Conditions: Adenocarcinoma, Gastric Neoplasm, Breast
Keywords: Stomach cancer Cancer where the esophagus meets the stomach Human epidermal growth factor 2 HER2 Breast Cancer Adenocarcinoma, Gastroesophageal Junction (GEJ) Gastric Cancer Antibody drug conjugate (ADC) Oncology
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 12
Healthy volunteers: no

Brief summary:
HER2-positive cancer is a cancer that tests positive for a protein called human epidermal growth factor receptor 2 (HER2). HER2 promotes the growth of certain cancer cells. This study will test DS-8201a (trastuzumab deruxtecan), a HER2-targeted antibody and topoisomerase I inhibitor conjugate.

The safety and tolerability profile of DS-8201a will be assessed in Chinese patients with certain types of stomach and breast cancer that test positive for HER2. It also will test how DS-8201a moves within the body (pharmacokinetics).

Detailed description:
The expected time from the first subject's enrollment until the last subject's enrollment is approximately 8 months. The screening period is 28 days and each cycle of treatment is 21 days.

The number of treatment cycles is not fixed in this study. Subjects who continue to derive clinical benefit from the study drug in the absence of withdrawal of consent, progressive disease (PD), or unacceptable toxicity may continue the study drug.

Arms:
arm 1: DS-8201a administered by intravenous infusion on Day 1 of each cycle, once every 3 weeks (Q3W)

Interventions: intervention 1: DS-8201a
Intervention descriptions: intervention 1: An antibody drug conjugate

Protocol document:
Prot_SAP_001.pdf: 
Proprietary and Confidential 
Page 1 
CLINICAL STUDY PROTOCOL 
 
PHASE 1, MULTICENTER, OPEN-LABEL STUDY 
OF DS-8201a TO ASSESS SAFETY AND 
PHARMACOKINETICS IN SUBJECTS WITH 
HER2-POSITIVE ADVANCED AND/OR 
REFRACTORY GASTRIC, 
GASTROESOPHAGEAL JUNCTION 
ADENOCARCINOMA, OR BREAST CANCER 
 
 
DS8201-A-A103 
 
VERSION 5.0, 03 JUL 2020 
VERSION 4.0, 26 APR 2019 
VERSION 3.0, 16 MAR 2018 
VERSION 2.0, 02 FEB 2018 
VERSION 1.0, 25 OCT 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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INVESTIGATOR AGREEMENT 
PHASE 1, MULTICENTER, OPEN-LABEL STUDY OF DS-8201a TO ASSESS 
SAFETY AND PHARMACOKINETICS IN SUBJECTS WITH 
HER2-POSITIVE ADVANCED AND/OR REFRACTORY GASTRIC, 
GASTROESOPHAGEAL JUNCTION ADENOCARCINOMA, OR BREAST 
CANCER 
Sponsor Approval: 
This clinical study protocol has been reviewed and approved by the Daiichi Sankyo 
representative listed below. 
 
Print Name 
Signature 
Clinical Study Lead 
Title 
Date (DD MMM YYYY) 
Investigator’s Signature: 
I have fully discussed the objectives of this study and the contents of this protocol with the 
Sponsor’s representative. 
I understand that information contained in or pertaining to this protocol is confidential and should 
not be disclosed, other than to those directly involved in the execution or the ethical review of the 
study, without written authorization from the Sponsor.  It is, however, permissible to provide 
information to a subject in order to obtain consent. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in accordance 
with the Declaration of Helsinki, International Council for Harmonisation guidelines on Good 
Clinical Practice (ICH E6), and applicable regional regulatory requirements. 
I agree to make available to Sponsor personnel, their representatives and relevant regulatory 
authorities, my subjects’ study records in order to verify the data that I have entered into the case 
report forms.  I am aware of my responsibilities as a Principal Investigator as provided by the 
Sponsor. 
I understand that the Sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing.  Conversely, 
should I decide to withdraw from execution of the study, I will communicate my intention 
immediately in writing to the Sponsor. 
Print Name 
Signature 
Title 
Date (DD MMM YYYY) 
PPD


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PROTOCOL SYNOPSIS 
EudraCT: 
Not applicable 
IND Number: 
Not applicable 
Protocol Number: 
DS8201-A-A103 
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: 
Phase 1, Multicenter, Open-label Study of DS-8201a to Assess 
Safety and Pharmacokinetics in Subjects With HER2-Positive 
Advanced and/or Refractory Gastric, Gastroesophageal Junction 
Adenocarcinoma, or Breast Cancer 
Study Phase: 
Phase 1 
Indication Under 
Investigation: 
DS-8201a will be evaluated in subjects with human epidermal 
growth factor receptor 2 (HER2) positive advanced and/or 
refractory gastric, gastroesophageal junction (GEJ) 
adenocarcinoma, or breast cancer. 
Study Objectives: 
Primary Objective: 
1. To assess the safety and tolerability of DS-8201a 
Secondary Objectives: 
1. To assess the pharmacokinetic (PK) profiles of 
DS-8201a, total anti-HER2 antibody, and MAAA-1181a  
2. To investigate the anti-tumor activity of DS-8201a 
3. To assess the incidence of anti-drug antibodies (ADA) 
against DS-8201a 
Study Design: 
This is a Phase 1, multicenter, open-label study to evaluate the 
safety and tolerability of DS-8201a in Chinese subjects with 
HER2-positive advanced and/or refractory gastric, GEJ 
adenocarcinoma, or breast cancer. 
Approximately 12 eligible subjects will be enrolled at study sites 
in Taiwan. The primary analysis will be conducted after all 
subjects have either discontinued the study or completed at least 
4 cycles of the study drug. 
Study Duration: 
The expected time from the first subject’s enrollment until the 
last subject’s enrollment is approximately 8 months.  The 


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screening period is 28 days and each cycle of treatment is 
21 days. 
The number of treatment cycles is not fixed in this study.  
Subjects who continue to derive clinical benefit from the study 
drug in the absence of withdrawal of consent, progressive disease 
(PD), or unacceptable toxicity may continue the study drug. 
Study Sites and Location: 
This study will be conducted at study sites in Taiwan, Republic 
of China. 
Subject Eligibility Criteria: 
Inclusion Criteria 
Subjects must satisfy all of the following criteria to be included 
in the study:  
1. Chinese patients aged ≥20 years 
2. Pathologically documented HER2-positive 
advanced/unresectable or metastatic gastric, GEJ 
adenocarcinoma or breast cancer, with both: 
a. HER2-positive disease documented as: 
immunohistochemistry (IHC) 3+ positive, and/or 
fluorescence in situ hybridization (ISH) ≥2.0 that 
is refractory to or intolerable with standard 
treatment, or for which no standard treatment is 
available. For subject with gastric or GEJ 
adenocarcinoma cancers, it is preferable to 
determine HER2 status after completing the last 
HER2-targeting treatment. 
b. Documented disease progression (by 
investigator’s assessment) after at least one 
regimen of trastuzumab therapy in metastatic or 
unresectable locally advanced/recurrent setting. 
3. Eastern Cooperative Oncology Group Performance Status 
(ECOG PS) 0 to 1. 
4. Left ventricular ejection fraction (LVEF) ≥50% by either 
echocardiography (ECHO) or multiple-gated acquisition 
(MUGA) scan within 28 days before registration. 
5. Adequate organ function within 7 days before registration 
defined as: 
Item 
Laboratory value 
Platelet count 
100,000/mm3 
(platelet transfusion is not 
allowed within 1 week prior to 
screening assessment) 
Hemoglobin (Hb) 
≥9 g/dL 
(red blood cell transfusion is 


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not allowed within 1 week 
prior to screening assessment) 
Absolute neutrophil count 
(ANC) 
1500/mm3 
(granulocyte 
colony-stimulating factor 
administration is not allowed 
within 1 week prior to 
screening assessment) 
Creatinine 
≤1.5  upper limit of normal 
(ULN), or creatinine 
clearance ≥60 mL/min as 
calculated using the 
Cockcroft-Gault equation 
Aspartate 
aminotransferase 
(AST)/alanine 
aminotransferase (ALT) 
≤3  ULN  (if liver metastases 
are present, ≤5  ULN) 
Total bilirubin (TBL) 
≤1.5  ULN or < 3 × ULN in 
the presence of documented 
Gilbert’s Syndrome 
(unconjugated 
hyperbilirubinemia) or liver 
metastases at baseline 
Prothrombin time and 
activated partial 
thromboplastin time 
≤1.5 × ULN 
6. Adequate treatment washout period before registration, 
defined as: 
Treatment 
Washout period 
Major surgery 
4 weeks 
Radiation therapy 
≥4 weeks (if palliative 
stereotactic radiation therapy 
excludes abdomen, ≥2 weeks) 
Autologous transplantation 
3 months  
Hormonal therapy 
2 weeks 
Chemotherapy (including 
antibody drug therapy and 
retinoid therapy) 
3 weeks (or 5 half-lives 
before study drug treatment, 
whichever is longer, for small-
molecule targeted agents such 
as 5-fluorouracil-based agents, 
folinate agents, and/or weekly 
paclitaxel.  6 weeks for 
nitrosoureas or mitomycin C) 
Immunotherapy 
 4 weeks 


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Cytochrome P450 (CYP) 
3A4 strong inhibitor and 
inducer 
3 × elimination half-lives of 
the inhibitor 
Organic anion transporting 
polypeptide (OATP1BI) 
1B1 inhibitor 
3 × elimination half-lives of 
the inhibitor 
7. Life expectancy of at least 3 months. 
8. Subjects should be able to provide written informed 
consent.  Subjects must be fully informed about their 
illness and the investigational nature of the study protocol 
(including foreseeable risks and possible toxicities) and 
must sign and date an Institutional Review Board 
(IRB)-approved informed consent form (ICF) before 
performance of any study-specific procedures or 
examinations. 
9. Subjects should be willing to provide pre-existing 
diagnosis of HER2 status. 
10. 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 7 months for 
females and 4.5 months for males after the last dose of 
study drug.  Methods considered as highly effective 
methods of contraception include:  
a. Combined (estrogen and progestogen containing) 
hormonal contraception  associated with 
inhibition of ovulation: 
i. Oral 
ii. Intravaginal 
iii. Transdermal 
b. Progestogen-only hormonal contraception 
associated with inhibition of ovulation: 
i. Oral 
ii. Injectable 
iii. Implantable 
c. Intrauterine device 
d. Intrauterine hormone-releasing system 
e. Bilateral tubal occlusion 
f. Vasectomized partner  
g. Complete sexual abstinence defined as refraining 
from heterosexual intercourse during and upon 
completion of the study and for at least 7 months 


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for females and 4.5 months for males 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 >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 
child-bearing potential if they wish to continue their HRT 
during the study.  Otherwise, they must discontinue the 
HRT to allow confirmation of post-menopausal status 
prior to study enrollment.  For most forms of HRT, at 
least 2 weeks to 4 weeks will elapse between the 
cessation of therapy and the blood draw; this interval 
depends on the type and dosage of the HRT.  Following 
confirmation of their post-menopausal status, they can 
resume use of the HRT during the study without use of a 
contraceptive method. 
11. 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 
enrolment in this study. 
12. 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 7 months after the 
final study drug administration. 
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 enrollment, symptomatic congestive heart failure 
(CHF) (New York Heart Association Class II to IV), 
troponin levels consistent with myocardial infarction as 
defined according to the manufacturer 28 days prior to 
randomization. 
2. Corrected QT interval (QTcF) prolongation to >450 ms in 
males and >470 ms in females based on 12-lead 
electrocardiograms (ECGs) performed in triplicate. 


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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. Has any evidence of severe or uncontrolled systemic 
diseases (including uncontrolled hypertension, and active 
bleeding diatheses or active infection including hepatitis 
B, hepatitis C and human immunodeficiency virus (HIV), 
psychiatric illness/social situations, substance abuse, or 
other factors which in the Investigator’s opinion makes it 
undesirable for the subject to participate in the study or 
which would jeopardize compliance with the protocol. 
Screening for chronic conditions is not required. 
5. Have clinically significant corneal disease in the opinion 
of the investigator. 
6. Subjects who are pregnant (as confirmed by pregnancy 
tests performed within 7 days before registration) or 
breastfeeding, or planning to become pregnant. 
7. Have spinal cord compression or clinically active central 
nervous system metastases, defined as untreated and 
symptomatic, or requiring therapy with corticosteroids or 
anticonvulsants to control associated symptoms.  Subjects 
with clinically inactive brain metastases may be included 
in the study.  Subjects with treated brain metastases that 
are no longer symptomatic and who require no treatment 
with corticosteroids or anticonvulsants may be included 
in the study if they have recovered from the acute toxic 
effect of radiotherapy.  A minimum of 2 weeks must have 
elapsed between the end of whole brain radiotherapy and 
study enrollment. 
8. Has a history of severe hypersensitivity reactions to other 
monoclonal antibodies and/or to either the drug 
substances or inactive ingredients in the drug product. 
9. Unresolved toxicities from previous anticancer therapy, 
defined as toxicities (other than alopecia) not yet resolved 
to National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI-CTCAE) version 4.03, 
Grade ≤1 at baseline.  Subjects with chronic Grade 2 
toxicities may be eligible per the discretion of the 
Investigator after consultation with the Sponsor medical 
monitor or designee (eg, Grade 2 chemotherapy-induced 
neuropathy). 
10. Presence of other primary malignancies within 3 years, 
except adequately resected non-melanoma skin cancer, 
curatively treated in-situ disease, other solid tumors, or 
contralateral breast cancer. 


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Dosage Form, Dose and 
Route of Administration: 
 DS-8201a for injection 100mg will be provided as a 
sterile lyophilized powder containing 100 mg of DS-
8201a in a glass vial (Lyo-DP). 
 DS-8201a will be administered with 5% Dextrose as an 
intravenous (IV) infusion.  Subjects will receive 
6.4 mg/kg of DS-8201a on Day 1 of each cycle, once 
every 3 weeks [Q3w]. 
Study Endpoints: 
Safety Endpoints 
 Primary safety endpoints will include serious adverse 
events (SAEs), treatment-emergent adverse events 
(TEAEs), and adverse events (AEs) and adverse events of 
special interest (AESIs) leading to discontinuation. 
 Other safety endpoints will include physical examination 
findings (including ECOG PS), vital sign measurements, 
standard clinical laboratory parameters, ECG parameters, 
ECHO or MUGA findings, and ophthalmologic findings.  
TEAEs will be graded according to the NCI-CTCAE 
version 4.03. 
 ADA against DS-8201a will be assessed as a secondary 
safety endpoint. 
Pharmacokinetic Endpoints 
 Serum concentrations and PK parameters of DS-8201a, 
total anti-HER2 antibody, and MAAA-1181a.   
Efficacy Endpoints 
 Objective response rate (ORR) 
 Disease control rate (DCR) 
 Duration of response (DoR) 
 Progression-free survival (PFS) 
 Overall survival (OS) 
 Best percentage change in the sum of diameter(s) of 
target lesion(s) 
Planned Sample Size: 
Approximately 12 subjects will be allocated to the selected dose 
level.  The sample size of 12 subjects will provide the safety and 
tolerability data in Chinese subjects. 
Statistical Analyses: 
The data cutoff for the primary analysis will occur after all 
subjects have either discontinued the study or completed at least 
4 cycles of the study drug.  
Safety Analysis 


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All safety analyses and analysis of ADA will be performed on 
safety analysis set (which includes all subjects who have 
received at least 1 dose of DS-8201a). 
Safety endpoints will include AEs, SAEs, TEAEs, AEs and 
AESIs leading to discontinuation, physical examination findings 
(including ECOG PS), vital sign measurements, standard clinical 
laboratory parameters, ECG parameters, ECHO or MUGA 
findings and ophthalmologic assessments.  TEAEs will be graded 
according to the NCI-CTCAE version 4.03. 
Safety analyses in general will be descriptive and will be 
presented in tabular format with appropriate summary statistics. 
ADA assessment data will be listed and summarized as 
appropriate. 
Pharmacokinetic Analyses 
The PK analyses will be performed on the PK analysis set using 
actual sample times and noncompartmental methods. 
Cycle 1 is considered the single dose and Cycle 3 the multiple 
dose.  PK parameters will be estimated for both cycles.  The PK 
parameters of DS-8201a, total anti-HER2 antibody, and MAAA-
1181a (AUClast, AUC0-21d, Cmax, Tmax, Ctrough, and if 
applicable, AUCinf, Kel, T1/2, CL, Vz, and Vss) will be listed 
and summarized using descriptive statistics.  Descriptive 
statistics will also be provided for all serum concentration data. 
Efficacy Analyses 
The efficacy analyses will be performed on the efficacy analysis 
set (all subjects who have received at least 1 dose of DS-8201a 
and had both pre- and post-treatment efficacy assessment data). 
Efficacy endpoints will include ORR (the proportion of subjects 
who achieve a best overall response of complete response [CR] 
or partial response [PR]) and DCR (the proportion of subjects 
who achieve a best overall response of CR or PR or stable 
disease [SD]), DoR, PFS based on Response Evaluation Criteria 
in Solid Tumors (RECIST) version 1.1, OS, and best percentage 
change in the sum of diameter of target lesion(s).  The point 
estimate of ORR and its two-sided corresponding 95% exact 
binomial confidence interval (CI) will be provided.  The analysis 
of the DCR will be performed in the same manner as the ORR 
analysis.  DoR, PFS, and OS will be summarized using the 
Kaplan-Meier method with median event time and two-sided 
95% CI for the median.  Descriptive statistics for the best 
percentage change in the sum of diameter(s) of target lesion(s) 
will be provided.  A waterfall plot of the best percentage change 
from Screening in the sum of longest dimensions (SLD) for each 
subject will be presented. 


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TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT ................................................................... 2 
PROTOCOL SYNOPSIS ................................................................................. 3 
TABLE OF CONTENTS ................................................................................ 11 
LIST OF TABLES .......................................................................................... 17 
LIST OF ABBREVIATIONS ......................................................................... 18 
1. 
INTRODUCTION ......................................................................... 22 
1.1. 
Background .................................................................................... 22 
1.2. 
Data Summary ................................................................................ 22 
1.2.1. 
Physical, Chemical, Pharmaceutical Properties and Formulation . 22 
1.2.2. 
Nonclinical Studies ........................................................................ 23 
1.2.2.1. 
Pharmacology ................................................................................. 23 
1.2.2.2. 
Pharmacokinetics Properties .......................................................... 23 
1.2.2.3. 
Nonclinical Safety data .................................................................. 23 
1.2.3. 
Clinical Experience ........................................................................ 24 
1.3. 
Study Rationale .............................................................................. 28 
1.4. 
Risks and Benefits for Study Subjects ........................................... 28 
2. 
STUDY OBJECTIVES AND HYPOTHESIS ............................... 30 
2.1. 
Study Objectives ............................................................................ 30 
2.1.1. 
Primary Objectives ......................................................................... 30 
2.1.2. 
Secondary Objectives ..................................................................... 30 
2.1.3. 
Exploratory Objectives .................................................................. 30 
2.2. 
Study Hypotheses ........................................................................... 30 
2.3. 
Study Endpoints ............................................................................. 30 
2.3.1. 
Primary Endpoints .......................................................................... 30 
2.3.2. 
Key Secondary Endpoints .............................................................. 30 
2.3.3. 
Other Secondary Endpoints ........................................................... 30 
2.3.4. 
Exploratory Endpoints ................................................................... 30 
3. 
STUDY DESIGN ........................................................................... 32 
3.1. 
Overall Design ............................................................................... 32 
3.2. 
Discussion of Study Design ........................................................... 32 
3.2.1. 
Duration of the Study ..................................................................... 32 
3.2.2. 
Duration of Subject Participation ................................................... 32 
3.2.3. 
Study Endpoints ............................................................................. 33 
3.2.4. 
Selection of Doses .......................................................................... 33 


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3.2.5. 
Management of Subjects with Adverse Events of Special Interest 33 
3.2.5.1. 
Cardiac-Related Events including Decreased Ejection Fraction 
(Cardiotoxicity) .............................................................................. 33 
3.2.5.2. 
Interstitial Lung Disease/Pneumonitis ........................................... 35 
4. 
STUDY POPULATION ................................................................ 38 
4.1. 
Inclusion Criteria ............................................................................ 38 
4.2. 
Exclusion Criteria .......................................................................... 40 
4.3. 
Subject Replacement ...................................................................... 41 
4.4. 
Subject Re-screening Procedures ................................................... 41 
5. 
STUDY TREATMENT ................................................................. 42 
5.1. 
Assigning Subjects to Treatment Group/Sequences and Blinding 42 
5.1.1. 
Treatment Group/Sequences .......................................................... 42 
5.1.2. 
Method of Treatment Group/Sequences Allocation ...................... 42 
5.1.3. 
Enrollment ...................................................................................... 42 
5.1.4. 
Blinding .......................................................................................... 42 
5.1.5. 
Emergency Unblinding Procedure ................................................. 42 
5.2. 
Study Drug ..................................................................................... 43 
5.2.1. 
Description ..................................................................................... 43 
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 ....................................................................... 44 
5.3. 
Control Treatment .......................................................................... 44 
5.4. 
Dose Interruptions and Reductions ................................................ 44 
5.4.1. 
Dose Interruptions .......................................................................... 44 
5.4.2. 
Dose Reductions ............................................................................ 45 
5.5. 
Method of Assessing Treatment Compliance ................................ 49 
5.6. 
Prior and Concomitant Medications .............................................. 49 
5.6.1. 
Prohibited Concomitant Medications/Activities ............................ 49 
5.6.2. 
Restricted products ......................................................................... 50 
5.6.3. 
Dietary and Lifestyle Restrictions .................................................. 50 
5.7. 
Subject Withdrawal/Discontinuation ............................................. 50 
5.7.1. 
Reasons for Withdrawal ................................................................. 50 
5.7.2. 
Withdrawal Procedures .................................................................. 51 


