LIST OF TABLES .........................................................................................................................17 
LIST OF FIGURES .......................................................................................................................18 
LIST OF ABBREVIATIONS ........................................................................................................19 
1. 
INTRODUCTION AND BACKGROUND INFORMATION .....................................22 
1.1. 
Background ...................................................................................................................22 
1.1.1. 
Investigational Product..................................................................................................22 
1.1.1.1. 
Name .............................................................................................................................22 
1.1.1.2. 
Description ....................................................................................................................22 
1.1.1.3. 
Intended Use Under Investigation .................................................................................23 
1.1.1.4. 
Nonclinical Studies .......................................................................................................23 
1.1.1.5. 
Clinical Experience .......................................................................................................25 
1.1.1.6. 
Summary of Clinical Pharmacokinetics ........................................................................26 
1.2. 
Study Rationale .............................................................................................................28 
1.3. 
Risks and Benefits for Study Subjects ..........................................................................30 
2. 
STUDY OBJECTIVES AND HYPOTHESIS ..............................................................32 
2.1. 
Study Objectives ...........................................................................................................32 
2.1.1. 
Primary Objectives ........................................................................................................32 
2.1.2. 
Secondary Objectives ....................................................................................................32 
2.1.3. 
Exploratory Objectives..................................................................................................32 
2.2. 
Study Hypothesis ..........................................................................................................32 
2.3. 
Study Endpoints ............................................................................................................32 
2.3.1. 
Primary Endpoints .........................................................................................................32 
2.3.2. 
Secondary Endpoints .....................................................................................................32 
2.3.3. 
Exploratory Endpoints ..................................................................................................33 
3. 
STUDY DESIGN ..........................................................................................................34 
3.1. 
Overall Design ..............................................................................................................34 

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3.1.1. 
Overview .......................................................................................................................34 
3.1.2. 
Duration of the Study ....................................................................................................35 
3.1.3. 
Duration of Subject Participation ..................................................................................35 
3.1.4. 
Definition of the End of the Study ................................................................................35 
3.2. 
Discussion of Study Design ..........................................................................................36 
3.2.1. 
Selection of Dose ..........................................................................................................36 
4. 
STUDY POPULATION ...............................................................................................37 
4.1. 
Inclusion Criteria ...........................................................................................................37 
4.2. 
Exclusion Criteria..........................................................................................................39 
5. 
STUDY TREATMENT(S) ...........................................................................................42 
5.1. 
Assigning Subjects to Treatments .................................................................................42 
5.1.1. 
Treatment Group(s) .......................................................................................................42 
5.1.2. 
Method of Treatment Allocation ...................................................................................42 
5.1.3. 
Blinding .........................................................................................................................42 
5.2. 
Study Drug(s) ................................................................................................................42 
5.2.1. 
Description ....................................................................................................................42 
5.2.2. 
Labeling and Packaging ................................................................................................43 
5.2.3. 
Preparation ....................................................................................................................43 
5.2.4. 
Administration ..............................................................................................................43 
5.2.5. 
Storage...........................................................................................................................43 
5.2.6. 
Drug Accountability ......................................................................................................43 
5.3. 
Control Treatment .........................................................................................................44 
5.4. 
Dose Interruptions and Reductions ...............................................................................44 
5.5. 
Method of Assessing Treatment Compliance ...............................................................50 
5.6. 
Concomitant Medications, Treatments, And Procedures ..............................................50 
5.7. 
Removal of Subjects From Treatment and/or Study .....................................................52 
5.7.1. 
Reasons for Discontinuation of Study Treatment .........................................................52 
5.7.2. 
Reasons for Discontinuation of Study Participation .....................................................52 
5.7.3. 
Withdrawal Procedures .................................................................................................53 
5.7.4. 
Subject Replacement .....................................................................................................53 
5.7.5. 
Subject Re-screening Procedures ..................................................................................53 
6. 
STUDY PROCEDURES ..............................................................................................54 
6.1. 
Tissue Screening ...........................................................................................................54 

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6.2. 
Screening .......................................................................................................................54 
6.3. 
Randomization ..............................................................................................................56 
6.4. 
Treatment Period ...........................................................................................................56 
6.4.1. 
Cycle 1 to Cycle 4 and Subsequent Cycles ...................................................................56 
6.4.2. 
Every 6 Weeks (±7 days) ..............................................................................................59 
6.5. 
End of Treatment...........................................................................................................59 
6.6. 
Follow-up ......................................................................................................................60 
7. 
EFFICACY ASSESSMENTS .......................................................................................67 
7.1. 
Primary Efficacy Endpoint ............................................................................................67 
7.2. 
Secondary Efficacy Endpoints ......................................................................................67 
7.3. 
Exploratory Efficacy Endpoints ....................................................................................67 
8. 
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS ........................68 
8.1. 
Pharmacokinetic (PK) ...................................................................................................68 
8.2. 
Pharmacodynamic .........................................................................................................70 
8.3. 
Immunogenicity (Anti-Drug Antibodies, ADA) ...........................................................70 
8.4. 
Pharmacogenomic Analysis ..........................................................................................70 
8.4.1. 
Tumor Sampling ...........................................................................................................70 
8.4.2. 
Genomic or Genetic Banking and Analysis ..................................................................71 
8.4.2.1. 
Disclosure of the Results of Genomic or Genetic Analysis ..........................................71 
8.4.2.2. 
Storage and Disposal of Specimens for Genomic or Genetic Banking and 
Analysis .........................................................................................................................71 
8.5. 
Biomarker and Exploratory Variables ..........................................................................71 
9. 
SAFETY EVALUATION AND REPORTING ...........................................................72 
9.1. 
Adverse Event Collection and Reporting ......................................................................72 
9.2. 
Safety Endpoint Event(s) ..............................................................................................72 
9.3. 
Adverse Events of Special Interest ...............................................................................73 
9.3.1. 
Interstitial Lung Disease/Pneumonitis ..........................................................................73 
9.3.1.1. 
Clinical Summary .........................................................................................................73 
9.3.1.2. 
Management Guidance..................................................................................................73 
9.3.1.3. 
Interstitial Lung Disease Adjudication Committee .......................................................74 
9.3.2. 
Cardiotoxicity (Cardiac Related Events including QT Prolongation and LVEF 
Decrease) .......................................................................................................................74 
9.3.2.1. 
Clinical Summary .........................................................................................................74 

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9.3.2.2. 
Management Guidance..................................................................................................74 
9.3.3. 
Infusion-related Reactions ............................................................................................74 
9.3.3.1. 
Clinical Summary .........................................................................................................74 
9.3.3.2. 
Management Guidance..................................................................................................74 
9.4. 
Adverse Event ...............................................................................................................75 
9.4.1. 
Definition of Adverse Event .........................................................................................75 
9.4.2. 
Serious Adverse Event ..................................................................................................75 
9.4.3. 
Severity Assessment .....................................................................................................76 
9.4.4. 
Causality Assessment ....................................................................................................76 
9.4.5. 
Action Taken Regarding Study Drug(s) .......................................................................76 
9.4.6. 
Other Action Taken for Event .......................................................................................77 
9.4.7. 
Adverse Event Outcome ...............................................................................................77 
9.5. 
Serious Adverse Events and Adverse Events of Special Interest Reporting
Procedure for Investigators ...........................................................................................77 
9.6. 
Notifying Regulatory Authorities, Investigators, and Institutional Review 
Board/Ethics Committee ...............................................................................................78 
9.7. 
Exposure In Utero During Clinical Studies ..................................................................79 
9.8. 
Clinical Laboratory Evaluations ...................................................................................79 
9.9. 
Vital Signs .....................................................................................................................80 
9.10. 
Electrocardiograms .......................................................................................................80 
9.11. 
Physical Examinations ..................................................................................................80 
9.12. 
Other Examinations .......................................................................................................80 
10. 
OTHER ASSESSMENTS .............................................................................................81 
11. 
STATISTICAL METHODS .........................................................................................82 
11.1. 
Analysis Sets .................................................................................................................82 
11.1.1. 
Full Analysis Set/Safety Analysis Set ...........................................................................82 
11.1.2. 
Response Evaluable Set ................................................................................................82 
11.1.3. 
Per Protocol Set .............................................................................................................82 
11.1.4. 
Pharmacokinetic Set ......................................................................................................82 
11.2. 
General Statistical Considerations ................................................................................82 
11.3. 
Study Population Data ..................................................................................................82 
11.4. 
Statistical Analysis ........................................................................................................83 
11.4.1. 
Efficacy Analyses..........................................................................................................83 

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11.4.1.1. Primary Efficacy Analysis ............................................................................................83 
11.4.1.2. Secondary Efficacy Analyses ........................................................................................83 
11.4.1.3. Exploratory Efficacy Analyses .....................................................................................84 
11.4.2. 
Pharmacokinetic/Pharmacodynamic Analyses .............................................................85 
11.4.2.1. Pharmacokinetic Analyses ............................................................................................85 
11.4.2.2. Pharmacodynamic Analyses .........................................................................................85 
11.4.2.3. Biomarker Analyses ......................................................................................................85 
11.4.2.4. Pharmacogenomic Analyses .........................................................................................85 
11.4.3. 
Safety Analyses .............................................................................................................85 
11.4.3.1. Adverse Event Analyses ...............................................................................................86 
11.4.3.2. Clinical Laboratory Evaluation Analyses .....................................................................86 
11.4.3.3. Vital Sign Analyses .......................................................................................................86 
11.4.3.4. Electrocardiogram Analyses .........................................................................................86 
11.4.3.5. Physical Examination Analyses ....................................................................................86 
11.4.3.6. Concomitant Medication Analyses ...............................................................................87 
11.4.3.7. Exploratory Safety Analyses .........................................................................................87 
11.4.3.8. Immunogenicity (Anti-Drug Antibody, ADA) Analyses..............................................87 
11.4.3.9. Other Safety Analyses ...................................................................................................87 
11.4.4. 
Other Analysis ...............................................................................................................87 
11.5. 
Dose Selection Analysis ................................................................................................87 
11.5.1. 
Data Monitoring Committee .........................................................................................87 
11.6. 
Sample Size Determination ...........................................................................................88 
11.7. 
Statistical Analysis Process ...........................................................................................88 
12. 
DATA INTEGRITY AND QUALITY ASSURANCE ................................................89 
12.1. 
Monitoring and Inspections ..........................................................................................89 
12.2. 
Data Collection..............................................................................................................89 
12.3. 
Data Management .........................................................................................................90 
12.4. 
Study Documentation and Storage ................................................................................90 
12.5. 
Record Keeping .............................................................................................................91 
13. 
FINANCING AND INSURANCE ...............................................................................92 
13.1. 
Finances.........................................................................................................................92 
13.2. 
Reimbursement, Indemnity, and Insurance ...................................................................92 
14. 
PUBLICATION POLICY .............................................................................................93 

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15. 
ETHICS AND STUDY ADMINISTRATIVE INFORMATION ................................94 
15.1. 
Subject Confidentiality..................................................................................................94 
15.2. 
Informed Consent ..........................................................................................................94 
15.3. 
Regulatory Compliance .................................................................................................94 
15.4. 
Compliance Statement, Ethics and Regulatory Compliance.........................................95 
15.5. 
Protocol Deviations .......................................................................................................95 
15.6. 
Supply of New Information Affecting the Conduct of the Study .................................96 
15.7. 
Protocol Amendments ...................................................................................................96 
15.8. 
Study Termination .........................................................................................................97 
15.9. 
Data and Safety Monitoring Board ...............................................................................97 
15.10. 
Address List ..................................................................................................................97 
16. 
REFERENCES ..............................................................................................................98 
17. 
APPENDICES ............................................................................................................100 
17.1. 
Cockcroft-Gault Equation ...........................................................................................100 
17.2. 
Eastern Cooperative Oncology Group Performance Status (ECOG PS) ....................101 
17.3. 
Response Evaluation Criteria in Solid Tumors, Version 1.1 ......................................102 
17.3.1. 
Measurability of Tumor at Baseline ............................................................................102 
17.3.1.1. Definitions ...................................................................................................................102 
17.3.1.2. Specifications by Methods of Measurements .............................................................103 
17.3.2. 
Tumor Response Evaluation .......................................................................................103 
17.3.2.1. Assessment of Overall Tumor Burden and Measurable Disease ................................103 
17.3.2.2. Baseline Documentation of “Target” and “Non-target” Lesions ................................104 
17.3.2.3. Response Criteria ........................................................................................................104 
17.3.2.4. Evaluation of Best Overall Response ..........................................................................107 
17.3.2.5. Frequency of Tumor Re-evaluation ............................................................................108 
17.4. 
New York Heart Association Functional Classification .............................................109 
17.5. 
Strong CYP3A4 and OATP1B Inhibitors ...................................................................110 
 

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LIST OF TABLES 
Table 1.1: PK Parameters of DS-8201a (± standard deviation) ...................................................27 
Table 1.2: PK Parameters of Total Antibody (± standard deviation) ..........................................27 
Table 1.3: PK Parameters of MAAA-1181a (± standard deviation) ...........................................28 
Table 5.1: Dose Reduction Levels of DS-8201a .........................................................................45 
Table 5.2: Dose modification for DS-8201a ................................................................................45 
Table 6.1: Schedule of Events  Part 1 PK Stage ........................................................................61 
Table 6.2: Schedule of Events  Part 1 Dose Finding Stage and Part 2 Stage ............................64 
Table 8.1: Blood Sampling for PK Analysis  Part 1 PK Stage ..................................................68 
Table 8.2: Blood Sampling for PK Analysis  Part 1 Dose Finding and Part 2 ..........................69 
Table 17.1: Eastern Cooperative Oncology Group Performance Status Scale ............................101 
Table 17.2: Overall Response: Subjects with Target (+/ Non-target) Disease ...........................107 
Table 17.3: New York Heart Association Functional Classification ...........................................109 
 
 

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LIST OF FIGURES 
Figure 3.1: Study Design Schema of DS8201-A-U201 ................................................................35 
 

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LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
AC 
Adjudication Committee  
ADA 
anti-drug antibody(ies) 
ADC  
antibody drug conjugate   
 
 
AE 
adverse event 
AESI 
adverse events of special interest 
ALP  
alkaline phosphatase  
ALT  
alanine aminotransferase (transaminase) 
ANC 
absolute neutrophil count 
ASCO-CAP 
American Society of Clinical Oncology – College of American 
Pathologists 
AST  
aspartate aminotransferase (transaminase) 
AUC 
area under the concentration-time curve 
BI  
before infusion  
CBR 
clinical benefit rate 
cfDNA 
cell free deoxyribonucleic acid 
CHF  
congestive heart failure 
CL 
clearance 
Cmax 
maximum plasma/serum concentration 
CR  
complete response 
CRF 
case report form 
eCRF 
electronic case report form 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DAR 
drug-to-antibody ratio  
DCR 
disease control rate 
DS1 
drug substance manufactured using MAAL-9001 
 
DS2 
drug substance manufactured using MAAL-9001 
 

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ABBREVIATION 
DEFINITION 
PD 
disease progression 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PT 
preferred term 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended Phase 2 dose 
Q3W 
once every 3 weeks 
QoL 
quality of life 
QTc 
corrected QT interval 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SLD 
sum of the longest diameters 
SOC 
system organ class 
SOP 
standard operating procedure 
SpO2 
peripheral oxygen saturation 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T1/2 
terminal elimination half-life 
T-DM1 
trastuzumab emtansine 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
US 
United States 
Vss 
volume of distribution at steady-state 

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comparability of FL-DP2 used in this study to FL-DP1 data reported from the DS8201-A-J101 
study will be performed as detailed in Section 1.2. 
1.1.1.3. 
Intended Use Under Investigation 
This study will examine the anti-tumor activity of DS-8201a in subjects with HER2-positive, 
unresectable and/or metastatic breast cancer who are resistant or refractory to trastuzumab 
emtansine (T-DM1). 
1.1.1.4. 
Nonclinical Studies 
1.1.1.4.1. 
Pharmacology 
DS-8201a inhibits tumor growth by mainly topoisomerase I inhibition-derived deoxyribonucleic 
acid damage, and induces apoptosis by the MAAA-1181a that is released from DS-8201a after 
internalization in cancer cells via HER2.  In vitro nonclinical pharmacology studies have 
confirmed that DS-8201a exhibits HER2 expression-dependent cell growth inhibition, and in 
vivo studies using tumor-bearing mouse models suggest that the administration of DS-8201a 
results in the regression of a broad array of HER2-expressing tumors, including multiple models 
unresponsive to T-DM1.  In addition, in vivo studies in tumor-bearing mouse models have 
confirmed that DS-8201a has antitumor activity against HER2 low-expressing tumors which are 
insensitive to T-DM1.  Moreover, DS-8201a demonstrated potent efficacy in mice inoculated 
with a mixture of HER2-positive and negative cells while T-DM1 did not, due to more potent 
bystander killing and higher cell membrane permeability of the conjugated toxin.7,8  The effect 
therefore supports the efficacy of DS-8201a against tumors with HER2 heterogeneity. 
1.1.1.4.2. Safety Pharmacology 
In a safety pharmacology study in monkeys treated with single IV doses of DS-8201a, no effects 
on the cardiovascular system, the respiratory system, or the central nervous system were 
observed under the study condition.  In addition, in human ether a-go-go related gene (hERG) 
studies of MAAA-1181a, the drug component, MAAA-1181a did not inhibit the hERG channel 
current. 
1.1.1.4.3. Pharmacokinetics and Drug Metabolism 
The plasma DS-8201a concentrations decreased exponentially following a single IV 
administration of DS-8201a at 0.1 mg/kg to 3.0 mg/kg to cynomolgus monkeys.  The volume of 
distribution at steady-state (Vss) was close to the plasma volume.  The clearance (CL) decreased 
as the dose increased, and the pharmacokinetics (PK) was found to be non-linear.  Both DS-
8201a and the total antibody, bound and unbound antibody combined, exhibited similar plasma 
concentration-time profiles at all dose levels, as well as similar AUC.  All individual plasma 
concentrations of MAAA-1181a, the released drug from DS-8201a, were below the lower limit 
of quantification (0.100 ng/mL) at 0.1 and 0.3 mg/kg.  A low-plasma level of MAAA-1181a was 
detected at limited time points at 1.0 and 3.0 mg/kg.  No anti-DS-8201a antibody was detected in 
any of the animals. 

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The mean plasma protein binding ratios of MAAA-1181a at 10 ng/mL to 100 ng/mL were from 
90.3% to 92.5% in mice, 94.2% to 96.7% in rats, 86.5% to 89.1% in monkeys, and 96.8% to 
98.0% in humans.   
The release rates of MAAA-1181a from DS-8201a increased gradually throughout the 
incubation period in mouse, rat, and monkey plasma with the release rates from 1.2% to 3.9% on 
Day 21.  On the other hand, the release rate reached a plateau on Day 14 in human plasma with 
the release rates from 2.2% to 2.4%.  These results indicate that most DS-8201a is stable in 
plasma. 
No major differences were found among the metabolite profiles of DS-8201a in rat, monkey, and 
human hepatocytes.  MAAA-1181a was metabolized by cytochrome P450 (CYP) enzymes; 
CYP3A4 was the primary CYP enzyme in the metabolism, CYP3A5 and CYP2D6 were also 
involved in the metabolism.  MAAA-1181a did not inhibit organic anion transporter (OAT) 3, 
organic cation transporter (OCT) 1, OCT2, organic anion- transporting polypeptide (OATP) 1B3, 
multidrug and toxin extrusion (MATE) 1, MATE2-K, P-glycoprotein, breast cancer resistance 
protein (BCRP), and bile salt export pump (BSEP) (IC50 >30 μmol/L).  MAAA-1181d inhibited 
OAT1 and OATP1B1 with the IC50 values of 12.7 and 14.4 μmol/L, respectively, however the 
values were much higher than the Cmax of MAAA-1181a in humans (9.25 ng/mL [0.019 
μmol/L] at 8.0 mg/kg of DS-8201a).  In addition, OATP1B were considered to contribute to the 
human hepatic uptake of MAAA-1181a. 
The plasma concentration time profiles following repeated administration of DS-8201a Q3W for 
3 cycles (Q3W × 3) to humans were simulated on the basis of the pharmacokinetics of DS-8201a 
in cynomolgus monkeys.  These estimates were compared to the plasma concentrations of DS-
8201a in the studies in tumor-bearing mice.  As a result, the minimum effective dose and the 
pharmacologically active dose were expected to be 0.8 and 4.8 mg/kg, respectively, with a 
dosage Q3W in humans. 
1.1.1.4.4. 
Toxicology 
In a study of intermittent IV dosing of DS-8201a in rats (Q3W dosing for 6 weeks), no deaths or 
moribund animals were found at dose levels up to 197 mg/kg, the maximum dose.  The major 
observed findings included testicular and intestinal toxicity at dose levels of 20 mg/kg and 
greater, and lymphatic/hematopoietic, skin, and incisor tooth, and renal toxicity at dose levels of 
60 mg/kg and greater.  Except for the testicular and incisor tooth changes, these changes were all 
found to recover. 
In an intermittent IV dosing study of DS-8201a in cynomolgus monkeys (Q3W, 6 weeks), one 
female was sacrificed moribund at 78.8 mg/kg, the highest dose level.  The major toxicity 
findings in this moribund animal were observed in the intestine, hematopoietic system, skin, and 
kidney.  The cause of the moribundity appeared to be the deteriorated condition of the animal 
which included decreased body weight and food consumption, as well as bone marrow toxicity 
and intestinal toxicity.  The major findings of toxicity in the surviving animals were observed in 
the intestine at dose levels of 10 mg/kg and greater, and in the lung, testes, and skin at dose 
levels of 30 mg/kg and greater.  In addition, hematopoietic system toxicity, renal toxicity, and 
electrocardiogram (ECG) abnormalities (shortened PR interval and corrected QT interval [QTc] 
prolongation) were found at 78.8 mg/kg.  Except for the pulmonary and skin toxicity 
(pigmentation), these findings tended to recover. 

