Conditions: Colorectal Neoplasm
Keywords: Oncology HER2 Colorectal cancer Antibody drug conjugate ADC
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 86
Healthy volunteers: no

Brief summary:
The main objective of this study is to test the safety and effectiveness of DS-8201a for participants with HER2-expressing advanced colorectal cancer.

Detailed description:
At study start, only Cohort A is active.

If, and when, Cohort B and C become active depends on the assessment of benefit and risk observed in the program.

The sponsor will inform the investigators if, and when, Cohort B and C are active.

Arms:
arm 1: Cohort A is comprised of participants with HER2-positive (IHC 3+ or IHC 2+/ISH +) who will receive DS-8201a once every 3 weeks arm 2: Cohort B is comprised of participants with HER2 IHC 2+/ISH - who will receive DS-8201a once every 3 weeks arm 3: Cohort C is comprised of participants with HER2 IHC 1+ who will receive DS-8201a once every 3 weeks

Interventions: intervention 1: DS-8201a
Intervention descriptions: intervention 1: DS-8201a is comprised of an antibody component conjoined to a drug component in a lyophilized powder, which is made into solution for intravenous administration

Protocol document:
Prot_SAP_001.pdf: 
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Page 1 
CLINICAL STUDY PROTOCOL 
 
A PHASE 2, MULTICENTER, OPEN-LABEL STUDY 
OF DS-8201A IN SUBJECTS WITH HER2-
EXPRESSING ADVANCED COLORECTAL CANCER 
[DESTINY-CRC01] 
 
 
DS8201-A-J203 
IND/EudraCT NUMBERS:136179/2017-003466-28 
 
VERSION 1.0, 31 AUG 2017 
VERSION 1.1, 4 OCT 2017 
VERSION 2.0, 25 JAN 2018 
VERSION 3.0, 5 JUL 2018 
VERSION 4.0, 26 APR 2019 
VERSION 5.0, 03 JUL 2020 
 
 
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 
A PHASE 2, MULTICENTER, OPEN-LABEL STUDY OF DS-8201A IN SUBJECTS 
WITH HER2-EXPRESSING ADVANCED COLORECTAL CANCER 
[DESTINY-CRC01] 
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 
Harmonization 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: 
2017-003466-28 
IND Number: 
136179 
Protocol Number: 
DS8201-A-J203 
Investigational Product: 
DS-8201a 
Active Ingredients/INN: 
DS-8201a consists of an antibody component, MAAL-
9001, covalently conjugated via a maleimide tetrapeptide 
linker, to a drug component, MAAA-1181a. 
Study Title: 
A Phase 2, multicenter, open-label study of DS-8201a in 
subjects with HER2-expressing advanced colorectal 
cancer[DESTINY-CRC01] 
Study Phase: 
Phase 2 
Indication Under 
Investigation: 
Human epidermal growth factor receptor 2 (HER2)-
expressing advanced colorectal cancer 
Study Objective: 
Primary Objectives: 
• To determine the objective response rate (ORR) of DS-
8201a in HER2-positive advanced metastatic colorectal 
cancer patients (Cohort A). 
Secondary Objectives: 
• To evaluate duration of response (DoR), disease control 
rate (DCR), progression-free survival (PFS), and 
overall survival (OS).  ORR assessed by the 
investigator is also evaluated. 
• To evaluate the safety of DS-8201a 
• To determine the pharmacokinetics (PK) of DS-8201a 
Study Design: 
This is a multicenter, open-label, 3 cohorts, Phase 2 study 
to investigate the safety and efficacy of DS-8201a in 
HER2-expressing advanced colorectal cancer subjects.  
Cohort A 
Approximately 50 subjects with HER2-positive 
(immnohistochemistry [IHC] 3+ or IHC 2+/in situ 
hybridization [ISH] +) advanced colorectal cancer in single 
arm.  
Sponsor monitors the data after at least 20 subjects 
completed tumor assessment at 12 weeks in Cohort A.  
Cohorts B and C will be opened depending on the 
assessment of benefit and risk observed in the program. 