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5.7.3. 
Subject Replacement ...................................................................... 51 
5.7.4. 
Subject Re-screening Procedures ................................................... 51 
6. 
STUDY PROCEDURES ............................................................... 52 
6.1. 
Screening ........................................................................................ 52 
6.2. 
Randomization ............................................................................... 53 
6.3. 
Treatment Period ............................................................................ 53 
6.3.1. 
Tumor Assessment ......................................................................... 53 
6.3.2. 
Cycle 1, Day 1 ................................................................................ 53 
6.3.2.1. 
Before Infusion .............................................................................. 53 
6.3.2.2. 
Administration and After Infusion ................................................. 54 
6.3.3. 
Cycle 1, Day 2 ................................................................................ 55 
6.3.4. 
Cycle 1, Day 4 ................................................................................ 55 
6.3.5. 
Cycle 1, Day 8 ................................................................................ 55 
6.3.6. 
Cycle 1, Day 15 .............................................................................. 55 
6.3.7. 
Cycle 1, Day 22 .............................................................................. 56 
6.3.8. 
Cycle 2, Day 1 ................................................................................ 56 
6.3.8.1. 
Before Infusion .............................................................................. 56 
6.3.8.2. 
Administration and After Infusion ................................................. 57 
6.3.9. 
Cycle 2, Day 8 and Day 15 ............................................................ 57 
6.3.10. 
Cycle 2, Day 22 .............................................................................. 58 
6.3.11. 
Cycle 3, Day 1 ................................................................................ 58 
6.3.11.1. Before Infusion .............................................................................. 58 
6.3.11.2. Administration and After Infusion ................................................. 58 
6.3.12. 
Cycle 3, Day 2 and Day 4 .............................................................. 59 
6.3.13. 
Cycle 3, Day 8 and Day 15 ............................................................ 59 
6.3.14. 
Cycle 3, Day 22 .............................................................................. 59 
6.3.15. 
Cycle 4 and All Subsequent Cycles, Day 1 ................................... 60 
6.3.15.1. Before Infusion .............................................................................. 60 
6.3.15.2. Administration and After Infusion ................................................. 61 
6.4. 
End of Treatment ........................................................................... 61 
6.5. 
Follow-up ....................................................................................... 62 
6.6. 
New Cancer Treatment and Survival Follow-up ........................... 63 
7. 
PHARMACOKINETIC/PHARMACODYNAMIC 
ASSESSMENTS ............................................................................ 64 
7.1. 
Pharmacokinetic Assessments ....................................................... 64 


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7.1.1. 
Serum Sampling ............................................................................. 64 
7.2. 
Pharmacodynamic Assessment(s) .................................................. 65 
7.3. 
Biomarker and Exploratory Assessment(s) .................................... 65 
7.4. 
Immunogenicity ............................................................................. 65 
7.4.1. 
Anti-Drug Antibodies .................................................................... 65 
7.4.2. 
SARS-CoV-2 Serum samples collection ....................................... 66 
7.5. 
Pharmacogenomic Analysis ........................................................... 66 
8. 
SAFETY EVALUATION AND REPORTING ............................ 67 
8.1. 
Assessment of Safety Endpoint Event(s) ....................................... 67 
8.2. 
Adverse Event Collection and Reporting ....................................... 67 
8.3. 
Adverse Events of Special Interest ................................................ 68 
8.3.1. 
Interstitial Lung Disease Adjudication Committee ........................ 68 
8.4. 
Adverse Event ................................................................................ 68 
8.4.1. 
Definition of Adverse Event .......................................................... 68 
8.4.2. 
Serious Adverse Event ................................................................... 69 
8.4.3. 
Severity Assessment ...................................................................... 69 
8.4.4. 
Causality Assessment ..................................................................... 70 
8.4.5. 
Action Taken Regarding Study Drug(s) ........................................ 70 
8.4.6. 
Other Action Taken for Event ........................................................ 70 
8.4.7. 
Adverse Event Outcome ................................................................ 71 
8.5. 
Serious Adverse Events Reporting-Procedure for Investigators .... 71 
8.6. 
Notifying Regulatory Authorities, Investigators, and Institutional 
Review Board/Ethics Committee ................................................... 72 
8.7. 
Exposure in Utero During Clinical Studies .................................... 73 
8.8. 
Clinical Laboratory Evaluations .................................................... 73 
8.9. 
Vital Signs ...................................................................................... 74 
8.10. 
Electrocardiograms ........................................................................ 74 
8.11. 
Physical Examinations ................................................................... 74 
8.12. 
Other Examinations ........................................................................ 74 
9. 
EFFICACY ASSESSMENTS ........................................................ 76 
9.1. 
Assessments for Efficacy Endpoints .............................................. 76 
9.2. 
Appropriateness of Selected Efficacy Assessments ....................... 76 
10. 
OTHER ASSESSMENTS .............................................................. 77 
11. 
STATISTICAL METHODS .......................................................... 78 
11.1. 
General Statistical Considerations ................................................. 78 


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11.2. 
Analysis Sets .................................................................................. 78 
11.2.1. 
Enrolled Analysis Set ..................................................................... 78 
11.2.2. 
Safety Analysis Set ........................................................................ 79 
11.2.3. 
Pharmacokinetic Analysis Set ........................................................ 79 
11.2.4. 
Efficacy Analysis Set ..................................................................... 79 
11.3. 
Study Population Data ................................................................... 79 
11.4. 
Statistical Analysis ......................................................................... 79 
11.4.1. 
Efficacy Analyses .......................................................................... 79 
11.4.2. 
Pharmacokinetic Analyses ............................................................. 80 
11.4.3. 
Safety Analyses .............................................................................. 80 
11.4.3.1. Adverse Event Analyses ................................................................ 81 
11.4.3.2. Clinical Laboratory Evaluation Analyses ...................................... 81 
11.4.3.3. Vital Sign Analyses ........................................................................ 81 
11.4.3.4. Electrocardiogram Analyses .......................................................... 81 
11.4.3.5. Other Safety Analyses .................................................................... 82 
11.5. 
Interim Analyses ............................................................................ 82 
11.6. 
Data Monitoring Committee .......................................................... 82 
11.7. 
Safety Monitoring Team ................................................................ 82 
11.8. 
Sample Size Determination ............................................................ 82 
11.9. 
Statistical Analysis Process ............................................................ 82 
12. 
DATA INTEGRITY AND QUALITY ASSURANCE ................. 83 
12.1. 
Monitoring and Inspections ........................................................... 83 
12.2. 
Data Collection .............................................................................. 83 
12.3. 
Data Management .......................................................................... 84 
12.4. 
Study Documentation and Storage ................................................. 84 
12.5. 
Record Keeping .............................................................................. 85 
13. 
FINANCING AND INSURANCE ................................................ 86 
13.1. 
Finances ......................................................................................... 86 
13.2. 
Reimbursement, Indemnity, and Insurance .................................... 86 
14. 
PUBLICATION POLICY .............................................................. 87 
15. 
ETHICS AND STUDY ADMINISTRATIVE INFORMATION . 88 
15.1. 
Compliance Statement, Ethics and Regulatory Compliance ......... 88 
15.2. 
Subject Confidentiality .................................................................. 88 
15.3. 
Informed Consent ........................................................................... 88 
15.4. 
Regulatory Compliance .................................................................. 89 


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15.5. 
Protocol Deviations ........................................................................ 89 
15.6. 
Supply of New Information Affecting the Conduct of the Study .. 90 
15.7. 
Protocol Amendments .................................................................... 90 
15.8. 
Study Termination .......................................................................... 91 
15.9. 
Data Safety Monitoring Board ....................................................... 91 
15.10. 
Address List ................................................................................... 91 
15.10.1. Sponsor ........................................................................................... 91 
15.10.2. Contract Research Organization (CRO) ........................................ 91 
15.10.3. Electronic Data Capture (EDC) Vendor ........................................ 91 
15.10.4. Bioanalytical Laboratory (Pharmacokinetics and Anti-Drug 
Antibodies Assessment) ................................................................. 91 
16. 
REFERENCES ............................................................................... 92 
17. 
APPENDICES ............................................................................... 94 
17.1. 
Cockcroft-Gault Equation .............................................................. 94 
17.2. 
New York Heart Association ......................................................... 95 
17.3. 
Eastern Cooperative Oncology Group Performance Status (ECOG 
PS) .................................................................................................. 96 
17.4. 
Response Evaluation Criteria in Solid Tumors (Version 1.1) ....... 97 
17.4.1. 
Measurability of Tumor at Baseline ............................................... 97 
17.4.1.1. Definitions ...................................................................................... 97 
17.4.1.2. Specifications by Methods of Measurements ................................ 98 
17.4.2. 
Tumor Response Evaluation .......................................................... 98 
17.4.2.1. Assessment of Overall Tumor Burden and Measurable Disease ... 98 
17.4.2.2. Baseline Documentation of ‘Target’ and ‘Non-target’ Lesions ..... 98 
17.4.2.3. Response Criteria ........................................................................... 99 
17.4.2.4. Evaluation of Target Lesions ......................................................... 99 
17.4.2.5. Evaluation of Non-target Lesions ................................................ 100 
17.4.2.6. New Lesions ................................................................................. 101 
17.4.2.7. Evaluation of Best Overall Response ........................................... 101 
17.4.2.8. Frequency of Tumor Re-evaluation ............................................. 103 
17.5. 
Electronic Data Capture System .................................................. 104 
17.6. 
Schedule of Events ....................................................................... 105 
17.7. 
Instructions Related to Severe Acute Respiratory Syndrome 
Coronavirus 2 (SARS-CoV-2) ..................................................... 110 
 


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LIST OF TABLES 
Table 1.1: Pharmacokinetic Parameters of DS-8201a Following the First 
Dose ............................................................................................. 26 
Table 1.2: Pharmacokinetic Parameters of Total Anti-HER2 Antibody 
Following the First Dose ............................................................. 27 
Table 1.3: Pharmacokinetic Parameters of MAAA-1181a Following the 
First Dose ..................................................................................... 27 
Table 3.1: Actions Taken for Cardiac Toxicity ............................................ 34 
Table 3.2: Actions Taken for Pulmonary Toxicity ....................................... 35 
Table 5.1 
Reference Scheme of Dose Reduction ........................................ 45 
Table 5.2 
Dose or Schedule Modification for DS-8201a ............................ 46 
Table 7.1: Pharmacokinetic Sampling Time Points ...................................... 64 
Table 7.2: Schedule of PK Sample Collection for Subjects Administered 
Chloroquine or Hydroxychloroquine ........................................... 65 
Table 7.3: ADA Sampling Time Points ........................................................ 65 
Table 11.1: Pharmacokinetics Parameters ...................................................... 80 
Table 17.1: Eastern Cooperative Oncology Group Performance Status Scale 
Grade Description ........................................................................ 96 
Table 17.2: Time Point Response: Subjects With Target (+/–Non-Target) 
Disease ....................................................................................... 102 
Table 17.3: Schedule of Events for DS8201-A-A103 Study ........................ 106 
Table 17.4: SARS-CoV-2 Dose Modification Criteria ................................. 110 


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LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
AC 
Adjudication Committee 
ADA 
anti-drug antibodies 
ADC 
antibody-drug conjugate 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
BCRP 
breast cancer resistance protein 
BI 
before infusion 
BSEP 
bile salt export pump 
CDISC 
Clinical Data Interchange Standards Consortium 
CHF 
congestive heart failure 
CHO 
Chinese hamster ovary 
CI 
confidence interval 
CR 
complete response 
CRF 
case report form 
CRO 
contract research organization 
CT 
computed tomography 
CYP 
cytochrome P450 
DCR 
disease control rate 
DLCO 
diffusing capacity of the lungs for carbon monoxide 
DoR 
duration of response 
ECG 
electrocardiogram 
ECHO 
echocardiography 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EIU 
exposure in utero 
EOI 
end of infusion 
EOT 
end of treatment 
F/U 
follow-up  


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ABBREVIATION 
DEFINITION 
GCP 
Good Clinical Practice  
GEJ 
gastroesophageal junction 
GPP3 
Good Publication Practice for Communicating Company Sponsored 
Medical Research 
Hb 
hemoglobin 
HER 
human epidermal growth factor receptor 
hERG 
human ether-à-go-go-related gene 
HIV 
human immunodeficiency virus 
HRT 
hormone replacement therapy 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ICMJE 
International Comittee of Medical Journal Editors 
IgG1 
immunoglobulin G1 
IHC 
immunohistochemistry 
ILD 
interstitial lung disease 
IND 
investigational new drug 
INN 
international non-proprietary name 
IRB 
institutional review board 
ISMPP 
International Society for Medical Publication Professionals 
IV 
intravenous(ly) 
LVEF 
left ventricular ejection fraction 
MAPK 
mitogen-activated protein kinase 
MATE 
multidrug and toxin extrusion 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MUGA 
multiple-gated acquisition 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NE 
inevaluable 
OAT 
organic anion transporting 
OATP 
organic anion transporting polypeptide 
OCT 
organic cation transporter 
ORR 
objective response rate 


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ABBREVIATION 
DEFINITION 
OS 
overall survival 
PD 
progressive disease  
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PI3K 
phosphoinositide 3-kinase 
PK 
pharmacokinetic(s) 
PR 
partial response 
PT 
Preferred Term 
Q3w 
once every 3 weeks 
QTc 
corrected QT 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2, ie COVID-19 
SAVER 
serious adverse event report 
SD 
stable disease 
SLD 
sum of longest dimensions 
SOC 
System Organ Class 
SOP 
standard operating procedure 
SpO2 
peripheral oxygen saturation 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
UV 
ultraviolet 
 
List of Pharmacokinetic Parameters 
ABBREVIATION 
DEFINITION 
AUC 
area under the plasma/serum concentration-time curve 
AUCinf 
area under the plasma/serum concentration-time curve up to infinity 
AUClast 
area under the plasma/serum concentration-time curve up to the last 
quantifiable concentration 
AUCtau 
area under the plasma/serum concentration-time curve during dosing 
interval 


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ABBREVIATION 
DEFINITION 
AUC0-21d 
area under the s plasma/erum concentration-time curve from time zero 
to 21 days. 
CL 
total body clearance  
Cmax 
maximum plasma/serum concentration 
CrCl 
creatinine clearance rate 
Ctrough 
trough plasma/serum concentration  
IC50 
50% inhibitory concentration 
Kel 
elimination rate constant associated with the terminal phase 
Tmax 
time to reach maximum plasma/serum concentration 
T1/2 
terminal elimination half-life 
Vss 
volume of distribution at steady state 
Vz 
volume of distribution based on the terminal phase 
 
List of Terminology 
TERM 
DEFINITION 
DS1 
drug substance manufactured using MAAL-9001 produced in CHO
DS2 
drug substance manufactured using MAAL-9001 produced in CHO
Lyo-DP 
sterile lyophilized powder containing 100 mg of DS-8201a in a glass 
vial 
MAAA-1162a 
drug-linker, the complex of MAAA-1181a and a maleimide 
tetrapeptide linker 
MAAA-1181a 
the drug component of DS-8201a H a derivative of exatecan, a 
topoisomerase I inhibitor 
MAAL-9001 
the antibody component of DS-8201a H a recombinant humanized anti-
HER2 IgG1 monoclonal antibody produced in-house with reference to 
the same amino acid sequence of trastuzumab 
MAb1 
MAAL-9001 produced by CHO
MAb2 
MAAL-9001 produced by CHO
 
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1. 
INTRODUCTION 
1.1. 
Background 
Breast cancer is the second most common cancer in the world and, by far, the most 
frequent cancer among women with an estimated 1.67 million new cases diagnosed in 
2012 (25% of all cancers).1  Almost 1 million new cases of stomach cancer were 
estimated to have occurred in 2012 (952,000 cases, 6.8% of the total), making it the 
fifth most common malignancy in the world, after cancers of the lung, breast, 
colorectum and prostate.1  Human epidermal growth factor receptor 2 (HER2) is 
involved in the pathogenesis and poor outcomes of several types of cancer, including 
advanced gastric and gastroesophageal junction (GEJ) cancer.2  HER2 is a member of 
the HER superfamily, and initiates signal transduction via the phosphoinositide 3-
kinase (PI3K)/AKT and RAS/mitogen-activated protein kinase (MAPK) pathways.3,4  
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,5 gastric cancer,6,7 pancreatic cancer,8 lung cancer,9 colorectal cancer,10 and 
ovarian cancer.11 
As an antibody targeting HER2, trastuzumab has been approved in the United States 
for the indication of HER2-overexpressing breast cancer and HER2-overexpressing 
metastatic gastric or GEJ adenocarcinoma,12 in Europe for HER2-positive metastatic 
breast cancer and HER2-positive metastatic adenocarcinoma of the stomach or GEJ,13 
and in Japan for HER2-overexpressing breast cancer and HER2-overexpressing 
unresectable or advanced/recurrent gastric or GEJ adenocarcinoma.14 
DS-8201a is also an antibody-drug conjugate (ADC) targeting HER2, containing 
MAAA-1181a that inhibits topoisomerase I activity. 
Preliminary results from a Phase 1 study (DS8201-A-J101; NCT02564900) with 
DS-8201a in patients with HER2-positive solid tumors have demonstrated anti-tumor 
activity and a manageable safety profile.  This study is being conducted to evaluate  
the safety and tolerability profile of DS-8201a in a Chinese population. 
1.2. 
Data Summary 
1.2.1. 
Physical, Chemical, Pharmaceutical Properties and Formulation 
DS-8201a is an ADC comprised of a recombinant humanized anti-HER2 
immunoglobulin G1 (IgG1) monoclonal antibody produced in-house with reference to 
the same amino acid sequence of trastuzumab, MAAL-9001, covalently conjugated to 
a drug-linker, MAAA-1162a.  The released drug, MAAA-1181a, inhibits 
topoisomerase I and leads to apoptosis of the target cells. 
MAAL-9001 is expressed in Chinese hamster ovary (CHO) cells.  Two kinds of CHO 
cells are used for manufacturing MAAL-9001, and accordingly 2 kinds of drug 
substance are used for the development of DS-8201a.  MAAL-9001 produced by the 
CHO
is referred to as Mab1, and the DS-8201a drug substance manufactured 
using MAb1 is referred to as DS1.  MAAL-9001 produced by CHO
is referred to as 
MAb2 and the DS-8201a drug substance manufactured using MAb2 is referred to as 
DS2.  The development of DS-8201a was initiated with DS1.  However, to support 
further clinical development as well as commercialization, a transition to DS2 has 
been made.15 
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1.2.2. 
Nonclinical Studies 
1.2.2.1. 
Pharmacology 
DS-8201a binds specifically to the HER2 extracellular domain and does not bind to 
other HER family proteins has been confirmed by enzyme-linked immunosorbent 
assay using recombinant proteins.  DS-8201a is hypothesized to exhibit antitumor 
activity through MAAA-1181a induced apoptosis
 