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Thus, as described above, the severely toxic dose in 10% of the animals (STD10) in a rat 
intermittent IV dosing study of DS-8201a was found to be greater than 197 mg/kg.  In the 
monkey study, due to observed moribundity at 78.8 mg/kg and evidence of critical pulmonary 
toxicity (eg, interstitial inflammation and/or alveolar edema) in the surviving animals, it was 
concluded that the highest non-severely toxic dose (HNSTD) is 30 mg/kg.  
In an intermittent IV dose toxicity study of MAAA-1181a (morning dosing for 4 weeks), 
findings in the lymphatic/hematopoietic system, intestinal tract, and the cornea of the eye were 
observed at 3 mg/kg and greater in rats and there was no death or moribundity at up to 30 mg/kg.  
Findings similar to those in rats were observed in cynomolgus monkeys at dose levels of 1 mg/kg 
and greater.  In addition, 1 female monkey died and 1 male monkey was sacrificed moribund at 
12 mg/kg.  Although effects on the heart (focal myocardial cell degeneration/necrosis) were 
found in the moribund male along with the above mentioned toxicities, there were no abnormal 
heart findings in the female that died even though both animals exhibited worsening clinical 
conditions associated with sustained decreases in food consumption, bone marrow toxicity, and 
intestinal toxicity.  These changes were considered to be the cause of the death and moribundity.  
The common adverse findings with both DS-8201a and MAAA-1181a studies were intestinal 
and lymphatic/hematopoietic system toxicities.  For DS-8201a treatment, pulmonary, testicular, 
skin and renal toxicities were observed while heart, liver, and corneal toxicities were found only 
when MAAA-1181a was administered.   
In a human cross-reactivity study of DS-8201a with a panel of human tissues, DS-8201a-related 
cell membrane staining was found only in the placenta.  In a cross-reactivity study of DS-8201a 
with selected cynomolgus monkey tissues (eg, brain, liver, kidney, lung, heart, intestines, 
lymphoid organs, testis, and skin), neither membranous nor cytoplasmic staining was noted in 
any tissues.   
In an in vitro 3T3 NRU phototoxicity study, MAAA-1181a was found to be phototoxic to Balb/c 
3T3 mouse fibroblasts. However, in an in vivo single-dose phototoxicity study with MAAA-
1181d in pigmented rats, no phototoxic reaction was noted at 3 mg/kg, the highest dose tested. 
For additional nonclinical data supporting DS-8201a use in nonclinical studies, please refer to 
the current Investigator’s Brochure (IB). 
1.1.1.5. 
Clinical Experience 
The DS-8201a first-in-human (FIH) study (Protocol DS8201-A-J101) is an open-label, dose 
finding study to assess the safety and tolerability of DS-8201a in subjects with advanced solid 
tumors.  The study is being conducted in 2 parts; dose escalation (Part 1) and dose expansion 
(Part 2): Part 1 was a dose escalation phase in subjects with either advanced breast cancer or 
gastric/ gastro-esophageal junction (GEJ) adenocarcinoma.  Part 2 is the expansion phase and 
focuses on HER2 expressing breast (previously treated T-DM1 HER2 positive breast cancer) and 
gastric/GEJ junction adenocarcinoma, HER2 low-expressing breast cancer, as well as other 
HER2 expressing solid cancers.  Preliminary results from Part 1 indicate that DS-8201a has a 
favorable safety and PK profile and robust antitumor activity in breast cancer subjects, with 
tumors that were previously treated with T-DM1.  Events of special interest detailed in the Phase 
1 protocol included infusion reactions, cardiac events, and pneumonitis.  Periodic cardiac 
assessments are performed including echocardiogram (Echo) or multigated acquisition (MUGA) 
performed at every 2 cycles (42 days) and 12-lead triplicate ECGs performed at least every cycle 

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(21 days).  As of 08 Jun 2017, a total of 148 subjects, 24 in Part 1 and 124 in Part 2, have 
received DS-8201a in this study.  In Part 1, no dose limiting toxicities were reported and the 
maximum tolerated dose (MTD) was not reached.  Two doses were chosen for expansion in Part 
2: 5.4 mg/kg and 6.4 mg/kg.   
For 148 subjects who have received DS-8201a in the study, the most common AEs (>20%) of 
any grades were nausea (65%), decreased appetite (53%), vomiting (34%), platelet count 
decreased (31%), anemia (28%), alopecia (26%), diarrhea (24%), constipation (24%), neutrophil 
count decreased (24%), white blood cell count decreased (24%), and malaise (22%).  The 
majority of the AEs were of Grade 1 or 2 severity; 52 (35.1%) of 148 subjects experienced Grade 
3 AEs and 10 subjects (6.8%) experienced Grade 4 AEs as the worst grade experienced.  A total 
of 3 subjects died due to an AE; 1 due to mechanical ileus, 1 due to extradural 
hematoma/traumatic intracranial hemorrhage occurring more than 28 days after last dose of 
study drug, and 1 due to disease progression reported as an AE.  All these fatal events were 
considered not related to study drug by the investigators. 
As of 08 Jun 2017, 13 (8.7%) of 148 subjects experienced treatment-emergent adverse events 
(TEAEs) relating to cardiotoxicity in this on-going study.  Of these 13 subjects, 9 experienced 
QT prolongation (7 Grade 1 and 2 Grade 2, all non-serious), all considered related to the study 
therapy.  Two subjects experienced ejection fraction decreased (Grade 2, non-serious, related), 1 
subject experienced Grade 2 tachycardia and 1 subject experienced heart rate decreased (related).  
No action was taken regarding the study drug therapy and no subjects discontinued study therapy.   
Irrespective of the investigator/Sponsor causality, of the 148 treated subjects, there were 3 
subjects (where one received 8.0 mg/kg and the other 2 received 6.4 mg/kg) who had 
experienced one serious and 2 non-serious pneumonitis (one was Grade 1 and the other as Grade 
2).  There were also 2 subjects who experienced interstitial lung disease (ILD; 1 serious and 
Grade 3 in severity, and the other non-serious; with Grade 1 severity).   
Of the 148 subjects, a total of 2 subjects (1.4%) experienced infusion-related reactions (both 
Grade 1, non-serious) and 1 subject experienced infusion site extravasation (Grade 1, non-
serious).  Study drug administration was interrupted for 1 of 3 reported events.  The outcome was 
reported as resolved in all subjects. 
Overall efficacy results from all cohorts in Part 1 demonstrated an objective response rate (ORR) 
of 34.8% and disease control rate (DCR) of 91.3%.  Subjects in the higher dose levels (≥5.4 
mg/kg, 15 subjects) showed ORR of 53.3%.  Overall efficacy results from all cohorts in Part 2 
demonstrated an ORR of 48.8% and DCR of 85.7%.  Breast cancer cohorts with HER2 positive 
and low expression, Part 2a and 2c, showed ORR of 61.5% and 50.0%, and DCR of 96.2% and 
90.0% respectively.  The HER2 positive gastric cancer cohort showed ORR of 48.4% and DCR 
of 80.6%. 
Please see the current IB for an updated summary of clinical studies. 
1.1.1.6. 
Summary of Clinical Pharmacokinetics 
PK was evaluated in 22 Japanese subjects who received DS-8201a.  Following a single IV 
administration, the systemic exposure of DS-8201a increased approximately proportional to dose.  
The pharmacokinetic (PK) parameters at 5.4, 6.4, and 8.0 mg/kg are shown in Table 1.1, 
Table 1.2, and Table 1.3.  The maximum serum concentration (Cmax) of DS-8201a at 6.4 mg/kg 

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was achieved with a median time to Cmax (Tmax) of 2.16 h.  Cmax and AUC from the time of 
dosing to 21 days (AUC0 21d) at 6.4 mg/kg were 181 μg/mL and 900 μg·day/mL, respectively.  
The systemic exposure at 6.4 mg/kg in subjects in Cycle 1 was observed to exceed the systemic 
efficacious exposure observed during the non-clinical pharmacology evaluation.  At this dose, 
the mean terminal elimination half-life (T1/2) of DS-8201a was 7.33 days at 6.4 mg/kg, and Vss 
was 58.6 mL/kg which is similar to the serum volume. 
PK parameters of total antibody were close to that of DS-8201a. 
Cmax and AUC for the dosing interval (AUC0 21d), which were quite low, of MAAA-1181a was 
6.80 ng/mL and 31.0 ngday/mL at 6.4 mg/kg, respectively.  The T1/2 of MAAA-1181a was 
similar to that of DS-8201a. 
 
Table 1.1: 
PK Parameters of DS-8201a (± standard deviation) 
 
Cmax 
(g/mL) 
Tmaxa 
(h) 
AUC0-21d 
(gday/mL) 
AUCinf 
(gday/mL) 
T1/2 
(day) 
CL 
(mL/day/kg) 
Vss 
(mL/kg) 
5.4 mg/kg 
(N 6) 
127 ±17.2 
1.92 
(1.92, 2.16) 
542 ±163 
590 ±186 
6.03 ±0.603 
10.1 ±3.90 
75.2 
±24.2 
6.4 mg/kg 
(N 6) 
181 
±33.1 
2.16 
(1.44, 4.08) 
900 ±155 
1030 ±209 
7.33 ±1.64 
6.41 ±1.12 
58.6 
±11.0 
8.0 mg/kg 
(N 3) 
216 
±52.0 
1.92 
(1.92, 2.16) 
914 ±235 
1020 ±279 
6.97 ±0.357 
8.17 ±1.93 
69.7 
±13.1 
AUC  area under the concentration time curve; AUC0-21d  AUC from the time of dosing to 21 days; AUCinf  AUC from 0 
through infinity; CL  clearance; Cmax  maximum plasma/serum concentration; N  number of evaluable subjects; 
T1/2  terminal elimination half life; Tmax  time to Cmax; Vss  volume of distribution at steady state. 
a range 
 
Table 1.2: 
PK Parameters of Total Antibody (± standard deviation) 
 
Cmax 
(g/mL) 
Tmaxa 
(h) 
AUC0-21d 
(gday/mL) 
AUCinf 
(gday/mL) 
T1/2 
(day) 
5.4 mg/kg 
(N=6) 
116 ±13.9 
1.92  
(1.92, 6.96) 
606 ±147 
682±172 
6.78 ±2.39 
6.4 mg/kg 
(N=6) 
146 ±18.9 
3.84  
(2.16, 6.96) 
877±97.0 
1050±149 
8.25 ±2.16 
8.0 mg/kg 
(N=3) 
178 ±18.5 
2.16  
(1.92, 6.72) 
1090 ±213 
1270±296 
7.35 ±0.417 
AUC  area under the concentration time curve; AUC0-21d  AUC from the time of dosing to 21 days; AUCinf  AUC from 0 
through infinity; Cmax  maximum plasma/serum concentration; N  number of evaluable subjects; T1/2  terminal elimination 
half life; Tmax  time to Cmax. 
a range 
 

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Table 1.3: 
PK Parameters of MAAA-1181a (± standard deviation) 
 
Cmax 
(ng/mL) 
Tmax (h)a 
AUC0-21d 
(ngday/mL) 
AUCinf 
(ngday/mL) 
T1/2 (day) 
5.4 mg/kg 
(N=6) 
10.8 ±7.56 
5.28 
(3.84, 23.76) 
40.4 ±19.7 
43.6 ±21.2 
6.11 ±0.811 
6.4 mg/kg 
(N=6) 
6.80 ±1.72 
6.72 
(4.08, 7.20) 
31.0 ±5.10 
34.2 ±5.63 
6.28 ±1.17 
8.0 mg/kg 
(N=3) 
9.25 ±3.18 
6.72 
(6.72, 6.96) 
39.4 ±6.43 
43.4 ±9.16 
6.36 ±1.53 
AUC  area under the concentration time curve; AUC0-21d  AUC from the time of dosing to 21 days; AUCinf  AUC from 0 
through infinity; Cmax  maximum plasma/serum concentration; N  number of evaluable subjects; T1/2  terminal elimination 
half life; Tmax  time to Cmax. 
a range 
1.2. 
Study Rationale  
HER2 is a member of the HER superfamily that initiates signal transduction via the PI3K/AKT 
and RAS/MAPK pathways.9,10  In human advanced solid tumors, expression of HER2 protein 
has been reported in various tumor tissues and a variety of cultured tumor cell lines including 
breast cancer,11 gastric cancer,12,13  pancreatic cancer,14  lung cancer,15 colorectal cancer,16 and 
ovarian cancer.17  There are also many reports demonstrating an association between expression 
of HER2 protein and poor clinical prognosis.  In normal human tissue, low expression of HER2 
protein has been reported on cell membranes of epithelial cells in the gastro-intestinal, 
respiratory, reproductive, and urinary tract as well as in the skin, breast, and placenta.18   
Advanced HER2 positive breast cancer resistant or refractory to T-DM1 treatment remains an 
area of high unmet medical need.  For the past few decades, the main approaches to treatment of 
subjects with unresectable and/or metastatic breast cancer depended on the use of conventional 
cytotoxic chemotherapies and molecularly targeted agents, with no biomarkers that could 
potentially identify responsive subjects and/or safety risks.  Therefore, both efficacy and safety 
advances are needed in the treatment approaches for subjects with unresectable and/or metastatic 
breast cancer. 
In an effort to expand the treatments for subjects with unresectable and/or metastatic breast 
cancer, HER2-targeted drugs (eg, trastuzumab, pertuzumab, T-DM1) have been developed as 
individualized molecularly targeted therapy for HER2-positive breast cancer.  Anti-HER2 drugs 
have been reported to prolong PFS and OS, with higher levels of efficacy and safety in HER2-
positive breast cancer subjects, compared with conventional cytotoxic chemotherapies.  Anti-
HER2 drugs have also been reported to improve quality of life (QoL).  However, none of these 
treatments are curative and there are still many HER2-positive breast cancer subjects who have 
tumors that are unresponsive to approved HER2-targeted drugs, or acquire resistance to these 
drugs during treatment. 
Based on the results of the CLEOPATRA trial, current recommendations for HER2 positive 
metastatic breast cancer are for first line therapy with trastuzumab, pertuzumab, and a taxane.19  
In 2016, United States (US) prescribing patterns indicated that the large majority of HER2 
positive subjects received pertuzumab in the first or second line setting.  Slightly lower rates 

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same class, the benefit-risk balance supports clinical development of DS-8201a in this subject 
population. 
For up-to-date assessments of risks and benefits to subjects, please refer to the current IB for 
DS-8201a. 

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2. 
STUDY OBJECTIVES AND HYPOTHESIS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objectives 
 To determine ORR of DS-8201a in HER2-positive, unresectable and/or metastatic 
breast cancer subjects who are resistant or refractory to T-DM1. 
2.1.2. 
Secondary Objectives 
 To evaluate duration of response, best percent change in the sum of the longest 
diameters (SLD) of measurable tumors, DCR, clinical benefit rate (CBR), PFS, and 
OS 
 To further evaluate the safety of DS-8201a  
 To determine the PK of DS-8201a 
 To determine the RP2D of DS-8201a 
2.1.3. 
Exploratory Objectives 
 To evaluate duration of stable disease, and time to response 
 To evaluate potential biomarkers of response, such as the serum HER2-extracellular 
domain (ECD) 
 To evaluate exposure-response relationships for efficacy and safety endpoints 
2.2. 
Study Hypothesis 
DS-8201a confers a significant benefit in ORR in human epidermal growth factor receptor 2 
positive (HER2+) breast cancer subjects who are resistant or refractory to T-DM1. 
2.3. 
Study Endpoints 
2.3.1. 
Primary Endpoints 
ORR assessed by independent central imaging facility review based on Response Evaluation 
Criteria in Solid Tumors (RECIST) version 1.1. 
2.3.2. 
Secondary Endpoints 
 Efficacy Endpoints (based on central assessments unless otherwise stated): 
 Duration of response 
 Best percent change in the SLD of measurable tumors 
 DCR 
 CBR 

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 PFS 
 OS 
 ORR assessed by the investigator based on RECIST version 1.1. 
 Safety Endpoints will include: 
 serious adverse events (SAEs)  
 TEAEs  
 TEAEs leading to discontinuations 
 Adverse events of special interest (AESIs) 
 Elevated troponin levels 
 physical examination findings (including Eastern Cooperative Oncology Group 
performance status [ECOG PS])  
 vital sign measurements 
 standard clinical laboratory parameters (central lab) 
 ECG parameters  
 Echo/MUGA findings  
 ophthalmologic findings, and  
 anti-drug antibody (ADA). 
 Pharmacokinetic Endpoints (DS-8201a, total anti-HER2 antibody and MAAA-
1181a): 
 PK parameters (Cycle 1): Cmax, Tmax, AUClast, AUC0 21d, and, if appropriate, 
AUCinf, T1/2, CL and Vss 
 Serum concentrations 
2.3.3. 
Exploratory Endpoints 
 Exploratory efficacy endpoints: 
 Duration of stable disease 
 Time to response 
 Evaluate exposure-response relationships for efficacy and safety endpoints 
 Potential biomarkers of response, such as serum HER2ECD concentrations 

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3. 
STUDY DESIGN 
3.1. 
Overall Design 
3.1.1. 
Overview 
This is Phase 2, open-label, multicenter, 2-part, study designed to investigate the anti-tumor 
activity as well as the safety and efficacy of DS-8201a in HER2-positive, unresectable and/or 
metastatic breast cancer subjects who are resistant or refractory to T-DM1. 
Part 1 will enroll 120 subjects in a 2 stage design: a PK Stage and a Dose Finding Stage designed 
to define the RP2D that will be evaluated in Part 2.  
 PK Stage: approximately 20 subjects at 7.4 mg/kg dosing, 20 subjects at 6.4 mg/kg 
dosing and 20 subjects at 5.4 mg/kg dosing will be randomized in a 1:1:1 ratio.  Two 
dose levels will be selected based on the PK results. 
 Dose Finding Stage: approximately 30 subjects at each dose level will be randomized 
in a 1:1 ratio into 1 of 2 treatment groups selected after the PK analysis.  A dose 
selection analysis will be performed to evaluate both safety and efficacy in order to 
determine the optimal dose for DS-8201a. 
Part 2a will continue to enroll approximately 100 subjects at the RP2D of 5.4 mg/kg (see 
Section 11.5) as well as the Phase 1 trial DS8201-A-J101.  Part 2b will enroll an open-ended 
number of subjects that received T-DM1 but are not eligible for the primary analysis.  This is an 
exploratory cohort with the objective to explore the efficacy of DS-8201a in subjects who 
discontinued prior T-DM1 therapy for reasons other than progression of disease.  Part 2b will 
enroll an open-ended number of subjects.  The enrollment duration of Part 2b is determined 
based on enrollment in Part 2a.  Part 2a and Part 2b will begin enrollment simultaneously and 
complete enrollment when the target of approximately 100 subjects enrolled is reached for Part 
2a.  Approximately 10 to 15 subjects would be expected to enroll in Part 2b.  The exploratory 
analysis for Part 2b will be performed at the same time as the primary analysis cohort including 
all subjects in Part 1 and Part 2a treated at the RP2D of 5.4 mg/kg. 
DS-8201a will be administered 
 at a dose of 7.4 mg/kg, 6.4 mg/kg or 
5.4 mg/kg every 3 weeks. 
The study treatment will be continued according to the dosing criteria to derive clinical benefit in 
the absence of withdrawal of subject consent, PD, or unacceptable toxicity.  If the study 
treatment is delayed more than 4 weeks from the planned date of administration, the subject will 
be withdrawn from the study drug (see Section 5.7.3). 
 

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Figure 3.1: 
Study Design Schema of DS8201-A-U201 
 
History of past treatment with pertuzumab will be collected for all study subjects.  The study 
plans to enroll 100 or more subjects with history of prior pertuzumab treatment in the 
metastatic/advanced breast cancer setting.  If after 150 subjects have been enrolled at the RP2D 
(20 from the PK stage, 30 from the dose finding stage and 100 from Part 2a), less than 100 such 
subjects have been enrolled, the study may continue to enroll subjects but only those meeting this 
criteria, and until at least 100 such subjects have been enrolled.  This study also has a cap for 
subjects with moderate hepatic impairment at approximately 10 subjects (See Section 4.1, #10). 
3.1.2. 
Duration of the Study 
Enrollment is planned to occur over approximately 12 months, with treatment, and follow-up 
projected to be continued for at least 10 months after last subject enrolled.  Thus, the anticipated 
duration of the study is at least 22 months. 
Sponsor may terminate the study at any time and study termination may also be requested by (a) 
competent authority(ies).  
3.1.3. 
Duration of Subject Participation 
The screening period is up to 28 days.  Once subject is randomized, Cycle 1 Day 1 (first dose) 
should occur within 7 days from the randomization date.  Each cycle of treatment will be 21 days.  
The number of treatment cycles with DS-8201a is not fixed.  Upon commencing study treatment, 
subjects may continue receiving study drug until the occurrence of any of the events defined in 
Section 5.7.1.  Most subjects are expected to receive between 10 and 20 cycles of treatment. 
Regardless of reason for discontinuation from study treatment, all subjects, may be contacted 
every 3 months until death or until follow-up data collection is no longer of scientific value or 
otherwise needed (at the Sponsor’s discretion), to obtain information about subsequent 
treatment(s) and survival status. 
3.1.4. 
Definition of the End of the Study 
The end of the study is defined as the last subject visit or contact, including telephone contacts, 
for collection of any study-related data.  

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3.2. 
Discussion of Study Design 
It is estimated that approximately 230 subjects will be enrolled in the study at approximately 110 
sites in North America, Japan and other Asian countries, and Europe.  Other countries may also 
be considered.  
3.2.1. 
Selection of Dose 
The dose selection was based on clinical data from DS8201-A-J101 and subsequent exposure-
response analysis.  Dose up to 8.0 mg/kg was shown to be tolerable in DS8201-A-J101, and 
modeling results on efficacy and safety endpoints supported the selection of 5.4, 6.4, and 
7.4 mg/kg, given the risk benefit considerations.  
 

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4. 
STUDY POPULATION 
Each subject will sign an Informed Consent Form (ICF) provided by the site.  A subject is 
considered enrolled in the study upon the investigator or designee obtaining written informed 
consent from the subject, (Section 15.2) at the time of Screening and upon determination that all 
inclusion and exclusion criteria have been satisfied. 
Investigators will maintain a confidential screening log of all potential study candidates that 
includes limited subject information (initials, age, gender) and outcome of screening process (ie, 
enrollment in the study, reason for ineligibility, refused to participate). 
Investigators will be expected to maintain an Enrollment Log of all subjects enrolled in the study 
indicating their assigned study number. 
Investigators will maintain a confidential subject identification code list.  This confidential list of 
the names of all subjects, allocated study numbers on enrolling in the study, allows the 
investigator to reveal the identity of any subject when necessary. 
4.1. 
Inclusion Criteria 
Subjects must satisfy all of the following criteria to be included in the study: 
1. Men or women ≥ 20 years old in Japan and Korea, ≥ 18 years old in the US (for other 
countries, please follow the reference2) 
2. Pathologically documented breast cancer that: 
 is unresectable or metastatic; 
 has confirmed HER2 positive expression (estrogen receptor/progesterone receptor 
positive subjects may be enrolled if they are HER2 positive) according to American 
Society of Clinical Oncology  College of American Pathologists (ASCO-CAP) 
guidelines21 evaluated at a Central Laboratory.  See Laboratory Manual for details. 
3. Subjects must have an adequate tumor sample available for confirmation of HER2 status 
by Central Laboratory (based on most recent tumor tissue sample, see Section 6.1)   
4. Subject must have breast cancer which is resistant or refractory to T-DM1 with 
documented clinical or radiographic progression of disease during or after treatment with 
T-DM1 
 For Part 2b, subjects must have discontinued treatment with T-DM1 for reasons other 
than resistant or refractory disease 
5. Presence of at least one measurable lesion per RECIST version 1.1 
6. LVEF ≥ 50% 
7. ECOG PS 0 or 1 
8. Adequate bone marrow function, defined as: 
                                                 
2 https://hrpo.wustl.edu/wp-content/uploads/2015/01/5-Determining-Legal-Age-to-Consent.pdf 

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 Absolute neutrophil count (ANC) ≥ 1.5 × 109/L (G-CSF administration is not 
allowed within 1 week prior to screening assessment) 
 Platelet count ≥ 100 × 109/L (Platelet transfusion is not allowed within 1 week prior 
to screening assessment) 
 Hemoglobin level ≥ 9.0 g/dL (Red blood cell transfusion is not allowed within 1 
week prior to screening assessment) 
9. Adequate renal function, defined as: 
 Creatinine clearance ≥ 30 mL/min, as calculated using the Cockcroft Gault equation 
(Section 17.1), ([{140  age in years} × {actual weight in kg}] divided by [{72 × 
serum creatinine in mg/dL} multiplied by 0.85 if female])  
10. Adequate hepatic function, including mild-moderate hepatic impairment defined as the 
following: 
 Normal hepatic function to mild hepatic dysfunction: Total bilirubin ≤ 1.5 × ULN or 
< 3 × ULN in the presence of documented Gilbert’s syndrome or liver metastases at 
baseline and aspartate transaminase (AST)/alanine transaminase (ALT) ≤ 5 × ULN 
 Moderate hepatic dysfunction: total bilirubin > 1.5 × ULN and ≤ 3 × ULN and 
aspartate transaminase (AST)/alanine transaminase (ALT) ≤ 5 × ULN. After 
approximately 10 subjects with moderate hepatic dysfunction have been enrolled, 
subsequent subjects with moderate hepatic dysfunction will be excluded 
11. Adequate blood clotting function, defined as: 
 International normalized ratio and activated partial thromboplastin time ≤ 1.5 × 
ULN 
12. If <100 of the planned 150 subjects (20 from the PK stage, 30 from the dose finding stage 
and 100 from Part 2a) enrolled and dosed with the RP2D have a history of pertuzumab 
treatment in the metastatic setting, enrollment may continue to achieve this number, and 
prior 1st or 2nd line pertuzumab treatment in the advanced/metastatic breast cancer setting 
will be required for these additional subjects. 
13. Subjects should be able and willing to comply with protocol visits and procedures 
 Male and female subjects of reproductive/childbearing potential must agree to use a 
highly effective form of contraception or avoid intercourse during and upon 
completion of the study and for at least 4.5 months after the last dose of study drug.  
For the purpose of this protocol, methods considered as highly effective methods of 
contraception including: 
 Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
 Oral 
 Intravaginal 
 Transdermal 