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Cohort B 
Approximately 20 subjects with HER2 IHC 2+/ISH – 
advanced colorectal cancer  
Cohort C 
Approximately 20 subjects with HER2 IHC 1+ advanced 
colorectal cancer 
Study Duration: 
Enrollment is planned to occur over approximately 18 
months, and treatment and follow-up is projected to be 
completed within approximately 6 months thereafter.  
Anticipated duration of the study is at least 24 months. 
Study Sites and Location: 
Study sites in Japan, North America, and Europe.   
Subject Eligibility Criteria: 
Key Inclusion Criteria: 
1. Age ≥20 years old in Japan, ≥18 years old in other 
countries. 
2. Pathologically documented unresectable, recurrent, 
or metastatic colorectal adenocarcinoma.  Until 
sponsor’s notification to the study sites, subject 
must be a RAS/v-raf murine sarcoma viral 
oncogene homolog B1 (BRAF) wild-type cancer. 
3. Received at least 2 prior regimens of standard 
treatment. 
− The following therapies must be included in 
prior lines of therapy; 
a. Fluoropyrimidine, irinotecan, and 
oxaliplatin 
b. In subjects with RAS wild-type, anti- 
epidermal growth factor receptor antibody.  
4. Is willing and able to provide an adequate archival 
tumor sample available for tissue screening of 
HER2 status by Central Laboratory.  If any anti-
HER2 therapies (including pan-human epidermal 
growth factor receptor agents and study drugs) were 
received, tumor samples used should come from 
post anti-HER2 therapy. 
5. Appropriate HER2 expression assessed by Central 
Laboratory per Cohort setting 
Cohort A: HER2 IHC 3+ or IHC 2+/ISH +. 
Cohort B: HER2 IHC 2+/ISH –. 
Cohort C: HER2 IHC 1+. 
6. Presence of at least one measurable lesion assessed 
by the investigator per Response Evaluation Criteria 


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in Solid Tumors (RECIST) version 1.1. 
7. Has eastern Cooperative Oncology Group 
performance status (ECOG PS) of 0 to 1. 
8. Has left ventricular ejection fraction ≥50%  
9. Has adequate organ function defined as: 
Parameter 
Laboratory value 
Adequate bone marrow function 
Platelet count 
≥100,000/mm3 
(Platelet transfusion is not 
allowed within 1 week prior 
to screening assessment) 
Hemoglobin 
≥9.0 g/dL  
(Red blood cell transfusion 
is not allowed within 1 week 
prior to screening 
assessment) 
Absolute neutrophil 
count 
≥1500/mm3  
(granulocyte-colony 
stimulating factor [G-CSF] 
administration is not allowed 
within 1 week prior to 
screening assessment) 
Adequate renal function 
Creatinine  
Creatinine clearance 
≥30 mL/min, as calculated 
using the Cockcroft-Gault 
equation (Section 17.1) 
Adequate hepatic function 
Alanine 
aminotransferase 
(ALT), Aspartate 
aminotransferase (AST) 
≤5 × upper limit of normal 
(ULN) 
Total bilirubin 
≤1.5 × ULN if no liver 
metastases or < 3 x ULN in 
the presence of documented 
Gilbert’s Syndrome 
(unconjugated 
hyperbilirubinemia) or liver 
metastases at baseline 
Adequate blood clotting function 


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International 
normalized 
ratio/Prothrombin time 
and activated partial 
thromboplastin time 
≤1.5 × ULN 
10. Male and female subjects of 
reproductive/childbearing potential must agree to 
follow instructions for method(s) of contraception. 
 