 
  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 HER2-expressing tumors. 
1.2.2.2. 
Pharmacokinetics Properties 
In monkeys, the Vss of DS-8201a was close to the plasma volume.  The CL was 
much lower than hepatic flow and decreased as the dose increased, indicating 
non-linear process.  DS-8201a administered intravenously (IV) mostly circulates in 
plasma while remaining in its intact form.  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 DS-8201a is largely stable in plasma.  The protein binding ratio of MAAA-1181a 
(10 ng/mL) was 98.0% in human plasma.  In monkeys, the highest radioactivity of IV 
administration of 14C-DS-8201a was observed in the blood and in monkeys, excretion 
of radioactivity from administered 14C-DS-8201a into feces was predominant.  In rats, 
excretion of radioactivity from administered 14C-MAAA-1181a into feces via bile 
was predominant.  Cytochrome P450 (CYP) 3A4 is the primary CYP enzyme in the 
metabolism of MAAA-1181a in vitro.  No human-specific metabolites were detected 
in vitro.  MAAA-1181a did not exhibit any inhibitory potential to CYP1A2, CYP2B6, 
CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A (ie, with 50% inhibitory 
concentration [IC50] >50 P796-1181a did not show any induction 
potential to CYP3A4, CYP1A2, and CYP2B6 up to 30 P796-1181a did 
not inhibit organic anion transporting 3 (OAT3), organic cation transporter 1 (OCT1) 
, OCT2, organic anion transporting polypeptide 1B3 (OATP 1B3), multidrug and 
toxin extrusion 1 (MATE1), MATE2-K, P-glycoprotein (P-gp), breast cancer 
resistance protein (BCRP), and bile salt export pump (BSEP) (IC50 >30 P796
MAAA-1181a inhibited OAT1 and OATP1B1 with the IC50 values of 12.7 and 14.4 
P796</=:/->3@/6C+6>29?12>2/@+6?/=A/</7?-22312/<>2+8>2/7+B90
MAAA-1181a in humans (9.25 817)		
P796*+>	 mg/kg of DS-8201a, 
Table 1.1).  In addition, OATPs were appeared to contribute to the human hepatic 
uptake of MAAA-1181a. 
1.2.2.3. 
Nonclinical Safety data 
In a study of intermittent IV dosing of DS-8201a in rats (once every 3 week [Q3w] 
dosing for 6 weeks), no dead or moribund animals were found at dose levels of 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, incisor tooth, and renal toxicity at dose levels of 
60 mg/kg and greater.  In an intermittent IV dose toxicity study of DS-8201a in 
cynomolgus monkeys (Q3w, 6 weeks), one moribund female was found at 
78.8 mg/kg, the highest dose level. 
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The major toxicity findings in this moribund animal were intestinal toxicity, 
hematopoietic system toxicity, skin toxicity, and renal toxicity.  This animal exhibited 
decreased body weight and food intake.  The major findings of toxicity in the 
surviving animals were intestinal toxicity at dose levels of 10 mg/kg and greater, and 
pulmonary, testicular, and skin toxicity at dose levels of 30 mg/kg and greater.  In 
addition, hematopoietic system, and renal toxicity, as well as electrocardiogram 
(ECG) abnormalities (PR interval shortened and corrected QT interval [QTc] 
prolongation) were found at 78.8 mg/kg. 
Thus, as described above, the severely toxic dose in 10% of the animals in a rat 
intermittent IV dose toxicity study with DS-8201a was found to be greater than 197 
mg/kg.  In an intermittent IV dose toxicity study in cynomolgus monkeys, because 
moribundity caused by a severe worsening of the animal's condition was found at 78.8 
mg/kg in one animal and evidence of critical pulmonary toxicity (eg, interstitial 
inflammation and/or alveolar edema) were found even in the surviving animals, it was 
concluded that the highest non-severely toxic dose was 30 mg/kg. 
In an intermittent IV dose toxicity study with MAAA-1181a (once a week dosing for 
4 weeks), although lymphatic/hematopoietic system toxicity, intestinal toxicity, and 
corneal toxicity were observed at 3 mg/kg and greater in rats, no deaths occurred at 
dose levels of 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, in 
cynomolgus monkeys, 1 female died and 1 male was found moribund at 12 mg/kg.  
Although effects on the heart (focal myocardial cell degeneration/necrosis) were 
found in the moribund male in addition to other these toxicities, there were no such 
cardiomyopathies in the dead female even though both animals exhibited similar 
worsening clinical conditions which were associated with sustained decreases in food 
consumption, and with bone marrow and intestinal toxicity.  Therefore these changes 
were considered the cause of the death and moribundity.  Intestinal toxicity and 
lymphatic/hematopoietic system toxicity were commonly observed in studies of 
DS-8201a or MAAA-1181a. 
In safety pharmacology studies, when male cynomolgus monkeys equipped with a 
telemetry device received single IV doses of DS-8201a, no effects on the 
cardiovascular system, respiratory system, or central nervous system were found at 
dose levels of up to 78.8 mg/kg.  In addition, in human ether- à-go-go-related gene 
(hERG) studies of MAAA-1181a, the monohydrate of the drug component, 
MAAA-1181a did not inhibit the hERG channel current. 
In an in vitro 3T3 neutral red uptake phototoxicity study, MAAA-1181a was found to 
be phototoxic to Balb/c 3T3 mouse fibroblasts. However, in a single dose 
phototoxicity study of MAAA-1181a in pigmented rats, no phototoxic reaction was 
noted.   
For further details of nonclinical studies, please see the current Investigator's 
Brochure (IB) for DS-8201a.15 
1.2.3. 
Clinical Experience 
The ongoing study DS8201-A-J101 (NCT02564900) is a Phase 1, two-part, 
multicenter, non-randomized, open-label, multiple dose, first-in-human study of 
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This two-part study includes both a Dose Escalation part (Part 1), to identify the 
maximum tolerated dose (MTD) or the recommended Phase 2 dose (RP2D) of 
DS-8201a, and a Dose Expansion part (Part 2), to confirm the safety, tolerability and 
efficacy of DS-8201a at the MTD/RP2D. 
As of 8 June 2017, 148 subjects received DS-8201a in this study.  In Part 1, a total of 
24 patients received DS-8201a: 3 in 0.8 mg/kg cohort, 3 in 1.6 mg/kg cohort, 3 in 3.2 
mg/kg cohort, 6 in 5.4 mg/kg cohort, 6 in 6.4 mg/kg cohort and 3 in 8.0 mg/kg cohort.  
Seventeen breast cancer patients, 6 gastric cancer patients and 1 GEJ cancer patient 
have been enrolled.  No dose limiting toxicities (defined as occurring during Cycle 1) 
were reported in any patient.  Two doses, 5.4 mg/kg and 6.4 mg/kg were chosen for 
expansion in Part 2.  In Part 2, a total of 124 patients, 48 in Part 2a, 41 in Part 2b, 10 
in Part 2c, and 25 in Part 2d, received DS-8201a.  Of these, a total 47 patients 
(30 patients in Part 2a and 17 patients in Part 2b) received 5.4 mg/kg and the other 
77 patients received 6.4 mg/kg of DS-8201a.  In Part 2d, 11 colorectal cancer patients, 
6 non-small cell lung cancer patients, 4 parotid/submandibular gland cancer patients, 
2 Paget’s disease patients, 1 cholangiocarcinoma patient and 1 esophageal cancer 
patient have been enrolled. 
The most common adverse events (AEs) in 148 patients who have received DS-8201a 
in this study (AEs >20% of any grades) were nausea (65%), decreased appetite (53%), 
vomiting (34%), decreased platelet count (31%), anemia (28%), alopecia (26%), 
diarrhea (24%), constipation (24%), decreased neutrophil count (24%), decreased 
white blood cell count (24%), and malaise (22%).  The majority of the AEs were of 
Grade 1 or 2 severity; 52 of 148 patients (35.1%) experienced Grade 3 AEs and 10 
patients (6.8%) experienced Grade 4 AEs as the worst grade experienced. 
Adverse events of special interest (AESIs) detailed in the Phase 1 protocol included 
infusion reactions, cardiac events, and interstitial lung disease (ILD).  Periodic cardiac 
assessments are performed including echocardiography (ECHO) or multiple-gated 
acquisition (MUGA) scan performed at every 2 cycles (42 days) and 12-lead triplicate 
ECGs performed at least every cycle (21 days).  A total of 13 (8.7%) patients 
experienced treatment-emergent adverse events (TEAEs) relating to cardiotoxicity in 
the on-going study.  Of these 13 patients, 9 experienced QT prolongation (7 Grade 1 
and 2 Grade 2, all non-serious), all considered related to the study therapy.  Two 
patients experienced ejection fraction decreased (Grade 2, non-serious, related), 
1 patient experienced Grade 2 tachycardia and 1 patient experienced decreased heart 
rate (related).  No action was taken regarding the study drug and no patients 
discontinued study therapy.  Pulmonary assessments are performed at the time of 
imaging for tumor assessments as well as evaluation of peripheral oxygen saturation 
(SpO2) on Day 1 of every cycle and at end of treatment (EOT).  In the event of 
suspicion of drug induced lung disease, recommendations include consultation with a 
pulmonologist and interruption of DS-8201a treatment pending final diagnosis.  As of 
8 June 2017, there were 3 patients (where 1 received 8.0 mg/kg and the other 2 
received 6.4 mg/kg) who had experienced 1 serious and 2 non-serious pneumonitis (1 
was Grade 1 and the other was Grade 2).  There were also 2 patients who experienced 
ILD (1 serious and Grade 3 in severity, and the other non-serious Grade 1 in severity). 
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%.  Patients receiving 
higher dose levels of DS-8201a (≥5.4 mg/kg, 15 patients) showed ORR of 53.3%.  
Overall efficacy results from all cohorts in Part 2 demonstrated an ORR of 48.8% and 


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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%. 
Preliminary pharmacokinetic (PK) data are available from the 24 patients in the 
0.8 mg/kg to 8.0 mg/kg cohorts in Part 1 of DS8201-A-J101.  The PK parameters of 
MAAA-1181a, DS-8201a and total anti-HER2 antibody are shown in Table 1.1, 
Table 1.2 and Table 1.3. Systemic exposure (Cmax and AUClast) to DS-8201a over 
3.2 mg/kg exposures increased approximately dose proportionally.    Following a 
single IV administration of DS-8201a at 6.4 mg/kg, Cmax of DS-8201a was achieved 
with a median time of maximum observed serum concentration (Tmax) of 2.16 h and 
mean T1/2 of 7.33 days. 
The total antibody profile was similar to the PK profile for DS-8201a, and the PK 
parameters of total antibody were comparable to those of DS-8201a.  Serum 
MAAA-1181a concentrations gradually increased and reached peak concentrations 
with longer Tmax (6 hours to 7 hours, median Tmax) compared to those for 
DS-8201a.  The systemic exposure (Cmax and AUCs as reported in ng/mL and 
ng day/mL, respectively) to MAAA-1181a was much lower than that of DS-8201a (as 
reported in μg/mL and μg day/mL, respectively), where DS-8201a exposure was 
>10,000-fold to that of MAAA-1181a. 
Table 1.1: Pharmacokinetic Parameters of DS-8201a Following the First Dose 
Dosage 
(N) 
Cmaxa 
(ng/mL) 
Tmaxb 
(h) 
AUClast 
(gd/mL) 
AUCinf 
(gd/mL) 
T1/2 
(day) 
CL 
(mL/d/ 
kg) 
Vss 
(mL/kg) 
0.8 mg/kg 
(3) 
22.9 
(3.76) 
1.92 
(1.68, 1.92) 
51.7 
(13.1) 
55.0 
(11.9) 
2.18 
(0.671) 
15.0 
(2.89) 
45.0 
(8.96) 
1.6 mg/kg 
(3) 
36.2 
(4.98) 
4.08 
(1.92, 4.08) 
116 
(58.7) 
121 
(58.9) 
3.07 
(1.22) 
16.1 
(9.27) 
58.3 
 (10.0) 
3.2 mg/kg 
(3) 
78.2  
(16.1) 
4.08 
(1.92, 6.96) 
325 
(142) 
340  
(150) 
4.23 
(1.24) 
11.3 
(6.52) 
56.8 
 (14.4) 
5.4 mg/kg 
(6) 
127 
(17.2) 
1.92 
(1.92, 2.16) 
544 
(165) 
590 
(186) 
6.03 
(0.603) 
10.1 
(3.90) 
75.2 
 (24.2) 
6.4 mg/kg 
(6) 
181 
(33.1) 
2.16 
(1.44, 4.08) 
901 
(155) 
1030 
(209) 
7.33 
(1.64) 
6.41 
(1.12) 
58.6 
 (11.0) 
8.0 mg/kg 
(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) 
h = hour; N = Total number of observations;  
a Mean (standard deviation) 
b Tmax reported as median (min, max) 
 


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Table 1.2: Pharmacokinetic Parameters of Total Anti-HER2 Antibody 
Following the First Dose 
Dosage 
(N) 
Cmaxa 
(ng/mL) 
Tmaxb 
(h) 
AUClast 
(gd/mL) 
AUCinf 
(gd/mL) 
T1/2 
(day) 
0.8 mg/kg 
(3) 
19.3 
(4.30) 
1.68 
(1.68, 1.92) 
83.8 
(73.4) 
93.5 
(82.1) 
3.49  
(2.51) 
1.6 mg/kg 
(3) 
41.2 
(12.7) 
1.92 
(1.68, 4.08) 
200 
(191) 
227 
(225) 
4.35 
(2.77) 
3.2 mg/kg 
(3) 
67.5 
 (13.8) 
4.08 
(4.08, 6.96) 
302 
(97.8) 
313 
(102) 
3.93 
(0.863) 
5.4 mg/kg 
(6) 
116 
 (13.9) 
1.92 
(1.92, 6.96) 
609 
(151) 
682 
(172) 
6.78 
(2.39) 
6.4 mg/kg 
(6) 
146 
 (18.9) 
3.84 
(2.16, 6.96) 
878 
(97.1) 
1050 
(149) 
8.25 
(2.16) 
8.0 mg/kg 
(3) 
178 
 (18.5) 
2.16 
(1.92, 6.72) 
1090 
(213) 
1270 
(296) 
7.35 
(0.417) 
h = hour; N = Total number of observations;  
a Mean (standard deviation) 
b Tmax reported as median (min, max) 
 
Table 1.3: Pharmacokinetic Parameters of MAAA-1181a Following the First 
Dose 
Dosage 
(N) 
Cmaxa 
(ng/mL) 
Tmaxb 
(h) 
AUClasta 
(ng d/mL) 
AUCinfa 
(ng d/mL) 
T1/2a 
(day) 
0.8 mg/kg 
(3) 
1.17 
(0.757) 
6.72 
(6.72, 22.32) 
4.84 
(1.89) 
4.89 
(1.89) 
2.50 
(0.579) 
1.6 mg/kg 
(3) 
1.72 
(0.193) 
6.96 
(6.72, 24.00) 
8.53 
(2.15) 
8.76 
(2.34) 
3.48 
(1.09) 
3.2 mg/kg 
(3) 
5.69 
(0.530) 
6.96 
(4.08, 6.96) 
24.0 
(7.58) 
24.9 
(7.98) 
4.68 
(0.969) 
5.4 mg/kg 
(6) 
10.8 
(7.56) 
5.28 
(3.84, 23.76) 
40.6 
(19.8) 
43.6 
(21.2) 
6.11 
(0.811) 
6.4 mg/kg 
(6) 
6.80 
(1.72) 
6.72 
(4.08, 7.20) 
31.0 
(5.11) 
34.2 
(5.63) 
6.28 
(1.17) 
8.0 mg/kg 
(3) 
9.25 
(3.18) 
6.72 
(6.72, 6.96) 
39.4 
(6.43) 
43.4 
(9.16) 
6.36 
(1.53) 
h = hour; N = Total number of observations;  
a Mean (standard deviation) 
b Tmax reported as median (min, max) 
 
For further details on clinical studies, please see the current IB for DS-8201a.15 


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1.3. 
Study Rationale 
The results from the Phase 1 study DS8201-A-J101 (NCT02564900) have shown 
antitumor activity and a manageable safety profile.  As of 7 June 2017, there have 
been no reported dose limiting toxicities, and MTD was not reached in the 0.8 mg/kg 
to 8.0 mg/kg Q3w cohorts.  Although 8.0 mg/kg was shown to be tolerable, dose 
reductions were required in 2 out of 3 patients, and subsequent exposure response 
analysis showed that 5.4 mg/kg and 6.4 mg/kg were appropriate assessment doses in 
the expansion cohort of this Phase 1 study. On the basis of efficacy, tolerability, and 
PK profile established in the Phase 1 study and pre-clinical studies, the dose of 
6.4mg/kg will be used in this trial. 
1.4. 
Risks and Benefits for Study Subjects 
Based on the clinical observations in the Phase 1 study (DS8201-A-J101), DS-8201a 
demonstrated antitumor activity in HER2-overexpressing patients (see Section 1.2.3).  
Overall, the reported AEs were consistent with the safety profile of DS-8201a and as 
expected based on the nonclinical toxicology data.  The following TEAEs were 
considered as identified risk: nausea, decreased appetite, vomiting, decreased platelet 
count, anemia, alopecia, diarrhea, decreased neutrophil count, and decreased white 
blood cell count.  The majority of the TEAEs were of Grade 1 and Grade 2 severity.  
Patients receiving DS-8201a should be monitored for signs and symptoms of any of 
the toxicities observed in nonclinical studies and to other products of the same class, 
which are discussed below. 
In nonclinical toxicology studies, intestinal, hematopoietic, pulmonary (interstitial 
inflammation and/or alveolar edema), testicular, skin and renal toxicities were found 
in association with the administration of DS-8201a. Ophthalmologic safety 
monitoring, which includes visual acuity, slit lamp exam, and fundoscopy will also be 
part of the overall evaluation.  These assessments will be performed at baseline and at 
specific intervals described in the protocol and at the EOT, when an additional exam 
will also be performed.  Moreover, at the discretion of the Investigator, 
ophthalmologic testing can be performed at any time during the study.  In addition to 
these toxicities, as with other products of the same class, the possibility of 
cardiotoxicity, related to the potential for QT prolongation were found in association 
with the administration of DS-8201a and cannot be excluded.  Left ventricular 
ejection fraction (LVEF) will be measured by either ECHO or MUGA scan.  All 
ECHOs or MUGAs, will be evaluated by the Investigator or delegated physician to 
monitor cardiac function and troponin will be evaluated to assess cardiac function.  
Pulmonary toxicity was observed in association with the administration of DS-8201a 
in both preclinical and clinical studies.  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 interstitial lung disease (ILD)/pneumonitis cases reviewed by the 
independent ILD Adjudication Committee (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. 
Additional safety assessments should be conducted as needed, at the Investigator’s 
discretion.  It can also not be denied that hepatotoxicity, embryo-fetal toxicity, visual 
disturbances/corneal toxicity, or phototoxicity may occur in patients receiving DS-


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8201a.  As with any therapeutic antibodies, there is a possibility of infusion-related 
reactions, and immune responses causing allergic or anaphylactic reactions of DS-
8201a.  Based on the efficacy and safety data observed in the nonclinical studies, the 
current clinical experience of the Phase 1 study, and the information from other 
products of the same class, the benefit-risk balance supports clinical development of 
DS-8201a in this patient population. 
Please refer to the current IB for additional information.15 


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2. 
STUDY OBJECTIVES AND HYPOTHESIS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objectives 
1. To assess the safety and tolerability of DS-8201a 
2.1.2. 
Secondary Objectives 
1. To assess the PK profiles of DS-8201a, total anti-HER2 antibody, and 
MAAA-1181a 
2. To investigate the anti-tumor activity of DS-8201a 
3. To assess the incidence of anti-drug antibodies (ADA) against DS-8201a 
2.1.3. 
Exploratory Objectives 
Not applicable. 
2.2. 
Study Hypotheses 
The safety and tolerability profile of DS-8201a in Chinese patients. 
2.3. 
Study Endpoints 
2.3.1. 
Primary Endpoints 
Safety endpoints: 
 Safety endpoints will include serious adverse events (SAEs), TEAEs, AEs and 
AESIs leading to discontinuation. 
 Other safety endpoints will include physical examination findings (including 
Eastern Cooperative Oncology Group Performance Status [ECOG PS]), vital 
sign measurements, standard clinical laboratory parameters, ECG parameters, 
ECHO or MUGA findings, and ophthalmologic findings.  TEAEs will be 
graded according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI-CTCAE) version 4.03. 
2.3.2. 
Key Secondary Endpoints 
PK endpoints: 
 Serum concentration data at each time point and PK parameters of DS–8201a, 
total anti-HER2 antibody, and MAAA-1181a will be presented. 
2.3.3. 
Other Secondary Endpoints 
 Assessment of ADA 
2.3.4. 
Exploratory Endpoints 
Efficacy endpoints: 
Tumor response will be evaluated by the Investigators using Response Evaluation 
Criteria in Solid Tumors (RECIST) version 1.1: 


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 ORR 
 DCR 
 Duration of response (DoR) 
 Progression-free survival (PFS) 
 Overall survival (OS) 
 Best percentage change in the sum of diameter(s) of target lesion(s)  


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3. 
STUDY DESIGN 
3.1. 
Overall Design 
In this Phase 1, multicenter, open-label study, the safety and tolerability of DS-8201a 
in subjects with HER2-positive advanced and/or refractory gastric, GEJ 
adenocarcinoma, or breast cancer will be evaluated. 
Approximately 12 eligible subjects will be enrolled at study sites in Taiwan, Republic 
of China. 
DS-8201a at a dose of 6.4 mg/kg will be infused IV for approximately 90 minutes on 
Day 1 of Cycle 1.  If there are no infusion-related reactions after the initial dose in 
Cycle 1, dosing in subsequent cycles will be infused for approximately 30 minutes.  
Subjects will continue to receive DS-8201a Q3w (Day 1 of each cycle), until 
unacceptable toxicity, progressive disease (PD), or withdrawal of consent.  The 
subject’s weight at Screening (Baseline) will be used to calculate the initial dose.  If 
the subject’s weight changes by 10% of the baseline weight, the dose will be 
recalculated. 
3.2. 
Discussion of Study Design 
This is an open-label study and the main objective is to assess the safety and 
tolerability profile of DS-8201a in Chinese subjects. 
On the basis of efficacy, tolerability, and PK profiles established in the 
DS-8201-A-J101 study and preclinical studies, the dose of 6.4 mg/kg will be used in 
this study and subjects will continue to receive DS-8201a Q3w (Day 1 of each cycle) 
at the discretion of the iInvestigators, until unacceptable toxicity, PD, or withdrawal 
of consent. 
All subjects are required to have an adequate washout period from their previous 
oncology treatment before registration in this study (see inclusion criterion 6).  
Approximately 12 subjects will be enrolled in this study and the sample size of 12 
will provide the safety and tolerability data in Chinese subjects. 
3.2.1. 
Duration of the Study 
The expected time from the first subject’s enrollment until the last subject’s 
enrollment is approximately 8 months.  The screening period is 28 days and each 
cycle of treatment is 21 days. 
The date of registration will be the date that the subject is successfully enrolled as 
eligible in the study, confirmed by the Sponsor.  The date of discontinuation of 
treatment (EOT) will be the date the Investigator decides to discontinue treatment. 
The end of the study is defined as the last subject’s last visit or contact, including 
telephone contacts, for collection of any study-related data. 
3.2.2. 
Duration of Subject Participation 
The screening period is up to 28 days.  Each cycle of treatment will be 21 days.  The 
number of treatment cycles is not fixed in this study.  Subjects who continue to derive 
clinical benefit from the study drug in the absence of withdrawal of consent, PD, or 
unacceptable toxicity may continue the study drug.  If the study drug is delayed more 


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than 28 days from the planned date of administration, the subject will be withdrawn 
from the study (See sections 5.4.1 and 5.4.2). 
3.2.3. 
Study Endpoints 
See Section 2.3 for the study endpoints. 
The safety endpoints used in this study are standard in Phase 1 oncology studies.  To 
assess the safety profile of DS8201a, the SAEs, TEAEs, AEs and AESIs leading to 
discontinuation, physical examination findings (including ECOG PS), vital sign 
measurements, standard clinical laboratory parameters, ECG parameters, ECHO or 
MUGA findings, and ophthalmologic findings will be assessed. 
Secondary PK endpoints for Cycle 1 and Cycle 3 will assess single and multiple dose 
kinetics of DS-8201a. 
RECIST is a standard measure of efficacy in oncology studies.  To investigate the 
anti-tumor activity of DS-8201a, ORR, DCR, DOR, PFS, and OS will be analyzed 
appropriately. 
ADA data will also be analyzed to serve as a supportive indication of the safety 
profile. 
3.2.4. 
Selection of Doses 
In this study, all enrolled subjects will receive 6.4 mg/kg of DS-8201a IV on Day 1 of 
each 21-day cycle. 
In the Phase 1 study, DS8201-A-J101, although 8.0 mg/kg was shown to be tolerable, 
dose reductions were required in 2 out of 3 subjects, and subsequent 
exposure-response analysis showed that 5.4 mg/kg and 6.4 mg/kg were appropriate 
assessment doses in the expansion cohort of Phase 1 study. 
Two dose reductions will be permitted in this study.  The adjustment for reduced 
dosing of DS-8201a will be as follows: 
 
6.4 mg/kg → 5.4 mg/kg → 4.4 mg/kg 
After two reductions, further reduction is not allowed.  Once the dose of DS-8201a is 
reduced, no escalation is permitted. 
3.2.5. 
Management of Subjects with Adverse Events of Special Interest 
For the DS-8201a clinical program, based on the available pre-clinical data, review of 
the cumulative literature, reported toxicities for the same class of agents and 
biological plausibility, ILD and LVEF decreases are considered to be AESIs. 
3.2.5.1. 
Cardiac-Related Events including Decreased Ejection Fraction 
(Cardiotoxicity) 
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. Refer to the current IB for a summary of 
preliminary clinical trial data.15 
Management Guidance: 


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LVEF will be measured by either ECHO or MUGA scan.  All ECHOs or 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 the Investigator or 
delegated physician for the presence of abnormalities.  Whether or not measurement 
is performed, date performed, results, and findings for each parameter are to be 
recorded in the electronic case report form (eCRF). 
Subjects with confirmed symptomatic cardiac dysfunction will be discontinued from 
the study.  A symptomatic decline in LVEF will be managed according to the 
algorithm shown in Table 3.1. 
Table 3.1: 
Actions Taken for Cardiac Toxicity 
Worst toxicity NCI-
CTCAE version 4.03 
Grade (unless otherwise 
specified) 
Management Guidelines for DS-8201a 
Cardiac Toxicity 
Symptomatic congestive 
heart failure (CHF) 
Discontinue subject from study treatment 
Decrease in LVEF 10 to 
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 
LVEF 40% to ≤ 45% and 
decrease is 10-20% 
(absolute value) from 
baseline 
Interrupt DS-8201a dosing 
Repeat LVEF assessment within 3 weeks 
If LVEF has not recovered to within 10% (absolute value) 
from baseline, discontinue subject from study treatment 
If LVEF recovers to within 10% from baseline, resume 
study drug 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 
Electrocardiogram QT prolonged 
Grade 3 (QTc >≥ 501 ms 
on at least 2 separate 
ECGs) 
Delay dose until resolved to ≤ Grade 1 (corrected QT ≤ 480 
ms), determine if another medication the subject was taking 
may be responsible and can be adjusted or if there are any 
changes in serum electrolytes that can be corrected, then if 
attributed to DS-8201a, reduce dose 1 level 
Grade 4 (QTc ≥  501 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  
CHF = congestive heart failure; LVEF = left ventricular ejection fraction 


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3.2.5.2. 
Interstitial Lung Disease/Pneumonitis 
Clinical Summary 
 Interstitial lung disease/pneumonitis is considered an important identified risk based 
on a comprehensive cumulative review of the available safety data from the clinical 
development program as well as the results of potential interstitial lung disease 
(ILD)/pneumonitis cases reviewed by the independent ILD Adjudication Committee 
(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. 
Management Guidance:  
Please refer to Table 3.2. 
Table 3.2: 
Actions Taken for Pulmonary Toxicity 
Worst toxicity NCI-
CTCAE version 4.03 
Grade (unless otherwise 
specified) 
Management Guidelines for DS-8201a 
Pulmonary Toxicity 
 
If a subject develops radiographic changes potentially 
consistent with ILD or 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 (infectious disease 
consultation as clinically indicated) 
 
blood culture and CBC (other blood tests could be 
considered as needed) 
 
bronchoscopy and bronchoalveolar lavage if clinically 
indicated and feasible should be considered 
 
Pulmonary function tests and pulse oximetry (SpO2). 
 