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 Progestogen-only hormonal contraception associated with inhibition of ovulation: 
 Oral 
 Injectable 
 Implantable  
 Intrauterine device (IUD)  
 Intrauterine hormone-releasing system (IUS)  
 Bilateral tubal occlusion 
 Vasectomized partner 
 Complete sexual abstinence defined as refraining from heterosexual intercourse 
during and upon completion of the study and for at least 4.5 months after the last dose 
of study drug.  Periodic abstinence (calendar, symptothermal, post-ovulation 
methods) is not an acceptable method of contraception.  
Non-childbearing potential defined as pre-menopausal females with a documented tubal 
ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous 
amenorrhea (in questionable cases, a blood sample with simultaneous follicle-stimulating 
hormone [FSH] > 40 mIU/mL and estradiol < 40 pg/mL [< 147 pmol/L] is confirmatory).  
Females on hormone replacement therapy (HRT) and whose menopausal status is in 
doubt will be required to use one of the contraception methods outlined for women of 
childbearing potential if they wish to continue their HRT during the study.  Otherwise, 
they must discontinue HRT to allow confirmation of postmenopausal status prior to study 
enrollment.  For most forms of HRT, at least 2-4 weeks will elapse between the cessation 
of therapy and the blood draw; this interval depends on the type and dosage of HRT.  
Following confirmation of their postmenopausal status, they can resume use of HRT 
during the study without use of a contraceptive method.  
14. Men who are fertile and sexually active should be willing to use highly effective methods 
of contraception if their partners are of reproductive potential.  
15. Male subjects must not freeze or donate sperm starting at Screening and throughout the 
study period, and at least 4.5 months after the final study drug administration.  
Preservation of sperm should be considered prior to enrollment in this study. 
16. Female subjects must not donate, or retrieve for their own use, ova from the time of 
Screening and throughout the study treatment period, and for at least 4.5 months after the 
final study drug administration. 
17. Must have provided informed consent for study participation (see Section 15.2) before 
performance of any study-specific procedures or tests. 
4.2. 
Exclusion Criteria 
Subjects who meet any of the following criteria will be disqualified from entering the study: 
1. Medical history of myocardial infarction within 6 months before 
randomization/registration, symptomatic congestive heart failure (CHF) (New York 

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Heart Association Class II to IV, Section 17.4), troponin levels consistent with 
myocardial infarction as defined according to the manufacturer, unstable angina, or 
serious cardiac arrhythmia requiring treatment within 28 days before 
randomization/registration 
2. Has a corrected QT interval (QTc) prolongation to > 470 msec (females) or >450 msec 
(males) based on average of the screening triplicate12-lead ECG 
3. Has a history of (non-infectious) ILD/pneumonitis that required steroids, has current 
ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at 
screening 
4. Brain metastases that are untreated, symptomatic, or require therapy to control symptoms, 
as well as any history of radiation, surgery, or other therapy, including steroids or 
anticonvulsants, to control symptoms from brain metastases within 2 months (60 days) of 
randomization/registration.  After approximately 30 subjects with inactive brain 
metastases [20% of the 150 planned to receive the RP2D] have been enrolled at the 
RP2D, subsequent subjects with any current or past history of brain metastases will be 
excluded 
5. Has clinically significant corneal disease in the opinion of the investigator 
6. History of severe hypersensitivity reactions to other monoclonal antibodies 
7. Substance abuse or medical conditions such as clinically significant cardiac or pulmonary 
diseases or psychological conditions, that may, in the opinion of the investigator, 
interfere with the subject’s participation in the clinical study or evaluation of the clinical 
study results 
8. Social, familial, or geographical factors that would interfere with study participation or 
follow-up 
9. Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals  
10. Known human immunodeficiency virus (HIV) infection, or active hepatitis B surface 
antigen or C infection.  Subjects should be tested for HIV prior to randomization if 
required by local regulations or institutional review board (IRB)/ethics committee (EC) 
11. History of other malignancy(ies), except adequately treated non-melanoma skin cancer, 
curatively treated in-situ disease, or other solid tumors curatively treated, with no 
evidence of disease for ≥ 3 years 
12. Prior treatment with an ADC which consists of an exatecan derivative that is a 
topoisomerase I inhibitor.  
13. Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than 
alopecia) not yet resolved to grade ≤ 1 or baseline.  Subjects with chronic Grade 2 
toxicities may be eligible per the discretion of the investigator after consultation with the 
Sponsor Global Clinical Lead or designee (eg, Grade 2 chemotherapy-induced 
neuropathy) 
14. Therapeutic radiation therapy or major surgery within 4 weeks before study drug 
treatment or palliative radiation therapy within 2 weeks before study drug treatment 

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15. Systemic treatment with anticancer therapy, antibody-based therapy, retinoid therapy, or 
hormonal therapy within 3 weeks before study drug treatment; or treatment with 
nitrosoureas or mitomycin C within 6 weeks before study drug treatment; or treatment 
with small-molecule targeted agents within 2 weeks, or 5 half-lives before study drug 
treatment, whichever is longer 
16. Current treatment with CYP3A4 strong inhibitors and OATP1B inhibitors (Section 17.5) 
(washout period of ≥ 3 elimination half-lives of the inhibitor is required) 
17. Participation in a therapeutic clinical study within 3 weeks before study drug treatment 
(for small-molecule targeted agents [eg, inhibitors], this non-participation period is 
2 weeks or 5 half-lives, whichever is longer), or current participation in other 
investigational procedures 
18. Pregnant or breastfeeding, or planning to become pregnant 
19. Subject must not be a family member of study site personnel or of Sponsor personnel.  
20. Has a history of severe hypersensitivity reactions to either the drug substances or inactive 
ingredients in the drug product. 

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A Drug Accountability Record will be provided for the investigational product.  The record must 
be kept current and should contain the following: 
 dates and quantities of drug received,  
 subject’s identification number and/or initials or supply number (as applicable),  
 the date and quantity of investigational product dispensed and remaining (if from 
individual subject drug units),  
 the initials of the dispenser.  
At the end of the study, as per local laws and/or directed by Sponsor, all unused DS-8201a will 
be returned or destroyed as per local laws or site policy and only after the study monitor has 
completed a final inventory.  As applicable, the study site must file a copy of the appropriate 
institution policy within their investigator site file and provide a copy to the Sponsor.  Please see 
Pharmacy Manual for details.  
All investigational product inventory forms must be made available for inspection by a Sponsor 
authorized representative or designee and regulatory agency inspectors.  
5.3. 
Control Treatment 
Not applicable. 
5.4. 
Dose Interruptions and Reductions 
The investigator will evaluate which toxicities are attributed to the study drug and adjust the dose 
of the drug as recommended below.  All dose modifications should be based on the worst 
preceding toxicity (common toxicology criteria [CTC]AE version 4.03).  Specific criteria for 
interruption, re-initiation, dose reduction and/or discontinuation of DS-8201a are listed in 
Table 5.2. All interruptions or modifications must be recorded on the AE and drug administration 
case report form (CRF).  Appropriate clinical experts should be consulted as deemed necessary.  
For Grade 3 or Grade 4 events, monitoring (including local laboratory tests when appropriate) 
should be performed at intervals no greater than 7 days until AE is determined to be resolving or 
subject is discontinued at end of treatment. 
Prophylactic or supportive treatment for expected toxicities, including management of study-
drug induced AEs will be as per treating physician discretion and institutional guidelines.  
Dose Reduction Guidelines: 
NOTE: There will be no dose modifications for Grade 1 or Grade 2 AEs unless specified below 
in Table 5.2. 
Two dose reductions will be permitted.  The adjustment for reduced dosing of DS-8201a is as 
shown in Table 5.1.   

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Table 5.1: 
Dose Reduction Levels of DS-8201a 
Starting Dose 
Dose Level -1 
Dose Level -2 
7.4 mg/kg 
6.4 mg/kg 
5.4 mg/kg 
6.4 mg/kg 
5.4 mg/kg 
4.4 mg/kg 
5.4 mg/kg 
4.4 mg/kg 
3.2 mg/kg 
Once the dose of DS-8201a has been reduced because of toxicity, all subsequent cycles should 
be administered at that lower dose level unless further dose reduction is required.  More than 2 
dose reductions are not allowed and the subject will be withdrawn from the study treatment if 
further toxicity meeting the requirement for dose reduction occurs.  DS-8201a dose increases are 
not allowed in the study. 
Dose can be interrupted for up to 28 days from the planned date of administration.  If a subject is 
assessed as requiring a dose delay longer than 28 days, the subject will be withdrawn from the 
study. 
Treatment cycles for a subject for whom DS-8201a dosing was temporarily withheld for any 
reason may have future cycles scheduled based on the date of the last DS-8201a dose. 
Investigators may contact the Sponsor’s Global Clinical Lead or designee to discuss questions 
regarding dose modification or discontinuation of study drug. 
Table 5.2: 
Dose modification for DS-8201a 
Worst toxicity CTCAE v4.03 
Grade (unless otherwise 
specified) 
Dose or schedule modification for DS-8201a 
No toxicity 
Maintain dose and schedule 
Infusion Reaction 
Grade 1 (Mild transient 
reaction; infusion interruption 
not indicated; intervention not 
indicated) 
If infusion-related reaction (such as fever and chills, with and without 
nausea/vomiting, pain, headache, dizziness, dyspnea, hypotension) is observed 
during administration, the infusion rate should be reduced by 50% and subjects 
should be closely monitored.  
If no other reactions appear, the subsequent infusion rate could be resumed at the 
initial planned rate.  
Grade 2 (Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment (eg, 
antihistamines, nonsteroidal 
anti-inflammatory drugs 
(NSAIDs), narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 h) 
Administration of DS-8201a should be interrupted and symptomatic treatment 
started (eg, antihistamines, NSAIDs, narcotics, intravenous fluids). 
If the event resolves or improves to grade 1, infusion can be re-started at a 50% 
reduced infusion rate. 
Subsequent administrations should be conducted at the reduced rate. 
Grade 3 or 4 (Prolonged or life-
threatening consequences, 
urgent intervention indicated) 
Administration of DS-8201a should be discontinued immediately and 
permanently. 
Urgent intervention indicated.  Antihistamines, steroids, epinephrine, 
bronchodilators, vasopressors, intravenous fluid therapy, oxygen inhalation etc., 
should be administered. 

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Table 5.2: 
Dose modification for DS-8201a (Continued) 
Worst toxicity CTCAE v4.03 
Grade (unless otherwise 
specified) 
Dose or schedule modification for DS-8201a 
Hematologic Toxicity 
Neutrophil Count Decreased and/or White Blood Cell Count Decreased 
Grade 3  
Delay dose until resolved to ≤ Grade 2, then maintain dose 
Grade 4  
Delay dose until resolved to ≤ Grade 2,  
Reduce dose 1 level 
Febrile Neutropenia (absolute 
neutrophil count < 1 × 109/L, 
fever > 38.3°C or a sustained 
temperature of ≥ 38°C for more 
than one hour) 
Delay dose until resolved,  
Reduce dose by 1 level 
Lymphocyte Count Decreased 
Grade 1 to Grade 3 
lymphopenia 
No dose modification 
Grade 4 (< 0.2 × 109/L) 
Delay dose until resolved to ≤ Grade 2: 
 
If resolved in ≤ 14 days, maintain dose 
 
If resolved in > 14 days, reduce dose 1 level 
Anemia 
Grade 3 (Hemoglobin (Hg) 
<8.0 g/dL); transfusion 
indicated 
Transfuse.  Delay dose until resolved to ≤ Grade 2, then maintain dose 
Grade 4 (Hg <8.0 g/dL) Life 
threatening consequences; 
urgent intervention indicated 
Transfuse.  Delay dose until resolved to ≤ Grade 2, then reduce dose 1 level 
Platelet Count Decreased 
Grade 3 
(platelets <50 to 25 × 109/L) 
Delay dose until resolved to ≤ Grade 1: 
 
If resolved in ≤ 7 days, maintain dose 
 
If resolved in > 7 days, reduce dose 1 level 
Grade 4 (platelets  
< 25 × 109/L) 
Delay dose until resolved to ≤ Grade 1, then reduce dose 1 level 
Cardiac Toxicity 
Symptomatic congestive heart 
failure (CHF) 
Discontinue subject from study treatment 
Decrease in left ventricular 
ejection fraction (LVEF) 
10-20% (absolute value), but 
LVEF > 45% 
Continue treatment with DS-8201a 
LVEF 40% to ≤ 45% and 
decrease is < 10% (absolute 
value) from baseline 
Continue treatment with DS-8201a 
Repeat LVEF assessment within 3 weeks 

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Table 5.2: 
Dose modification for DS-8201a (Continued) 
Worst toxicity CTCAE v4.03 
Grade (unless otherwise 
specified) 
Dose or schedule modification for DS-8201a 
LVEF 40% to ≤ 45% and 
decrease is ≥ 10% (absolute 
value) from baseline 
Interrupt DS-8201a dosing 
Repeat LVEF assessment within 3 weeks. 
If LVEF has not recovered to within 10% from baseline, discontinue subject 
from study treatment 
LVEF < 40% or > 20% 
(absolute value) drop from 
baseline 
Interrupt DS-8201a dosing 
Repeat LVEF assessment within 3 weeks. 
If LVEF < 40% or > 20% drop from baseline is confirmed, discontinue subject 
from study treatment 
Corrected QT (QTc) Prolongation 
Grade 3 (QTc> 500 ms on 2 
separate electrocardiograms) 
Delay dose until resolved to ≤ Grade 1 (QTc ≤ 480 ms), determine if another 
medication the subject was taking may be responsible and can be adjusted, then 
if attributed to DS-8201a, reduce dose 1 level 
Grade 4 (QTc > 500 or > 60 ms 
change from baseline and 
Torsade de pointes or 
polymorphic ventricular 
tachycardia or signs/symptoms 
of serious arrhythmia) 
Discontinue subject from study treatment 
Troponin  
Grade 1 (Levels above the upper 
limit of normal and below the 
level of myocardial infarction as 
defined by the manufacturer) 
If troponin levels are above the upper limit of normal and below the level of 
myocardial infarction as defined by the manufacturer (CTCAE Grade 1) at 
baseline, no repeat testing is required if the troponin level is not Grade 3 
 
Repeat troponin testing at 3 ± 1 hours after initial troponin test.  
 
 
If repeat troponin level at 3 ± 1 hours rises significantly per institutional 
guidelines,  
- 
perform ECG in triplicate; 
- 
repeat troponin testing at 6 ± 1 hours after initial troponin test; 
- 
follow institutional guidelines for management of detectable 
troponin testing. 
 
 
If repeat troponin level at 3 ± 1 hours does not rise significantly per 
institutional guidelines,  
- 
repeat troponin testing at 6 ± 1 hours or at 24 ± 2 hours after initial 
troponin test.  
 
Continue treatment with DS-8201a. 
Grade 3 (Levels consistent with 
myocardial infarction as defined 
by the manufacturer) 
Perform ECG in triplicate 
Repeat troponin testing at 6 hours and 12 hours after initial troponin test. 
Follow institutional guidelines for management of detectable troponin testing.  If 
AMI confirmed, discontinue subject from study therapy. 
Delay dose until resolved to ≤ Grade 1: 
 
If resolved in ≤ 7 days, maintain dose 
 
If resolved in > 7 days, reduce dose 1 level 

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Table 5.2: 
Dose modification for DS-8201a (Continued) 
Worst toxicity CTCAE v4.03 
Grade (unless otherwise 
specified) 
Dose or schedule modification for DS-8201a 
Pulmonary Toxicity 
If a subject develops an acute onset of new or worsening pulmonary or other 
related signs/symptoms such as dyspnea, cough or fever, rule out 
ILD/pneumonitis.  
If the AE is confirmed to have an etiology other than ILD/pneumonitis, follow 
the management guidance outlined in the “Other Non-Laboratory Adverse 
Events” dose modification section below. 
If the AE is suspected to be ILD/pneumonitis, treatment with study drug should 
be interrupted pending further evaluations.  
Evaluations should include: 
 
High resolution CT  
 
Pulmonologist consultation 
 
Pulmonary function tests and pulse oximetry (SpO2) 
 
Arterial blood gases if clinically indicated 
 
One blood sample collection for PK and exploratory biomarker 
analysis as soon as ILD/pneumonitis is suspected, if feasible 
Other tests could be considered as needed.  
As soon as ILD/pneumonitis is suspected, corticosteroid treatment should be 
started promptly as per clinical treatment guidelines (Kubo K, et al 2013 for 
guidance22).  
If the AE is confirmed to be ILD/pneumonitis, follow the management guidance 
as outlined below. 
All events of ILD regardless of severity or seriousness will be followed until 
resolution including after drug discontinuation. 
Grade 1 
The administration of DS-8201a must be interrupted for any ILD event 
regardless of grade. 
For Grade 1 events, DS-8201a can be restarted only if the event is fully resolved 
to Grade 0: 
 
If resolved in ≤ 28 days from day of onset, maintain dose 
 
If resolved in > 28 days from day of onset, reduce dose 1 level 
Grade2, 3, or 4 
Permanently discontinue subject from study treatment. 
Ocular 
Grade 3 
Delay dose until resolved to ≤ Grade 1: 
 
If resolved in ≤ 7 days, maintain dose 
 
If resolved in > 7 days, reduce dose 1 level 
Grade 4 
 
Discontinue subject from study treatment 
Renal Toxicity (serum creatinine) 
Grade 3 (> 3 to 6 × upper limit 
of normal [ULN]) 
Delay dose until resolved to ≤ Grade 2 or baseline, then reduce dose 1 level 
Grade 4 (> 6 × ULN) 
Discontinue subject from study treatment 

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Table 5.2: 
Dose modification for DS-8201a (Continued) 
Worst toxicity CTCAE v4.03 
Grade (unless otherwise 
specified) 
Dose or schedule modification for DS-8201a 
Hepatic Toxicity 
Aspartate Transaminase (AST) or Alanine Transaminase (ALT) with Simultaneous Total Bilirubin (TBL) 
Increased 
AST/ALT ≥3.0 × ULN with 
simultaneous TBL >2.0 × ULN 
Delay study medication until drug-induced liver injury can be ruled out.  
If drug-induced liver injury is ruled out, the subject should be treated 
accordingly, and resumption of study drug may occur after discussion between 
the investigator and Sponsor.  
If drug-induced liver injury cannot be ruled out from diagnostic workup, 
permanently discontinue study treatment. 
Monitor AST/ALT and TBL twice weekly until resolution or return to baseline. 
Aspartate Transaminase (AST) or Alanine Transaminase (ALT) 
Grade 2 (> 3.0 - 5.0 × ULN) 
No action for Grade 2 AST/ALT  
Grade 3:> 5.0 - 20.0 × ULN 
In subjects without liver 
metastases and subjects with 
liver metastases and baseline 
level ≤ 3 × ULN: 
Repeat testing within 3 days. Delay dose until resolved to ≤ Grade 1, then: 
 
If resolved in ≤ 7 days from day of onset, maintain dose 
 
If resolved in > 7 days from day of onset, reduce dose 1 level 
Grade 3 (> 8.0 - 20.0 × ULN) 
In subjects with liver 
metastases, if the baseline level 
was > 3 × ULN 
Repeat testing within 3 days. Delay dose until resolved to ≤ baseline level, then: 
 
If resolved in ≤ 7 days from day of onset, maintain dose 
 
If resolved in > 7 days from day of onset, reduce dose 1 level 
Grade 4 (> 20 × ULN) 
Discontinue subject from study treatment 
Total Bilirubin 
Grade 2 (> 1.5 - 3.0 × ULN) 
If no documented Gilbert’s syndrome or liver metastases at baseline, delay dose 
until resolved to ≤ Grade 1: 
 
If resolved in ≤ 7 days from day of onset, maintain dose 
 
If resolved in > 7 days from day of onset, reduce dose 1 level 
If documented Gilbert’s syndrome or liver metastases at baseline, continue study 
treatment 
Grade 3 (> 3.0 – 10.0 × ULN) 
If no documented Gilbert’s syndrome or liver metastases at baseline, repeat 
testing within 3 days.  Delay dose until resolved to ≤ Grade 1: 
 
If resolved in ≤ 7 days from day of onset, reduce dose 1 level 
 
If resolved in > 7 days from day of onset, discontinue DS-8201a 
If documented Gilbert’s syndrome or liver metastases at baseline, repeat testing 
within 3 days. Delay dose until resolved to < Grade 2: 
 
If resolved in ≤ 7 days from day of onset, reduce dose 1 level 
 
If resolved in > 7 days from day of onset, discontinue DS-8201a 
Grade 4 (> 10.0 × ULN) 
Discontinue subject from study treatment 
Alkaline Phosphatase Increased 
Grade 3 or 4 (>5.0 × ULN) 
No modification unless determined by the investigator to be clinically significant 
or life-threatening 

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Table 5.2: 
Dose modification for DS-8201a (Continued) 
Worst toxicity CTCAE v4.03 
Grade (unless otherwise 
specified) 
Dose or schedule modification for DS-8201a 
Gastrointestinal 
Nausea 
Grade 3  
Delay dose until resolved to ≤ Grade 1:  
 
If resolved in ≤ 7 days, maintain dose 
 
If resolved in > 7 days, reduce dose 1 level 
Diarrhea/Colitis 
Grade 3 
Delay dose until resolved to ≤ Grade 1: 
 
If resolved in ≤ 3 days, maintain dose 
 
If resolved in > 3 days, reduce dose 1 level 
Grade 4 
Discontinue subject from study treatment 
Other Laboratory Adverse Events 
Grade 3 
Delay dose until resolved to ≤ Grade 1 or baseline level:  
 
If resolved in ≤ 7 days, maintain dose 
 
If resolved in > 7 days, reduce dose 1 level 
Grade 4 
Discontinue subject from study treatment 
Other Non-laboratory Adverse Events 
Grade 3 
Delay dose until resolved to ≤ Grade 1 or baseline:  
 
If resolved in ≤ 7 days, maintain dose 
 
If resolved in > 7 days, reduce dose 1 level  
Grade 4 
Discontinue subject from study treatment 
All dose modifications should be based on the worst preceding toxicity.  
CTCAE: Common Terminology Criteria for Adverse Events. 
In addition, investigators may consider dose reductions or discontinuations of the study drug 
according to the subject’s condition and after discussion with the Sponsor Global Clinical Lead 
or designee. 
5.5. 
Method of Assessing Treatment Compliance 
DS-8201a will be administered IV only to subjects participating in the study and under the 
supervision of clinical study personnel at the site.  Start and stop times of injection and amount 
of drug administered are to be recorded by clinical study personnel. 
5.6. 
Concomitant Medications, Treatments, And Procedures 
Medications used from the time the subject signs the informed consent form to 40 days (+ 7 
days) after the last administration of DS-8201a will be recorded.  All concomitant medications 
will be recorded on the CRF. 
The following medications, treatment and procedures will be prohibited during the treatment 
period (see Section 4.2 for required washout periods): 

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 Other anticancer therapy, including cytotoxic, targeted agents, immunotherapy, 
antibody, retinoid, or anti-cancer hormonal treatment. 
 Other investigational therapeutic agents. 
 Radiotherapy (except for palliative radiation to known metastatic sites as long as it 
does not affect assessment of response or interrupt treatment for more than the 
maximum time specified in dose modification section). 
 Radiotherapy to the thorax. 
 Concomitant use of chronic systemic (IV or oral) corticosteroids or other 
immunosuppressive medications. (Inhaled steroids or intra articular steroid injections 
are permitted in this study.) 
- 
Subjects with bronchopulmonary disorders who require intermittent use of 
bronchodilators (such as albuterol) will not be excluded from this study.  
 CYP3A4 strong inhibitors (eg, boceprevir, clarithromycin, conivaptan, indinavir, 
itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, saquinavir, 
telaprevir, telithromycin, voriconazole).  Please consult with your local resources as 
needed to evaluate potential CYP3A4 inhibitors (see Section 17.5 for more extensive 
list). 
If concomitant use of strong CYP3A4 inhibitors is unavoidable, consider delaying 
DS-8201a treatment until the strong CYP3A4 inhibitors have cleared from the 
circulation (approximately 3 elimination half-lives of the inhibitors) when possible.  
If a strong CYP3A4 inhibitor is co-administered and DS-8201a treatment cannot be 
delayed, subjects should be closely monitored for adverse reactions. 
 Organic anion transporting polypeptide (OATP)1B inhibitors including but are not 
limited to: atazanavir, clarithromycin, cyclosporine, erythromycin, gemfibrozil, 
lopinavir, rifampin, ritonavir, simeprevir.  Consult with your local resources as 
needed to evaluate potential OATP1B inhibitors (see Section 17.5 for more extensive 
list).  
 If concomitant use of OATP1B inhibitors is unavoidable, consider delaying DS-
8201a treatment until the OATP1B inhibitors have cleared from the circulation 
(approximately 3 × the elimination half-life of the inhibitors) as long as possible.  
 If an OATP1B inhibitor is co-administered and DS-8201a treatment cannot be 
delayed, subjects should be closely monitored for adverse reactions. 
 Foods or beverages containing grapefruit; 
Hematopoietic growth factors may be used for prophylaxis or treatment based on the clinical 
judgment of the investigator. 
Prophylactic or supportive treatment of study-drug induced AEs will be otherwise as per 
investigator’s discretion and institutional guidelines. 
Concomitant use of dietary supplements, medications not prescribed by the investigator, and 
alternative/complementary treatments is discouraged, but not prohibited.  