Key Exclusion Criteria 
1. Medical history of myocardial infarction within 6 
months before enrollment (study treatment), 
symptomatic congestive heart failure (New York 
Heart Association Class II to IV, Section 17.4), 
troponin levels consistent with myocardial 
infarction as defined according to the manufacturer 
28 days prior to enrollment (study treatment) 
2. Has a corrected QT interval (QTcF) prolongation to 
>470 ms (females) or >450 ms (males) based on 
average of the screening triplicate 12-lead 
electrocardiogram (ECG). 
3. Has a history of (non-infectious) ILD/pneumonitis 
that required steroids, has current ILD/pneumonitis, 
or where suspected ILD/pneumonitis cannot be 
ruled out by imaging at screening. 
4. Has clinically significant corneal disease. 
5. Has 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.  
Dosage Form, Dose and 
Route of Administration: 
The DS-8201a product is provided as a lyophilized powder 
containing 100 mg of DS-8201a in a glass vial (Lyo-DP).  
DS-8201a will be administered as an intravenous solution. 
Subjects will receive the 6.4 mg/kg of DS-8201a on Day 1 
of each cycle, once every 3 weeks. 
Study Endpoints: 
Primary Endpoint: 
• ORR assessed by the independent central imaging 
facility review based on RECIST version 1.1 in Cohort 


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A. 
Secondary Endpoints: 
• Efficacy Endpoints (based on central review unless 
otherwise stated): 
− ORR based on RECIST version 1.1 in Cohorts B 
and C 
− DoR 
− DCR 
− ORR assessed by the investigator based on 
RECIST version 1.1  
− PFS 
− OS 
Exploratory Endpoints: 
− Time to response 
− Best percent change in the sum of the longest 
diameters of measurable tumors 
Safety Endpoints: 
• Serious adverse events 
• Treatment-emergent adverse events (TEAEs) 
• Physical examination findings (including ECOG PS) 
• Vital sign measurements 
• Standard clinical laboratory parameters 
• ECG parameters 
• Echocardiogram/multigated acquisition acquisition 
findings 
• Ophthalmologic findings 
• Anti-drug antibodies (ADA)  
PK endpoints (DS-8201a, total anti-HER2 antibody, and 
MAAA-1181a): 
• PK parameters: Cmax, Tmax, and AUClast, and other 
parameters will be calculated if appropriate. 
• Serum concentrations. 
Biomarker endpoints 


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• Serum extracellular domain of HER2 
• Biomarker analysis using cell free deoxyribonucleic 
acid 
• Analysis of biopsies for mechanisms of  resistance to 
DS-8201a  
• Markers of prior COVID-19 infection 
Planned Sample Size: 
The total planned number of subjects is 90. 
Cohort A: 50; Cohort B: 20; and Cohort C: 20 
Statistical Analyses: 
The primary analysis will be performed after all subjects 
have either discontinued the study or at least completed 
tumor assessment at 18 weeks in Cohort A.  
Efficacy analyses: 
Performed for all subjects that who received at least 1 dose 
of study drug.  The primary efficacy endpoint is ORR 
assessed by independent radiologic facility review.  The 
point estimate of ORR and its 2-sided exact 95% 
confidence interval (CI) will be provided using Clopper-
Pearson method by cohort.  
The secondary efficacy endpoints are DoR, DCR, PFS 
(based on central assessments unless otherwise stated), and 
OS.  ORR assessed by the investigator and DCR will be 
analyzed in the same manner as the primary ORR analysis.  
DoR, PFS, and OS will be summarized using Kaplan-Meier 
method by cohort with median event times and their 2-
sided 95% CIs using Brookmeyer and Crowley method. 
Safety analyses: 
Safety analyses in general will be descriptive and will be 
presented in tabular format with the appropriate summary 
statistics by cohort. 
PK analyses: 
Serum concentrations for DS-8201a, total anti-HER2 
antibody and MAAA-1181a will be listed, plotted, and 
summarized using descriptive statistics by cohort at each 
time point.  PK parameters will be listed and summarized 
using descriptive statistics by cohort.  Population PK and 
PK-PD modeling will be conducted and reported 
separately. 
 