Arterial blood gases if clinically indicated 
 
One blood sample collection for PK analysis as soon 
as ILD/pneumonitis is suspected, if feasible. 
Other tests could be considered, as needed. 
 
If the AE is confirmed to be ILD/pneumonitis, follow the ILD 
management guidance as outlined below.  
All events of ILD regardless of severity or seriousness will be 
followed until resolution including after drug discontinuation. 


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Grade 1 
The administration of trastuzumab deruxtecan must be 
interrupted for any ILD events regardless of grade.  
 
Monitor and closely follow-up in 2 to 7 days for onset 
of clinical symptoms and pulse oximetry 
 
Consider follow-up imaging in 1-2 weeks (or as 
clinically indicated). 
 
Consider starting systemic steroids (e.g. at least 0.5 
mg/kg/day prednisone or equivalent) until 
improvement, followed by gradual taper over at least 
4 weeks. 
 
If worsening of diagnostic observations despite 
initiation of corticosteroids, then follow Grade 2 
guidelines.* 
For Grade 1 events, trastuzumab deruxtecan 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 
However, if the event grade 1 ILD occurs beyond cycle day 22 
and has not resolved within 49 days from the last infusion, the 
drug should be discontinued.  
* If patient is asymptomatic, then patient should still be 
considered as Grade 1 even if steroid treatment is given 
Grade 2 
Permanently discontinue subject from study treatment 
• 
Promptly start and treat with systemic steroids (e.g., at 
least 1mg/kg/day prednisone or equivalent) for at least 
14 days or until complete resolution of clinical and 
chest CT findings, then followed by a gradual taper 
over at least 4 weeks. 
• 
Monitor symptoms closely. 
• 
Re-image as clinically indicated. 
• 
If worsening or no improvement in clinical or 
diagnostic observations in 5 days,  
• 
Consider increasing dose of steroids (e.g., 2 
mg/kg/day prednisone or equivalent) and 
administration may be switched to intravenous 
(e.g. methylprednisolone). 
• 
Re-consider additional work-up for alternative 
etiologies as described above. 
• 
Escalate care as clinically indicated. 
Grade 3 and 4 
Permanently discontinue subject from study treatment. 
• 
Hospitalization required. 
• 
Promptly initiate empiric high-dose 
methylprednisolone IV treatment (e.g., 500-1000 
mg/day for 3 days), followed by at least 1.0 mg/kg/day 
of prednisone (or equivalent) for at least 14 days or 
until complete resolution of clinical and chest CT 
findings, then followed by a gradual taper over at least 
4 weeks. 
• 
Re-image as clinically indicated. 
• 
If still no improvement within 3 to 5 days,  


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 Re-consider additional work-up for alternative 
etiologies as described above. 
Consider other immuno-suppressants and/or treat per local 
practice. 


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4. 
STUDY POPULATION 
All subjects must sign and date the informed consent form (ICF) provided by the 
study site before any study-specific qualification procedures are conducted. 
4.1. 
Inclusion Criteria 
Subjects must satisfy all of the following criteria to be included in the study:  
1. Chinese patients aged ≥20 years 
2. Pathologically documented HER2-positive advanced/unresectable or 
metastatic gastric, GEJ adenocarcinoma, or breast cancer, with both: 
a. HER2-positive disease documented as: immunohistochemistry (IHC) 
3+ positive, and/or fluorescence in situ hybridization (ISH) ≥2.0 that is 
refractory to or intolerable with standard treatment, or for which no 
standard treatment is available.  For subject with gastric or GEJ 
adenocarcinoma cancers, it is preferable to determine HER2 status 
after completing the last HER2-targeting treatment. 
b. Documented disease progression (by the Investigator’s assessment) 
after at least one regimen of trastuzumab therapy in metastatic or 
unresectable locally advanced/recurrent setting. 
3. ECOG PS 0 to 1. 
4. LVEF ≥50% by either ECHO or MUGA scan within 28 days before 
registration. 
5. Adequate organ function within 7 days before registration defined as: 
Item 
Laboratory value 
Platelet count 
100,000/mm3 
(platelet transfusion is not allowed within 
1 week prior to screening assessment) 
Hemoglobin (Hb) 
≥9 g/dL 
(red blood cell transfusion is not allowed 
within 1 week prior to screening 
assessment) 
Absolute neutrophil count 
(ANC) 
1500/mm3 
(granulocyte colony-stimulating factor 
administration is not allowed within 1 week 
prior to screening assessment) 
Creatinine 
≤1.5  upper limit of normal (ULN), or 
creatinine clearance ≥60 mL/min as 
calculated using the Cockcroft-Gault 
equation 
Aspartate 
aminotransferase 
(AST)/alanine 
aminotransferase (ALT) 
≤3  ULN  (if liver metastases are present, 
≤5  ULN) 


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Total bilirubin (TBL) 
≤1.5  ULN or < 3 × ULN in the presence 
of documented Gilbert’s Syndrome or liver 
metastases at baseline 
Prothrombin time and 
activated partial 
thromboplastin time 
≤1.5 × ULN 
6. Adequate treatment washout period before registration, defined as: 
Treatment 
Washout period 
Major surgery 
4 weeks 
Radiation therapy  
≥4 weeks (if palliative stereotactic radiation 
therapy excludes abdomen, ≥2 weeks) 
Autologous 
transplantation 
3 months 
Hormonal therapy 
2 weeks 
Chemotherapy 
(including antibody 
drug therapy and, 
retinoid therapy) 
3 weeks (or 5 half-lives before study drug 
treatment, whichever is longer, for 
small-molecule targeted agents such as 
5-fluorouracil-based agents, folinate agents, 
and/or weekly paclitaxel.  6 weeks for 
nitrosoureas or mitomycin C) 
Immunotherapy 
4 weeks 
CYP3A4 strong 
inhibitor and inducer 
3 × elimination half-lives of the inhibitor 
OATP1B1 inhibitor 
3 × elimination half-lives of the inhibitor 
7. Life expectancy of at least 3 months. 
8. Subjects should be able to provide written informed consent.  Subject must be 
fully informed about their illness and the investigational nature of the study 
protocol (including foreseeable risks and possible toxicities) and must sign 
and date an Institutional Review Board (IRB) approved ICF before 
performance of any study-specific procedures or examinations. 
9. Subjects should be willing to provide pre-existing diagnosis of HER2 status. 
10. 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 7 months for females and 4.5 
months for males after the last dose of study drug.  Methods considered as 
highly effective methods of contraception include:  
a. Combined (estrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation: 
i. Oral 
ii. Intravaginal 
iii. Transdermal 


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b. Progestogen-only hormonal contraception associated with inhibition of 
ovulation: 
i. Oral 
ii. Injectable 
iii. Implantable 
c. Intrauterine device 
d. Intrauterine hormone-releasing system 
e. Bilateral tubal occlusion 
f. Vasectomized partner 
g. Complete sexual abstinence defined as refraining from heterosexual 
intercourse during and upon completion of the study and for at least 7 
months for females and 4.5 months for males after the last dose of 
study drug. Periodic abstinence (calendar, symptothermal, post-
ovulation methods) is not an acceptable method of contraception. 
Non-childbearing potential is 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 >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 
child-bearing potential if they wish to continue their HRT during the study.  
Otherwise, they must discontinue the HRT to allow confirmation of 
post-menopausal status prior to study enrollment.  For most forms of HRT, at 
least 2 weeks to 4 weeks will elapse between the cessation of therapy and the 
blood draw; this interval depends on the type and dosage of the HRT.  
Following confirmation of their post-menopausal status, they can resume use 
of the HRT during the study without use of a contraceptive method. 
11. 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 enrolment 
in this study. 
12. 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 
7 months after the final study drug administration. 
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 enrollment, 
symptomatic CHF (New York Heart Association Class II to IV), troponin 
levels consistent with myocardial infarction as defined according to the 
manufacturer 28 days prior to randomization. 


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2. QTcF prolongation of >450 ms in males and >470 ms in females based on 
12-lead ECG performed in triplicate. 
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. Has any evidence of severe or uncontrolled systemic diseases (including 
uncontrolled hypertension, and active bleeding diatheses or active infection 
including hepatitis B, hepatitis C and human immunodeficiency virus (HIV), 
psychiatric illness/social situations, substance abuse, or other factors which in 
the Investigator’s opinion makes it undesirable for the subject to participate in 
the study or which would jeopardize compliance with the protocol. Screening 
for chronic conditions is not required. 
5. Have clinically significant corneal disease in the opinion of the Investigator. 
6. Subjects who are pregnant (as confirmed by pregnancy tests performed within 
7 days before registration) or breastfeeding, or planning to become pregnant. 
7. Have spinal cord compression or clinically active central nervous system 
metastases, defined as untreated and symptomatic, or requiring therapy with 
corticosteroids or anticonvulsants to control associated symptoms.  Subjects 
with clinically inactive brain metastases may be included in the study.  
Subjects with treated brain metastases that are no longer symptomatic and who 
require no treatment with corticosteroids or anticonvulsants may be included 
in the study if they have recovered from the acute toxic effect of radiotherapy.  
A minimum of 2 weeks must have elapsed between the end of whole brain 
radiotherapy and study enrollment. 
8. Has a history of severe hypersensitivity reactions to other monoclonal 
antibodies and/or to either the drug substances or inactive ingredients in the 
drug product. 
9. Unresolved toxicities from previous anticancer therapy, defined as toxicities 
(other than alopecia) not yet resolved to NCI-CTCAE version 4.03, Grade ≤1 
at baseline.  Subjects with chronic Grade 2 toxicities may be eligible per the 
discretion of the Investigator after consultation with the Sponsor medical 
monitor or designee (eg, Grade 2 chemotherapy-induced neuropathy). 
10. Presence of other primary malignancies within 3 years, except adequately 
resected non-melanoma skin cancer, curatively treated in-situ disease, other 
solid tumors, or contralateral breast cancer. 
4.3. 
Subject Replacement 
Subject replacement is not allowed in this study. 
4.4. 
Subject Re-screening Procedures 
The study will allow re-screening for any subject who failed to meet eligibility criteria 
upon initial screening.  Re-screening will be allowed only once and requires an 
approval from the Sponsor.  The subject number must remain the same at the time of 
re-screening.  The initial screening information and the reason why the subject was 
ineligible for the initial evaluation will be recorded on the screening log. 


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5. 
STUDY TREATMENT 
5.1. 
Assigning Subjects to Treatment Group/Sequences and 
Blinding 
5.1.1. 
Treatment Group/Sequences 
There is a single treatment group in this study. The study drug, dosage, and study 
procedures are the same for all subjects enrolled in this study. 
5.1.2. 
Method of Treatment Group/Sequences Allocation 
This is an open-label, non-randomized study. 
5.1.3. 
Enrollment 
Investigators will maintain a confidential screening log of all potential study 
candidates that includes limited information of the subjects (initials, age, sex) date 
and outcome of screening process (eg, enrolled 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 Subject Number.  The unique Subject Number for 
all subjects who provide written informed consent will be assigned by the Sponsor.  
The date of registration is defined as the date that subject is successfully enrolled as 
eligible, confirmed by the Sponsor.  The date of screen failure is defined as the date 
that subject is considered as ineligible.  Investigators will maintain a confidential 
subject identification code list.  This confidential list of names of all subjects, 
allocated Subject Numbers on enrolling in the study, allows the Investigator to reveal 
the identity of any subject when necessary. 
Each subject will be provided with information about the study, will have all 
questions answered to their satisfaction, and will sign and date an ICF.  This will be 
completed before any study-specific procedures are performed.  Additional 
information about informed consent procedures is provided in Section 15.3. 
After assigning subject number to each subject at Screening at each site, Investigators 
will assess the eligibility of a subject based on the inclusion and exclusion criteria 
after obtaining written informed consent from the subject. 
Data for all study visits will be recorded on the eCRF for subjects who receive study 
drug.  Only minimal data will be recorded on the eCRF for subjects who do not meet 
the eligibility criteria and/or do not receive study drug (screen failures).  Further data, 
such as AEs, will not be collected from subjects once they are considered screen 
failures or have decided to withdraw prior to receiving study drug. 
5.1.4. 
Blinding 
This is an open-label study; no blinding will be performed. 
5.1.5. 
Emergency Unblinding Procedure 
Not applicable. 


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5.2. 
Study Drug 
The Investigators must ensure that the study drug will be used only in accordance 
with the protocol. 
5.2.1. 
Description 
DS-8201a for injection 100mg will be provided as a sterile lyophilized powder 
containing 100 mg of DS-8201a in a glass vial (Lyo-DP).  Each glass vial should be 
reconstituted with 5 mL water for Injection to a concentration of 20 mg/mL (ie, 
100mg/5mL).  DS-8201a will be administered with 5% Dextrose as an IV infusion. 
Each vial is designed for single use only and is not to be used to treat more than one 
subject. 
5.2.2. 
Labeling and Packaging 
DS-8201a for injection 100mg will be supplied by Daiichi Sankyo.  This will be 
labeled and packaged in compliance with regulatory requirements.  The packaging 
will clearly display the name of the study drug, the study drug manufacturing code, 
the drug number, storage conditions, and other required information in accordance 
with local regulations. 
5.2.3. 
Preparation 
The drug solution for IV infusion is prepared by dilution of the required volume of the 
study drug calculated based on the subject’s body weight.  Prepared medicinal 
solutions should be used immediately.  The preparation will be conducted in 
accordance with the pharmacy manual provided by Daiichi Sankyo.  Procedures for 
proper handling and disposal of anticancer drugs should be followed in compliance 
with the standard operating procedures (SOPs) of the study site.  Refer to the 
pharmacy manual for detailed information about preparation and administration of 
DS-8201a. 
5.2.4. 
Administration 
The study drug will be administered  at 6.4 mg/kg Q3w.  The initial dose of DS-8201a 
will be infused IV into each subject for approximately 90 minutes on Day 1 of 
Cycle 1.  If there is no infusion-related reaction after the initial dose, the second and 
subsequent doses of DS-8201a will be infused over approximately 30 minutes.  The 
subject’s weight at Screening (Baseline) will be used to calculate the initial dose.  If 
the subject’s weight changes by 10% or more from the baseline weight, the dose will 
be recalculated. 
5.2.5. 
Storage 
Drug supplies must be stored in a secure, limited access storage area under the storage 
conditions listed below: 
 Stored at 2°C to 8°C (protected from light) 
If storage conditions are not maintained per specified requirements, the Sponsor or the 
contract research organization (CRO) should be contacted. 


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5.2.6. 
Drug Accountability 
When a drug shipment is received, the Investigator or designee will check the amount 
and condition of the drug, check for appropriate local language in the label, drug 
expiration date, and sign the receipt of shipment form provided by the Sponsor.  The 
receipt of shipment form should be signed and the original form will be retained at the 
site.  In addition, the Investigator or designee shall contact the Sponsor as soon as 
possible if there is a problem with the shipment. 
A drug accountability record will be provided for the study drug.  The record must be 
kept current and should contain the dates and quantities of drug received, subject’s 
(identification number and/or initials or supply number as applicable), for whom the 
study drug was dispensed, the date and quantity of study drug dispensed and 
remaining, if from individual subject drug units as well as the initials/seal of the 
dispenser. 
At the end of the study, or as directed, all unused DS-8201a will be returned to a 
designee as instructed by the Sponsor.  The study drug will be returned only after the 
study monitor has completed a final inventory to verify the quantity to be returned.  
The return of study drug must be documented and the documentation included in the 
shipment.  At the end of the study, a final study drug reconciliation statement must be 
completed by the Investigator or designee and provided to the Sponsor. Unused drug 
supplies may be destroyed by the supervisor of study drugs when approved in writing 
by Sponsor and Sponsor has received copies of the site’s drug handling and 
disposition SOPs. 
All study drug inventory forms must be made available for inspection by a sponsor 
authorized representative or designee and regulatory agency inspectors.  The 
Investigators or designees will be responsible for the accountability of all used and 
unused study supplies at the site. 
5.3. 
Control Treatment 
Not applicable. 
5.4. 
Dose Interruptions and Reductions 
All confirmed or suspected severe acute respiratory syndrome coronavirus 2 (SARS-
CoV-2) infection events must be recorded in the eCRF. Please refer to Section 17.7 
for additional information on dose modification. 
5.4.1. 
Dose Interruptions 
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 (NCI-CTCAE version 4.03).  Specific criteria 
for interruption, re-initiation, dose reduction and/or discontinuation of DS-8201a are 
listed in Table 5.2.  For Grade 3 or Grade 4 events, monitoring (including local lab 
tests when appropriate) should be performed at intervals no greater than 7 days until 
the AE is determined to be resolving or discontinuation of study treatment is decided. 
Prophylactic or supportive treatment for expected toxicities, including management of 
study-drug induced AEs will be as per the treating physician’s discretion and 
institutional guidelines. 


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In addition, Investigators may consider dose reductions or discontinuations of the 
study drug according to the subject’s condition and after discussion with  
the Daiichi Sankyo’s Medical Monitor or designee. 
5.4.2. 
Dose Reductions 
Note: There will be no dose modifications for Grade 1 or Grade 2 AEs unless 
specified in Table 5.2 and Section 3.2.5. 
Two dose reductions are permitted in this study.  The adjustment for reduced dosing 
of DS-8201a will be as shown in Table 5.1.   
Table 5.1 
Reference Scheme of Dose Reduction 
Dose level before dose 
interruption 
 
Dose level after first 
dose reduction 
 
Dose level after second 
dose reduction 
6.4 mg/kg 
→ 
5.4 mg/kg 
→ 
4.4 mg/kg 
The Investigator may consider dose reductions or discontinuation of the study drug 
according to the condition of the subject and after discussion with the Sponsor. 
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. 
Dose Interruption and Modification/Toxicity Management Guidelines: 
A dose can be delayed for up to 28 days from the planned date of administration, or 
49 days from the previously administered dose.  If a subject is assessed as requiring a 
dose delay of longer than 28 days from the planned date of administration, the subject 
will be withdrawn from the study. 
Treatment cycles for a subject for whom DS-8201a dosing is temporarily withheld for 
any reason may have future cycles scheduled based on the date of the last DS-8201a 
dose. 
All confirmed or suspected COVID-19 infection events must be recorded in the 
eCRF.  Please refer to Section 17.7  for additional information on dose modification.  
The dose modification schedule is presented in Table 5.2.   