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5.7. 
Removal of Subjects From Treatment and/or Study 
5.7.1. 
Reasons for Discontinuation of Study Treatment 
Subjects may be withdrawn from study treatment after signing informed consent for the 
following reasons:  
 Progressive disease per criteria set forth in RECIST version 1.1;  
 Clinical progression (definitive clinical signs of (PD), but a recent radiographic 
assessment did not meet the criteria for Progressive Disease according to RECIST 
version 1.1); 
 Adverse event; 
 Withdrawal of consent by subject; 
 Physician Decision; 
 Death; 
 Pregnancy; 
 Study terminated by Sponsor; 
 Lost to follow-up; 
 Other, specify. 
If there is evidence that the subject is receiving benefit from treatment even though the subject 
has met a criterion for discontinuation as listed above, the subject may remain on study treatment 
after discussion with the Global Clinical Lead.  
All subjects who are withdrawn from study treatment should complete protocol-specified 
withdrawal procedures (Section 5.7.3) and follow-up procedures (Section 6.6). 
Record the reason for any subject who discontinues study treatment.  Discontinued subjects will 
be followed for survival, either through direct contacts or by collecting public records (eg, death 
certificates) as allowed by local laws. 
5.7.2. 
Reasons for Discontinuation of Study Participation 
 Subject withdraws consent to participate in study procedures; 
 Subject dies; 
 Study is terminated;  
 Subject is lost to follow-up; 
 Other, specify. 
Note: All subjects will be followed for survival status even after consent for study procedures is 
withdrawn.  Subjects discontinued from the study because of withdrawal of consent will be 
followed for survival by collecting public records (eg, death certificates) every 3 months from 
the last study visit, unless prohibited by local laws.   

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5.7.3. 
Withdrawal Procedures 
If a subject is withdrawn from the study treatment, the investigator will complete and report the 
observations as thoroughly as possible up to the date of withdrawal including the date of last 
treatment and the reason for withdrawal. 
If the subject is withdrawn from the study treatment due to an AE, the investigator will follow 
the subject until the AE has resolved or stabilized. 
All subjects who are withdrawn from the study treatment should complete protocol-specified 
withdrawal procedures.  Protocol-specified withdrawal procedures will be obtained during the 
end of treatment visit (+7 days) and the follow-up 40 day visit (+7 days) conducted after the last 
administration of DS-8201a (Section 6.5 and Section 6.6). 
5.7.4. 
Subject Replacement 
Subjects that have been enrolled and administered study medication will not be replaced.  
However, it is allowable to replace a subject that was enrolled but was not administered any 
study medication. 
5.7.5. 
Subject Re-screening Procedures 
Re-screening is permitted for any subject who failed to meet eligibility criteria upon initial 
screening.  The subject identification (SID) number must remain the same at the time of re-
screening.  The initial screening information and the reason why the subject is ineligible for the 
initial evaluation will be recorded on the Screening Log.  No data from the initial evaluation will 
be entered into the clinical database for a subject who is re-screened. 

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6. 
STUDY PROCEDURES 
A study visit schedule in tabular format is provided below in Table 6.1 and Table 6.2. 
6.1. 
Tissue Screening 
To determine eligibility, subjects must meet tumor biomarker criteria.   
Note: Subjects may continue on prior therapy while tissue testing takes place.   
Please refer to the study Laboratory Manual for required tumor sample specifications and 
shipping instructions.  
The following procedures will be conducted: 
 Obtain a signed and dated written consent from the subject to collect tissue and/or 
perform a biopsy as needed. 
 If a tumor biopsy is needed, record any SAEs directly related to tissue screening 
procedure (ie, tumor biopsy).  
 Obtain adequate archived or recent tumor tissue sample for HER2 testing.  Most 
recent tumor tissue sample should be submitted.  If prior tissue specimen is 
submitted, document reason why most recent tumor sample is unavailable. 
 Send the sample to the Central Laboratory to confirm HER2 status 
 Additional slides for exploratory biomarker assessment are requested (see Laboratory 
Manual). 
 For subjects who sign only the Informed Consent Form for tissue screening, report 
only serious adverse events (SAEs) directly related to tissue screening procedure (ie, 
tumor biopsy).  Unless documentation of other AEs is required by local law, only 
SAEs directly related to tumor biopsy will be recorded during tissue screening.  
6.2. 
Screening 
Obtain a signed and dated ICF before any study-related procedures or assessments are 
conducted.   
The following activities and/or assessments will be performed during the screening period: 
Within 28 days before registration/randomization  
 Perform a human immunodeficiency virus (HIV) antibody test.  HIV antibody test 
must be performed for Japanese subjects, and is optional for other subjects unless 
required by local regulations or IRB/ECs.  
 Ophthalmologic assessments.  The assessments will include visual acuity testing, slit 
lamp examination, and fundoscopy.  
 Perform an Echo or MUGA (note: the same test must be used for the subject 
throughout the study).  

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 Perform tumor assessment by computed tomography (CT) or magnetic resonance 
imaging (MRI) scans of the chest, abdomen, pelvis, and any other sites of disease.  A 
CT or MRI of the brain is to be included for all subjects.   
NOTE: To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use it as comparator for subsequent measurement.  
Therefore, all lesions (target and non-target) have to be assessed at Screening according 
to RECIST version 1.1 (Section 17.3). 
The following activities and/or assessments will be performed during the screening period within 
14 days before starting study drug except as indicated: 
 Obtain demographics (eg, birth date, sex, race, ethnicity), medical and surgical 
history, including all previous, now resolved, significant medical conditions, date of 
diagnosis, extent of disease, disease staging, estrogen/progesterone receptor status, 
previous cancer therapies (including prior radiation therapy) and oncology surgical 
history. 
 Perform a complete physical examination (see Section 9.11) including weight and 
height. 
 Assess AEs throughout the screening period (from the time the subject signed the 
ICF). 
 Record concomitant medications (from the time the subject signed the ICF)  
 Obtain vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, 
body temperature and SpO2). 
 Assess functional status using the ECOG PS Scale (Section 17.2). 
 Obtain urine sample for urinalysis (protein, glucose, blood, microscopy assessment [if 
indicated], and specific gravity) and blood sample for coagulation testing 
(prothrombin time and activated partial thromboplastin time).  
 Obtain blood samples for hematology and blood chemistry tests (includes calculated 
creatinine clearance.  See Section 9.8, Section 17.1), troponins (preferably troponin-
T) and HER2ECD. 
 Perform a 12-lead ECG in triplicate*.  
*ECGs will be taken in close succession, approximately 3 minutes apart, while in a 
supine/semi-recumbent position. 
 Obtain a serum or urine sample for pregnancy testing in women of childbearing 
potential.  Test must be confirmed negative within 72 hours prior to 
randomization/registration.  For postmenopausal subjects (no childbearing potential, 
as indicated by an elapse of at least 12 months after the last menstruation) or subjects 
who have no possibility of pregnancy due to sterilization surgery, etc., no pregnancy 
test will be required.  Subjects who have been amenorrheic for 12 months or longer 
for medical reasons other than sterilization surgery (eg, effect of medication) will be 
regarded as women of childbearing potential and required to undergo the pregnancy 
test.   
 Review inclusion/exclusion criteria. 

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6.3. 
Randomization 
For the PK Stage of Part 1, eligible subjects will be randomized by the IXRS in a 1:1:1 ratio into 
1 of 3 initial treatment groups: 5.4 mg/kg, 6.4 mg/kg, and 7.4mg/kg.  
For the Dose Finding Stage of Part 1, an additional of approximately 30 subjects per dose will be 
randomized by the IXRS in a 1:1 ratio into 1 of 2 treatment groups selected after the PK Stage. 
Randomization will be stratified by region (Asia, rest of world). 
For Part 2, eligible subjects will not be randomized, but will instead be registered in IXRS.  
Once the subject is randomized, first dose / Cycle 1 Day 1 should occur within 7 days from the 
randomization date. 
6.4. 
Treatment Period 
6.4.1. 
Cycle 1 to Cycle 4 and Subsequent Cycles 
Treatment and procedures performed on Day 1 of Cycle 1 and beyond are specified in Table 6.1 
and Table 6.2 below.  Procedures are to be performed within 3 days of the Day 1 visit of each 
cycle unless otherwise specified.   
Physical examination, weight, ECOG PS assessment, 12-lead ECG, hematology, blood 
chemistry, coagulation test, and vital signs (including SpO2) evaluations do not need to be 
repeated at the Cycle 1, Day 1 visit if performed within 3 days before the first dose of study 
drug.  However, vital sign information must be collected at EOI of Cycle 1, 2, and 3. 
Before Dosing: 
 Record concomitant medications  
 Blood plasma samples for exploratory biomarkers, such as cell free deoxyribonucleic 
acid (cfDNA) analysis in plasma, will be collected before treatment on Day 1 of 
Cycle 1 and every 3 cycles thereafter(eg, Cycle 4, Cycle 7, etc.). 
 Physical examination (Section 9.11) will be performed on the scheduled day even if 
study treatment is being withheld.  More frequent examinations may be performed at 
the discretion of the investigator and if medically indicated.   
 Ophthalmologic assessments to include visual acuity testing, slit lamp examination 
and fundoscopy will be performed at Day 1 of Cycle 2 (within 3 days before 
administration) and every 4 cycles (±7 days) thereafter (Day 1 Cycle 2, 6, 10, 14, etc).  
If the planned date of study drug administration is delayed after examination of 
ophthalmologic assessments, and there are no abnormal findings on the examination, 
it is up to the investigator’s judgment as to whether ophthalmologic assessments need 
to be repeated. 
 Vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, body 
temperature and SpO2) will be performed as per the Schedule of Events.  More 
frequent examinations may be performed at the discretion of the investigator and if 
medically indicated. 
 ECOG PS will be assessed as per the Schedule of Events. 

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 Safety will be monitored by assessment as well as by collection of the AEs at every 
visit.  For details on AE collection and reporting, refer to Section 9. 
 Blood samples for hematology and blood chemistry assessments will be collected as 
per the Schedule of Events.  Refer to Section 9.8 for a list of parameters to be 
evaluated.  
 Triplicate 12-lead ECG will be performed as per the Schedule of Events, 
approximately 3 minutes apart.  ECGs should be performed before PK blood draws at 
respective time points.  
 Perform an Echo or MUGA scan assessment (note: the same test must be used for the 
subject throughout the study) every 4 cycles (±7 days) (Cycle 5, 9, 13, etc).  If the 
planned date of study drug administration is delayed after examination of Echo or 
MUGA, and there are no abnormal findings on the examination, it is up to the 
investigator’s judgment as to whether Echo or MUGA need to be repeated. 
 Obtain a blood sample for pharmacogenetic assessment within Cycle 1 only.  (This 
sample is not required for study participation and will be collected from subjects who 
have provided consent by signing the pharmacogenetics sample banking consent 
form.)  
 Blood samples for PK assessments will be obtained before infusion (-8 hours) on Day 
1 of each cycle through Cycle 4; then at Day 1 of Cycle 6 and Cycle 8. 
 Blood samples for ADA will be obtained according to the time points indicated in the 
Schedule of Events. 
 Blood samples for HER2ECD assessment will be collected on Cycle 3 Day 1 and 
every other cycle thereafter (eg, Cycle 3, 5, 7, 9...). 
Dosing and Postinfusion Assessments: 
 Administer DS-8201a IV infusion 90 ± 10 minutes for the initial dose and, if no 
infusion-related reaction after the initial dose, infuse subsequent doses over 30 ± 5 
minutes.  Record start and stop times.  DS-8201a is to be administered every 3 weeks 
± 2 days. 
 Collect blood samples within 15 minutes after end of infusion (EOI) for PK analysis 
for on Day 1 of each cycle through Cycle 4; then at Day 1 of Cycle 6 and Cycle 8.  
 Collect blood samples for troponin (preferably high sensitivity troponin-T) 2-3 hours 
after end of infusion.  The test used to test troponin should remain the same 
throughout the course of a subject’s time on study.  An additional sample should be 
submitted for central laboratory troponin-T testing. 
Repeat troponin testing at 3 ± 1 hours after initial troponin test.  
 If repeat troponin level at 3 ± 1 hours rises significantly per institutional 
guidelines,  
 perform ECG in triplicate; 
 repeat troponin testing at 6 ± 1 hours after initial troponin test; 

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 follow institutional guidelines for management of detectable troponin testing. 
 If repeat troponin level at 3 ± 1 hours does not rise significantly per institutional 
guidelines,  
 repeat troponin testing at 6 ± 1 hours or at 24 ± 2 hours after initial troponin 
test.  
 If troponin levels are consistent with myocardial infarction as defined according 
to manufacturer (CTCAE Grade 3), perform a 12-lead ECG testing in triplicate, 
repeat troponin testing 6 ± 1 hours and 12 ± 1 hours after initial troponin test was 
drawn, and follow institutional guidelines.  
If troponin levels are above the upper limit of normal at baseline and below the level 
of myocardial infarction as defined by the manufacturer (CTCAE Grade 1), no repeat 
testing is required after the first EOI 3-hour troponin test if the troponin level is not 
Grade 3. 
 Collect vital signs at EOI of Cycle 1, 2, and 3. 
Part 1 PK Stage Only: Obtain blood sample for PK assessments at the following time points: 
 Cycle 1 Day 1 
 2 hours after the start of drug administration (± 15 minutes)  
 4 hours after the start of drug administration (± 15 minutes) 
 7 hours after the start of drug administration (± 15 minutes) 
 Cycle 1 Day 2 and Day 4: Obtain blood sample for PK assessments at the following 
time points 
 24 hours (Day 2) and 72 hours (Day 4) after the start of drug administration (± 2 
hours) 
 Cycle 1 Day 8 (± 1 day) and Day 15 (± 1 day): 
 Cycle 3 Day 1: 
 4 hours after the start of drug administration (± 15 minutes) 
 7 hours after the start of drug administration (± 15 minutes) 
All subjects dose finding stage and continuation stage: Obtain blood sample for PK 
assessments at the following time points 
 Cycle 1 Day 1 
 4 hours after the start of drug administration (± 15 minutes) 
 7 hours after the start of drug administration (± 15 minutes) 
 Cycle 1 Day 8 (± 1 day) and Day 15 (± 1 day): 
 Cycle 3 Day 1: 
 4 hours after the start of drug administration (± 15 minutes) 

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 7 hours after the start of drug administration (± 15 minutes) 
If the schedule on Day 1 of Cycles 2, 3 or 4 is delayed for 3 days or more, or if the subject 
cannot continue onto the next cycle, PK blood sample will be collected on Day 22 of Cycle 1, 
Cycle 2 or Cycle 3 as per the Schedule of Event (Table 6.1 and Table 6.2) and Section 8.1.  
6.4.2. 
Every 6 Weeks (±7 days) 
 Record concomitant medications and AEs at every visit. 
 Tumor assessments, based on sites of disease identified at Screening and any 
additional newly suspected sites of progressive disease, will be conducted every 
6 weeks (± 7 days) from Cycle 1 Day 1, independent of treatment cycle.  CT or MRI 
scans of the suspected sites of disease in the chest, abdomen and pelvis are 
mandatory.  Computerized tomography and/or MRI (spiral CT or MRI with ≤ 5 mm 
cuts) of chest, abdomen, and pelvis should be used for tumor assessment unless 
another modality of disease assessment is necessary for the lesions.  The same 
assessment modality should be used throughout the study for all assessments for each 
subject unless prior approval is obtained from Sponsor or its designee.  Unscheduled 
tumor assessments may be performed if progression is suspected.  
 A CT or MRI of the brain is mandatory for all subjects included with baseline stable 
brain metastases.  Subjects without brain metastases do not need additional brain 
scans for tumor assessment unless clinically indicated. 
Imaging results will be reviewed by an independent radiologic facility. 
6.5. 
End of Treatment 
The EOT is defined as the date the investigator decides to discontinue study treatment (+7 days).  
The following procedures will be performed as specified in the Schedule of Events.  However, if 
the EOT assessments have been performed within 30 (±7) days of their last treatment, they can 
be considered to be the EOT data and there is no need to repeat them, otherwise these 
assessments need to be repeated.  
 Physical examination.  Weight will be recorded.  
 Ophthalmologic assessments to include visual acuity testing, slit lamp examination, 
and fundoscopy. 
 Vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, body 
temperature and SpO2). 
 ECOG PS. 
 AEs and concomitant medications will be recorded. 
 Blood samples for hematology, troponin, and blood chemistry assessments will be 
collected.  Refer to Section 9.8 for a list of parameters to be evaluated.  
 Blood plasma sample for exploratory biomarkers, such as cfDNA analysis in plasma, 
will be collected. 

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 Blood sample for HER2ECD assessment.  
 Triplicate 12-lead ECG, approximately 3 minutes apart, while in a supine/semi-
recumbent position. 
 Echo or MUGA (note: the same test must be used for the subject throughout the 
study). 
 Serum or urine sample for pregnancy testing in women of childbearing potential.   
 Follow-up evaluations should include all sites of disease identified at screening and 
any other locations if progressive disease is suspected (eg, MRI of the brain if brain 
metastases are suspected) should also be imaged, per RECIST 1.1 (Section 17.3).  If 
the previous scan was within the last 6 weeks, this assessment does not need to be 
performed at the EOT Visit. 
 An MRI of the brain is mandatory for all subjects included with baseline stable brain 
metastases.  Subjects without brain metastases do not need brain scan for tumor 
assessment unless clinically indicated. 
6.6. 
Follow-up 
Forty days (+7 days) after last study drug administration or before starting new anticancer 
treatment, whichever comes first, the following procedures will be performed as specified in the 
Schedule of Events.  If EOT is > 40 (+7) days after last treatment, then the EOT assessments can 
also function as the follow-up visit.  
 Vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, body 
temperature and SpO2).  
 Physical examination.  Weight will be recorded.  
 ECOG PS.  
 Hematology, blood chemistry, and troponin assessments will be performed.  
 AEs and concomitant medications will be recorded. 
 For subjects with positive ADA at the follow-up visit, additional serum ADA samples 
must be collected every 3 months (± 1 month) up to 1 year from the last dose of study 
drug, or until the ADA becomes negative, or until the ADA titer becomes less than 
baseline (applicable when pre-existing ADA is observed), or until the subject starts 
another therapy for cancer, or withdraws consent from the study, whichever occurs 
first.  
Subjects will also be assessed every three months (±14 days), from the date of follow-up visit, 
for survival and subsequent anticancer therapy until death, withdrawal of consent, loss to follow-
up, or study closure; whichever occurs first.  This information may be collected in a visit or via 
phone contact, or (as necessary for survival status, in the case of withdrawal of consent or loss to 
follow-up) from public records as allowed by law. 
Further follow-up may be required for ongoing AEs (see Section 9.1). 

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Table 6.1: 
Schedule of Events – Part 1 PK Stage 
 
Tiss
ue 
Scre
en 
S
C
R 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
and 
subsequ
ent  
cycles 
Ev
ery 
6 
wk
s  
(±7 
da
ys) 
E
O
T 
(a) 
40-
da
y 
F/
U 
(b) 
q3 
m
o 
F/
U  
(±
14 
da
ys) 
Day 1 
D
ay 
2 
D
ay 
4 
D
ay 
8 
D
ay 
15 
Da
y 
22v 
Day 1 
Da
y 
22v 
Day 1 
Da
y 
22v 
Day 1 
(-14 
d or 
as 
not
ed) 
BI 
E
OI 
 
 
(±
 1 
da
y) 
(±
 1 
da
y) 
(± 
2 
da
ys) 
B
I 
E
O
I 
(± 
2 
da
ys) 
B
I 
E
OI 
(± 
2 
da
ys) 
BI 
E
O
I 
Informed 
Consent 
(may sign 
> 1 d
● 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer 
DS 8201a 
 
 
● 
 
 
 
 
 
● 
 
● 
 
● 
 
 
 
 
Medical 
Hi
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demograp
hi
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy 
T
 
●(
)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
● 
 
 
Vital Signs 
 
● 
●(
● 
 
 
● 
● 
 
●(
● 
 
●(
● 
 
●(
 
 
● 
● 
 
Physical 
E
i
ti
 
●  
●(
d)
 
 
 
 
 
 
●(
d)
 
 
●(
d)
 
 
●(
d)
 
 
● 
● 
 
SpO2 
 
● 
●(
d) 
 
 
 
 
 
 
●(d
) 
 
 
●(
d) 
 
 
●(
d) 
 
 
● 
● 
 
Inclusion/E
xclusion 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight, 
ECOG PS
 
● 
●(
d)
 
 
 
 
 
 
●(
d)
 
 
●(
d)
 
 
●(
d)
 
 
● 
● 
 
Urinalysis 
and 
coagulatio
n testing 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematolog
y & Blood 
Chemistry 
Tests 
 
● 
●(
d) 
 
 
 
● 
● 
 
●(
d) 
 
 
●(
d)  
 
 
●(
d) 
 
 
● 
● 
 
Troponin 
(e) 
 
● 
 
● 
 
 
 
 
 
 
● 
 
 
● 
 
 
● 
 
● 
● 
 
Biomarker 
Blood 
Samples (f) 
 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
● 
 
 
● 
 
 
Pharmacog
enomics 
Blood 
Sample 
 
 
●(
g) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK Blood 
(Serum) 
Sample 
 
 
●(
h) 
●(
i,j) 
●(
k) 
●(
k) 
● 
● 
●(l
) 
●(h
)  
●(
i) 
●(l
) 
●(
h)  
●(
i,j)  
●(l
) 
●(
h)  
●(
i)  
 
 
 
 
ADA 
Blood 
Sample 
 
 
●(
m) 
 
 
 
 
 
 
●(
m)  
 
 
 
  
 
●(
m)  
 
 
 
● 
●(
n) 
HIV 
Antibody 
Test (as 
required by 
local 
regulations
 
●(
o) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Tiss
ue 
Scre
en 
S
C
R 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
and 
subsequ
ent  
cycles 
Ev
ery 
6 
wk
s  
(±7 
da
ys) 
E
O
T 
(a) 
40-
da
y 
F/
U 
(b) 
q3 
m
o 
F/
U  
(±
14 
da
ys) 
Day 1 
D
ay 
2 
D
ay 
4 
D
ay 
8 
D
ay 
15 
Da
y 
22v 
Day 1 
Da
y 
22v 
Day 1 
Da
y 
22v 
Day 1 
(-14 
d or 
as 
not
ed) 
BI 
E
OI 
 
 
(±
 1 
da
y) 
(±
 1 
da
y) 
(± 
2 
da
ys) 
B
I 
E
O
I 
(± 
2 
da
ys) 
B
I 
E
OI 
(± 
2 
da
ys) 
BI 
E
O
I 
) 
Blood 
Sample for 
HER ECD
 
● 
 
 
 
 
 
 
 
 
 
 
●(
p)  
 
 
●(
p) 
 
 
● 
 
 
Echo or 
MUGA 
 
●(
o) 
 
 
 
 
 
 
 
 
 
 
 
 
 
● 
 
 
● 
 
 
12 lead 
ECG in 
 
● 
●(
d) 
 
 
 
 
 
 
●(d
) 
 
 
●(
d)  
 
 
●(
d) 
 
 
● 
 
 
CT/MRI of 
 
●(
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
●(s
●(
 
 
Tumor 
 
●(
)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
● 
● 
 
 
Ophthalmo
logic 
 
●(
o) 
 
 
 
 
 
 
 
●(d,
t) 
 
 
 
 
 
●(
d,t
 
 
● 
 
 
Tumor 
Sample for 
HER2 
Status and
●(
u) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomita
nt 
Medication
 