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Table 5.2 
Dose or Schedule Modification for DS-8201a 
Worst toxicity NCI-
CTCAE version 4.03 
Grade (unless otherwise 
specified) 
Management Guidelines for DS-8201a 
No toxicity 
Maintain dose and schedule 
Infusion-Related Reaction  
See Section 3.2.5.1 for management of infusion-related reactions 
Hematologic Toxicity 
Neutrophil Count Decreased 
Grade 3 (<1.0× 109/L to 
0.5 × 109/L) 
Delay dose until resolved to ≤Grade 2, then maintain dose 
Grade 4 (<0.5 × 109/L) 
Delay dose until resolved to ≤Grade 2,  
Reduce dose by 1 level 
Febrile neutropenia (ANC 
<1 × 109/L, fever >38.3°C 
or a sustained temperature 
of ≥38°C for more than 
1 hour) 
Delay dose until resolved,  
Reduce dose by 1 level 
Lymphocyte Count Decreaseda 
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 from day of onset, maintain dose 
 
If resolved in >14 days from day of onset, reduce dose 1 level 
Anaemia 
Grade 3 (Hb <8.0 g/dL); 
transfusion indicated 
Delay dose until resolved to ≤Grade 2, then maintain dose 
Grade 4 Life threatening 
consequences; urgent 
intervention indicated 
Delay dose until resolved to ≤Grade 2, then reduce dose 1 level 
Platelet Count Decreased 
Grade 3  
(platelets <50 × 109/L to 
25 × 109/L) 
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 
Grade 4  
(platelets <25 × 109/L) 
Delay dose until resolved to ≤Grade 1, then reduce dose 1 level 
Cardiac Toxicity 
See Section 3.2.5.1 for management of cardiac toxicities 
Ocular 
Grade 3 
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 
Grade 4 
Discontinue subject from study treatment 
Pulmonary Toxicity 
Please see Section 3.2.5.2  for management of pulmonary toxicity  
Blood creatinine increased 
Grade 3 (>3.0 to 6.0 ×ULN) 
Delay dose until resolved to ≤Grade 2 or Baseline, then reduce dose 
1 level 
Grade 4 (>6.0 × ULN) 
Discontinue subject from study treatment 
 


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Hepatic Toxicity 
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) with Simultaneous 
total Bilirubin (TBL) 
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 the 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 Aminotransferase (AST) or alanine Aminotransferase (ALT) 
Grade 2 (>3.0 to 5.0 × ULN 
) 
No action for Grade 2 AST/ALT 
Grade 3 : >5.0 to 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 
if baseline ≤ 3 x ULN, otherwise delay dose until resolved to ≤ 
baseline, 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 to 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 (TBL) 
Grade 2 (>1.5 to 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 to 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 
Blood Alkaline Phosphatase (ALP) Increased 
Grade 3 or 4 (>5.0 × ULN)  
No modification unless determined by the Investigator to be 
clinically significant or life-threatening. 
Gastrointestinal 
Nausea 
Grade 3 
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 
Diarrhea/Colitis 
Grade 3 
Delay dose until resolved to ≤Grade 1 


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 
If resolved in ≤3 days from day of onset, maintain dose 
 
If resolved in >3 days from day of onset, 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 from day of onset, maintain dose 
 
If resolved in >7 days from day of onset, 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 from day of onset, maintain dose 
 
If resolved in >7 days from day of onset, reduce dose 1 level  
Grade 4 
Discontinue subject from study treatment 
Troponin 
Grade 1 (Levels above the 
ULN 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. 
 
For new diagnosed grade 1, repeat troponin testing at 3 hours (± 1 
hour) after initial troponin test.  
 
If levels at 3 hours (6 hours post-infusion) rises significantly per 
institutional guidelines,  
 
Perform ECG in triplicate; 
 
Repeat troponin testing at 6 hours (± 1 hour) 
 
Follow institutional guidelines for management of 
detectable troponin testing. 
 
If levels at 3 hours (± 1 hour) does not rise significantly per 
institutional guidelines, 
 
Repeat troponin testing at 6 hours (± 1 hour) or at 24 hours 
(± 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 (± 1 hour) and 12 hours (± 1 hour) 
after initial troponin test. 
Follow institutional guidelines for management of detectable 
troponin testing. If AMI confirmed, discontinue subject from study 
therapy. 
Otherwise, 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. 
ALT = alanine aminotransferase, AST = aspartate aminotransferase, NCI-CTCAE = National Cancer 
Institute Common Terminology Criteria for Adverse Events, ECG = electrocardiogram, Hb = 
hemoglobin, TBL = total bilirubin, ULN = upper limit of normal 
a. There will be no dose modifications for Grade 1 to Grade 3 lymphopenia.  All dose modifications 
should be based on the worst preceding toxicity. 


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In addition, investigators may consider dose reductions or discontinuations of the 
study drug according to the subject’s condition and after discussion with the Daiichi 
Sankyo’s Medical Monitor or designee. 
5.5. 
Method of Assessing Treatment Compliance 
All doses of the study drug will be administered by the Investigator or other 
designated study personnel.  Therefore, treatment compliance will be guaranteed as 
long as the subject attends each visit for the administration of study drug. Start and 
stop date/time of injection, amount of drug administered, and reason for change or 
interruption (if applicable) must be recorded in medical record by clinical study 
personnel.  These data will be recorded in the electronic case report form (eCRF). 
5.6. 
Prior and Concomitant Medications 
Medications used from the time the subject signs the ICF to Follow-up (F/U) (+7 
days) will be recorded.  All concomitant medications will be recorded in the eCRF. 
5.6.1. 
Prohibited Concomitant Medications/Activities 
With the exception of medications that are under investigation in the study (e.g. 
standard of care, comparators, or combination therapies), the following medications 
and products are prohibited during this study.  The Sponsor must be notified if a 
patient receives any of these during the study. 
 
Other anticancer therapy, including cytotoxics, targeted agents, 
immunotherapy, antibody, retinoid or hormonal therapy.  Concurrent use of 
hormones for no cancer-related conditions (e.g. insulin for diabetes and 
hormone replacement therapy) is acceptable. 
 
Other investigational 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 except for managing AEs; (inhaled steroids 
and 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. 
 
Concomitant treatment with chloroquine or hydroxychloroquine is not 
allowed during the study treatment. Refer to Section 17.7 for further details. 
Permitted Therapies/Products 
1. Hematopoietic growth factors may be used for prophylaxis or treatment based 
on the clinical judgment of the Investigator.  


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2. Concomitant use of dietary supplements, medications not prescribed by the 
Investigator, and alternative/complementary treatments is discouraged, but not 
prohibited. 
3. Prophylactic or supportive treatment of study-drug induced AEs will be 
otherwise as per Investigator’s discretion and institutional guidelines. 
4. Based on the currently available clinical safety data, it is recommended that 
patients receive prophylactic anti-emetic agents prior to infusion of T-DXd 
and on subsequent days. Antiemetics such as 5-hydroxytryptamine receptor 
(5-HT3) antagonists or Neurokinin-1 (NK1) receptor antagonists and/or 
steroids (e.g. dexamethasone) should be considered and administered in 
accordance with the prescribing information or institutional guidelines. 
5.6.2. 
Restricted products 
Use of e-cigarettes and vaping is strongly discouraged but not prohibited. 
5.6.3. 
Dietary and Lifestyle Restrictions 
The following food products are prohibited during this study: 
 
Foods containing Hypericum perforatum (Saint John's wort).  
5.7. 
Subject Withdrawal/Discontinuation 
5.7.1. 
Reasons for Withdrawal 
Any subject who discontinues from the study drug for any reason will have their 
study drug discontinuation recorded. 
The date of discontinuation of treatment (EOT) is defined as the date the Investigator 
decides to discontinue treatment. 
Subjects may be withdrawn from the study after signing informed consent for the 
following reasons: 
 PD (per RECIST) 
 Clinical Progression (provide date) 
 AE 
 Death 
 Withdrawal by subject  
 Lost to F/U 
 Protocol violation (specify) 
 Physician Decision 
 Pregnancy 
 Study terminated by the Sponsor 
 Other, specify (eg, discretion of the Investigator) 


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If a subject withdraws from the study, 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 due to an AE, the Investigator will follow the subject until 
the AE has resolved or stabilized as possible. 
All subjects who are withdrawn from the study and received study drug should 
complete the protocol specified withdrawal procedures (Section 5.7.2). 
5.7.2. 
Withdrawal Procedures 
Protocol-specified withdrawal procedures will involve an EOT visit and a F/U visit 40 
days after the last administration of DS-8201a.  Protocol-specified withdrawal 
procedures are the same as those to be performed at the EOT visit and the F/U visit 
(Sections 6.4 and 6.5). 
5.7.3. 
Subject Replacement 
Subject replacement is not allowed in this study. 
5.7.4. 
Subject Re-screening Procedures 
Please refer to Section 4.4. 


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6. 
STUDY PROCEDURES 
A study visit schedule (Schedule of Events) is provided in Section 17.6 (Table 17.3).  
All assessments will be performed at time points specified in the schedule of events. 
6.1. 
Screening 
Obtain of a signed and dated ICF before any study-related procedures or assessments 
are conducted.  In this study, registration process will be followed as per 
Section 5.1.3. 
The following activities and/or assessments will be performed during the screening 
period: 
 Check eligibility criteria 
Before registration 
 Assign a subject number. 
 Record demographic (eg, birth date, sex, race, ethnicity), primary cancer 
history, significant medical history and prior cancer treatment history. 
 Record historical HER2 status. 
 Review eligibility criteria. 
 Assess subjects for AEs. 
Within 90 days before registration 
 Perform a HIV antibody test (as required by local regulations or IRB/ECs). 
Within 28 days before registration  
 Perform either ECHO or MUGA to measure LVEF. 
 Perform tumor assessment by CT or magnetic resonance imaging (MRI) 
scans of the brain, chest, abdomen, pelvis, and any other sites of disease 
(Section 17.4). 
 Perform ophthalmologic examinations: the assessments will include visual 
acuity testing, slit lamp examination, and fundoscopy. 
Within 7 days before registration 
 Perform a complete physical examination and record the subject’s height and 
weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure and 
pulse rate, respiratory rate and body temperature). 
 Assess functional status using the ECOG PS scale (Section 17.3). 
 Obtain blood samples for clinical laboratories (Section 8.8), prothrombin 
time and activated partial thromboplastin time, and troponin (preferably 
troponin-T) testing by study site. 
 Obtain a serum or urine sample for pregnancy testing in women of 
childbearing potential.  For postmenopausal subjects (no childbearing 
potential, as indicated by an elapse of at least 12 months after the last 


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menstruation) or female subjects who have no possibility of pregnancy due to 
sterilization surgery, etc., no pregnancy test will be required.  Female 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 child-bearing potential and required to undergo the pregnancy test. 
 Obtain urine samples for other urinalysis (Section 8.8). 
 Perform a 12-lead ECG in triplicate. 
6.2. 
Randomization 
Not applicable. 
6.3. 
Treatment Period 
In consideration of the subject’s safety, the subjects will be hospitalized as required 
during the study to allow careful safety monitoring, at the Investigator’s discretion.   
Additional safety assessments should be conducted as needed, at the Investigator’s 
discretion. 
6.3.1. 
Tumor Assessment 
The same imaging tumor assessment as at Screening by CT or MRI scans will be 
performed every 6 weeks (± 7 days) in the first 24 weeks after Day 1 of Cycle 1 and 
thereafter every 12 weeks (± 7 days) regardless of a delay in dosing.  The assessment 
will be conducted before Day 1 of each Cycle if possible.  CT or MRI (spiral CT or 
MRI with ≤5 mm cuts) of the brain, chest, abdomen, and pelvis and other areas of 
disease should be used for tumor assessments unless another modality of disease 
assessment is necessary for the lesions at Screening.  Every effort should be made to 
use the same assessment modality for all assessments for each subject, and 
confirmatory scan are required for responding patients.  However, if there is no brain 
metastasis at Screening, CT or MRI should only be done when symptoms associated 
with brain metastasis occur during study period.  If no clinical symptoms are 
observed, brain CT or MRI is not mandatory during study period (Section 17.4). 
Detailed instructions for the handling of images are included in a separate document. 
6.3.2. 
Cycle 1, Day 1 
6.3.2.1. 
Before Infusion 
The following procedures will be completed at predose on Day 1; 
 Assess subjects for AEs. 
 Record concomitant medications. 
Within 3 days before the first dose of the study drug 
 Perform a 12-lead ECG in triplicate.  ECGs will be taken in close succession, 
a few minutes apart, after being in a supine/semi-recumbent position for 
5 minutes. 
Within 8 hours before administration 
 Obtain PK blood sampling (Section 7.1.1). 


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 Obtain blood sampling for ADA (Section 7.4.1). 
Latest data within 3 days before administration: If assessments at Screening are 
performed within this period, they can be considered to be Day 1 data and there is 
no need to repeat them: 
 Perform a complete physical examination and record the subject’s weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure and 
pulse rate, respiratory rate, body temperature and SpO2). 
 Assess functional status using the ECOG PS scale (Section 17.3). 
 Obtain blood samples for clinical laboratories (Section 8.8). 
6.3.2.2. 
Administration and After Infusion 
 Administer DS-8201a as per Section 5.2.4. 
The following procedures will be completed postdose on Day 1: 
 Obtain vital sign measurements (systolic and diastolic blood pressure and 
pulse rate, respiratory rate and body temperature). 
 Perform a 12-lead ECG in triplicate within 30 minutes after end of infusion 
(EOI), and 2 hours to 4 hours after the start of administration. 
 Obtain PK blood samples at the following time points: within 15 minutes after 
EOI, 2 hours, 4 hours, and 7 hours (± 15 minutes) after the start of 
administration (Section 7.1.1). 
 Collect blood samples for troponin (preferably high-sensitivity troponin-T) 2 
hours to 3 hours after EOI. 
- 
If troponin levels are consistent with myocardial infarction as defined 
according to manufacturer (NCI-CTCAE Grade 3), perform ECG testing 
in triplicate, repeat troponin testing 6 hours (± 1 hour) and 12 hours (± 1 
hour) after initial troponin test was drawn, and follow institutional 
guidelines.       
- 
If troponin levels are above the ULN and below the level of myocardial 
infarction as defined by the manufacturer (NCI-CTCAE Grade 1), repeat 
troponin testing at 3 hours (± 1 hour) after initial troponin test was drawn. 
If troponin level at 3 hours (6 hours post-infusion): 
o Significantly increases per institutional guidelines, then repeat 
troponin testing at 6 hours (± 1 hour) and follow institutional 
guidelines. 
o Otherwise, repeat troponin testing at 6 hours (± 1 hour) or at 24 
hours (± 2 hours) after initial troponin test. 
- 
If troponin levels are above the ULN 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. 
 Record concomitant medications. 


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 Assess subjects for AEs. 
6.3.3. 
Cycle 1, Day 2 
The following procedures will be performed on Day 2: 
 Obtain vital sign measurements (systolic and diastolic blood pressure and 
pulse rate, respiratory rate and body temperature). 
 Obtain blood samples for clinical laboratories (Section 8.8). 
 Obtain PK blood samples at the 24 hours (± 2 hours) after the start of Day 1 
administration (Section 7.1.1). 
 Perform a 12-lead ECG in triplicate. 
 Record concomitant medications. 
 Assess subjects for AEs. 
6.3.4. 
Cycle 1, Day 4 
The following procedures will be performed on Day 4: 
 Obtain vital sign measurements (systolic and diastolic blood pressure and 
pulse rate, respiratory rate and body temperature). 
 Obtain PK blood samples at the 72 hours (± 2 hours) after the start of Day 1 
administration (Section 7.1.1). 
 Record concomitant medications. 
 Assess subjects for AEs.  
6.3.5. 
Cycle 1, Day 8 
The following procedures will be performed on Day 8 (± 1 day): 
 Obtain vital sign measurements (systolic and diastolic blood pressure and 
pulse rate, respiratory rate and body temperature). 
 Obtain blood samples for clinical laboratories (Section 8.8). 
 Obtain PK blood samples (Section 7.1.1). 
 Obtain a blood samples for ADA (Section 7.4.1). 
 Perform a 12-lead ECG in triplicate. 
 Record concomitant medications. 
 Assess subjects for AEs.  
6.3.6. 
Cycle 1, Day 15 
The following procedures will be performed on Day 15 (± 1 day): 
 Obtain vital sign measurements (systolic and diastolic blood pressure and 
pulse rate, respiratory rate and body temperature). 
 Obtain blood samples for clinical laboratories (Section 8.8). 
 Obtain PK blood samples (Section 7.1.1). 


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 Perform a 12-lead ECG in triplicate. 
 Record concomitant medications. 
 Assess subjects for AEs. 
6.3.7. 
Cycle 1, Day 22 
If Day 1 of the next cycle is delayed for 3 days or more, or if the subject cannot 
continue into the next cycle, the following procedures will be performed on Day 22 
(± 2 days): 
 Obtain PK blood samples (Section 7.1.1)  
 Record concomitant medications. 
 Assess subjects for AEs. 
6.3.8. 
Cycle 2, Day 1 
6.3.8.1. 
Before Infusion 
The following procedures will be completed at predose on Day 1: 
 Record concomitant medications. 
 Assess subjects for AEs. 
Within 8 hours before administration 
 
Obtain PK blood samples (Section 7.1.1). If blood sample is collected on 
Day 22 of Cycle 1, the blood sample will be collected before infusion (BI) 
on Day 1 of Cycle 2, if possible. 
 Obtain a blood samples for ADA (Section 7.4.1). 
Within 3 days before administration 
 Ophthalmologic assessments: The assessments will include visual acuity 
testing, slit lamp examination, and fundoscopy.  If the planned date of study 
drug administration is delayed after examination of ophthalmologic 
assessments, and there are no abnormal findings on the examination, 
ophthalmologic assessments may not be repeated at the Investigator’s 
judgment. 
 Perform a complete physical examination and record the subject’s weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure and 
pulse rate, respiratory rate, body temperature and SpO2). 
 Assess functional status using the ECOG PS scale (Section 17.3). 
 Obtain blood samples for clinical laboratories (Section 8.8). 
 Perform either ECHO or MUGA to measure LVEF.  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, ECHO or MUGA 
may not be repeated at the Investigator’s judgment. 
 Perform a 12-lead ECG in triplicate. 


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6.3.8.2. 
Administration and After Infusion 
 Administer DS-8201a per Section 5.2.4. 
The following procedures will be completed postdose on Day 1: 
 Obtain vital sign measurements (systolic and diastolic blood pressure and 
pulse rate, respiratory rate and body temperature). 
 Obtain PK blood samples within 15 minutes after EOI (Section 7.1.1). 
 Perform a 12-lead ECG in triplicate. 
 Collect blood samples for troponin (preferably high-sensitivity troponin-T) 2 
hours to 3 hours after EOI. 
- 
If troponin levels are consistent with myocardial infarction as defined 
according to manufacturer (NCI-CTCAE Grade 3), perform ECG testing 
in triplicate, repeat troponin testing 6 hours (± 1 hour) and 12 hours (± 1 
hour) after initial troponin test was drawn, and follow institutional 
guidelines.       
- 
If troponin levels are above the ULN and below the level of myocardial 
infarction as defined by the manufacturer (NCI-CTCAE Grade 1), repeat 
troponin testing at 3 hours (± 1 hour) after initial troponin test was drawn. 
If troponin level at 3 hours (6 hours post-infusion): 
o Significantly increases per institutional guidelines, then repeat 
troponin testing at 6 hours (± 1 hour) and follow institutional 
guidelines. 
o Otherwise, repeat troponin testing at 6 hours (± 1 hour) or at 24 
hours (± 2 hours) after initial troponin test. 
- 
If troponin levels are above the ULN 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. 
 Record concomitant medications. 
 Assess subjects for AEs. 
6.3.9. 
Cycle 2, Day 8 and Day 15 
The following procedures will be performed on Day 8 (± 2 days) and Day 15 
(± 2 days): 
 Obtain vital sign measurements (systolic and diastolic blood pressure and 
pulse rate, respiratory rate and body temperature). 
 Obtain blood samples for clinical laboratories (Section 8.8). 
 Record concomitant medications. 
 Assess subjects for AEs. 


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6.3.10. 
Cycle 2, Day 22 
If Day 1 of the next cycle is delayed for 3 days or more, or if the subject cannot 
continue into the next cycle, the following procedures will be performed on Day 22 
(± 2 days): 
 Obtain PK blood samples (Section 7.1.1). 
 Record concomitant medications. 
 Assess subjects for AEs. 
6.3.11. 
Cycle 3, Day 1 
6.3.11.1. Before Infusion 
The following procedures will be completed predose on Day 1: 
 Record concomitant medications. 
 Assess subjects for AEs. 
Within 8 hours before administration 
 Obtain PK blood samples (Section 7.1.1). 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 if 
possible. 
Within 3 days before administration 
 Perform a complete physical examination and record the subject’s weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure and 
pulse rate, respiratory rate, body temperature and SpO2). 
 Assess functional status using the ECOG PS scale (Section 17.3). 
 Obtain blood samples for clinical laboratories (Section 8.8). 
 Perform either ECHO or MUGA to measure LVEF.  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, ECHO or MUGA 
may not be repeated at the Investigator’s judgment. 
 Perform a 12-lead ECG in triplicate. 
6.3.11.2. Administration and After Infusion 
 Administer DS-8201a per Section 5.2.4. 
The following procedures will be completed postdose on Day 1: 
 Obtain vital sign measurements (systolic and diastolic blood pressure and 
pulse rate, respiratory rate and body temperature). 
 Obtain PK blood samples at the following time points: within 15 minutes after 
EOI, 2 hours, 4 hours and 7 hours (± 15 minutes) after the start of 
administration (Section 7.1.1). 
 Collect blood samples for troponin (preferably high-sensitivity troponin-T) 2 
hours to 3 hours after EOI. 