● 
 
Adverse 
●(
● 
 
Survival 
F ll
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
● 
AE = adverse event; ACC = American College of Cardiologists; BI = before infusion, cfDNA = cell free 
deoxyribonucleic acid; CT = computed tomography; d = days; Echo = echocardiogram; ECG = electrocardiogram; 
ECOG PS = Eastern Cooperative Oncology Group performance status; EOI = end of infusion; EOT = end of 
treatment; F/U = follow-up; ADA = anti-drug antibody; HER2 = human epidermal growth factor receptor 2; 
HER2ECD = extracellular domain of HER2; HIV = human immunodeficiency virus; IXRS = interactive web/voice 
response system; LVEF = left ventricular ejection fraction; MRI = magnetic resonance imaging; 
MUGA = multigated acquisition (scan); PK = pharmacokinetic; q3 mo = every 3 months; SCR: screening; 
SpO2 = peripheral oxygen saturation. 
a The date the investigator decides to discontinue study treatment (+ 7 days).  See Section 6.5 for whether new tests 
need to be conducted. 
b 40 days (+ 7 days) after the last study drug administration or before starting new anticancer treatment, whichever 
comes first.  See Section 6.6 for whether new tests need to be conducted. 
c Within 72 hours before randomization  
d Within 3 days before administration. The blood collections should be done after ECG (if performed on the same 
day as ECG). 
e Collect blood samples for troponin (preferably high-sensitivity troponin-T) 2-3 hours after end of infusion (EOI). 
An additional sample should be submitted for central laboratory troponin-T testing.  Repeat troponin testing at 3 ± 
1 h after initial troponin test.  If repeat troponin level at 3 ± 1 h rises significantly per institutional guidelines, 
perform ECG in triplicate; repeat troponin testing at 6 ± 1 h after initial troponin test; and follow institutional 
guidelines for management of detectable troponin testing.  If repeat troponin level at 3 ± 1 h does not rise 
significantly per institutional guidelines, repeat troponin testing at 6 ± 1 h or at 24 ± 2 h after initial troponin test.  
If troponin levels are consistent with myocardial infarction as defined according to manufacturer (CTCAE Grade 
3), perform a 12-lead ECG testing in triplicate, repeat troponin testing 6 ± 1 h and 12 ± 1 h after initial troponin 
test was drawn, and follow institutional guidelines. If troponin levels are above the upper limit of normal at 

Protocol DS8201-A-U201 
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baseline and below the level of myocardial infarction as defined by the manufacturer (CTCAE Grade 1), no repeat 
testing is required after the first EOI 3-hour troponin test if the troponin level is not Grade 3. 
f Samples will be collected at Cycle 1 and then every 3 cycles (Cycles 4, 7, etc) until EOT for exploratory 
biomarkers such us cfDNA in plasma. 
g Participation in this part of the study is optional for all subjects. 
h Within 8 hours BI on Day 1 of each cycle through Cycle 4 and then every 2 cycles until Cycle 8 ( Cycle 1, 2, 3, 4, 
6, 8). 
i Within 15 minutes of EOI on Day 1 of each cycle through Cycle 4 (Cycle 1, 2, 3 and 4) and then at Day 1 of Cycle 
6 and Cycle 8. 
j 2 h, 4 h and 7 h after the start of administration (± 15 minutes) for Cycle 1 and 4 h and 7 h after the start of 
administration (± 15 minutes) for Cycle 3. 
k 24 h and 72 h after the start of administration (± 2 hours). 
l If treatment of next cycle is delayed for 3 days or more, or subject is discontinued, collect PK blood on this day, 
Day 22 of the current cycle (± 2 days).  Also see footnote v. 
m Within 8 hours BI on Day 1 in Cycles 1, 2 and 4, and then every 4 cycles.  
n For subjects with positive ADA at F/U visit, additional serum ADA samples must be collected every 3 months (± 
1 month) up to 1 year from the last dose of study drug, or until the ADA becomes negative, or until ADA titer 
becomes less than baseline (applicable when pre-existing ADA was observed), or until the subject starts another 
therapy for cancer, or withdraws consent from the study, whichever occurs first. 
o Within 28 days before randomization/registration. 
p Before administration at every 2 cycles from Cycle 3 (Cycle 3, 5, 7, 9, etc). 
q  Echo or MUGA scan assessments (note: the same test must be used for the subject throughout the study) will be 
performed at Screening and every 4 cycles (±7 days) (Cycle 5, 9, 13, etc) 
r ECGs will be taken in close succession, approximately 3 minutes apart, while in a supine/semi-recumbent position. 
s An MRI of the brain is mandatory for all subjects who were enrolled with baseline stable brain metastases.  
Subjects without brain metastases do not need additional brain scans for tumor assessment unless clinically 
indicated.  
t Ophthalmologic assessments to include visual acuity testing, slit lamp examination and fundoscopy will be 
performed at Day 1 of Cycle 2 (within 3 days before administration) and every 4 cycles (±7 days) thereafter (Day 1 
Cycle 2, 6, 10, 14, etc). 
u  Archived tissue appropriate for central laboratory HER2 testing.  If archived tissue is not available, fresh biopsy is 
required.  Up to 5 additional slides are requested for optional biomarker analysis. 
v Based on no delays and a 21-day cycle, Day 22 should be the same as Day 1 of the next cycle.  In the event that 
there is a delay in the start of the next cycle, the goal is to still obtain the PK sample on Day 22 of the earlier cycle. 
w DS-8201a is to be administered every 3 weeks ± 2 days unless discontinuation criteria are required. 
x For subjects who sign only the Informed Consent Form for tissue screening, report only serious adverse events 
(SAEs) directly related to tissue screening procedure (ie, tumor biopsy).  Unless documentation of other AEs is 
required by local law, only SAEs directly related to tumor biopsy will be recorded during tissue screening. 
For suspected ILD/pneumonitis, treatment with study drug should be interrupted pending evaluation.  
Evaluations should include: 
 
High resolution CT  
 
Pulmonologist consultation  
 
Pulmonary function tests and pulse oximetry (SpO2)  
 
Arterial blood gases if clinically indicated  
 
One blood sample collection for PK and exploratory biomarker analysis as soon as ILD/pneumonitis is 
suspected, if feasible. 
 
Other tests could be considered, as needed. 
 

Protocol DS8201-A-U201 
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Table 6.2: 
Schedule of Events – Part 1 Dose Finding Stage and Part 2 Stage 
 
Tiss
ue 
Scr
een 
SC
R 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
and 
subseque
nt cycles 
Ev
ery 
6 
wk
s 
(± 
7 
day
s) 
E
O
T 
(a) 
40
-
d
ay 
F/
U 
(b
) 
q3 
mo 
F/
U 
(± 
14 
da
ys) 
Day 1 
Da
y 
8 
Da
y 
15 
Da
y 
22u 
Day 1 
Day 
22u 
Day 1 
Da
y 
22u 
Day 1 
(-14 
day
s or 
as 
not
ed) 
BI 
E
OI 
(± 1 
day
) 
(± 1 
day
) 
(± 
2 
da
ys) 
BI 
E
O
I 
(± 2 
day
s) 
BI 
E
OI 
(± 
2 
da
ys) 
BI 
E
O
I 
Informed 
Consent 
(may sign >
● 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer 
DS 8
 
 
● 
 
 
 
● 
 
● 
 
● 
 
 
 
 
Medical 
History  
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographi
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy 
 
●(c
 
 
 
 
 
 
 
 
 
 
 
 
 
 
● 
 
 
Vital Signs 
 
● 
●(
d)
● 
● 
● 
 
●(d
)
● 
 
●(
d)
● 
 
●(d
)
 
 
● 
● 
 
Physical 
E
i
ti
 
●  
●(
d)
 
 
 
 
●(d
)
 
 
●(
d)
 
 
●(d
)
 
 
● 
● 
 
SpO2 
 
● 
●(
d) 
 
 
 
 
●(d
) 
 
 
●(
d) 
 
 
●(d
) 
 
 
● 
● 
 
Inclusion/E
xclusion 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight, 
ECOG PS
 
● 
●(
d)
 
 
 
 
●(d
)
 
 
●(
d)
 
 
●(d
)
 
 
● 
● 
 
Urinalysis 
and 
coagulation 
testing 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
& Blood 
Chemistry 
Tests 
 
● 
●(
d) 
 
● 
● 
 
●(d
) 
 
 
●(
d)  
 
 
●(d
) 
 
 
● 
● 
 
Troponin 
(e) 
 
● 
 
● 
 
 
 
 
● 
 
 
● 
 
 
● 
 
● 
● 
 
Biomarker 
Blood 
Samples (f) 
 
 
● 
 
 
 
 
 
 
 
 
 
 
● 
 
 
● 
 
 
Pharmacoge
nomics 
Blood 
Sample 
 
 
●(
g) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK 
Blood 
(Serum) 
Sample 
 
 
●(
h) 
●(i,j
) 
● 
● 
●(k
) 
●(h
)  
●(
i) 
●(k) 
●(
h)  
●(i
,j)  
●(k
) 
●(h
)  
●(
i)  
 
 
 
 
ADA Blood 
Sample 
 
 
●(
l) 
 
 
 
 
●(l
)  
 
 
 
  
 
●(l
)  
 
 
 
● 
●(
m) 
HIV 
Antibody 
Test (as 
required by 
local 
regulations) 
 
●(n
) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol DS8201-A-U201 
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Tiss
ue 
Scr
een 
SC
R 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
and 
subseque
nt cycles 
Ev
ery 
6 
wk
s 
(± 
7 
day
s) 
E
O
T 
(a) 
40
-
d
ay 
F/
U 
(b
) 
q3 
mo 
F/
U 
(± 
14 
da
ys) 
Day 1 
Da
y 
8 
Da
y 
15 
Da
y 
22u 
Day 1 
Day 
22u 
Day 1 
Da
y 
22u 
Day 1 
(-14 
day
s or 
as 
not
ed) 
BI 
E
OI 
(± 1 
day
) 
(± 1 
day
) 
(± 
2 
da
ys) 
BI 
E
O
I 
(± 2 
day
s) 
BI 
E
OI 
(± 
2 
da
ys) 
BI 
E
O
I 
Blood 
Sample for 
HER ECD
 
● 
 
 
 
 
 
 
 
 
●(
o)  
 
 
●(o
) 
 
 
● 
 
 
Echo or 
MUGA 
(LVEF) ( )
 
●(n
) 
 
 
 
 
 
 
 
 
 
 
 
● 
 
 
● 
 
 
12 lead 
ECG in 
triplicate (q)
 
● 
●(
d) 
 
 
 
 
●(d
) 
 
 
●(
d)  
 
 
●(d
) 
 
 
● 
 
 
CT/MRI of 
 
●(n
 
 
 
 
 
 
 
 
 
 
 
 
 
●(r) 
●(r
 
 
Tumor 
 
●(n
)
 
 
 
 
 
 
 
 
 
 
 
 
 
● 
● 
 
 
Ophthalmol
ogic 
 
●(n
) 
 
 
 
 
 
●(d
,s) 
 
 
 
 
 
●(d
,s) 
 
 
● 
 
 
Tumor 
Sample for 
HER2 
Status and
●(t) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitan
 
● 
 
AEs 
●(w
)
● 
 
Survival 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
● 
AE = adverse event; ACC = American College of Cardiologists; ADA = anti-drug antibodies; BI = before infusion, 
cfDNA = cell free deoxyribonucleic acid; CT = computed tomography; d = days; Echo = echocardiogram; 
ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group performance status; EOI = end of 
infusion; EOT = end of treatment; F/U = follow-up; HER2 = human epidermal growth factor receptor 2; 
HER2ECD = extracellular domain of HER2; HIV = human immunodeficiency virus; IXRS = interactive web/voice 
response system; LVEF = left ventricular ejection fraction; MRI = magnetic resonance imaging; 
MUGA = multigated acquisition (scan); PK = pharmacokinetic; q3 mo = every 3 months; SCR: screening; 
SpO2 = peripheral oxygen saturation. 
a The date the investigator decides to discontinue study treatment (+ 7 days).  See Section 6.5 for whether new tests 
need to be conducted. 
b 40 days (+ 7 days) after the last study drug administration or before starting new anticancer treatment, whichever 
comes first.  See Section 6.6 for whether new tests need to be conducted. 
c Within 72 hours before randomization. 
d Within 3 days before administration. The blood collections should be done after ECG (if performed on the same 
day as ECG). 
e Collect blood samples for troponin (preferably high-sensitivity troponin-T) 2-3 hours after end of infusion (EOI). 
An additional sample should be submitted for central laboratory troponin-T testing.  Repeat troponin testing at 3 ± 
1 h after initial troponin test.  If repeat troponin level at 3 ± 1 h rises significantly per institutional guidelines, 
perform ECG in triplicate; repeat troponin testing at 6 ± 1 h after initial troponin test; and follow institutional 
guidelines for management of detectable troponin testing.  If repeat troponin level at 3 ± 1 h does not rise 
significantly per institutional guidelines, repeat troponin testing at 6 ± 1 h or at 24 ± 2 h after initial troponin test.  
If troponin levels are consistent with myocardial infarction as defined according to manufacturer (CTCAE Grade 
3), perform a 12-lead ECG testing in triplicate, repeat troponin testing 6 ± 1 h and 12 ± 1 h after initial troponin 
test was drawn, and follow institutional guidelines. If troponin levels are above the upper limit of normal at 
baseline and below the level of myocardial infarction as defined by the manufacturer (CTCAE Grade 1), no repeat 
testing is required after the first EOI 3-hour troponin test if the troponin level is not Grade 3.   

Protocol DS8201-A-U201 
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f Samples will be collected at Cycle 1 and then every 3 cycles (Cycles 4, 7, etc) until EOT for exploratory 
biomarkers such us cfDNA in plasma. 
g  Participation in this part of the study is optional for all subjects. 
h Within 8 hours BI on Day 1 of each cycle through Cycle 4 and then every 2 cycles until Cycle 8 (eg, Cycle 1, 2, 3, 
4, 6, 8).  
i Within 15 minutes of EOI on Day 1 of each cycle until Cycle 4 (eg, Cycle 1, 2, 3 and 4) and then at Day 1 of 
Cycle 6 and Cycle 8. 
j 4 h and 7 h after the start of administration (± 15 minutes). 
k If treatment of next cycle is delayed for 3 days or more, or subject is discontinued, collect PK blood on this day, 
Day 22 of the current cycle (± 2 days).  Also refer to footnote u for further explanation.  
l Within 8 hours BI on Day 1 in Cycles 1, 2 and 4, and then every 4 cycles.  
m For subjects with positive ADA at F/U visit, additional serum ADA samples must be collected every 3 months (± 
1 month) up to 1 year from the last dose of study drug, or until the ADA becomes negative, or until ADA titer 
becomes less than baseline (applicable when pre-existing ADA was observed), or until the subject starts another 
therapy for cancer, or withdraws consent from the study, whichever occurs first. 
n Within 28 days before randomization/registration.  
o  Before administration at every 2 cycles from Cycle 3 (eg, Cycle 3, 5, 7, 9...). 
p Echo or MUGA scan assessments (note: the same test must be used for the subject throughout the study) will be 
performed at Screening and every 4 cycles (±7 days) (eg, Cycle 5, 9, 13…). 
qECGs will be taken in close succession, approximately 3 minutes apart, while in a supine/semi-recumbent position. 
r An MRI of the brain is mandatory for all subjects who were enrolled with baseline stable brain metastases.  
Subjects without brain metastases do not need additional brain scans for tumor assessment unless clinically 
indicated.  
s Ophthalmologic assessments to include visual acuity testing, slit lamp examination and fundoscopy will be 
performed at Day 1 of Cycle 2 (within 3 days before administration) and every 4 cycles (±7 days) thereafter (Day 
1 Cycle 2, 6, 10, 14, etc). 
t  Archived tissue appropriate for central laboratory HER2 testing.  If archived tissue is not available, fresh biopsy is 
required.  Up to 5 additional slides are requested for optional biomarker analysis.  
u Based on no delays and a 21-day cycle, Day 22 should be the same as Day 1 of the next cycle.  In the event that 
there is a delay in the start of the next cycle, the goal is to still obtain the PK sample on Day 22 of the earlier cycle. 
v  DS-8201a is to be administered every 3 weeks ± 2 days unless discontinuation criteria are required. 
w For subjects who sign only the Informed Consent Form for tissue screening, report only serious adverse events 
(SAEs) directly related to tissue screening procedure (ie, tumor biopsy).  Unless documentation of other AEs is 
required by local law, only SAEs directly related to tumor biopsy will be recorded during tissue screening. 
For suspected ILD/pneumonitis, treatment with study drug should be interrupted pending evaluation.  
Evaluations should include: 
 
High resolution CT  
 
Pulmonologist consultation  
 
Pulmonary function tests and pulse oximetry (SpO2)  
 
Arterial blood gases if clinically indicated  
 
One blood sample collection for PK and exploratory biomarker analysis as soon as ILD/pneumonitis is 
suspected, if feasible. 
 
Other tests could be considered, as needed. 
 
 

Protocol DS8201-A-U201 
Version 5.0, 26 APR 2019 
Proprietary and Confidential 
Page 67 
7. 
EFFICACY ASSESSMENTS 
7.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is ORR assessed by independent central imaging facility review 
based on RECIST version 1.1.  Refer to Section 17.3 for details regarding RECIST for 
radiological tumor assessments. 
7.2. 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints include duration of response, best percent change in the SLD of 
measurable tumors, DCR, clinical benefit ratio (CBR), PFS, OS, and ORR assessed by the 
investigator based on RECIST version 1.1. 
7.3. 
Exploratory Efficacy Endpoints 
Exploratory efficacy endpoints include duration of stable disease, time to response, evaluation of 
exposure-response relationships for efficacy and safety endpoints, and potential biomarkers of 
response, such as serum HER2ECD concentrations. 

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8. 
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS 
8.1. 
Pharmacokinetic (PK)  
Blood samples for DS-8201a PK analyses will be obtained at the time points specified in the 
Schedule of Events (Table 6.1 and Table 6.2) and in Table 8.1 and Table 8.2 below.   
Table 8.1: 
Blood Sampling for PK Analysis – Part 1 PK Stage  
Cycle 
Day 
Sampling Time Point (Acceptable Ranges) 
Cycle 1 
Day 1 
BI (– 8 hours)  
EOI: Within 15 minutes after EOI 
2 hours after the start of drug administration (± 15 minutes) 
4 hours after the start of drug administration (± 15 minutes) 
7 hours after the start of drug administration (± 15 minutes) 
Day 2 
24 hours after the start of drug administration (± 2 hours) 
Day 4 
72 hours after the start of drug administration (± 2 hours) 
Day 8 
7 days after the start of drug administration (± 1 day) 
Day 15 
14 days after the start of drug administration (± 1 day) 
Day 22 
If the schedule on Day 1 of the next cycle is delayed for 3 days 
or more, including if the subject cannot continue onto the next 
cycle, collect blood sample 21 days after the start of drug 
administration (± 2 days) 
Cycle 2 
Day 1 
BI (– 8 hours) 
If blood sample is collected on Day 22 of Cycle 1, the blood 
sample will be collected at BI on Day 1 of Cycle 2.  
EOI: Within 15 minutes after EOI 
Day 22 
If the schedule on Day 1 of the next cycle is delayed for 3 days 
or more, including if the subject cannot continue onto the next 
cycle, collect blood sample on 21 days after the start of drug 
administration (± 2 days) 
Cycle 3 
Day 1 
BI (– 8 hours)  
If blood sample is collected on Day 22 of Cycle 2, the blood 
sample will be collected at BI on Day 1 of Cycle 3. 
EOI: Within 15 minutes after EOI 
4 hours after the start of drug administration (± 15 minutes) 
7 hours after the start of drug administration (± 15 minutes) 
Day 22 
If the schedule on Day 1 of the next cycle is delayed for 3 days 
or more, including if the subject cannot continue onto the next 
cycle, collect blood sample on 21 days after the start of drug 
administration (± 2 days) 

Protocol DS8201-A-U201 
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Cycle 
Day 
Sampling Time Point (Acceptable Ranges) 
Cycle 4, 6, 8 
Day 1 
BI (– 8 hours)  
If blood sample is collected on Day 22 of Cycle 3, the blood 
sample will be collected at BI on Day 1 of Cycle 4. 
EOI: Within 15 minutes after EOI 
BI = before infusion; EOI = end of infusion.  
 
Table 8.2: 
Blood Sampling for PK Analysis – Part 1 Dose Finding and Part 2 
Cycle 
Day 
Sampling Time Point (Acceptable Range) 
Cycle 1 
Day 1 
BI (– 8 hours)  
EOI: Within 15 minutes after EOI 
4 hours after the start of drug administration (± 15 minutes) 
7 hours after the start of drug administration (± 15 minutes) 
Day 8 
7 days after the start of drug administration (± 1 day) 
Day 15 
14 days after the start of drug administration (± 1 day) 
Day 22 
If the schedule on Day 1 of the next cycle is delayed for 3 days or 
more, including if the subject cannot continue onto the next cycle, 
collect blood sample 21 days after the start of drug administration (± 2 
days) 
Cycle 2 
Day 1 
BI (– 8 hours) 
If blood sample is collected on Day 22 of Cycle 1, the blood sample 
will be collected at BI on Day 1 of Cycle 2. 
EOI: Within 15 minutes after EOI 
Day 22 
If the schedule on Day 1 of the next cycle is delayed for 3 days or 
more, including if the subject cannot continue onto the next cycle, 
collect blood sample on 21 days after the start of drug administration 
(± 2 days) 
Cycle 3 
Day 1 
BI (– 8 hours)  
If blood sample is collected on Day 22 of Cycle 2, the blood sample 
will be collected at BI on Day 1 of Cycle 3. 
EOI: Within 15 minutes after EOI 
4 hours after the start of drug administration (± 15 minutes) 
7 hours after the start of drug administration (± 15 minutes) 
Day 22 
If the schedule on Day 1 of the next cycle is delayed for 3 days or 
more, including if the subject cannot continue onto the next cycle, 
collect blood sample on 21 days after the start of drug administration 
(± 2 days) 

Protocol DS8201-A-U201 
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Cycle 
Day 
Sampling Time Point (Acceptable Range) 
Cycle 4, 6, 8 
Day 1 
BI (– 8 hours)  
If blood sample is collected on Day 22 of Cycle 3, the blood sample 
will be collected at BI on Day 1 of Cycle 4. 
EOI: Within 15 minutes after EOI 
BI = before infusion; EOI = end of infusion.  
At each time point, blood will be collected for DS-8201a analysis.  The actual time of study drug 
administration and the exact time of blood sampling for DS-8201a PK analysis must be recorded 
on the electronic case report form (eCRF).  
Instructions for the handling of blood samples and shipping of serum samples for DS-8201a PK 
analyses are included in a separate document (ie, Laboratory Manual).  The DS-8201a PK 
samples will be shipped to a central laboratory for forwarding to a Sponsor designated 
bioanalytical laboratory. 
Serum concentrations of DS-8201a, total anti-HER2 antibody and MAAA-1181a will be 
measured using validated assays at the bioanalytical laboratory. 
The serum PK parameters (listed in Section 2.3.2) for DS-8201a, total anti-HER2 antibody and 
MAAA-1181a for each subject will be estimated using standard noncompartmental method. 
8.2. 
Pharmacodynamic  
Not Applicable. 
8.3. 
Immunogenicity (Anti-Drug Antibodies, ADA) 
Blood samples for ADA analyses will be collected at the time points specified in Table 6.1 and 
Table 6.2.  A blood sample will be drawn at each time point.  Serum concentrations of DS-8201a 
and/or total anti-HER2 antibody may be measured using the same ADA samples for purpose of 
ADA assessment.  
Instructions for the handling and shipping of ADA serum samples are included in a separate 
document (ie, Laboratory Manual).  The ADA samples will be shipped to a central laboratory for 
forwarding to a Sponsor designated bioanalytical laboratory. 
The immunogenicity testing will be performed using validated ADA assay following tiered assay 
steps including screening, confirmatory as well as titer determination.  Samples confirmed 
positive will be banked until availability of the neutralizing anti-drug antibody (NAB) assay. 
8.4. 
Pharmacogenomic Analysis 
8.4.1. 
Tumor Sampling 
In addition to the tumor sample required for confirmation of HER2 status, additional slides (up to 
5) for exploratory biomarker analysis are requested (if the subject signs the additional optional 
informed consent form for Pharmacogenomics analysis).  The detailed instructions for the 
handling of tumor samples and shipping of tumor samples are included in the Laboratory Manual. 