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- 
If troponin levels are consistent with myocardial infarction as defined 
according to manufacturer (NCI-CTCAE Grade 3), perform ECG testing 
in triplicate, repeat troponin testing 6 hours (± 1 hour) and 12 hours (± 1 
hour) after initial troponin test was drawn, and follow institutional 
guidelines.       
- 
If troponin levels are above the ULN and below the level of myocardial 
infarction as defined by the manufacturer (NCI-CTCAE Grade 1), repeat 
troponin testing at 3 hours (± 1 hour) after initial troponin test was drawn. 
If troponin level at 3 hours (6 hours post-infusion): 
o Significantly increases per institutional guidelines, then repeat 
troponin testing at 6 hours (± 1 hour) and follow institutional 
guidelines. 
o Otherwise, repeat troponin testing at 6 hours (± 1 hour) or at 24 
hours (± 2 hours) after initial troponin test. 
- 
If troponin levels are above the ULN 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. 
 Record concomitant medications. 
 Assess subjects for AEs. 
6.3.12. 
Cycle 3, Day 2 and Day 4 
The following procedures will be performed on Day 2 and Day 4. 
 Obtain PK blood samples (Section 7.1.1). 
 Record concomitant medications. 
 Assess subjects for AEs. 
6.3.13. 
Cycle 3, Day 8 and Day 15 
The following procedures will be performed on Day 8 (± 2 days) and Day 15 
(± 2 days): 
 Obtain vital sign measurements (systolic and diastolic blood pressure and 
pulse rate, respiratory rate and body temperature). 
 Obtain blood samples for clinical laboratories (Section 8.8). 
 Obtain PK blood samples (Section 7.1.1). 
 Record concomitant medications. 
 Assess subjects for AEs. 
6.3.14. 
Cycle 3, Day 22 
If Day 1 of the next cycle is delayed for 3 days or more, or if the subject cannot 
continue into the next cycle, the following procedures will be performed on Day 22 
(± 2 days): 
 Obtain PK blood samples (Section 7.1.1). 


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 Record concomitant medications. 
 Assess subjects for AEs. 
6.3.15. 
Cycle 4 and All Subsequent Cycles, Day 1 
6.3.15.1. Before Infusion 
The following procedures will be completed predose on Day 1: 
 Record concomitant medications. 
 Assess subjects for AEs. 
 Obtain a serum or urine sample for pregnancy testing in women of 
childbearing potential.  For postmenopausal subjects (no childbearing 
potential, as indicated by an elapse of at least 12 months after the last 
menstruation) or female subjects who have no possibility of pregnancy due to 
sterilization surgery, etc., no pregnancy test will be required.  Female 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 child-bearing potential and required to undergo the pregnancy test. 
Within 8 hours before administration 
On Day 1 in Cycle 4, 6, and 8 
 Obtain PK blood samples (Section 7.1.1). 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 if 
possible. 
On Day 1 every 2 cycles from Cycle 4 to the EOT (eg, Day 1 in Cycle 4, 6, 8, 10, 
and so on) 
 Obtain a blood samples for ADA (Section 7.4.1).  A portion of ADA 
blood sample from each subject who provides consent will be used for 
future central lab analysis for SARS-CoV-2 testing once protocol version 
5.0 is applied for a subject. SARS-CoV-2 testing will be conducted every 
4 cycles from Cycle 4 (Cycle 4, Cycle 8 etc.). 
Within 3 days before administration 
 Perform a complete physical examination and record the subject’s weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure and 
pulse rate, respiratory rate, body temperature and SpO2). 
 Assess functional status using the ECOG PS scale (Section 17.3). 
 Obtain blood samples for clinical laboratories (Section 8.8). 
 Perform a 12-lead ECG in triplicate. 
On Day 1 every 2 cycles from Cycle 3 to the EOT (eg, Day 1 in Cycle 3, 5, 7, 9, 
11, and so on) 
 Perform either ECHO or MUGA to measure LVEF.  If the planned date of 
study drug administration is delayed after examination of ECHO or MUGA, 


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and there are no abnormal findings on the examination, ECHO or MUGA 
may not be repeated at the Investigator’s judgment. 
On Day 1 every 4 cycles from Cycle 2 to the EOT (eg, Day 1 in Cycle 2, 6, 10, 14, 
and so on) 
 
6.3.15.2. Administration and After Infusion 
 Administer DS-8201a per Section 5.2.4. 
The following procedures will be completed postdose on Day 1: 
 Record concomitant medications. 
 Assess subjects for AEs. 
After Cycle 4 at every 2 cycles until Cycle 8 at the maximum (ie, Day 1 of cycle 
4, 6, and 8) 
 Obtain PK blood samples within 15 minutes after EOI (Section 7.1.1). 
6.4. 
End of Treatment 
The date of discontinuation of treatment (EOT) is defined as the date the Investigator 
decides to discontinue treatment.  The following assessments will be performed at the 
EOT visit (within 7 days after the date of discontinuation).   
 Ophthalmologic assessments: the assessments will include visual acuity 
testing, slit lamp examination, and fundoscopy. 
 Perform a complete physical examination and record the subject’s weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure and 
pulse rate, respiratory rate, body temperature and SpO2). 
 Assess functional status using the ECOG PS scale (Section 17.3). 
 Obtain blood samples for clinical laboratories (Section 8.8) and ADA 
(Section 7.4.1).  A portion of ADA blood sample from each subject who 
provides consent will be used for future central lab analysis for SARS-
CoV-2 testing once protocol version 5.0 is applied for a subject. SARS-
CoV-2 testing will be conducted every 4 cycles from Cycle 4 (Cycle 4, 
Cycle 8 etc.). 
 Obtain a serum or urine sample for pregnancy testing in women of 
childbearing potential.  For postmenopausal subjects (no childbearing 
potential, as indicated by an elapse of at least 12 months after the last 
menstruation) or female subjects who have no possibility of pregnancy due to 
sterilization surgery, etc., no pregnancy test will be required.  Female 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 child-bearing potential and required to undergo the pregnancy test. 
 Perform a 12-lead ECG in triplicate. 
 Perform either ECHO or MUGA to measure LVEF. 


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 Perform same imaging tumor assessment as at Screening by CT or MRI scans.  
CT or MRI (spiral CT or MRI with ≤5 mm cuts) of the brain, chest, abdomen, 
and pelvis should be used for tumor assessments unless another modality of 
disease assessment is necessary for the lesions at Screening.  Every effort 
should be made to use the same assessment modality for all assessments for 
each subject.  However, if there is no brain metastasis at Screening, CT or 
MRI should only be done when symptoms associated with brain metastasis 
occur during study period.  If no clinical symptoms are observed, brain CT or 
MRI is not mandatory during study period (Section 17.4).  If progression is 
identified in a prior examination, only the chest is examined by CT to monitor 
the pulmonary status. 
 Record concomitant medications. 
 Assess subjects for AEs. 
 Record reason for treatment discontinuation. 
6.5. 
Follow-up 
The F/U visit should occur 40 days (+ 7 days) days after the last administration of 
DS-8201a.  If the subject begins another anticancer therapy before the end of the 
40 days (+ 7 days), every effort will be made to complete all the F/U assessments 
prior to commencing the new therapy.  In case of unresolved AEs, including 
significant abnormal clinical laboratory values at the end of study assessment, these 
events will be followed until resolution or until they become clinically not relevant.  If 
assessments at EOT or treatment period are performed within this period, they can be 
considered to be the F/U data and there is no need to repeat them.  If discontinuation 
of treatment is decided later than 40 days after the last administration of DS-8201a, 
there is no need to perform the F/U assessments. 
The following information will be collected at this F/U visit: 
 Obtain vital sign measurements (systolic and diastolic blood pressure and 
pulse rate, respiratory rate and body temperature). 
 Perform a complete physical examination and record the subject’s weight. 
 Assess functional status using the ECOG PS scale (Section 17.3). 
 Obtain blood samples for clinical laboratories (Section 8.8) and ADA 
(Section 7.4.1).  For subjects with positive ADA at F/U visit, additional 
serum ADA samples may be collected every 3 months (± 1 month) up to 
1 year from the last dose of study drug, or if the ADA becomes negative, 
or if ADA titer becomes less than Baseline (applicable when pre-existing 
ADA is observed), or if the subject starts another therapy for cancer, or 
withdraws consent from the study, whichever occurs first.  A portion of 
ADA blood sample from each subject who provides consent will be used 
for future central lab analysis for SARS-CoV-2 testing once protocol 
version 5.0 is applied for a subject. SARS-CoV-2 testing will be conducted 
every 4 cycles from Cycle 4 (Cycle 4, Cycle 8 etc.). 
 Obtain a serum or urine sample for pregnancy testing in women of 
childbearing potential.  For postmenopausal subjects (no childbearing 
potential, as indicated by an elapse of at least 12 months after the last 


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menstruation) or female subjects who have no possibility of pregnancy due to 
sterilization surgery, etc., no pregnancy test will be required.  Female 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 child-bearing potential and required to undergo the pregnancy test. 
 Obtain SpO2. 
 Record concomitant medications. 
 Assess subjects for AEs. 
6.6. 
New Cancer Treatment and Survival Follow-up 
Not Applicable. 


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7. 
PHARMACOKINETIC/PHARMACODYNAMIC 
ASSESSMENTS 
7.1. 
Pharmacokinetic Assessments 
The PK sampling will be performed at time points indicated in Section 7.1.1. 
Detailed instructions on collection, processing, handling, storage, and sample 
shipment are described in the separate Laboratory Manual. 
7.1.1. 
Serum Sampling 
Blood samples for PK will be collected into blood sampling tubes supplied by the 
Sponsor.  The collected blood will be centrifuged to separate the serum.  The serum 
samples will be shipped to a central laboratory. 
Instructions for the handling and shipping of serum samples are included in a separate 
document (eg, laboratory manual) 
Blood samples of approximately 7 mL for PK analyses will be collected at the time 
points specified in Section 17.6 and tabulated in Table 7.1. 
The actual time of study drug administration (start and EOI) and the exact time of 
blood sampling must be recorded in source document and the eCRF.  Any delays or 
interruptions in the infusion of dose should also be recorded. 
Table 7.1: 
Pharmacokinetic Sampling Time Points 
Cycle  
Day 
Sampling Time Point (Acceptable Range)  
Cycle 1 and 
Cycle 3 
Day 1 
Predose (within 8 hours of BI) 
EOI (within 15 minutes after dose administration) 
2 hours after start of administration (± 15 minutes) 
4 hours after start of administration (± 15 minutes) 
7 hours after start of administration (± 15 minutes) 
 
Day 2 
24 hours after start of administration (± 2 hours) 
 
Day 4 
72 hours after start of administration (± 2 hours) 
 
Day 8 
168 hours after start of administration (± 1 day) 
 
Day 15 
336 hours after start of administration (± 1 day) 
 
Day 22 
504 hours after start of administration (± 2 days), collect 
only if the next cycle is delayed by 3 or more days, 
including if the subject cannot continue onto the next cycle, 
collect blood sample 21 days after the start of administration 
Cycle 2, 
Cycle 4, 
Cycle 6, and 
Cycle 8 
Day 1 
Predose (within 8 hours of BI) 
EOI (within 15 minutes after EOI) 
 
Day 22 
 
504 hours after start of administration (± 2 days), collect 
only if the next cycle is delayed by 3 or more days, 
including if the subject cannot continue onto the next cycle, 
collect blood sample 21 days after the start of administration 
BI = before infusion; EOI = end of infusion 
In case of chloroquine or hydroxychloroquine administration for SARS-CoV-2 
infection, additional PK serum samples should be collected at the time points 
specified in Table 7.2. 


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Table 7.2: 
Schedule of PK Sample Collection for Subjects Administered 
Chloroquine or Hydroxychloroquine 
Day of CQ or HCQ Administration 
Sampling Time Point (Acceptable 
Ranges) 
Day 1 
Prior to CQ/HCQ dose 
Day 3 or Day 4 
Prior to CQ/HCQ dose (within 4 hrs) 
End of CQ or HCQ treatment 
Prior to CQ/HCQ dose (within 4 hrs) 
Prior to resumption of DS-8201a (after 
CQ/HCQ wash-out period)a 
Before infusion of study treament 
(within 8 hrs) 
CQ = chloroquine; HCQ = hydroxychloroquine.  
a Washout period of no less than 14 days is required before resumption of DS-8201a. 
7.2. 
Pharmacodynamic Assessment(s) 
Not applicable. 
7.3. 
Biomarker and Exploratory Assessment(s) 
Not applicable. 
7.4. 
Immunogenicity 
7.4.1. 
Anti-Drug Antibodies 
Blood samples for ADA analyses of approximately 4 mL will be collected at the time 
points specified in Table 7.3. Serum concentrations of DS-8201a and/or total 
anti-HER2 antibody may be measured using the same ADA samples for the purpose 
of ADA assessment.  
Instructions for the handling and shipping of serum samples are included in a separate 
document (eg, laboratory manual). 
Table 7.3: 
ADA Sampling Time Points 
Cycle 
Day 
Sampling Time Point (Acceptable Range) 
Cycle 1 
Day 1 
BI (within 8 hours before administration)  
Day 8 
± 1 day 
Cycle 2 
Day 1 
BI (within 8 hours before administration) 
After Cycle 4 at every 2 
cycles (eg, Cycle 4, 6, 8, 10, 
12, and so on) 
Day 1 
BI (within 8 hours before administration) 
EOT 
- 
The date investigator decides the 
discontinuation of the study drug (+ 7 days).   
F/U* 
- 
40 days (+7 days) after the last study drug 
administration or until starting new 
anticancer treatment, whichever comes first. 
BI = before infusion; EOT = end of treatment; F/U = follow-up; ADA = anti-drug antibodies; 


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* For subjects with positive ADA at F/U visit, additional serum ADA samples may be collected every 
3 months (± 1 month) up to 1 year from the last dose of study drug, or if the ADA becomes negative, or 
if ADA titer becomes less than Baseline (applicable when pre-existing ADA is observed), or if the 
subject starts another therapy for cancer, or withdraws consent from the study, whichever occurs first. 
7.4.2. 
SARS-CoV-2 Serum samples collection 
Portion of ADA blood sample from each subject who provides consent will be used 
for future central lab analysis for SARS-CoV-2 testing once protocol version 5.0 is 
applied for a subject. Samples will be sent to the central laboratory and stored until 
the tests will become available. 
7.5. 
Pharmacogenomic Analysis 
Not applicable. 


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8. 
SAFETY EVALUATION AND REPORTING 
8.1. 
Assessment of Safety Endpoint Event(s) 
Safety endpoints will include SAEs, TEAEs, AEs and AESIs leading to 
discontinuation, physical examination findings (including ECOG PS), vital sign 
measurements, standard clinical laboratory parameters, ECG parameters, ECHO or 
MUGA findings, and ophthalmologic assessments.  TEAEs will be graded according 
to the NCI-CCAE version 4.03. 
8.2. 
Adverse Event Collection and Reporting 
All clinical AEs occurring after the subject signs the ICF and up to the F/U visit after 
the last dose of study drug (ie, the F/U period) defined as 40 + 7 days, whether 
observed by the Investigator or reported by the subject, will be recorded on the AE 
Case Report Form (CRF) page.  Medical conditions (including clinical 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 and SAEs are to be reported according to the procedures in Section 8.5. 
All clinical laboratory results, vital sign measurements, and ECG results should be 
assessed by the Investigator to determine their clinical significance.  Isolated 
abnormal clinical laboratory results, vital signs, 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 time point, the Investigator will determine whether any AEs have occurred by 
evaluating the subject.  AEs may be directly observed, reported spontaneously by the 
subject or by questioning the subject at each time point.  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 8.4.  The Investigator’s 
assessment must be clearly documented in the study 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 8.4.2 for Definitions). 
For deaths, the underlying or immediate cause of death should always be reported as 
an SAE. 


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PD 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, “Progressive 
disease” should be reported as an SAE.  In addition, any serious, untoward event that 
may occur subsequent to the reporting period that the Investigator assesses as related 
to the study drug should also be reported and managed as an SAE.  The Investigator 
should follow subjects with AEs until the event has resolved or the condition has 
stabilized.  In case of unresolved AEs, including significant abnormal clinical 
laboratory values at the end of study assessment, these events will be followed until 
resolution or until they become clinically not relevant. 
8.3. 
Adverse Events of Special Interest 
For the DS-8201a clinical program, based on the available pre-clinical data, review of 
the cumulative literature, reported toxicities for the same class of agents and 
biological plausibility, ILD and LVEF decreases are considered to be AESI.  
Additional relevant information regarding the AESIs 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. 
For broad surveillance of LVEF decrease, relevant AEs under the MedDRA SMQs of 
Cardiac Failure is included for enhanced data collection; additional data for these AEs 
are collected via TQs of heart failure.  
For broad surveillance of ILD, selected 42 Preferred Terms (PTs) [all from the ILD 
Standard MedDRA Query (SMQ)] plus 2 PTs of acute respiratory failure and 
respiratory failure are included for enhanced data collections. 
Please refer to Section 3.2.5 for management of AESIs in this study. 
8.3.1. 
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 
collection will cover a more in-depth relevant medical history (eg smoking, radiation, 
COPD and other chronic lung conditions), diagnostic evaluation, treatment and 
outcome of the event. This data collection will be triggered for adverse events 
reported using selected 42 Preferred Terms [all from the ILD Standard MedDRA 
Query (SMQ)] plus 2 PTs of acute respiratory failure and respiratory failure. 
8.4. 
Adverse Event 
8.4.1. 
Definition of Adverse Event 
An AE is any untoward medical occurrence in a subject 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 clinical 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 
Council for Harmonisation [ICH] E2A Guideline.  Clinical Safety Data Management: 
Definitions and Standards for Expedited Reporting, Oct 1994). 


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It is the responsibility of investigators, based on their knowledge and experience, to 
determine those circumstances or abnormal clinical laboratory findings which should 
be considered AEs. 
8.4.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death, 
 Is life-threatening, 
 Requires inpatient 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 (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. 
8.4.3. 
Severity Assessment 
All AEs will be graded (1 to 5; see below) according to the 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 vs. 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).  This is not the same as "seriousness," which is based on 


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patient/event outcome at the time of the event.  For example, the NCI-CTCAE 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 based on the NCI-CTCAE grades may or may not be assessed as serious 
based on the seriousness criteria. 
8.4.4. 
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. 
 Unrelated: 
 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).  
8.4.5. 
Action Taken Regarding Study Drug(s) 
 Dose Not Changed: No change in study drug dosage was made. 
 Drug Withdrawn: The study product was permanently stopped. 
 Dose Reduced: The dosage of study product was reduced. 
 Drug Interrupted: The study product was temporarily stopped. 
 Not Applicable 
8.4.6. 
Other Action Taken for Event 
 None. 
 No treatment was required. 
 Medication required. 
 Prescription and/or OTC medication was required to treat the 
AE. 
 Hospitalization or prolongation of hospitalization required. 


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 Hospitalization was required or prolonged due to the AE, 
whether or not medication was required. 
 Other. 
8.4.7. 
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. 
 Recovered/Resolved with Sequelae 
 The residual effects of the AE are still present and observable. 
 Include sequelae/residual effects. 
 Not Recovered/Not Resolved 
 The AE itself is still present and observable. 
 Fatal 
 Fatal should be used when death is a direct outcome of the AE. 
 Unknown 
8.5. 
Serious Adverse Events Reporting-Procedure for 
Investigators 
All AEs, SAEs and AESIs, and medication errors including overdose will be reported 
in the eCRF. 
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 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.  A treatment-emergent adverse event 
(TEAE) is defined as an AE that occurs, having been absent before the first dose of 
study drug, or has worsened in severity or seriousness after the initiating the study 
drug until 47 days after last dose of the study drug.  SAEs with an onset or worsening 
48 days or more after the last dose of study drug, if considered related to the study 
treatment, are also TEAEs. 
 SAEs (see Section 8.4.2 for definition) 
 All potential ILD cases should be reported within 24 hours; including both 
serious and non-serious potential ILD cases (potential ILD is defined by the 
Event Adjudication Site Manual List of PTs). 


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 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 either at different time points or 
simultaneously during the study conduct. A targeted questionnaire is in-built 
within the eCRF to collect relevant additional information for these potential 
cases. 
 Overdose, defined as the accidental or intentional administration of any dose 
of a product that is considered both excessive and medically important. An 
“excessive and medically important” overdose includes any overdose in which 
either a serious adverse event, a non-serious adverse event, or no adverse 
event occurs and is considered by the Investigator as clinically relevant, i.e. 
poses an actual or potential risk to the subject. 
Overdose is always serious. By definition an overdose is medically important, which 
meets the seriousness criterion of important medical event. An overdose can occur 
with or without an AE. AEs can either be serious or non-serious. Details of the 
overdose including trastuzumab deruxtecan dosage, clinical course, associated AEs, 
and outcome must be captured in the Narrative form of the CRF within eDC.Disease 
progression/worsening of primary cancer (gastric, gastroesophageal junction [GEJ] 
adenocarcinoma, or breast cancer) will not be recorded as an AE on the Adverse 
Event eCRF.  However, events associated with disease progression may be recorded 
as AEs. 
Death due to disease progression should be recorded on the Death eCRF. 
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 site and should not 
be submitted to the Sponsor for SAE reporting purposes. 
Urgent safety queries must be followed up and addressed promptly.  F/U information 
and response to non-urgent safety queries should be combined for reporting to 
provide the most complete data possible within each F/U. 
Please call the local SAE Hotline (see Study Manual) or your study monitor for any 
questions on SAE reporting.  
8.6. 
Notifying Regulatory Authorities, Investigators, and 
Institutional Review Board/Ethics Committee 
Daiichi Sankyo and/or CRO will inform Investigators, IRBs, and regulatory 
authorities of any Suspected Unexpected Serious Adverse Reactions (SUSARs) 
occurring in other sites as appropriate per local reporting requirements.  Daiichi 
Sankyo and/or CRO will comply with any additional local safety reporting 
requirements. 


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In Taiwan, upon receipt of the Sponsor’s notification of SUSARs, it is the 
Investigator’s responsibility to report all SUSARs to the IRB according to the 
reporting guideline of the IRB. 
8.7. 
 Exposure in Utero During Clinical Studies 
Daiichi Sankyo must be notified of any subject who becomes pregnant while 
receiving or within 4 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 or a partner of male subject 
using the Exposure in Utero (EIU) Reporting form, within 24 hours of learning of the 
pregnancy.  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 or partner 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 an SAE (ie, post-
partum complications, spontaneous or induced 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 8.5. 
8.8. 
Clinical Laboratory Evaluations 
Blood samples for laboratory evaluations will be collected according the time points 
indicated in the schedule of events (Table 17.3). 
Instructions for the handling and shipping of blood samples are included in a separate 
document (eg, laboratory manual). 
The following clinical laboratory tests will be performed: 
Laboratory tests 
Parameters 
Hematology 
Red blood cell count, Hb, hematocrit, platelet count, white 
blood cell count, differential white blood cell count 
(neutrophils, lymphocytes, monocytes, eosinophils, 
basophils) 
Chemistry 
Total protein, albumin, ALP, ALT, AST, TBL, troponin, 
blood urea nitrogen, calcium, chloride, serum creatinine, 
lactate dehydrogenase, potassium, sodium, and magnesium 
Urinalysis 
Protein, blood. gravity, glucose, PH, ketone, nitrite, 
leukocyte esterase, urobilinogen, bilirubin, color, 
clarity/turbidity 
In addition, the following parameters will be analyzed at the visits indicated in 
appendix Section 17.6. 


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 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 assessed 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 SAE 
information should be reported according to the procedures (see Section 8.5).  
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. 
8.9. 
Vital Signs 
Vital sign evaluations will be performed according to the time points indicated in the 
schedule of events (Table 17.3). 
Vital sign measurements will include systolic and diastolic blood pressure, pulse rate, 
respiratory rate and body temperature.  Additionally, SpO2 will be measured before 
administration on Day 1 of each cycle and EOT. 
8.10. 
Electrocardiograms 
ECG evaluations will be performed according to the time points indicated in the 
schedule of events (Table 17.3). 
Standard supine 12-lead ECGs in triplicate will be performed in the schedule of 
events (Table 17.3).  Standard ECG parameters will be measured, including RR, PR, 
QT intervals, and QRS duration.  All ECGs must be evaluated by the Investigator or 
delegated physician for the presence of abnormalities. 
8.11. 
Physical Examinations 
Physical examinations will be performed according to the time points indicated in the 
schedule of events (Table 17.3). 
Physical examination findings will include the following body systems/organs: 
general appearance; dermatological; head and eyes; 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. 
8.12. 
Other Examinations 
Other evaluations such as ECHO or MUGA, ECOG PS, and ophthalmologic 
assessments will be performed according to the time points indicated in the schedule 
of events (Table 17.3). 
LVEF will be measured by either ECHO or MUGA.  Ophthalmologic assessments 
will include visual acuity testing, slit lamp examination, fundoscopy testing.  All 
ECHOs or MUGAs, and the ophthalmologic assessments must be evaluated by the 
Investigator or delegated physician.   
 Pulmonary Assessments 


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 Pulmonary assessment 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 ILD on an ongoing basis.  
Description of the ILD AC is available in Section 8.3.1 . 
Additional safety assessments should be conducted as needed, at the Investigator’s 
discretion. 


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9. 
EFFICACY ASSESSMENTS 
9.1. 
Assessments for Efficacy Endpoints 
Efficacy assessments will be based on tumor assessments.  The same imaging tumor 
assessment as at Screening by CT or MRI scans will be performed every 6 weeks 
(± 7 days) in the first 24 weeks after Day 1 of Cycle 1 and thereafter every 12 weeks 
(± 7 days) regardless of the delay in dosing.  The clinical activity of DS-8201a will be 
assessed by evaluating tumor response.  Tumor response will be evaluated using 
RECIST version 1.1 (Section 17.4). 
CT or MRI (spiral CT or MRI with 5 mm cuts) of the brain, chest, abdomen, and 
pelvis should be used for tumor assessments unless another modality of disease 
assessment is necessary for the lesions at Screening.  Every effort should be made to 
use the same assessment modality for all assessments for each subject.  However, if 
there is no brain metastasis at Screening, CT or MRI should only be done when 
symptoms associated with brain metastasis occur during study period.  If no clinical 
symptoms are observed, brain CT or MRI is not mandatory during study period. 
The following efficacy endpoints will be assessed.  The efficacy variable(s) will be 
also evaluated at 18 weeks after Day 1 of Cycle 1: 
 ORR (the sum of complete response [CR] rate and partial response [PR] rate) 
 DCR (the sum of CR rate, PR rate, and SD rate) 
 DoR 
 PFS 
 OS 
 Best percentage change in the sum of diameter(s) of target lesion(s) 
9.2. 
Appropriateness of Selected Efficacy Assessments 
The anti-tumor effect of DS-8201a will be assessed by evaluating tumor response 
according to RECIST version 1.1 as it is generally recognized as standard tumor 
response criteria. 


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10. 
OTHER ASSESSMENTS 
Not applicable. 


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11. 
STATISTICAL METHODS  
11.1. 
General Statistical Considerations 
The data-cutoff for the primary analysis will occur after all subjects have either 
discontinued the study or completed at least 4 cycles of the study drug.  After the 
data-cutoff date for primary analysis, data of interest will be followed for subjects 
who are still benefiting from the study drug until study completion.  
Descriptive statistics will be provided for selected demographic, safety, and PK data 
by dose level/cohort, if applicable.  
 Continuous variables: number of nonmissing observations, mean, standard deviation, 
median, minimum, and maximum as well as geometric means and geometric 
coefficient of variation for PK parameters, if applicable. 
  Categorical variables: frequencies and percentages. 
  Time-to-event variables: number of nonmissing observations (N), median, minimum, 
and maximum.  Kaplan-Meier event rates may also be provided if applicable for 
specific time-to-event variables. 
 
Assessments of change from Baseline to post-treatment or the ratio of post-treatment 
to Baseline will include only subjects with both baseline and post-treatment 
measurements.  The last nonmissing value of a variable taken before the first dose of 
study drug 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. 
Safety analyses will be performed based on the safety analysis set.  Analysis of PK 
parameters will be based on the PK analysis set.  Efficacy endpoints will be analyzed 
based on the efficacy analysis set.  Data will be summarized by dose level/cohort. 
Data will be listed and summarized using Statistical Analysis System (SAS®) Version 
9.4 or higher (SAS Institute, Inc., Cary, North Carolina) according to the 
Sponsor-agreed reporting standards, where applicable.  Complete details of the 
statistical analyses will be documented in the statistical analysis plan (SAP).  
PK parameters will be derived using standard noncompartmental methods using 
Phoenix WinNonlin® 6.4 or higher (Pharsight Corp., Certara Company, Princeton, 
New Jersey, United States); and/or SAS Version 9.2 or higher.  Graphics may be 
prepared with SAS® Version 9.2, or higher; SigmaPlot® 12.5, or higher (Systat 
Software, Inc., San Jose, California, United States); or Phoenix WinNonlin 6.4, or 
higher. 
 
11.2. 
Analysis Sets 
11.2.1. 
Enrolled Analysis Set 
The enrolled analysis set will include all subjects who signed an ICF and were 
enrolled in the study. 


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11.2.2. 
Safety Analysis Set 
The safety analysis set will include all subjects who receive at least 1 dose of 
DS-8201a. 
11.2.3. 
Pharmacokinetic Analysis Set 
The PK analysis set will include all subjects in the enrolled analysis set who received 
at least 1 dose of DS-8201a and had at least 1 evaluable postdose serum concentration 
of DS-8201a without major protocol deviations or events (eg, incomplete dosing, 
disallowed concomitant medications, etc.) affecting PK. 
11.2.4. 
Efficacy Analysis Set 
The efficacy analysis set will include all subjects who received at least 1 dose of 
DS-8201a and had both pre- and post-treatment efficacy assessment data. 
11.3. 
Study Population Data 
Subject disposition and reasons for treatment and study discontinuation will be 
summarized at each dose level and in total, if applicable, in the enrolled analysis set 
and safety analysis set. 
Demographic and baseline characteristics such as age, sex, race, ethnicity, baseline 
ECOG PS, cancer stage, histology will be summarized for the enrolled analysis set, 
safety analysis set, and efficacy analysis set. 
11.4. 
Statistical Analysis 
11.4.1. 
Efficacy Analyses 
The efficacy analyses will be performed for the efficacy analysis set.  The efficacy 
endpoints will include ORR, DCR, and time-to-event assessments including DoR, 
PFS, OS, and Best percent change in the sum of diameter(s) of target lesion(s). 
All efficacy endpoints will be listed and summarized. 
ORR and DCR: 
ORR is the proportion of subjects who achieved a best overall response of CR or PR.  
The point estimate of ORR and corresponding 95% exact binomial confidence 
intervals (CIs) will be provided. 
DCR is the proportion of subjects who achieved a best overall response of CR, PR or 
SD.  The analyses of DCR will be performed in the same manner as the ORR 
analyses. 
DoR, PFS and OS: 
DoR is defined as the time from the date of the first documentation of objective 
response (CR or PR) to the date of the first objective documentation of PD. DoR will 
be measured for responding subjects (CR or PR) only.  Detailed censoring rules for 
DoR will be specified in the SAP. 
PFS is defined as the time interval from the date of the first dose of the study drug to 
the date of first objective documentation of radiographic PD or death due to any 
cause.  Detailed censoring rules for the PFS analysis will be specified in the SAP. 


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OS is defined as the time interval from the date of the first dose to the date of death 
for any cause.  Subjects will be censored at the time last known to be alive if the 
subjects have not been reported to have died by the time of cutoff for the primary 
analysis. 
The time-to-event variables, including DoR, PFS and OS will be summarized 
descriptively using the Kaplan-Meier method to provide the median event time and 
the corresponding 95% CI. 
Best percent change in the sum of diameter(s) of target lesion(s): 
Descriptive statistics for the best percent change in the sum of diameter(s) of target 
lesion(s) will be provided.  A waterfall plot of the best percentage change from 
Screening in the sum of the longest dimensions (SLD) for each subject will be 
presented. 
11.4.2. 
Pharmacokinetic Analyses 
The PK analyses will be performed on the PK Analysis Set using actual sample times 
and noncompartmental methods.  Serum concentration-time data for DS-8201a will 
be listed, and summarized using descriptive statistics by study cycle at each nominal 
collection time.  Applicable plots will illustrate the appropriate data. 
PK parameters will be estimated for both cycles.  The PK parameters of DS-8201a, 
total anti-HER2 antibody, and MAAA-1181a (AUClast, AUC0-21d, Cmax, Tmax, and 
Ctrough) will be listed and summarized using descriptive statistics. AUCinf, Kel, T1/2, 
CL, Vz, and Vss will be estimated if determined to be appropriate. Descriptive 
statistics will be provided for all serum concentration data at each time point and PK 
parameters for each analyte as appropriate.  Primary PK parameters are presented in 
Table 11.1 and all other parameters are considered secondary. 
Table 11.1: 
Pharmacokinetics Parameters 
Cycle 1 
1. AUClast 
2. AUC0-21d 
3. Cmax 
4. Tmax 
Cycle 3 
1. AUClast 
2. AUCtau 
3. Cmax 
4. Tmax 
11.4.3. 
Safety Analyses 
Safety analyses will be performed on the safety analysis set.  Safety endpoints will 
include AEs, SAEs, TEAEs, AEs and AESIs leading to discontinuation, physical 
examination findings (including ECOG PS), vital sign measurements, standard 
clinical laboratory parameters, ECG parameters, ECHO or MUGA findings and 
ophthalmologic assessments.  AEs will be graded according to the NCI-CTCAE 


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version 4.03.  Safety analysis in general will be descriptive and will be presented in 
tabular format with appropriate summary statistics. 
11.4.3.1. Adverse Event Analyses 
A TEAE is defined as an AE that emerges during the treatment period (from first dose 
date until F/U visit after the last dose of study medication), having been absent at 
pre-treatment; or reemerges during treatment, having been present at Baseline but 
stopped prior to treatment; or worsens in severity after starting treatment relative to 
the pre-treatment state, when the AE is continuous. 
The number and percentages of subjects reporting TEAEs will be tabulated by the 
worst NCI-CTCAE grade, System Organ Class (SOC) and Preferred Term (PT). 
Similarly, the number and percentage of subjects reporting treatment-emergent SAEs 
will be tabulated, as well as TEAEs/SAEs considered related to DS-8201a. 
The time interval from the date of first dose of the study drug to the first onset date of 
AESIs will be summarized by AESI category. 
A by-subject AE (including TEAE) data listing will be provided including, but not 
limited to, verbatim term, PT, SOC, NCI-CTCAE grade, and relationship to study 
drug. 
Deaths, other SAEs, and other significant AEs, including those leading to permanent 
discontinuation from DS-8201a, will be listed. 
11.4.3.2. Clinical Laboratory Evaluation Analyses 
Descriptive statistics will be provided for selected clinical laboratory test results 
(hematology, coagulation, chemistry, and urinalysis and changes from Baseline by 
scheduled time of evaluation, including the EOT visit.  In addition, the change from 
Baseline will be summarized for the maximum post-treatment value and minimum 
value. 
Abnormal laboratory results for selected clinical laboratory tests will be graded 
according to the NCI-CTCAE version 4.03, if applicable.  A shift table, presenting the 
2-way frequency tabulation for Baseline and the worst value according to 
NCI-CTCAE grade, will be provided for selected clinical laboratory tests.  Abnormal 
clinical laboratory test results that are 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 sign measurements and changes 
from Baseline by scheduled time of evaluation, including the EOT visit.  In addition, 
the change from Baseline will be summarized for the maximum and minimum value. 
11.4.3.4. Electrocardiogram Analyses 
A shift table, presenting the 2-way frequency tabulation for Baseline and each 
scheduled time, including the EOT visit according to the categories for ECG (normal 
and abnormal) will be provided.  Other ECG data will be listed. 


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11.4.3.5. Other Safety Analyses 
Abnormal ECHO or MUGA findings and ophthalmologic findings will be 
summarized. 
ADA assessment data will be listed and summarized appropriately. 
11.5. 
Interim Analyses 
No interim analyses are planned for this study. 
11.6. 
Data Monitoring Committee 
Not applicable. 
11.7. 
Safety Monitoring Team 
There is a safety monitoring team established for the purpose of assessing safety and 
tolerability of subject. The meeting will be held regularly. The members may include 
medical expert/medical monitor of Daiichi Sankyo and medical advisor of Quintiles. 
This meeting will be held after 6 patients have completed Cycle 1 and when 
necessary. Detailed procedures will be specified in the medical monitoring plan and 
relative study plans. 
11.8. 
Sample Size Determination 
Approximately 12 subjects will be allocated to the selected dose level.  The sample 
size of 12 subjects will provide the safety and tolerability data in Chinese subjects. 
11.9. 
Statistical Analysis Process 
The clinical study will be analyzed by QuintilesIMS followed by this protocol and the 
SAP will demonstrate all methodologies and displays for statistical analyses. 
The SAP will provide the statistical methods and the analysis of the efficacy, safety, 
and PK 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. 


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12. 
DATA INTEGRITY AND QUALITY ASSURANCE 
The Investigator/investigational site will permit study-related monitoring, audits, IRB 
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 or 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, CRFs, source data, and 
other pertinent documents). 
The verification of 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 will be accomplished through a 
combination of onsite visits by the monitor and review of study data remotely.  The 
frequency of the monitoring visit will vary based on the activity at each site.  The 
monitor is responsible for inspecting the CRFs 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 CRFs.  
Detailed information is provided in the monitoring plan. 
The monitor will communicate deviations from the protocol, SOPs, GCP, and 
applicable regulations to the Investigator and will ensure that appropriate action (s) 
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 to the satisfaction of 
the Sponsor and documented. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study site may be 
selected for audit by representatives from the Sponsor.  Audit of site facilities (eg, 
pharmacy, drug storage areas, laboratories) 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.  The Investigator should respond to 
audit findings.  In the event that a regulatory authority informs the Investigator that it 
intends to conduct an inspection, the Sponsor shall be notified immediately. 
12.2. 
Data Collection 
The Investigator or study staff will enter the data in the eCRF in accordance with the 
CRF Completion Guidelines that are provided by the Sponsor. 
eCRF completion should be kept current to enable the monitor to review the subject’s 
status throughout the course of the study.  eCRF will be completed, reviewed and 
signed off or e-signed by the Investigator after all queries have been satisfactorily 
resolved. 
The Investigator will e-sign according to the study data flow. 


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Any data recorded on the study CRF will be collected and included in the database 
according to Clinical Data Interchange Standards Consortium (CDISC) standards and 
subjected to the same procedures as other data. 
12.3. 
Data Management 
Each subject will be identified in the database by a unique Subject Number as defined 
by the Sponsor. 
To ensure the quality of clinical data across all subjects and study sites, a Clinical 
Data Management review will be performed on subject data according to 
specifications given to the Sponsor or CRO.  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 Electronic Data Capture (EDC) application.  During this 
review, subject data will be checked for consistency, completeness, and any apparent 
discrepancies. To resolve any questions arising from the Clinical Data Management 
review process for eCRFs queries will be raised and resolved within the EDC 
application. 
Data received from external sources such as central laboratories will be reconciled to 
the clinical database. 
SAEs in the clinical database will be reconciled with the safety database. 
All AEs will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA). All prior cancer therapy and prior/concomitant medications entered into 
the database will be coded using the latest version of World Health Organization Drug 
Dictionary. 
Refer to Section 17.5 for details of the EDC system used for completing eCRF. 
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. 
Investigators will maintain a confidential screening log of all potential study 
candidates that includes limited information of the subjects, date and outcome of 
screening process. 
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 names of all subjects allocated to study numbers on enrolling in the 
study allows the Investigator to reveal the identity of any subject when necessary. 
Source documents are original documents, data, and records from which the subject’s 
CRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, X-rays, and 
correspondence. 
Records of subjects, source documents, monitoring visit logs, data correction forms, 
CRFs, inventory of study drug, regulatory documents (eg, protocol and amendments, 


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IRB correspondence and approvals, approved and signed ICFs, Investigator’s 
Agreement, clinical supplies receipts, distribution and return records), and other 
ponsor correspondence pertaining to the study must be kept in appropriate study files 
at the study site (Trial Master File).  Source documents include all recordings and 
observations or notations of clinical activities and all reports and records necessary 
for the evaluation and reconstruction of the clinical study.  These records will be 
retained in a secure file for the period required by the institution or study site policy.  
Prior to transfer or destruction of these records, the Sponsor must be notified in 
writing and be given the opportunity to further store such records. 
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 documentation, 
suitable for inspection at any time by representatives from the Sponsor and/or 
applicable regulatory authorities.  Trial Master File includes: 
 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 IRB and the Sponsor. 
  Records related to the study drug(s) including acknowledgment of receipt at 
site, accountability records, final reconciliation, and applicable 
correspondence. 
In addition, all original source documents supporting entries in the CRFs must 
be maintained and be readily available. 
Trial Master File will be retained by the Investigator until at least 3 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 3 years have lapsed 
since the formal discontinuation of clinical development of the investigational drug.  
These documents should be retained for a longer period, however, if required by the 
applicable regulatory requirements or by an agreement with the Sponsor.  It is the 
responsibility of the Sponsor to inform the Investigator/institution as to when these 
documents no longer need to be retained. 
Subject’s medical files should be retained in accordance with applicable legislation 
and in accordance with the maximum period of time permitted by the hospital, 
institution, or private practice. 
No study document should be destroyed without prior written agreement between the 
Sponsor 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 Sponsor 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 a CRO.  This agreement will include the 
financial information agreed upon by the parties. 
13.2. 
Reimbursement, Indemnity, and Insurance 
The Sponsor will provide 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 
Daiichi Sankyo is committed to meeting the highest standards of publication and 
public disclosure of information arising from clinical trials sponsored by the 
company.  Daiichi Sankyo will comply with US, European Union, Asian, and 
Japanese policies for public disclosure of the clinical trial protocol and clinical trial 
results, and for sharing of clinical trial data.  Daiichi Sankyo follows the principles set 
forth in “Good Publication Practice for Communicating Company-Sponsored Medical 
Research (GPP3)” published by the International Society for Medical Publication 
Professionals (ISMPP), and publications will adhere to the “Recommendations for the 
Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals” 
established by the International Comittee of Medical Journal Editors (ICMJE). 
In order to ensure that Daiichi Sankyo is in compliance with public disclosure policies 
and the ICMJE recommendations, and to protect proprietary information generated 
during the study, all publications (manuscripts, abstracts, or other public disclosure) 
based on data generated in this study must be accepted, reviewed, and approved in 
writing by the Sponsor prior to submission. 


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15. 
ETHICS AND STUDY ADMINISTRATIVE 
INFORMATION 
15.1. 
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 ICH consolidated Guideline 
E6 for GCP (CPMP/ICH/135/95), and applicable regulatory requirement(s). 
15.2. 
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 
assigned by a unique subject number 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(s), and the IRB 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. 
15.3. 
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.  The consent form should be signed and personally dated 
by the subject or legally acceptable representative prior to his/her participation in the 
study. 
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 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. 


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If the subject cannot read, then according to ICH GCP Guideline, Section 4.8.9, an 
impartial witness should be present during the entire informed consent discussion.  
This witness should sign the ICF after the subject has consented to the subject’s 
participation and, if possible, signed the ICF.  By signing the ICF, the witness attests 
that the information in the ICF and any other written information was adequately 
explained to and apparently understood by the subject and that informed consent was 
freely given by the subject. 
For studies conducted outside the US, a separate special consent for 
Pharmacogenomic testing will be obtained from patients in accordance with health 
authorities in their particular region/country. 
15.4. 
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 the 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 the Sponsor must submit and, where necessary, obtain 
approval from the IRB for all subsequent protocol amendments and changes to the 
informed consent document or changes of the investigational site, facilities or 
personnel.  The Investigator should notify the IRB of deviations from the protocol or 
SAEs occurring at the site and other AE reports received from Sponsor or 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 of 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 the appropriate notification of or approval 
by the relevant regulatory bodies. 
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. 
15.5. 
Protocol Deviations 
The Investigator should conduct the study in compliance with the protocol agreed to 
by the Sponsor and, if required, by the regulatory authority(ies), and which was given 
approval/favorable opinion by the IRB. 
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.  The Sponsor must be notified of all intended or unintended deviations to the 


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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 drug, and had at 
least 1 administration of study drug, data should be collected for safety purposes. 
If applicable, the Investigator should notify the IRB 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, 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 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 sites 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 site(s) 
and/or in a particular region/country.  The Sponsor approval of local amendments will 
be clearly documented. 
A protocol amendment may be implemented after it has been approved by the IRB 
and by regulatory authorities where appropriate, unless immediate implementation of 
the change is necessary for subject safety. 