Protocol DS8201-A-U201 
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8.4.2. 
Genomic or Genetic Banking and Analysis 
A single blood sample for pharmacogenomics analysis will be collected from each subject, who 
consented to this test, before drug administration on Day 1 of Cycle 1.  Participation in this part 
of the study is optional for all subjects. 
The following procedures will be used for the long-term preservation (banking) of DNA 
specimens extracted from subjects' blood samples.  Pharmacogenomic samples may be analyzed 
for genes involved in absorption, distribution, metabolism, elimination, safety, and efficacy of 
DS-8201a.  Additionally, samples may be analyzed for genes involved in DS-8201a related 
signaling pathways, or to examine diseases or physiologic processes related to DS-8201a DNA 
samples will not be immortalized or sold to anyone.  This information may be useful in 
increasing the knowledge of differences among individuals in the way they respond to the study 
drug, as well as helping in the development of new drugs or improvement of existing drugs. 
Specimen shipping and handling details will be included in the Laboratory Manual. 
8.4.2.1. 
Disclosure of the Results of Genomic or Genetic Analysis 
Because the nature and value of future pharmacogenomic research cannot be known at this time, 
any results obtained from research involving pharmacogenomic samples will not be disclosed to 
the subject or investigators now or in the future. 
8.4.2.2. 
Storage and Disposal of Specimens for Genomic or Genetic Banking and 
Analysis 
Samples will be retained until exhausted or until the Sponsor requests disposition.  
If the subject withdraws consent, the banked blood samples will be promptly managed regarding 
proper disposition.  However, the data will not be discarded if genetic analysis has been 
completed before the subject withdraws consent. 
8.5. 
Biomarker and Exploratory Variables 
Exploratory biomarkers such as HER2EDC in serum may be measured by a central laboratory.  
Other exploratory biomarkers in tumor tissue or blood such as cfDNA in plasma may be 
measured. 
 

Protocol DS8201-A-U201 
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Page 72 
9. 
SAFETY EVALUATION AND REPORTING 
9.1. 
Adverse Event Collection and Reporting 
All clinical AEs (see Section 9.4.1 for definitions) occurring after the subject signs the ICF and 
up to 40 (+ 7) days after last treatment (ie, the follow-up period), whether observed by the 
investigator or reported by the subject, will be recorded on the Adverse Event CRF page.  All 
SAEs occurring after subject signs the ICF and up to 40 (+ 7) days after last treatment will be 
recorded on CRF.  Medical conditions (including laboratory values/vital signs that are out of 
range) that were diagnosed or known to exist prior to Informed Consent will be recorded as part 
of medical history.   
All AEs, SAEs, and events of special interest are to be reported according to the procedures in 
Section 9.5.   
All laboratory results, vital signs, and ECG results or findings should be appraised by the 
investigator to determine their clinical significance.  Isolated abnormal laboratory results, vital 
sign findings, or ECG findings (ie, not part of a reported diagnosis) should be reported as AEs if 
they are symptomatic, lead to study drug discontinuation, dose reduction, require corrective 
treatment, or constitute an AE in the investigator’s clinical judgment. 
At each visit, the investigator will determine whether any AEs have occurred by evaluating the 
subject.  Adverse events may be directly observed, reported spontaneously by the subject or by 
questioning the subject at each study visit.  Subjects should be questioned in a general way, 
without asking about the occurrence of any specific symptoms.  The investigator must assess all 
AEs to determine seriousness, severity, and causality, in accordance with the definitions in 
Section 9.4.  The investigator’s assessment must be clearly documented in the site’s source 
documentation with the investigator’s signature.   
Always report the diagnosis as the AE or SAE term.  When a diagnosis is unavailable, report the 
primary sign or symptom as the AE or SAE term with additional details included in the narrative 
until the diagnosis becomes available.  If the signs and symptoms are distinct and do not suggest 
a common diagnosis, report them as individual entries of AE or SAE.   
For events that are serious due to hospitalization, the reason for hospitalization must be reported 
as the SAE (diagnosis or symptom requiring hospitalization).  A procedure is not an AE or SAE, 
but the reason for the procedure may be an AE or SAE.  Pre-planned (prior to signing the ICF) 
procedures or treatments requiring hospitalization for pre-existing conditions that do not worsen 
in severity should not be reported as SAEs (see Section 9.4.2 for Definitions).   
For deaths, the underlying or immediate cause of death should always be reported as an SAE.  
Disease progression is a study endpoint and consequently, should not be reported as an AE/SAE.  
However, when a subject dies from PD with no other immediate causes, “disease progression” 
should be reported as an SAE.   
Any serious, untoward event that may occur subsequent to the reporting period that the 
investigator assesses as related to study drug should also be reported and managed as an SAE. 
9.2. 
Safety Endpoint Event(s) 

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Safety parameters will include SAEs, TEAEs, Echo/MUGA findings; ophthalmologic findings, 
physical examination findings (including ECOG PS), vital sign measurements, standard clinical 
laboratory parameters (central lab) (blood chemistry, coagulation, and hematology), anti-drug 
antibodies (ADA), and ECG parameters.  Adverse events will be categorized using the Medical 
Dictionary for Regulatory Activities (MedDRA).  Adverse events and abnormal laboratory test 
results, if applicable, will be graded using National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. 
9.3. 
Adverse Events of Special Interest 
Information regarding the AESIs, except infusion-related reactions, specified below for the DS-
8201a clinical program will be collected through the targeted questionnaires, in-built within the 
eCRF in the study clinical database. 
9.3.1. 
Interstitial Lung Disease/Pneumonitis 
9.3.1.1. 
Clinical Summary  
As of 13 Dec 2017, 3 clinical studies have subjects dosed with DS-8201a: DS8201-A-J101, 
DS8201-A-U201, and DS8201-A-J202.  There have been no events of ILD/pneumonitis reported 
in the DS8201-A-U201 and DS8201-A-J202 studies.  Due to the limited number of subjects 
dosed and short treatment duration in these 2 studies, ILD/pneumonitis data has been 
summarized from the DS8201-A-J101 study. 
Interstitial lung disease/pneumonitis is considered an important identified risk based on a 
comprehensive cumulative review of the available safety data from the DS8201-A-J101 clinical 
study as well as the results of potential ILD/pneumonitis cases reviewed by the independent ILD 
AC, available data from recent epidemiology/literature, biological plausibility, and safety 
information from drugs of similar class.  Refer to the current IB for a summary of preliminary 
clinical study data. 
9.3.1.2. 
Management Guidance 
Interstitial lung disease/pneumonitis should be ruled out if a subject develops an acute onset of 
new or worsening pulmonary or other related signs/symptoms such as dyspnea, cough or fever.  
If the AE is confirmed to have an etiology other than ILD/pneumonitis, follow the management 
guidance outlined in the designated “Other Non-Laboratory Adverse Events” dose modification 
section of the study protocol (Section 5.4).  
If the AE is suspected to be ILD/pneumonitis, treatment with study drug should be interrupted 
pending further evaluations. Evaluations should include high resolution CT, pulmonologist 
consultation, pulmonary function tests and SpO2, arterial blood gases if clinically indicated, and 
one blood sample collection for PK and exploratory biomarker analysis as soon as 
ILD/pneumonitis is suspected, if feasible. Other tests could be considered, as needed. As soon as 
ILD/pneumonitis is suspected, corticosteroid treatment should be started promptly as per clinical 
treatment guidelines (Kubo K, et al 2013 for guidance22). 
If the AE is confirmed to be ILD/pneumonitis, follow the management guidance outlined in the 
designated “Pulmonary Toxicity” dose modification section of the study protocol (Section 5.4). 

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All events of ILD regardless of severity or seriousness will be followed until resolution including 
after drug discontinuation. 
9.3.1.3. 
Interstitial Lung Disease Adjudication Committee 
An independent ILD Adjudication Committee for the DS-8201a program is responsible for 
reviewing all cases of potential ILD/pneumonitis. To ensure adequate and relevant independent 
evaluation, systematic additional data collection will be conducted for all cases that will be 
brought for adjudication. These additional data collections will cover a more in-depth relevant 
medical history (eg smoking, radiation, chronic obstructive pulmonary disease and other chronic 
lung conditions), diagnostic evaluation, treatment and outcome of the event. This data collection 
will be triggered for adverse events reported using MedDRA preferred terms (PTs) from the 
current ILD Standardised MedDRA Query (SMQ).   
9.3.2. 
Cardiotoxicity (Cardiac Related Events including QT Prolongation and LVEF 
Decrease) 
9.3.2.1. 
Clinical Summary  
Cardiotoxicity in association with DS-8201a is considered to be an important potential risk based 
on the available pre-clinical data, literature and available safety information for drugs of similar 
class. 
9.3.2.2. 
Management Guidance 
LVEF will be measured by either Echo or MUGA scan.  All Echos/MUGAs will be evaluated by 
the investigator or delegated physician for monitoring cardiac function. Troponin will be 
measured at screening and after each infusion and as needed based on subject reported cardiac 
symptoms. Triplicate ECGs will be performed and standard ECG parameters will be measured, 
including RR, PR, QT intervals, and QRS duration.  All ECGs must be evaluated by investigator 
or delegated physician for the presence of abnormalities.  Whether or not measurement is 
performed, date performed, results, and findings for each parameter will be recorded in the 
eCRF. 
9.3.3. 
Infusion-related Reactions 
9.3.3.1. 
Clinical Summary  
As with any therapeutic antibodies, there is a possibility of infusion-related reactions and 
immune responses causing allergic or anaphylactic reactions following the administration of 
DS-8201a.  Immune responses causing allergic or anaphylactic reactions are considered to be an 
AESI for the DS-8201a clinical program.  Refer to the current IB for a summary of preliminary 
clinical trial data.   
9.3.3.2. 
Management Guidance 
Subjects receiving DS-8201a should be monitored by means of vital signs, physical examination, 
and signs and symptoms of infusion-related reaction: fever, chills, nausea, vomiting, headache, 
cough, dizziness, rash, and/or lower back pain usually of mild to moderate severity and may lead 
to shortness of breath and severe lowering of blood pressure.   

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9.4. 
Adverse Event 
9.4.1. 
Definition of Adverse Event 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product 
and that does not necessarily have to have a causal relationship with this treatment.  An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product (International Conference on 
Harmonization [ICH] E2A Guideline: Clinical Safety Data Management: Definitions and 
Standards for Expedited Reporting, Oct 1994). 
It is the responsibility of investigators, based on their knowledge and experience, to determine 
those circumstances or abnormal laboratory findings which should be considered AEs. 
9.4.2. 
Serious Adverse Event 
A serious adverse event is any untoward medical occurrence that at any dose: 
 Results in death, 
 Is life-threatening, 
 Requires in-subject hospitalization or prolongation of existing hospitalization, 
 Results in persistent or significant disability/incapacity, 
 Is a congenital anomaly/birth defect, or 
 Is an important medical event. 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe (International Conference on 
Harmonisation [ICH] E2A Guideline.  Clinical Safety Data Management: Definitions and 
Standards for Expedited Reporting, Oct 1994). 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above.  Examples 
include allergic bronchospasm, convulsions, and blood dyscrasias or development of drug 
dependency or drug abuse. 
Note:  
 Procedures are not AEs or SAEs, but the reason for the procedure may be an AE or 
SAE.   
 Pre-planned (prior to signing the ICF) procedures or treatments requiring 
hospitalizations for pre-existing conditions that do not worsen in severity are not 
SAEs. 

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9.4.3. 
Severity Assessment 
All AEs will be graded (1 to 5; see below) according to the latest NCI-CTCAE version 4.03: 
 Grade 1 Mild AE 
 Grade 2 Moderate AE 
 Grade 3 Severe AE 
 Grade 4 Life-threatening consequences; urgent intervention indicated 
 Grade 5 Death related to AE 
Severity versus Seriousness: Severity is used to describe the intensity of a specific event while 
the event itself, however, may be of relatively minor medical significance (such as severe 
headache).  Seriousness of an event is based upon a universal and global Regulatory definition 
for reporting SAEs to regulatory agencies.  For example, Grade 4 (life threatening consequences; 
urgent intervention indicated) is assessed based on unique clinical descriptions of severity for 
each AE, and these criteria may be different from those used for the assessment of AE 
seriousness.  An AE assessed as Grade 4 may or may not be assessed as serious based on the 
seriousness criteria.  Overall, the severity of an event may be graded by the investigator as Grade 
1 or 2, but if the subject presents to the emergency facility for evaluation and is hospitalized 
overnight for observation that immediately makes the event serious based upon hospitalization 
without regard to the investigator assessment of severity. 
9.4.4. 
Causality Assessment 
The investigator should assess causal relationship between an AE and the study drug on the basis 
of his/her clinical judgment and the following definitions.  The causality assessment must be 
made based on the available information and can be updated as new information becomes 
available. 
 Related: 
 The AE follows a reasonable temporal sequence from study drug administration, 
and cannot be reasonably explained by the subject’s clinical state or other factors 
(eg, disease under study, concurrent diseases, and concomitant medications). 
or 
 The AE follows a reasonable temporal sequence from study drug administration, 
and is a known reaction to the drug under study or its chemical group, or is 
predicted by known pharmacology. 
 Not Related: 
 The AE does not follow a reasonable sequence from study drug administration, or 
can be reasonably explained by the subject’s clinical state or other factors (eg, 
disease under study, concurrent diseases, and concomitant medications).  
9.4.5. 
Action Taken Regarding Study Drug(s) 
 Dose Not Changed: No change in study drug dosage was made. 

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 Drug Withdrawn: The study drug was permanently stopped. 
 Dose Reduced: The dosage of study drug was reduced. 
 Drug Interrupted: The study drug was temporarily stopped. 
9.4.6. 
Other Action Taken for Event 
 None. 
 No treatment was required. 
 Medication required. 
 Prescription and/or over the counter (OTC) medication was required to treat the 
AE. 
 Hospitalization or prolongation of hospitalization required. 
 Hospitalization was required or prolonged due to the AE, whether or not 
medication was required. 
 Other. 
9.4.7. 
Adverse Event Outcome 
 Recovered/Resolved 
 The subject fully recovered from the AE with no residual effect observed. 
 Recovering/Resolving 
 The AE improved but has not fully resolved. 
 Not Recovered/Not Resolved 
 The AE itself is still present and observable. 
 Recovered/Resolved with Sequelae 
 The residual effects of the AE are still present and observable. 
 Include sequelae/residual effects. 
 Fatal 
 Fatal should be used when death is a direct outcome of the AE. 
9.5. 
Serious Adverse Events and Adverse Events of Special Interest 
Reporting–Procedure for Investigators   
All AEs, AESIs, SAEs and medication errors including overdose, will be reported in the eCRF. 
Additional relevant information regarding the AESIs ILD/pneumonitis and cardiotoxicity 
(cardiac-related events including QT prolongation and LVEF) for the DS-8201a clinical program 
regardless of seriousness is to be collected through the targeted questionnaires built within the 
applicable eCRFs in the clinical study database.   
Serious events that are also efficacy endpoints (eg, PD) and/or safety endpoints will be exempted 
from SAE processing and expedited reporting.  Disease progression should not be reported as an 
AE/SAE.  However, when a subject dies from PD with no other immediate causes, “disease 
progression” should be reported as an SAE and captured on designated eCRF.  These events are 

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clinically anticipated events in the target treatment population, and will be periodically reviewed 
by the Daiichi Sankyo safety teams to ensure prompt identification of any clinically concerning 
safety issues. 
The following types of events should be reported by the investigator in electronic data capture 
(EDC) within 24 hours of awareness: 
 SAEs (see Section 9.4.2 for definition) 
 Hepatic events (both serious and non-serious) which meet the potential Hy’s Law 
criteria defined as an elevated (ALT or AST) ≥3 × ULN and an elevated TBL ≥2 × 
ULN that may occur at different time points during the study conduct.  A targeted 
questionnaire is in-built as an eCRF to collect relevant additional information for 
these potential cases. 
All events (serious and non-serious) must be reported with investigator’s assessment of the 
event’s seriousness, severity, and causality to the study drug.  A detailed narrative summarizing 
the course of the event, including its evaluation, treatment, and outcome should be provided.  
Specific or estimated dates of event onset, treatment, and resolution should be included when 
available.  Medical history, concomitant medications, and laboratory data that are relevant to the 
event should also be summarized in the narrative.  For fatal events, the narrative should state 
whether an autopsy was or will be performed, and include the results if available.  Source 
documents (including medical reports) will be retained at the study center and should not be 
submitted to the Sponsor for SAE reporting purposes. 
Urgent safety queries must be followed up and addressed promptly.  Follow-up information and 
response to non-urgent safety queries should be combined for reporting to provide the most 
complete data possible within each follow-up.  In the event that eCRF is unavailable, report 
SAEs by faxing the paper Serious Adverse Event Report (SAVER) Form to CRO using the 
provided fax cover sheet and the appropriate fax number provided for your country.  Once eCRF 
becomes available, please enter SAEs reported on the SAVER Form into eCRF as soon as 
possible.  Please refer to eCRF Completion Guide for additional instructions. 
See Section 15.10 for contact information for SAE reporting.  Please call the local SAE Hotline 
(see Study Manual) or your study monitor for any questions on SAE reporting.   
9.6. 
Notifying Regulatory Authorities, Investigators, and Institutional 
Review Board/Ethics Committee 
Daiichi Sankyo and/or CRO will inform investigators IRBs/ECs, and regulatory authorities of 
any Suspected Unexpected Serious Adverse Reactions (SUSARs) occurring in other study 
centers or other studies of the investigational drug, as appropriate per local reporting 
requirements.  Daiichi Sankyo and/or CRO will comply with any additional local safety 
reporting requirements. 
In the US, upon receipt of the Sponsor’s notification of SUSARs that occurred with the study 
drug, unless delegated to the Sponsor, it is the investigator’s responsibility to inform the IRB/EC 
per Sponsor’s instruction. 
In the European Economic Area states, it is the Sponsor’s responsibility to report SUSARs to all 
ECs. 

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9.7. 
Exposure In Utero During Clinical Studies 
Daiichi Sankyo must be notified of any subject or their female partner who becomes pregnant 
while receiving or within 4.5 months of discontinuing the study drug.  
Although pregnancy is not technically an AE, all pregnancies must be followed to conclusion to 
determine their outcome.  This information is important for both drug safety and public health 
concerns.  It is the responsibility of the investigator, or designee, to report any pregnancy in a 
female subject using the Exposure In Utero (EIU) Reporting form.  Please contact your study 
monitor to receive the EIU Reporting form upon learning of a pregnancy.  The investigator 
should make every effort to follow the subject until completion of the pregnancy and complete 
the EIU Reporting Form with complete pregnancy outcome information, including normal 
delivery and induced abortion.  The adverse pregnancy outcome, either serious or non-serious, 
should be reported in accordance with study procedures.  If the outcome of the pregnancy meets 
the criteria for immediate classification as a SAE (ie, post-partum complications, spontaneous 
abortion, stillbirth, neonatal death, or congenital anomaly, including that in an aborted fetus), the 
investigator should follow the procedures for reporting SAEs outlined in Section 9.5. 
9.8. 
Clinical Laboratory Evaluations 
The following clinical laboratory tests will be performed: 
1. Hematology tests 
 Red blood cell count, hemoglobin, hematocrit, platelet count, white blood cell count, 
differential white blood cell count (neutrophils, lymphocytes, monocytes, eosinophils, 
basophils). 
2. Blood chemistry tests 
 Total protein, albumin, alkaline phosphatase (ALP), ALT, AST, total bilirubin, blood 
urea nitrogen (BUN)/urea, calcium, chloride, serum creatinine, lactate dehydrogenase 
(LDH), potassium, sodium, and magnesium) 
 A coagulation test (prothrombin time and activated partial thromboplastin time) will 
be performed at screening and thereafter as needed,  
 Creatinine clearance (mL/min) will be calculated using the Cockcroft-Gault equation 
(Section 17.1).  
3. Urinalysis 
 Protein, glucose, blood, microscopy assessment (if indicated), and specific gravity. 
In addition, the following parameters will be analyzed at the visits indicated in the Schedule of 
Events, Table 6.1 and Table 6.2.  
 Pregnancy test (serum or urine) for all female subjects of childbearing potential must 
be performed during the Screening Period.  A positive urine pregnancy test result 
must be confirmed immediately using a serum test. 
All laboratory values must be appraised by the investigator as to clinical significance and used to 
take appropriate clinical management measures.  All abnormal laboratory values considered 
clinically significant by the investigator should be recorded on the AE page of the eCRF.  If the 
abnormal laboratory value constitutes an SAE, a SAVER form should be submitted and other 

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relevant procedures must be followed (see Section 9.5).  Abnormal laboratory values (NCI-
CTCAE grade 3 or 4) occurring during the clinical study will be followed until repeat test results 
return to normal (or baseline), stabilize, or are no longer clinically significant. 
9.9. 
Vital Signs 
Vital sign measurements will include systolic and diastolic blood pressure, pulse rate, respiratory 
rate, and body temperature.  Additionally, SpO2 will be measured at Screening, before 
administration on Day 1 of each cycle, EOT and F/U. 
9.10. 
Electrocardiograms 
Standard supine/semi-recumbent 12-lead ECGs in triplicate (taken in close succession, 
approximately 3 minutes apart) will be performed as described in the Schedule of Events.  
Standard ECG parameters will be measured, including RR, PR, QT intervals, and QRS duration.  
All ECGs must be evaluated by investigator or delegated physician for the presence of 
abnormalities. 
9.11. 
Physical Examinations 
Physical examination findings will evaluate the following body systems/organs: general 
appearance; dermatological; head and; ears, nose, mouth, and throat; pulmonary; cardiovascular; 
abdominal; genitourinary (optional); lymphatic; musculoskeletal/ extremities; and neurological.  
Weight and height will also be recorded in kilograms and centimeters, respectively. 
9.12. 
Other Examinations 
ECOG PS 
Cardiac Assessments 
 Either Echo or MUGA will be performed as described in the Schedule of Events 
(Table 6.1 and Table 6.2).  LVEF will be measured. 
Ophthalmic Assessments 
 Will include visual acuity testing, slit lamp examination and fundoscopy. 
Pulmonary Assessments 
 Will include CT or MRI of the chest, SpO2 and will be performed as described in 
schedule of events.  For more details please refer to Section 6 of the protocol. 
 An ILD AC will review all cases of (potential) ILD on an ongoing basis.  Description 
of the ILD AC is available in Section 9.3.1.3. 

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10. 
OTHER ASSESSMENTS 
Not applicable 

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11. 
STATISTICAL METHODS  
11.1. 
Analysis Sets 
11.1.1. 
Full Analysis Set/Safety Analysis Set 
The Full Analysis Set (FAS)/Safety Analysis Set will include all subjects enrolled in Part 1 or 
Part 2 who received at least one dose of study drug. 
11.1.2. 
Response Evaluable Set 
The Response Evaluable Set will include all subjects enrolled in Part 1 or Part 2 who received at 
least one dose of study drug and had measurable tumors assessed by independent central imaging 
facility review at baseline. 
11.1.3. 
Per Protocol Set 
Not Applicable. 
11.1.4. 
Pharmacokinetic Set 
The PK Analysis Set will include all subjects enrolled in Part 1 or Part 2 who received at least 
one dose of study drug and had measurable serum concentrations of DS-8201a. 
11.2. 
General Statistical Considerations 
A data cut-off date for the primary analysis will be identified during Part 2. 
Data in Part 1 and Part 2a will be combined by the starting dose level.  Summary statistics will 
be presented by part/dose group.  Continuous variables will be summarized by the number of 
observations, mean, standard deviation, median, minimum, and maximum values.  Categorical 
variables will be summarized using frequency counts and percentages.  
Assessments of change from baseline to post-treatment or the ratio of post-treatment to baseline 
will include only those subjects with both baseline and post-treatment measurements.  The last 
non-missing value of a variable taken before the first dose of study treatment will be used as the 
baseline value, unless otherwise specified.  In general, missing or dropout data will not be 
imputed for the purpose of data analysis, unless otherwise specified. 
Analyses of ORR, DCR, and CBR will be performed on the Response Evaluable Set.  The other 
efficacy analyses will be performed on the Full Analysis Set (FAS).  Safety analyses will be 
performed using the Safety Analysis Set.  Analysis of PK parameters will be based on the PK 
Analysis Set.  All other exploratory analyses will be performed based on the FAS and 
availability of assessment. 
11.3. 
Study Population Data 
Subject disposition will be summarized for the enrolled subjects in each part/dose group.  The 
total number of subjects for each defined analysis set will also be tabulated for each part/dose 
group.  The demographic and baseline characteristics will be summarized descriptively for the 

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FAS/Safety Analysis Set and Response Evaluable Set.  Study drug exposure, treatment duration, 
and compliance with study therapy as well as prior and concomitant medications will be 
summarized using descriptive statistics for the Safety Analysis Set. 
11.4. 
Statistical Analysis 
11.4.1. 
Efficacy Analyses 
The convention to be followed when assessing response or progression will be to assign a single 
date to evaluations performed within that time point.  The date of response (CR, PR, SD, or NE) 
will be recorded as the date of the last radiographic evaluation included in the series for that 
assessment.  The date of progression (PD) will be recorded as the date of the earliest 
radiographic evaluation included in the series for that assessment. 
11.4.1.1. Primary Efficacy Analysis 
The primary endpoint is ORR (the proportion of subjects who achieved a best overall response of 
CR or partial response [PR]).  Tumor responses will be assessed by an independent central 
imaging facility based on RECIST version 1.1.  The primary efficacy analysis will be performed 
for all subjects who initially received the RP2D of DS-8201a in Part 1 and Part 2a of the 
Response Evaluable Set.  Confirmation of CR/PR is required for this study. 
The estimate of ORR and its two-sided 95% exact confidence intervals (CI) will be provided.  In 
addition, ORR until fixed time points (eg, 3, 6, 9, 12 months) along with their 2-sided 95% exact 
CIs will be provided. 
11.4.1.2. Secondary Efficacy Analyses 
11.4.1.2.1. 
Analyses of ORR in the Other Dose Levels of Part 1 and Part 2b 
The same analyses as described in the primary efficacy analyses (Section 11.4.1.1) will be 
performed by dose group for subjects from Part 1 and for Part 2b as part of the Response 
Evaluable Set. 
11.4.1.2.2. 
Other Secondary Efficacy Analyses 
The secondary efficacy endpoints include duration of response, best percent change in the SLD 
of measurable tumors, DCR, (the proportion of subjects who achieved a best overall response of 
CR or PR or stable disease [SD]), CBR (the proportion of subjects who achieved a best overall 
response of CR or PR or more than 6 months SD), PFS, OS, and ORR assessed by the 
investigator based on RECIST version 1.1.  
Duration of response is defined as the time from the date of the first documentation of objective 
response (CR or PR) to the date of the first documentation of PD or death due to any cause.  
Duration of response will be measured for responding subjects (CR or PR) only.  Detailed 
censoring rules for duration of response will be specified in the statistical analysis plan (SAP).  
PFS is defined as the time from the date of randomization/registration to the earlier of the dates 
of the first objective documentation of radiographic PD via independent radiologic facility 
review based on RECIST version 1.1 or death due to any cause.  Detailed censoring rules for 
PFS will be specified in the SAP.  

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OS is defined as the time from the date of randomization/registration to the date of death for any 
cause.  If there is no death reported for a subject before the data cut-off for OS analysis, OS will 
be censored at the last contact date at which the subject is known to be alive. 
Duration of response, PFS, and OS will be summarized with median event times and their 2-
sided 95% CI for the median using Brookmeyer and Crowley methods for each part/dose group. 
Descriptive statistics for the best (minimum) percent change from baseline in the SLD will be 
provided by part/dose group. 
DCR, CBR, ORR assessed by the investigator based on RECIST version 1.1 will be analyzed for 
each part/dose group in the same manner as the primary ORR analysis. 
11.4.1.3. Exploratory Efficacy Analyses 
The exploratory efficacy analyses include subgroup analyses of the primary and secondary 
endpoints and analyses of exploratory efficacy endpoints.  Any additional analysis plans will be 
specified in the SAP. 
11.4.1.3.1. 
Subgroup Analyses 
The subgroup analyses for ORR, duration of response, DCR, CBR, PFS, and OS will be 
performed.  Subgroup analyses will include: 
 ERs (positive, negative). 
 Progesterone receptors (positive, negative). 
 Lines of prior systemic therapy not including hormone therapy (<3, ≥3). 
 Prior pertuzumab (yes, no) 
 Prior pertuzumab in 1st or 2nd line in advanced/metastatic breast cancer (yes, no) 
 Renal impairment at baseline (within normal range, mild/moderate impairment) 
 Hepatic impairment at baseline (within normal range, mild-moderate impairment) 
 Best response to T-DM1 therapy (CR/PR/SD, PD). 
 Brain metastases (brain metastases, no brain metastases) 
 Age (<65, ≥ 65 years). 
 Race (Asian, others). 
 Region (Asia, rest of world). 
 Ethnicity (Hispanic/Latino, others). 
 ECOG PS (0, 1). 
The subgroups are based on baseline values (ie, the last non-missing values before the first drug 
administration).  In each subgroup defined above, the analysis will be carried out using the same 
type of methodology as described for the overall analysis of the corresponding endpoint.  These 
results will be considered exploratory because of smaller sample sizes that cannot be pre-
specified. 

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11.4.1.3.2. 
Analyses of Exploratory Efficacy Endpoints 
Duration of stable disease, time to response, exposure-response relationships for efficacy and 
safety endpoints, and potential biomarkers of response, such as serum HER2ECD concentrations, 
will be evaluated and considered as exploratory efficacy endpoints.  
Duration of stable disease and time to response will be summarized with median event times and 
their 2-sided 95% CI for the median by part/dose group using Brookmeyer and Crowley methods. 
11.4.2. 
Pharmacokinetic/Pharmacodynamic Analyses 
11.4.2.1. Pharmacokinetic Analyses 
Serum concentrations for DS-8201a, total anti-HER2 antibody and MAAA-1181a will be listed, 
plotted, and summarized using descriptive statistics by Part (and Stage)/dose level/study day at 
each time point.  PK parameters will be listed and summarized using descriptive statistics by Part 
(and Stage)/dose level.  A dose selection analysis will also be conducted based on the data from 
Part 1, and based on comparative PK results, 2 doses will be selected for dose-finding stage of 
Part 1. 
The population pharmacokinetic and exposure-response analysis will be conducted for all 
evaluable subjects in the study.  An interim population PK and exposure response analysis may 
also be conducted based on the data from Part 1.  Modeling results will be presented in separate 
reports. 
11.4.2.2. Pharmacodynamic Analyses 
Not Applicable. 
11.4.2.3. Biomarker Analyses 
Biomarkers will be listed and summarized using descriptive statistics. 
11.4.2.4. Pharmacogenomic Analyses 
Not Applicable. 
11.4.3. 
Safety Analyses 
Safety analyses in general will be descriptive and will be presented in tabular format with the 
appropriate summary statistics.  A summary and display of TEAEs will be performed. 
Terminology of the MedDRA will be used to assign system organ class (SOC) and PT 
classification to AEs and diseases, based on the original terms entered on the eCRF. 
The incidence of TEAEs will be summarized by SOC, PT, relationship to the study treatment, 
and severity for each part/dose group.  A by-subject listing will be provided for those subjects 
who experience an SAE, including death, or experience an AE associated with early withdrawal 
from the study or study treatment. 

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11.4.3.1. Adverse Event Analyses 
TEAEs are AEs that occur, having been absent before the first dose of study treatment, or have 
worsened in severity after the initiating the study treatment.  TEAEs will be coded using 
MedDRA and assigned grades based on version 4.03 of the National Cancer Institute’s Common 
Terminology Criteria for Adverse Events (NCI CTCAE).  The number and percentage of 
subjects reporting TEAEs will be tabulated by system organ class (SOC), and PT, relationship to 
the study treatment, and the worst CTCAE grade.  Similarly, the number and percentage of 
subjects reporting treatment-emergent SAEs will be tabulated, as well as TEAEs leading to 
discontinuation of study treatments. 
A by-subject AE (including treatment-emergent) data listing including but not limited to 
verbatim term, SOC, PT, CTCAE grade, and relationship to study treatment will be provided.  
Deaths, other SAEs, and other significant AEs, including those leading to discontinuation of 
study treatments, will be listed. 
11.4.3.2. Clinical Laboratory Evaluation Analyses 
Descriptive statistics will be provided for the central clinical laboratory results by scheduled time 
of evaluation, as well as for the change from baseline.  In addition, the change from baseline will 
be summarized for the maximum and minimum post-treatment values. 
Abnormal clinical laboratory results will be graded according to NCI CTCAE version 4.03, if 
applicable, and the grade will be presented in a by-subject data listing.  A shift table, presenting 
the 2-way frequency tabulation for baseline and the worst post-treatment value according to the 
NCI CTCAE grade, will be provided for clinical laboratory tests. 
All clinical laboratory test results and abnormal clinical laboratory test results deemed of clinical 
significance or of Grade 3 or 4 will be listed. 
11.4.3.3. Vital Sign Analyses 
Descriptive statistics will be provided for the vital signs measurements by scheduled time of 
evaluation, as well as for the change from baseline.  In addition, the change from baseline will be 
presented for the maximum and minimum post-treatment values.  All vital sign data will be also 
listed. 
11.4.3.4. Electrocardiogram Analyses 
Descriptive statistics will be provided for ECG parameters and changes from baseline by 
scheduled time of evaluation, including the maximum post-treatment values and the values at the 
EOT Visit.  In addition, the number and percentage of subjects with ECG interval values meeting 
the criteria will be tabulated (eg, QTc ≤ 450 ms, > 450 to ≤ 480 ms, > 480 ms to ≤ 500 ms, and > 
500 ms).  The QT intervals will be corrected for heart rate by Fridericia’s formula (QTcF  
QT/[RR]1/3).  ECG data will also be listed. 
11.4.3.5. Physical Examination Analyses 
Physical examination findings will be listed. 

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11.4.3.6. Concomitant Medication Analyses 
Concomitant medications will be coded using the World Health Organization drug dictionary 
(most recent version).  Number and percentage of subjects taking concomitant medications will 
be summarized.  Concomitant medications will also be listed. 
11.4.3.7. Exploratory Safety Analyses 
Not applicable. 
11.4.3.8. Immunogenicity (Anti-Drug Antibody, ADA) Analyses 
Immunogenicity will be assessed through characterization of incidence and titer of ADA.  The 
number and percentage of subjects will be calculated for the presence or absence of development 
of ADA after the start of administration, defining subjects who are negative for ADA at all-time 
points as negative and subjects who are positive for ADA at least one time point post drug 
treatment as positive.  The raw values and change from baseline for ADA titers will be 
summarized by time point and treatment group using descriptive statistics. 
11.4.3.9. Other Safety Analyses 
All other safety variables per Section 9.12 will be listed. 
11.4.4. 
Other Analysis 
11.5. 
Dose Selection Analysis 
In the PK Stage, DS-8201a of FL-DP2 material will be administered at 5.4, 6.4 or 7.4 mg/kg to 
approximately 20 subjects/dose on Day 1 of a 21 day cycle.  Serial PK samples will be collected 
over 21 days in Cycle 1 following each dose administration.  Two doses, with PK profiles (eg, 
Cmax, AUC) matching those from the administration of 5.4 and 6.4 mg/kg of FL-DP1 material 
in study DS8201-A-J101, will be selected for further evaluation in the Dose Finding Stage.  The 
two dose levels will be selected based on the PK results. 
The next dose selection analysis will be conducted during the dose finding stage.  The purpose of 
the analysis is to determine one optimal dose level for Part 2.  The optimal dose level will be 
decided based on overall assessment of efficacy and safety data.  The following criteria will be 
included as part of the information used for dose selection.  Additional factors such as depth of 
response, duration of response, and chronic toxicity will also be included. 
 The high dose level will be considered efficacious compared with the low dose level 
if the posterior probability given the observed ORR data suggest that: Pr (ORRhigh  
ORRlow > 5% | data) > 80%. 
 The high dose level will be considered toxic compared with the low dose level if the 
posterior probability given the observed percent change from baseline in neutrophil 
count (PCNC) data suggest that: Pr (PCNChigh  PCNClow < 10% | data) > 80%. 
11.5.1. 
Data Monitoring Committee 
A Data Monitoring Committee is not applicable for this trial given that it is an open label trial.  
However, measures are put in place for monitoring the safety of the subjects participating in the 

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study.  Individual subject data will be reviewed on an ongoing basis and aggregate safety data 
will be monitored monthly by the study team across the duration of the trial following the 
Sponsor’s established safety monitoring SOPs.  The data review and analysis will be based on 
the available investigator reported data in the clinical database. 
11.6. 
Sample Size Determination 
The sample size of approximately 230 subjects was chosen to further confirm the safety profile 
and secure adequate accuracy to determine ORR of DS-8201a.  A sample size of 150 subjects 
(50 subjects from Part 1 who receive the optimal dose level and 100 subjects from Part 2a) 
provides ORR with 95% CI within plus or minus 10% of the ORR.  The probabilities of 
observing the lower bound of the 95% CI > 20% and ORR ≥ 30% are 98.2% and 91.6% under 
the expected ORR 35%, respectively.  The probability values for the sample size are derived 
based on binomial distribution using SAS® version 9.3 or higher. 
11.7. 
Statistical Analysis Process 
The SAP will provide the statistical methods and definitions for the analysis of the efficacy and 
safety data, as well as describe the approaches to be taken for summarizing other clinical study 
information such as subject disposition, demographic and baseline characteristics, study drug 
exposure, and prior and concomitant medications.  The SAP will also include a description of 
how missing, unused, and spurious data will be addressed. 
To preserve the integrity of the statistical analysis and clinical study conclusions, the SAP will be 
finalized prior to database lock. 
All statistical analyses will be performed using SAS® version 9.3 or higher (SAS Institute Inc., 
Cary, NC 27513). 

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12. 
DATA INTEGRITY AND QUALITY ASSURANCE 
The investigator/investigational site will permit study related monitoring, audits, IRB/EC review 
and regulatory inspections by providing direct access to source data/documents.  Direct access 
includes permission to examine, analyze, verify, and reproduce any records and reports that are 
important to the evaluation of a clinical study. 
12.1. 
Monitoring and Inspections 
The Sponsor, CRO monitor and regulatory authority inspectors are responsible for contacting 
and visiting the investigator for the purpose of inspecting the facilities and, upon request, 
inspecting the various records of the study (eg, eCRFs, source data, and other pertinent 
documents). 
The monitor is responsible for visiting sites at regular intervals throughout the study to verify 
adherence to the protocol; completeness, accuracy, and consistency of the data; and adherence to 
ICH Good Clinical Practice (GCP) and local regulations on the conduct of clinical research.  The 
monitor is responsible for inspecting the eCRFs and ensuring completeness of the study essential 
documents.  The monitor should have access to subject medical records and other study related 
records needed to verify the entries on the eCRFs. 
The monitor will communicate deviations from the protocol, SOPs, GCP, and applicable 
regulations to the investigator and will ensure that appropriate action designed to prevent 
recurrence of the detected deviations is taken and documented. 
The investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits are addressed and documented. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study may be selected for audit 
by representatives from the Sponsor.  Inspection of site facilities (eg, pharmacy, drug storage 
areas, laboratories, etc.) and review of study related records will occur in order to evaluate the 
study conduct and compliance with the protocol, ICH GCP, and applicable regulatory 
requirements. 
12.2. 
Data Collection 
All relevant observations and data related to the study, as per the study protocol, will be recorded 
on eCRF pages.  A representative of Daiichi Sankyo or their designee will provide instruction for 
completing the eCRF.  Adequate and accurate case records should be maintained, including the 
evaluation of inclusion and exclusion criteria, medical history, physical examinations, clinical 
assessments, a record of clinical safety laboratory sample collection drug administration, AEs, 
and final evaluation  
The eCRF should be kept current to enable the monitor to review the subject’s status throughout 
the course of the study.  The information should be entered into the eCRF within 5 days of the 
visit and should be completed, reviewed, and signed off by the investigator within 2 weeks of the 
last subject visit.  Query resolution should be completed within 48 hours. 

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An eCRF must be completed for each subject who signs an ICF and undergoes any screening 
procedures.  For subjects who are screened but not randomized, minimal data will be recorded on 
the eCRF, including demography, subject status, and AEs.  All study related data for these 
subjects will be maintained in the medical records at the site. 
The investigator will sign and date the indicated places on the eCRF via the EDC system’s 
electronic signature.  These signatures will indicate that the investigator inspected or reviewed 
the data on the eCRF, the data queries, and the site notifications, and agrees with the content. 
All written information and other material to be used by subjects and investigative staff must use 
vocabulary and language that are clearly understood. 
12.3. 
Data Management 
Each subject will be identified in the database by a unique subject identifier as defined by the 
Sponsor. 
To ensure the quality of clinical data across all subjects and study centers, a Clinical Data 
Management review will be performed on subject data according to specifications given to 
Sponsor or Designee.  Data will be vetted both electronically and manually for CRFs and the 
data will be electronically vetted by programmed data rules within the application.  Queries 
generated by rules and raised by reviewers will be generated within the EDC application.  During 
this review, subject data will be checked for consistency, completeness and any apparent 
discrepancies.   
Data received from external sources such as central labs will be reconciled to the clinical 
database. 
Serious Adverse Events in the clinical database will be reconciled with the safety database. 
All Adverse Events will be coded using MedDRA.   
All concomitant medications and prior cancer therapies will be coded using the World Health 
Organization Drug Reference List Dictionary and MedDRA. 
12.4. 
Study Documentation and Storage 
The investigator will maintain a Signature List of appropriately qualified persons to whom 
he/she has delegated study duties.  All persons authorized to make entries and/or corrections on 
eCRFs will be included on the Signature List. 
Source documents are original documents, data, and records from which the subject’s eCRF data 
are obtained.  These include but are not limited to hospital records, clinical and office charts, 
laboratory and pharmacy records, diaries, X rays, and correspondence. 
In addition, all original source documents supporting entries in the CRFs must be maintained and 
be readily available. 
All essential documentation will be retained by the institution for at least 5 years after 
completion of the study or for a longer period, where so required by other applicable regulations 
or requirements.  It is the responsibility of the Sponsor to inform the investigator/institution as to 
when these documents no longer need to be retained. 

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No study document should be destroyed without prior written agreement between Daiichi 
Sankyo and the investigator.  Should the investigator wish to assign the study records to another 
party or move them to another location, he/she must notify Daiichi Sankyo in writing of the new 
responsible person and/or the new location. 
12.5. 
Record Keeping 
The investigator and study staff are responsible for maintaining a comprehensive and centralized 
filing system (Trial Master File) of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from the Sponsor and/or applicable regulatory 
authorities.  Essential documents include: 
 Subject files containing completed CRFs, ICFs, and supporting copies of source 
documentation (if kept). 
 Study files containing the protocol with all amendments, IB, copies of relevant 
essential documents required prior to commencing a clinical study, and all 
correspondence to and from the EC/IRB and the Sponsor. 
 Records related to the study drug(s) including acknowledgment of receipt at study 
center, accountability records and final reconciliation and applicable correspondence. 
In addition, all original source documents supporting entries in the CRFs must be maintained and 
be readily available. 
No study document should be destroyed without prior written agreement between Daiichi 
Sankyo and the investigator.  Should the investigator wish to assign the study records to another 
party or move them to another location, he/she must notify Daiichi Sankyo in writing of the new 
responsible person and/or the new location. 

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13. 
FINANCING AND INSURANCE 
13.1. 
Finances 
Prior to starting the study, the principal investigator and/or institution will sign a clinical study 
agreement with the Sponsor or the CRO.  This agreement will include the financial information 
agreed upon by the parties. 
13.2. 
Reimbursement, Indemnity, and Insurance 
The Sponsor provides insurance for study subjects to make available compensation in case of 
study-related injury. 
Reimbursement, indemnity and insurance shall be addressed in a separate agreement on terms 
agreed upon by the parties. 

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14. 
PUBLICATION POLICY 
A study site may not publish results of a study until after a coordinated multicenter publication 
has been submitted for publication or until 1 year after the study has ended, whichever occurs 
first.  Therefore, the study site will have the opportunity to publish the results of the study, 
provided that Daiichi Sankyo has had the opportunity to review and comment on the study site’s 
proposed publication prior to its being submitted for publication with the advice of company 
patent council and in accord with needs for subject protection. 

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15. 
ETHICS AND STUDY ADMINISTRATIVE INFORMATION 
15.1. 
Subject Confidentiality 
The investigators and the Sponsor will preserve the confidentiality of all subjects taking part in 
the study, in accordance with GCP and local regulations. 
The investigator must ensure that the subject’s anonymity is maintained.  On the CRFs or other 
documents submitted to the Sponsor or the CRO, subjects should be identified by a unique 
subject identifier as designated by the Sponsor.  Documents that are not for submission to the 
Sponsor or the CRO (eg, signed ICF) should be kept in strict confidence by the investigator. 
In compliance with ICH GCP Guidelines, it is required that the investigator and institution 
permit authorized representatives of the company, of the regulatory agency(ies), and the IRB/EC 
direct access to review the subject’s original medical records for verification of study-related 
procedures and data.  The investigator is obligated to inform the subject that his/her study-related 
records will be reviewed by the above named representatives without violating the 
confidentiality of the subject. 
15.2. 
Informed Consent  
Before a subject’s participation in the study, it is the investigator’s responsibility to obtain freely 
given consent, in writing, from the subject after adequate explanation of the aims, methods, 
anticipated benefits, and potential hazards of the study and before any protocol-specific 
procedures or any study drugs are administered.  Subjects should be given the opportunity to ask 
questions and receive satisfactory answers to their inquiries, and should have adequate time to 
decide whether or not to participate in the study.  The written ICF should be prepared in the local 
language(s) of the potential subject population. 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirements, and should adhere to GCP and to the ethical principles that 
have their origin in the Declaration of Helsinki.  The consent form and any revision(s) should be 
approved by the EC or IRB prior to being provided to potential subjects. 
The subject’s written informed consent should be documented in the subject’s medical records.  
The ICF should be signed and personally dated by the subject and by the person who conducted 
the informed consent discussion (not necessarily the investigator).  The original signed ICF 
should be retained in accordance with institutional policy, and a copy of the signed consent form 
should be provided to the subject.  The date and time (if applicable) that informed consent was 
given should be recorded on the CRF. 
15.3. 
Regulatory Compliance 
The study protocol, subject information and consent form, the IB, any subject written 
instructions to be given to the subject, available safety information, subject recruitment 
procedures (eg, advertisements), information about payments and compensation available to the 
subjects, and documentation evidencing the investigator’s qualifications should be submitted to 

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the EC or IRB for ethical review and approval according to local regulations, prior to the study 
start.  The written approval should identify all documents reviewed by name and version. 
Changes in the conduct of the study or planned analysis will be documented in a protocol 
amendment and/or the SAP. 
The investigator and/or Sponsor must submit and, where necessary, obtain approval from the EC 
or IRB for all subsequent protocol amendments and changes to the ICF.  The investigator should 
notify the EC or IRB of deviations from the protocol or SAEs occurring at the study center and 
other AE reports received from the Sponsor/CRO, in accordance with local procedures. 
As required by local regulations, the Sponsor’s local Regulatory Affairs group or representative 
to whom this responsibility has been delegated will ensure all legal aspects are covered, and 
approval from the appropriate regulatory bodies obtained, prior to study initiation, and that 
implementation of changes to the initial protocol and other relevant study documents happen 
only after approval by the relevant regulatory bodies. 
In the event of any prohibition or restriction imposed (eg, clinical hold) by an applicable 
Regulatory Authorities in any area of the world, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the investigational 
drug, the Sponsor should be informed immediately.   
In addition, the investigator will inform the Sponsor immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of any 
suspected/actual serious GCP non-compliance that the investigator becomes aware of. 
15.4. 
Compliance Statement, Ethics and Regulatory Compliance 
This study will be conducted in compliance with the protocol, the ethical principles that have 
their origin in the Declaration of Helsinki, the International Conference on Harmonisation (ICH) 
consolidated Guideline E6 for Good Clinical Practice (GCP) (CPMP/ICH/135/95), and 
applicable regulatory requirement(s) including the following: 
 US Food and Drug Administration (FDA) GCP Regulations: Code of Federal 
Regulations (CFR) Title 21, parts 11, 50, 54, 56 and 312 as appropriate and/or; 
 Japanese Ministry of Health, Labor and Welfare Ordinance No. 28 of 27 March, 1997 
and/or; 
 Directive 2001/20/EC of the European Parliament and of the Council on the 
approximation of the laws, regulations and administrative provisions of the Member 
States relating to the implementation of good clinical practice in the conduct of 
clinical trials on medicinal product for human use; 
 Other applicable local regulations. 
15.5. 
Protocol Deviations 
The investigator should conduct the study in compliance with the protocol agreed to by Sponsor 
and, if required, by the regulatory authority(ies), and which was given approval/favorable 
opinion by the IRBs/ECs. 