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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 2017 Jul 7. 
2. Boku N. HER2-positive gastric cancer. Gastric Cancer. 2014;17(1):1-12. 
3. 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. 
4. Esteva FJ, Guo H, Zhang S, et al. PTEN, PIK3CA, p-AKT, and p-p70S6K 
status: association with trastuzumab response and survival in patients with 
HER2-positive metastatic breast cancer. Am J Pathol. 2010;177(4):1647-56. 
5. 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. 
6. 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. 
7. Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a 
novel therapeutic target. Ann Oncol. 2008;19(9):1523-9. 
8. Harder J, Ihorst G, Heinemann V, et al. Multicentre phase II trial of 
trastuzumab and capecitabine in patients with HER2 overexpressing 
metastatic pancreatic cancer. Br J Cancer. 2012;106(6):1033-8. 
9. 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. 
10. 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. 
11. 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. 
12. Food and Drug Administration (United States) [Internet]. Herceptin: Full 
prescribing information. Revised: 2015 Apr [cited 2017 Oct 10]. Available 
from:http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/103792s5327
lbl.pdf 
13. European public assessment reports (Europe) [Internet]. Herceptin: EPAR - 
Product Information, Updated: 2015 Apr 21 [cited 2017 Oct 10]. Available 
from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/000278/WC500074922.pdf 


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14. Pharmaceuticals and Medical Devices Agency (Japan) [Internet]. Herceptin: 
Package Insert, Revised: 2015 Dec  [cited 2017 Oct 10]. Available from: 
http://www.info.pmda.go.jp/go/pack/4291406D3021_1_02/ 
15. DS-8201a Investigator’s Brochure. Version 3.0. 2017 Jul 27.  


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17. 
APPENDICES 
17.1. 
Cockcroft-Gault Equation 
The estimated creatinine clearance rate (CrCl; mL/min) will be calculated using the 
Cockcroft-Gault equation based on actual weight in kg (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
 
 
mol/L)
(in 
 
creatinine
 
serum
kg)
(in 
 weight 
  
years)]
(in 
 
age
 - 
[140



 
 
Female: 
CrCl (mL/min) = 
0.0113
 
 
72
 
 
mol/L)
(in 
 
creatinine
 
serum
kg)
(in 
 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. 
New York Heart Association 
The ninth edition, revised by the Criteria Committee of the American Heart 
Association, New York City Affiliate, was released March 14, 1994. The new 
classifications are summarized below for the many physicians and scientists who use 
them to describe the status of individual patients. 
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. Classification of Functional Capacity and 
Objective Assessment. Available from: 
http://my.americanheart.org/professional/StatementsGuidelines/ByPublicationDate/Pr
eviousYears/Classification-of-Functional-Capacity-and-Objective-
Assessment_UCM_423811_Article.jsp 


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17.3. 
Eastern Cooperative Oncology Group Performance Status 
(ECOG PS) 
Table 17.1: 
Eastern Cooperative Oncology Group Performance Status Scale 
Grade Description 
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, et al. Toxicity and Response Criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-55. 


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17.4. 
Response Evaluation Criteria in Solid Tumors (Version 1.1) 
Assessment of tumor responses will be performed according to revised RECIST 
guidelines, version 1.1. 
17.4.1. 
Measurability of Tumor at Baseline 
17.4.1.1. Definitions 
At Baseline, tumor lesions/lymph nodes will be categorized measurable or non-
measurable as follows: 
17.4.1.1.1. Measurable 
Tumor lesions: Must be accurately measured in at least one 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 and 
during F/U, 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. 
17.4.1.1.2. 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, abdominal masses/abdominal organomegaly identified 
by physical exam that is not measurable by reproducible imaging techniques. 
17.4.1.1.3. Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment: 
Bone lesions: 
 Bone scan, 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 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. 


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Lesions with prior local treatment: 
 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. 
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 since the therapy. 
17.4.1.2. Specifications by Methods of Measurements 
17.4.1.2.1. 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 4 weeks before the beginning of the treatment. 
17.4.1.2.2. 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 F/U.  Imaging 
based evaluation should always be done 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). 
17.4.2. 
Tumor Response Evaluation 
17.4.2.1. 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.  
17.4.2.2. Baseline Documentation of ‘Target’ and ‘Non-target’ Lesions 
When more than one measurable lesion is present at Baseline all lesions up to a total 
of two lesions per organ and a maximum of five 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 one or two 
organ sites involved a maximum of two and four lesions respectively will be 
recorded). 


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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 two 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’). 
17.4.2.3. Response Criteria 
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions. 
17.4.2.4. 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. 
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 


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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 one 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. 
17.4.2.4.1. 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 CRF.  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 unlikely 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’. 
17.4.2.5. 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 need not be measured and instead should be assessed 
only qualitatively at the time points specified in the protocol. 


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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 one 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 one or more new lesions is also considered progression). 
17.4.2.5.1. 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 one 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. 
17.4.2.6. 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 pre-existing lesions). This is particularly important when the subject’s 
baseline lesions show partial 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 F/U 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 the subject who has visceral disease at Baseline and while on study 
has a CT or MRI of brain 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 F/U 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 that indicated its presence. 
17.4.2.7. Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the study 
treatment until the EOT.  No confirmatory measurement for CR, PR or SD is required 
in this study; however, this can be decided by study personnel.  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. 


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17.4.2.7.1. 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. 
Table 17.2: 
Time Point 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 = inevaluable.  
17.4.2.7.2. Missing Assessments and In-evaluable Designation 
When no imaging/measurement is done at all at a particular time point, the subject is 
not evaluable (NE) at that time point.  If only a subset of lesion measurements are 
made at an assessment, usually the case is also considered NE at that time point, 
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 three measured lesions and at F/U only two 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. 
17.4.2.7.3. Best Overall Response: All Time Points 
The best overall response is determined once all the data for the subject are known. 
Best response determination in trials where confirmation of complete or PR is not 
required: Best response in these trials is defined as the best response across all time 
points (for example, a subject who has SD at first assessment, PR at second 
assessment, and PD on last assessment has a best overall response of PR).  When SD 
is believed to be best response, it must also meet the protocol specified minimum time 
from Baseline, 7 weeks, in the case of scan intervals of 8 weeks or “5 weeks”, in 
the case of scan intervals of 6 weeks.  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 a 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 F/U after the first SD assessment would be considered 
NE. 


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17.4.2.7.4. 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 
CRF. 
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. If a radiographic tumor assessment has not 
been performed within 4 weeks of the time of clinical progression, then another 
radiographic assessment should be performed without waiting for the next regularly 
scheduled scan.  
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. 
17.4.2.8. Frequency of Tumor Re-evaluation 
In this study, tumor measurement will be conducted at Screening, and then at the 
intervals specified or sooner if clinically indicated.  Tumor measurement will be 
performed during the EOT visit if it was not done within the previous 8 weeks <<or 
other number of weeks depending upon the scan interval>> or the previous 
assessment demonstrated disease progression. 
Baseline tumor assessments must be performed within 4 weeks prior to the first dose 
of treatment. 
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 the chest, abdomen, 
and pelvis.  Any additional suspected sites of disease 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.  
Source: Eisenhauer EA, Therasse P, Bogaerts J, et al.  New response evaluation 
criteria in solid tumours: Revised RECIST guideline (version 1.1).  Eur J Cancer. 
2009;45:228-47. 


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17.5. 
Electronic Data Capture System 
The EDC system used for completing eCRF in this study is shown below. 
Name of EDC system 
Medidata Rave® 
EDC system developer 
Medidata Solutions Inc. 
Entry method 
Web-based data entry 
Input terminal 
Desktop/laptop computer at the study site 
Incompatible operating 
systems 
None 
Recommended browsers 
The Medidata Rave® supports any browser which is HTML 5 and 
CSS2 compliant.  Browsers must have JavaScript enabled. 
Screen Resolution 
The minimum screen resolution required to properly display 
Medidata Rave applications is 1024 x 764. 
Connection Speed 
128kbps is the minimum connection speed recommended for using 
Medidata Rave. 
Other 
Adobe Flash Player : ver. 10 or above is required 
Abbreviations: eCRF = electronic case report form; EDC = electronic data capture. 


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17.6. 
Schedule of Events 
The schedule of events and assessments for this study is presented in Table 17.3. 
 


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Table 17.3: 
Schedule of Events for DS8201-A-A103 Study 
 
SC
R 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
and 
subseque
nt cycles 
EOT 
a 
F/Ub 
Day 1 
Day 
 2  
Day 
4 
Day 
8 
Day 
15 
(Day 
22) 
Day 1 
Day 
8 
Day 
15 
(Da
y 
22) 
Day 1 
Da
y 2, 
4 
Da
y 
8 
Day 
15 
(Da
y 
22) 
Day 1 
 
 
BI 
EOI 
 
 
(± 1 
day) 
(± 1 
day) 
(± 2 
days
) 
BI 
E
OI 
(± 2 
days
) 
(± 2 
days
) 
(± 2 
day
s) 
BI 
E
OI 
 
 
 
(± 2
day
s) 
(± 2
 da
ys) 
(± 2
 da
ys) 
BI 
E
O
I 
(+ 7  
days) 
(+ 7  
days) 
Informed 
consent 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administratio
n DS-8201a 
 
● 
 
 
 
 
 
● 
 
 
 
● 
 
 
 
 
● 
 
 
Demographic 
information 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital sign 
●c 
●d 
● 
● 
● 
● 
● 
 
●d 
● 
● 
● 
 
●d 
● 
 
● 
● 
 
●d 
 
● 
● 
Physical 
examination 
●c 
●d 
 
 
 
 
 
 
●d 
 
 
 
 
●d 
 
 
 
 
 
●d 
 
● 
● 
SpO2 
 
● d 
 
 
 
 
 
 
●d 
 
 
 
 
●d 
 
 
 
 
 
●d 
 
● 
● 
Inclusion/Exc
lusion Criteria 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight, 
ECOG PS 
●c 
●d 
 
 
 
 
 
 
●d 
 
 
 
 
●d 
 
 
 
 
 
●d 
 
● 
● 
Laboratory 
testst 
●c 
●d 
 
● 
 
● 
● 
 
●d 
 
● 
● 
 
●d 
 
 
● 
● 
 
●d 
 
● 
● 
Prothrombin 
time, 
activated 
partial 
thromboplasti
n time 
●c 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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SC
R 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
and 
subseque
nt cycles 
EOT 
a 
F/Ub 
Day 1 
Day 
 2  
Day 
4 
Day 
8 
Day 
15 
(Day 
22) 
Day 1 
Day 
8 
Day 
15 
(Da
y 
22) 
Day 1 
Da
y 2, 
4 
Da
y 
8 
Day 
15 
(Da
y 
22) 
Day 1 
 
 
BI 
EOI 
 
 
(± 1 
day) 
(± 1 
day) 
(± 2 
days
) 
BI 
E
OI 
(± 2 
days
) 
(± 2 
days
) 
(± 2 
day
s) 
BI 
E
OI 
 
 
 
(± 2
day
s) 
(± 2
 da
ys) 
(± 2
 da
ys) 
BI 
E
O
I 
(+ 7  
days) 
(+ 7  
days) 
PK 
 
●e 
●f, g 
●h 
●h 
● 
● 
●i 
●e 
●f 
 
 
●i 
●e 
●f, 
g 
●h 
● 
● 
●i 
●e 
●f 
 
 
ADAv 
 
●k 
 
 
 
● 
 
 
●k 
 
 
 
 
 
 
 
 
 
 
●k 
 
● 
●q 
HIV antibody 
test (as require 
by 
local 
regulations or 
IRB/ECs) 
●l 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Troponinn  
●c 
 
● 
 
 
 
 
 
 
● 
 
 
 
 
● 
 
 
 
 
 
 
 
 
ECHO 
or 
MUGA 
(LVFF) 
●o 
 
 
 
 
 
 
 
●d 
 
 
 
 
●d, 
m 
 
 
 
 
 
●d,m 
 
● 
 
12-lead ECG 
in triplicate 
●c 
●d 
●p 
● 
 
● 
● 
 
●d 
● 
 
 
 
●d 
 
 
 
 
 
●d 
 
● 
 
Tumor 
assessment 
●o 
 
 
 
Every 6 weeks (± 7 days) in the first 24 weeks after Day1 of Cycle 1, and thereafter every 12 weeks (± 7 days) 
● 
 
Pregnancy test 
●c 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
● 
● 
Ophthalmolog
ic assessments 
●o 
 
 
 
 
 
 
 
●r 
 
 
 
 
 
 
 
 
 
 
 
 
● 
 
Urinalysis 
●c 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications  
 
●s 
AEs 
●u 


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ADA = anti-drug antibodies; AE = adverse event; BI = before infusion; ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group 
Performance Status; ECHO = echocardiography; EOI = end of infusion; EOT = end of treatment; F/U = follow-up; HIV = human immunodeficiency virus; IRB 
= institutional review board; MUGA = multiple-gated acquisition; PK = pharmacokinetics; SCR = screening; SpO2 = peripheral oxygen saturation 
 
a The date investigator decides the discontinuation of the study drug (+ 7 days) 
b 40 days (+ 7 days) after the last study drug administration or before starting new anticancer treatment, whichever comes first 
c Latest data within 7 days before registration 
d Latest data within 3 days before administration 
e Within 8 hours BI on Day 1 of each cycle until Cycle 4 and then every 2 cycles until Cycle 8 (ie, Cycle 1, 2, 3, 4, 6, 8) 
f 
Within 15 minutes at EOI on Day 1 of each cycle until Cycle 4 and then every 2 cycles until Cycle 8 (ie, Cycle 1, 2, 3, 4, 6, 8) 
g After 2, 4, 7 hours from the start of administration (± 15 minutes) 
h 24 hours (± 2 hours) and 72 hours (± 2 hours) after the start of administration 
i 
If Day 1 of the next cycle is delayed for 3 days or more, or if the subject cannot continue into the next cycle, collect blood sample for PK analysis on Day 22 
of this cycle (Cycle 1, 2, 3, 4, 6 and 8) 
j 
4 hours after the start of administration (± 15 minutes)  
k Within 8 hours BI on Day 1 in Cycle 1 and 2, and then every 2 cycles until the end (eg, Cycle 1, 2, 4, 6, 8, 10, 12, and so on) 
l 
Latest data within 90 days before registration.  
m Before administration at every 2 cycles from Cycle 3 (eg, Cycle 3, 5, 7, 9, and so on) 
n Collect blood samples for troponin (preferably high-sensitivity troponin-T) 2 hours to 3 hours after EOI. If troponin levels are consistent with myocardial 
infarction as defined according to manufacturer (NCI-CTCAE Grade 3), perform ECG testing in triplicate, repeat troponin testing 6 hours (± 1 hour) and 12 
hours (± 1 hour) after initial troponin test was drawn, and follow institutional guidelines. If troponin levels are above the ULN and below the level of 
myocardial infarction as defined by the manufacturer (NCI-CTCAE Grade 1), repeat troponin testing at 3 hours (± 1 hour) after initial troponin test was 
drawn. 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.  
o Latest data within 28 days before registration 
p Within 30 minutes after EOI, and 2 hours to 4 hours after the start of administration 
q For subjects with positive ADA at F/U visit, additional serum ADA samples may be collected every 3 months (± 1 month) up to 1 year from the last dose of 
study drug, or if the ADA becomes negative, or if ADA titer becomes less than Baseline (applicable when pre-existing ADA is observed), or if the subject 
starts another therapy for cancer, or withdraws consent from the study, whichever occurs first 
r 
Ophthalmologic assessments will be performed on Day 1 of Cycle 2 (within 3 days before administration) and every 4 cycles (± 7 days) thereafter (eg, Day 
1 of Cycle 2, 6, 10, 14, and so on) and as clinically indicated. 
s Concomitant medications used from the time the subject signs the ICF to Follow-up will be recorded.  
t 
Hematology tests will include red blood cell count, Hb, hematocrit, platelet count, white blood cell count, and differential white blood cell count 
(neutrophils, lymphocytes, monocytes, eosinophils, basophils) and clinical chemistry tests will include total protein, albumin, ALP, ALT, AST, TBL, blood 
urea nitrogen, calcium, chloride, serum creatinine, lactate dehydrogenase, potassium, sodium, and magnesium.  At Screening, prothrombin time, either 
partial thromboplastin or activated partial thromboplastin time, and urinalysis (visual, microscopic, and chemical analyses: color, clarity/turbidity, pH, 


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specific gravity, glucose, ketones, nitrites, leukocyte esterase, bilirubin, urobilirubin, blood, protein, red blood cells, white blood cells, squamous epithelial 
cells, casts, crystals, bacteria, and yeast) will be performed. 
 
u For suspected ILD/pneumonitis, treatment with study drug should be interrupted pending evaluations. 
Evaluations should include: 
 
High resolution CT  
 
Pulmonologist consultation (Infectious Disease consultation as clinically indicated) 
 
Blood culture and CBC. Other BLOOD tests could be considered as needed 
 
Consider bronchoscopy and bronchoalveolar lavage if clinically indicated and feasible 
 
Pulmonary function tests and pulse oximetry (SpO2) 
 
Arterial blood gases if clinically indicated 
 
One blood sample collection for PK analysis as soon as ILD/pneumonitis is suspected, if feasible. 
v A portion of ADA blood sample from each subject who provides consent will be used for future central lab analysis for SARS-CoV-2 testing once protocol 
version 5.0 is applied for a subject. SARS-CoV-2 testing will be conducted every 4 cycles from Cycle 4 (Cycle 4, Cycle 8 etc.). 
Other tests could be considered, as needed. 
 


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17.7. 
Instructions Related to Severe Acute Respiratory Syndrome 
Coronavirus 2 (SARS-CoV-2) 
Due to the potential impact of SARS-CoV-2, ie COVID-19, on subject safety, the Sponsor 
recommends the following dose modification and management plan for subjects with 
confirmed or suspected SARS-CoV-2 while being treated with DS-8201a.  Dose 
modifications will be based on the worst CTCAE grade.  Use CTCAE version 5.0 general 
grading criteria to evaluate SARS-CoV-2.  All dose modifications (discontinuation, 
interruptions or reductions) must be recorded on the AE and drug administration eCRFs. 
Dose Modification Criteria for Suspected or Confirmed SARS-CoV-2 
If SARS-CoV-2 infection is suspected, interrupt DS-8201a and rule out SARS-CoV-2 per 
local guidance. 
 
If SARS-CoV-2 is ruled out, follow dose modification and management guidance 
as outlined in Table 17.4. 
 
If SARS-CoV-2 is confirmed or is still suspected after evaluation follow dose 
modification as outlined in Table 17.4 below and manage SARS-CoV-2 per local 
guidance until recovery of SARS-CoV-2.  SARS-CoV-2 recovery is defined as no 
signs/symptoms of SARS-CoV-2, at least 1 negative real-time reverse 
transcription polymerase chain reaction (RT-PCR) test result, and nearly or 
completely resolved chest CT findings. 
Table 17.4: 
SARS-CoV-2 Dose Modification Criteria 
SARS-CoV-2 Worst 
Toxicity NCI-CTCAE 
Version 5.0 Grade 
(unless otherwise 
specified) 
Schedule Modification for DS-8201a 
Grade 1 
Resume study drug at the same dosea 
Grade 2 
Resume study drug at the same dose if chest CT findings are 
completely resolveda 
Reduce by 1 dose level if chest CT findings are nearly resolved 
Grade 3 
Reduce by 1 dose level if chest CT findings are completely 
resolved 
Discontinue study drug if chest CT findings are not completely 
resolved 
SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); CT = computed 
tomography  
a 
Closely monitor signs/symptoms after resuming DS-8201a, initially with a phone call every 3 days for 
the first week, and then with a weekly phone call thereafter, for a total of 6 weeks. 
In addition to the recommendations outlined in Table 17.4, Investigators may consider 
dose modifications of the study drug according to the subject’s condition and after 
discussion with the study Medical Monitor or designee. 


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If an event is suspected to be drug-related ILD, manage per protocol ILD management 
guideline (Table 3.2). 
Prior and Concomitant Medications - Prohibited Therapies/Products 
• 
Chloroquine or hydroxychloroquine; 
 Concomitant treatment is not allowed during the study treatment (Section 
5.6.1). 
 If treatment is absolutely required for SARS-CoV-2 DS-8201a must be 
interrupted.  
 If administered, then a washout period of no less than 14 days is required 
before resumption of DS-8201a. 
PK Assessment(s) if Chloroquine or Hydroxychloroquine is Administered 
Additional PK serum samples should be collected, if chloroquine or hydroxychloroquine 
is administered for SARS-CoV-2 infection, at the time points specified in the Schedule of 
Events (Table 7.3). 
The chloroquine or hydroxychloroquine administration time and the exact time of blood 
sample collection for PK analysis must be recorded on the eCRF. 
SARS-CoV-2 Assessment(s) 
All confirmed or suspected SARS-CoV-2 infection events must be recorded in the eCRF.  
If a subject presents to the clinic with symptoms suggestive of SARS-CoV-2, but the real-
time RT PCR test is not available at the site, a sample kit will be provided for sample 
collection to be tested at a central laboratory.  The results will be provided to the site from 
the central laboratory. 
Serum samples will be used for SARS-CoV-2 testing from each subject who provides 
consent.  Samples will be collected prior to the study drug infusion, shipped to a central 
laboratory, and stored there until the tests become available. 
If subjects consent, the remaining serum samples will also be stored for future analysis. 
Sample collection, preparation, handling, storage, and shipping instructions are provided 
in the Study Laboratory Manual. 
Statistical Analysis - Assessment of the Impact of SARS-CoV-2 
If deemed appropriate, analyses will be performed to explore the impact of SARS-CoV-2 
on the safety, efficacy, and any other endpoints, as appropriate, reported for the study. 
As a result of the impact of SARS-CoV-2 on study conduct, adjustments to the statistical 
analysis and interpretation will be made, if required.  These will be described in the 
statistical analysis plan.