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A deviation to any protocol procedure or waiver to any stated criteria will not be allowed in this 
study except where necessary to eliminate immediate hazard(s) to the subject.  Sponsor must be 
notified of all intended or unintended deviations to the protocol (eg, inclusion/exclusion criteria, 
dosing, missed study visits) on an expedited basis. 
The investigator, or person designated by the investigator, should document and explain any 
deviation from the approved protocol. 
If a subject was ineligible or received the incorrect dose or study treatment, and had at least 1 
administration of study drug, data should be collected for safety purposes. 
 If applicable, the investigator should notify the IRB/EC of deviations from the 
protocol in accordance with local procedures. 
15.6. 
Supply of New Information Affecting the Conduct of the Study 
When new information becomes available that may adversely affect the safety of subjects or the 
conduct of the study, the Sponsor will inform all investigators involved in the clinical study, 
ECs/IRBs, and regulatory authorities of such information, and when needed, will amend the 
protocol and/or subject information. 
The investigator should immediately inform the subject whenever new information becomes 
available that may be relevant to the subject’s consent or may influence the subject’s willingness 
to continue participation in the study.  The communication should be documented on medical 
records, for example, and it should be confirmed whether the subject is willing to remain in the 
study.  
If the subject information is revised, it must be re-approved by the EC/IRB.  The investigator 
should obtain written informed consent to continue participation with the revised written 
information even if subjects were already informed of the relevant information.  The investigator 
or other responsible personnel who provided explanations and the subject should sign and date 
the revised ICF. 
15.7. 
Protocol Amendments 
Any amendments to the study protocol that seem to be appropriate as the study progresses will 
be communicated to the investigator by Daiichi Sankyo or the CRO.  Also, the Sponsor will 
ensure the timely submission of amendments to regulatory authorities. 
A global protocol amendment will affect study conduct at all study centers in all regions of the 
world.  Such amendments will be incorporated into a revised protocol document.  Changes made 
by such amendments will be documented in a Summary of Changes document.  These protocol 
amendments will undergo the same review and approval process as the original protocol.   
A local protocol amendment will affect study conduct at a particular study center(s) and/or in a 
particular region/country.  Sponsor approval of local amendments will be clearly documented. 
A protocol amendment may be implemented after it has been approved by the IRB/EC and by 
regulatory authorities where appropriate, unless immediate implementation of the change is 
necessary for subject safety. 

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15.8. 
Study Termination 
The Sponsor has the right to terminate the study at any time and study termination may also be 
requested by (a) competent authority(ies). 
15.9. 
Data and Safety Monitoring Board 
Not applicable 
15.10. 
Address List 
See the site Study Manual for all appropriate addresses. 
 
 

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16. 
REFERENCES 
1. Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and 
Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International 
Agency for Research on Cancer; 2013. Available from: http://globocan.iarc.fr, accessed 
on 09/05/2015. 
2. Pauletti G, Dandekar S, Rong H, et al. Assessment of methods for tissue-based detection 
of the HER-2/neu alteration in human breast cancer: a direct comparison of fluorescence 
in situ hybridization and immunohistochemistry. J Clin Oncol. 2000; 18:3651 3664. 
3. Loganzo F, Tan X, Sung M, et al. Tumor cells chronically treated with a trastuzumab-
maytansinoid antibody-drug conjugate develop varied resistance mechanisms but respond 
to alternate treatments. Molecular Cancer Therapeutics. 2015; 14: 952-63. 
4. Abou-Alfa GK, L. R et al. Randomized phase III study of exatecan and gemcitabine 
compared with gemcitabine alone in untreated advanced pancreatic cancer. J. Clin Oncol, 
2006; 24(27): 4441-7. 
5. Cheverton P, Friess H, Andras C, et al. Phase III results of exatecan (DX-8951f) versus 
gemcitabine (Gem) in chemotherapy-naïve subjects with advanced pancreatic cancer 
(APC). J Clin Oncol. 22:14s, 2004 (abstr 4005). 
6. De Jager R, Cheverton P, Tamanoi K, et al. DX-8951f: summary of phase I clinical trials. 
Ann N Y Acad Sci. 2000; 922:260-73. 
7. Ogitani Y, Aida T, Hagihara K, et al.  DS-8201a, A Novel HER2-Targeting ADC with a 
novel DNA topoisomerase I inhibitor, demonstrates a promising antitumor efficacy with 
differentiation from T-DM1. Clin Cancer Res.  2016; 22(20): 5097 108. 
8. Ogitani Y, Hagihara K, Oitate M, et al. Bystander killing effect of DS8201a, a novel 
anti-human epidermal growth factor 2 antibody-drug conjugate, in tumors with human 
epidermal growth factor receptor 2 heterogeneity. Cancer Sci. 2016; 107: 1039-46. 
9. Archer SG, Eliopoulos A, Spandidos D, et al. Expression of ras p21, p53 and c-erbB-2 in 
advanced breast cancer and response to first line hormonal therapy. Br J Cancer. 1995; 
72(5):1259-66.  
10. Esteva FJ, Guo H, Zhang S, et al. PTEN, PIK3CA, p-AKT, and p-p70S6K status: 
association with trastuzumab response and survival in subjects with HER2-positive 
metastatic breast cancer. Am J Pathol. 2010; 177(4):1647-56. 
11. Ross JS, Slodkowska EA, Symmans WF, et al. The HER-2 receptor and breast cancer: ten 
years of targeted anti-HER-2 therapy and personalized medicine. Oncologist. 2009; 
14(4):320-68.  
12. Hofmann M, Stoss O, Shi D, et al. Assessment of a HER2 scoring system for gastric cancer: 
results from a validation study. Histopathology. 2008; 52(7):797-805.  
13. Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a novel 
therapeutic target. Ann Oncol. 2008; 19(9):1523-9.  

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14. Harder J, Ihorst G, Heinemann V, et al. Multicentre phase II trial of trastuzumab and 
capecitabine in subjects with HER2 overexpressing metastatic pancreatic cancer. Br J 
Cancer. 2012; 106(6):1033-8.  
15. Yoshizawa A, Sumiyoshi S, Sonobe M, et al. HER2 status in lung adenocarcinoma: a 
comparison of immunohistochemistry, fluorescence in situ hybridization (FISH), dual-ISH, 
and gene mutations. Lung Cancer. 2014; 85(3):373-8.  
16. Blok EJ, Kuppen PJ, van Leeuwen JE, et al. Cytoplasmic overexpression of HER2: a key 
factor in colorectal cancer. Clin Med Insights Oncol. 2013; 7:41-51.  
17. Verri E, Guglielmini P, Puntoni M, et al. HER2/neu oncoprotein overexpression in epithelial 
ovarian cancer: evaluation of its prevalence and prognostic significance. Clinical study. 
Oncology. 2005; 68(2-3):154-61.  
18. Press MF, Cordon-Cardo C, Slamon DJ. Expression of the HER-2/neu proto-oncogene in 
normal human adult and fetal tissues. Oncogene. 1990; 5(7):953-62.  
19. Swain S, Baselga J, Kim S, et al. Pertuzumab, Trastuzumab, and Docetaxel in HER2-Positive 
Metastatic Breast Cancer. N Engl J Med. 2015; 372:724-34; 
https://www.ncbi.nlm.nih.gov/pubmed/25693012. 
20. Verma S, Miles D, Gianni L, et al. Trastuzumab Emtansine for HER2-Positive Advanced 
Breast Cancer. N Engl J Med. 2012; 367:1783-91; 
https://www.ncbi.nlm.nih.gov/pubmed/23020162. 
21. Wolff A, Hammond M, Hicks D, et al. Recommendations for human epidermal growth factor 
receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of 
American Pathologists Clinical Practice Guideline Update. 
http://ascopubs.org/doi/full/10.1200/jco.2013.50.9984. 
22. Kubo K, Azuma A, Kanazawa M, et al. Consensus statement for the diagnosis and treatment 
of drug-induced lung injuries. Respir Investig. 2013; 51(4):260-77. 
 

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17. 
APPENDICES 
17.1. 
Cockcroft-Gault Equation 
The estimated creatinine clearance rate (CrCl; mL/min) will be calculated using the modified 
Cockcroft-Gault equation based on actual weight, where weight is lean body mass in kilograms 
(1 kilogram  2.2 pounds): 
Conventional – serum creatinine in mg/dL: 
Male: 
CrCl (mL/min)  
72
 x 
mg/dL)
(in 
 
creatinine
 
serum
kg)
(in 
 x weight 
years)]
(in 
 
age
 - 
[140
 
Female: 
CrCl (mL/min)  
72
 x 
mg/dL)
(in 
 
creatinine
 
serum
kg)
(in 
 x weight 
years)]
(in 
 
age
 - 
[140
  0.85 
 
International System of Units (SI) – serum creatinine in μmol/L: 
Male: 
CrCl (mL/min)  
0.0113
 x 
72
 x 
mol/L)
(in 
 
creatinine
 
serum
kg)
(in 
 x weight 
years)]
(in 
 
age
 - 
[140

 
Female: 
CrCl (mL/min)  
0.0113
 x 
72
 x 
mol/L)
(in 
 
creatinine
 
serum
kg)
(in 
 x weight 
years)]
(in 
 
age
 - 
[140

  0.85 
 
Source: Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron 1976;16:31-41. 

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17.2. 
Eastern Cooperative Oncology Group Performance Status (ECOG 
PS) 
Table 17.1: 
Eastern Cooperative Oncology Group Performance Status Scale 
0 
Normal activity.  Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous activity, but ambulatory 
and able to carry out work of a light or sedentary nature (eg, light housework, office 
work) 
2 
In bed <50% of the time.  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 
In bed >50% of the time.  Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally confined 
to bed or chair 
5 
Dead 
Source: 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. 
 
 

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17.3. 
Response Evaluation Criteria in Solid Tumors, Version 1.1 
17.3.1. 
Measurability of Tumor at Baseline 
17.3.1.1. Definitions 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows: 
17.3.1.1.1. Measurable 
 Tumor lesions: Must be accurately measured in at least 1 dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size of:  
 10 mm by CT scan (CT scan slice thickness no greater than 5 mm)  
 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable)  
 20 mm by chest X-ray  
 Measurable malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥ 15 mm in short axis when assessed by CT scan 
(CT scan slice thickness recommended to be no greater than 5 mm).  At baseline (ie, 
screening for this study) and in follow-up (ie, all measurements past screening for this 
study), only the short axis will be measured and followed.  See also notes below on 
“Baseline documentation of target and non-target lesions” for information on lymph 
node measurement.  
17.3.1.1.2. Non-Measurable 
All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph 
nodes with ≥ 10 to < 15 mm short axis), as well as truly non-measurable lesions.  Lesions 
considered truly non-measurable include: leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, and abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques. 
17.3.1.1.3. Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment. 
17.3.1.1.3.1. Bone Lesions 
 Bone scan, positron emission tomography (PET) scan or plain films are not 
considered adequate imaging techniques to measure bone lesions.  However, these 
techniques can be used to confirm the presence or disappearance of bone lesions. 
 Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as CT 

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or MRI can be considered as measurable lesions if the soft tissue component meets 
the definition of measurability described above. 
 Blastic bone lesions are non-measurable. 
17.3.1.1.3.2. Cystic Lesions 
 Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts.  
 “Cystic lesions” thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above.  
However, if noncystic lesions are present in the same subject, these are preferred for 
selection as target lesions.  
17.3.1.1.3.3. Lesions with Prior Local Treatment 
 Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are not considered measurable unless there has been 
demonstrated progression in the lesion. 
17.3.1.2. Specifications by Methods of Measurements 
17.3.1.2.1. Measurement of Lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed.  All 
baseline evaluations should be performed as close as possible to the treatment start and NEVER 
more than 28 days before randomization/registration. 
17.3.1.2.2. Method of Assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging based evaluation should 
always be performed rather than clinical examination unless the lesion(s) being followed cannot 
be imaged but are assessable by clinical exam. 
CT, MRI: CT is the best currently available and reproducible method to measure lesions selected 
for response assessment.  This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less.  When CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  
MRI is also acceptable in certain situations (eg, for body scans). 
17.3.2. 
Tumor Response Evaluation 
17.3.2.1. Assessment of Overall Tumor Burden and Measurable Disease 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. 
In this study, only subjects with measurable disease at baseline should be included. 

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17.3.2.2. Baseline Documentation of “Target” and “Non-target” Lesions 
When more than 1 measurable lesion is present at baseline, all lesions up to a maximum of 5 
lesions total (representative of all involved organs) should be identified as target lesions and will 
be recorded and measured at baseline (this means in instances where subjects have only 1 or 2 
organ sites involved a maximum of 2 and 4 lesions respectively will be recorded). 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements.  It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor.  As noted above, pathological nodes which are 
defined as measurable and may be identified as target lesions must meet the criterion of a short 
axis of ≥ 15 mm by CT scan.  Only the short axis of these nodes will contribute to the baseline 
sum.  The short axis of the node is the diameter normally used by radiologists to judge if a node 
is involved by solid tumor.  Nodal size is normally reported as 2 dimensions in the plane in 
which the image is obtained (for CT scan this is almost always the axial plane; for MRI the plane 
of acquisition may be axial, sagittal, or coronal).  The smaller of these measures is the short axis.  
For example, an abdominal node which is reported as being 20 mm × 30 mm has a short axis of 
20 mm and qualifies as a malignant, measurable node.  In this example, 20 mm should be 
recorded as the node measurement.  All other pathological nodes (those with short axis ≥ 10 mm 
but < 15 mm) should be considered non-target lesions.  Nodes that have a short axis < 10 mm are 
considered non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum.  The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline.  Measurements are not required and 
these lesions should be followed as “present,” “absent,” or in rare cases “unequivocal 
progression.”  In addition, it is possible to record multiple non-target lesions involving the same 
organ as a single item on the case record form (eg, “multiple enlarged pelvic lymph nodes” or 
“multiple liver metastases”). 
17.3.2.3. Response Criteria 
This section provides the definitions of the criteria used to determine objective tumor response 
for target lesions. 
17.3.2.3.1. Evaluation of Target Lesions 
CR: Disappearance of all target lesions.  Any pathological lymph nodes (whether target or non-
target) must have reduction in short axis to < 10 mm. 

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PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the 
baseline sum diameters. 
PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline sum if that is the smallest on study).  In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at 
least 5 mm.  (Note: the appearance of 1 or more new lesions is also considered progression). 
SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum diameters while on study. 
17.3.2.3.2. Special Notes on the Assessment of Target Lesions 
Lymph nodes: Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), 
even if the nodes regress to below 10 mm on study.  This means that when lymph nodes are 
included as target lesions, the “sum” of lesions may not be zero even if CR criteria are met, since 
a normal lymph node is defined as having a short axis of < 10 mm.  For PR, SD, and PD, the 
actual short axis measurement of the nodes is to be included in the sum of target lesions. 
Target lesions that become “too small to measure”: While on study, all lesions (nodal and 
non-nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (eg, 2 mm).  However, sometimes lesions or lymph 
nodes which are recorded as target lesions at baseline become so faint on CT scan that the 
radiologist may not feel comfortable assigning an exact measure and may report them as being 
“too small to measure.”  When this occurs, it is important that a value be recorded on the eCRF.  
If it is the opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0 mm.  If the lesion is believed to be present and is faintly seen but too 
small to measure, a default value of 5 mm should be assigned.  (Note: It is less likely that this 
rule will be used for lymph nodes since they usually have a definable size when normal and are 
frequently surrounded by fat such as in the retroperitoneum; however, if a lymph node is 
believed to be present and is faintly seen but too small to measure, a default value of 5 mm 
should be assigned in this circumstance as well).  This default value is derived from the 5 mm 
CT slice thickness (but should not be changed with varying CT slice thickness).  The 
measurement of these lesions is potentially non-reproducible, therefore providing this default 
value will prevent false responses or progressions based upon measurement error.  To reiterate, 
however, if the radiologist is able to provide an actual measure, that should be recorded, even if 
it is below 5 mm. 
Lesions that split or coalesce on treatment: When non-nodal lesions “fragment,” the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum.  
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesion.  If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximal longest diameter for the “coalesced lesion.” 
17.3.2.3.3. Evaluation of Non-target Lesions 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions.  While some non-target lesions may actually be measurable, they 

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need not be measured and instead should be assessed only qualitatively at the time points 
specified in the protocol. 
CR: Disappearance of all non-target lesions and normalization of tumor marker level.  All lymph 
nodes must be non-pathological in size (< 10 mm short axis). 
Non-CR/Non-PD: Persistence of 1 or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
PD: Unequivocal progression (see comments below) of existing non-target lesions (Note: the 
appearance of 1 or more new lesions is also considered progression). 
17.3.2.3.4. Special Notes on Assessment of Progression of Non-target Disease 
The concept of progression of non-target disease requires additional explanation as follows: 
When the subject also has measurable disease: In this setting, to achieve “unequivocal 
progression” on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease such that, even in presence of SD or PR in target disease, the 
overall tumor burden has increased sufficiently to merit discontinuation of therapy.  A modest 
“increase” in the size of 1 or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status.  The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare. 
When the subject has only non-measurable disease: The same general concepts apply here as 
noted above, however, in this instance there is no measurable disease assessment to factor into 
the interpretation of an increase in non-measurable disease burden.  Because worsening in non-
target disease cannot be easily quantified (by definition: if all lesions are truly non-measurable) a 
useful test that can be applied when assessing subjects for unequivocal progression is to consider 
if the increase in overall disease burden based on the change in non-measurable disease is 
comparable in magnitude to the increase that would be required to declare PD for measurable 
disease (ie, an increase in tumor burden representing an additional 73% increase in ‘volume’ 
[which is equivalent to a 20% increase diameter in a measurable lesion]).  If ‘unequivocal 
progression’ is seen, the subject should be considered to have had overall PD at that point.  
While it would be ideal to have objective criteria to apply to non-measurable disease, the very 
nature of that disease makes it impossible to do so, therefore the increase must be substantial. 
17.3.2.3.5. New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: ie, not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some “new” 
bone lesions may be simply healing or flare of preexisting lesions).  This is particularly 
important when the subject’s baseline lesions show PR or CR.  For example, necrosis of a liver 
lesion may be reported on a CT scan report as a “new” cystic lesion, which it is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.  An example of this is 

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the subject who has visceral disease at baseline and while on study has a CT or MRI brain 
ordered which reveals metastases.  The subject’s brain metastases are considered to be evidence 
of PD even if he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-
up evaluation will clarify if it represents truly new disease.  If repeat scans confirm there is 
definitely a new lesion, then progression should be declared using the date of the initial scan. 
17.3.2.4. Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the study treatment until 
the EOT.  Confirmatory measurement for CR, PR, or SD is required in the study. 
The subject’s best overall response assignment will depend on the findings of both target and 
non-target disease and will also take into consideration the appearance of new lesions. 
17.3.2.4.1. Time Point Response 
It is assumed that at each protocol-specified time point, a response assessment occurs.  
Table 17.2 provides a summary of the overall response status calculation at each time point for 
subjects who have measurable disease at baseline. 
When subjects have non-measurable (therefore non-target) disease only, see Table 17.2. 
Table 17.2: 
Overall Response: Subjects with Target (+/–Non-target) Disease 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No  
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No  
PR 
SD 
Non-PD or not all evaluated 
No  
SD 
Not all Evaluated 
Non-PD  
No 
NE 
PD   
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = in-
evaluable. 
17.3.2.4.2. Missing Assessments and Inevaluable Designation 
When no imaging/measurement is performed at all at a particular timepoint, the subject is not 
evaluable (NE) at that timepoint.  If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered NE at that timepoint, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not change 
the assigned time point response.  This would be most likely to happen in the case of PD.  For 
example, if a subject had a baseline sum of 50 mm with 3 measured lesions and at follow-up 

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only 2 lesions were assessed, but those gave a sum of 80 mm, the subject will have achieved PD 
status, regardless of the contribution of the missing lesion. 
17.3.2.4.3. Best Overall Response: All Time Points 
The best overall response is determined once all the data for the subject is known. 
Best response determination in this study requires confirmation of CR or PR: Best response is 
defined as the lesser of the two best responses across 2 consecutive scans (eg, a subject who has 
PR at first assessment, SD at second assessment, and PD on last assessment; this would report as 
a best overall response of SD).  When SD is believed to be best response, it must also meet the 
protocol specified minimum time from baseline, 6 weeks (± 7 days).  If the minimum time is not 
met when SD is otherwise the best time point response, the subject’s best response depends on 
the subsequent assessments.  For example, a subject who has SD at first assessment, PD at 
second and does not meet minimum duration for SD, will have a best response of PD.  The same 
subject lost to follow-up after the first SD assessment would be considered inevaluable. 
17.3.2.4.4. Special Notes on Response Assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to “normal” 
size (< 10 mm), they may still have a measurement reported on scans.  This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 
based on increase in size of the nodes.  As noted earlier, this means that subjects with CR may 
not have a total sum of “zero” on the eCRF. 
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document objective progression 
even after discontinuation of treatment.  Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping study therapy.  The objective response status of 
such subjects is to be determined by evaluation of target and non-target disease. 
For equivocal findings of progression (eg, very small and uncertain new lesions; cystic changes 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment.  If at 
the next scheduled assessment, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected. 
The convention to be followed when assessing response or progression will be to assign a single 
date to evaluations performed within that time point.  The date of response (CR, PR, SD, or NE) 
will be recorded as the date of the last radiographic evaluation included in the series for that 
assessment.  The date of progression (PD) will be recorded as the date of the earliest 
radiographic evaluation included in the series for that assessment. 
17.3.2.5.  Frequency of Tumor Re-evaluation 
In this study, tumor measurement will be conducted every 6 weeks (± 7 days) while the subject 
remains on study until progression of disease, withdrawal of consent, death, or loss to follow-up.  
Scan dates should not be adjusted or rescheduled due to dose interruption of any type. 
Baseline tumor assessments must be performed within 28 days of randomization/registration. 

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All efforts should be made to ensure consistency between the baseline measurements and all 
subsequent measurements in reference to utilization of scanning method, equipment, technique 
(including slice thickness and field of view), and radiographic interpreter. 
The radiographic evaluation must include CT or MRI scanning of chest, abdomen, and pelvis at 
screening period.  An MRI of the brain is mandatory for all subjects included with baseline 
stable brain metastases.  Any additional suspected sites of disease should also be imaged.  Every 
effort should be made to use the same assessment modality for all assessments for each subject.  
Follow-up evaluations should include all sites of disease identified at screening and any other 
locations if progressive disease is suspected (eg, MRI of the brain if brain metastases are 
suspected) should also be imaged.  All evaluations should meet the standard of care for imaging 
of lesions in the respective organ(s) and should conform to the image acquisition guidelines 
according to institutional standards. 
All target and non-target sites are evaluated at each time point of tumor assessment. 
17.4. 
New York Heart Association Functional Classification 
Table 17.3: 
New York Heart Association Functional Classification 
Functional Capacity  
Objective Assessment  
Class I. Patients with cardiac disease but without resulting limitation of 
physical activity.  Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea, or anginal pain. 
A. No objective evidence of 
cardiovascular disease. 
Class II. Patients with cardiac disease resulting in slight limitation of 
physical activity.  They are comfortable at rest. Ordinary physical activity 
results in fatigue, palpitation, dyspnea, or anginal pain. 
B. Objective evidence of 
minimal cardiovascular 
disease. 
Class III. Patients with cardiac disease resulting in marked limitation of 
physical activity.  They are comfortable at rest.  Less than ordinary activity 
causes fatigue, palpitation, dyspnea, or anginal pain. 
C. Objective evidence of 
moderately severe 
cardiovascular disease. 
Class IV. Patients with cardiac disease resulting in inability to carry on 
any physical activity without discomfort.  Symptoms of heart failure or the 
anginal syndrome may be present even at rest.  If any physical activity is 
undertaken, discomfort is increased. 
D. Objective evidence of 
severe cardiovascular 
disease. 
Source: American Heart Association, Inc. Classification of Functional Capacity and Objective Assessment. 
Available from: 
http://my.americanheart.org/professional/StatementsGuidelines/ByPublicationDate/PreviousYears/Classification-of-
Functional-Capacity-and-Objective-Assessment UCM 423811 Article.jsp 
 

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17.5. 
Strong CYP3A4 and OATP1B Inhibitors  
 
CYP3A4 strong 
inhibitors 
boceprevir 
clarithromycin 
conivaptan 
indinavir 
itraconazole 
ketoconazole 
lopinavir/ritonavir 
mibefradil 
nefazodone 
nelfinavir 
posaconazole 
ritonavir 
saquinavir 
telaprevir 
telithromycin 
voriconazole 
OATP1B inhibitors 
atazanavir 
cyclosporine 
eltrombopag 
gemfibrozil 
lopinavir 
rifampin (single-dose) 
ritonavir 
saquinavir 
tipranavir