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TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT .................................................................................................. 2 
PROTOCOL SYNOPSIS ................................................................................................................ 3 
TABLE OF CONTENTS ................................................................................................................ 9 
LIST OF TABLES ........................................................................................................................ 15 
LIST OF FIGURES ....................................................................................................................... 16 
LIST OF ABBREVIATIONS ....................................................................................................... 17 
1. 
INTRODUCTION .......................................................................................................... 21 
1.1. 
Background ..................................................................................................................... 21 
1.2. 
Investigational Product ................................................................................................... 21 
1.2.1. 
Description ...................................................................................................................... 21 
1.2.2. 
Nonclinical Studies ......................................................................................................... 22 
1.2.2.1. Pharmacology .................................................................................................................. 22 
1.2.2.2. Safety Pharmacology ...................................................................................................... 22 
1.2.2.3. Pharmacokinetics and Drug Metabolism ........................................................................ 22 
1.2.2.4. Toxicology ...................................................................................................................... 23 
1.2.3. 
Clinical Experience ......................................................................................................... 24 
1.2.4. 
Summary of Clinical Pharmacokinetics .......................................................................... 25 
1.3. 
Study Rationale ............................................................................................................... 27 
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 Endpoint ............................................................................................................ 30 
2.3.2. 
Secondary Endpoints ....................................................................................................... 30 
2.3.3. 
Exploratory Endpoints .................................................................................................... 31 
3. 
STUDY DESIGN ............................................................................................................ 32 
3.1. 
Overall Design ................................................................................................................ 32 
3.1.1. 
Overview ......................................................................................................................... 32 


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3.1.2. 
Duration of the Study ...................................................................................................... 33 
3.1.3. 
Duration of Subject Participation .................................................................................... 33 
3.2. 
Discussion of Study Design ............................................................................................ 33 
3.3. 
Selection of Dose and Usage .......................................................................................... 33 
4. 
STUDY POPULATION ................................................................................................. 35 
4.1. 
Inclusion Criteria ............................................................................................................. 35 
4.2. 
Exclusion Criteria ........................................................................................................... 38 
5. 
STUDY TREATMENTS ................................................................................................ 40 
5.1. 
Assigning Subjects to Treatments and Blinding ............................................................. 40 
5.1.1. 
Treatment Groups/Sequences ......................................................................................... 40 
5.1.2. 
Method of Treatment Allocation ..................................................................................... 40 
5.1.3. 
Blinding ........................................................................................................................... 40 
5.1.4. 
Emergency Unblinding Procedure .................................................................................. 40 
5.2. 
Study Drug ...................................................................................................................... 40 
5.2.1. 
Description ...................................................................................................................... 40 
5.2.2. 
Labeling and Packaging .................................................................................................. 40 
5.2.3. 
Preparation ...................................................................................................................... 41 
5.2.4. 
Administration ................................................................................................................ 41 
5.2.5. 
Storage ............................................................................................................................ 41 
5.2.6. 
Drug Accountability ........................................................................................................ 41 
5.3. 
Control Treatment ........................................................................................................... 42 
5.4. 
Dose Modifications for Managing Adverse Events ........................................................ 42 
5.5. 
Method of Assessing Treatment Compliance ................................................................. 50 
5.6. 
Prior and Concomitant Medications ............................................................................... 50 
5.7. 
Subject Withdrawal/Discontinuation .............................................................................. 51 
5.7.1. 
Reasons for Discontinuation of Study Treatment ........................................................... 51 
5.7.2. 
Reasons for Discontinuation of Study Participation ....................................................... 52 
5.7.3. 
Withdrawal Procedures ................................................................................................... 52 
5.7.4. 
Subject Replacement ....................................................................................................... 52 
5.7.5. 
Subject Re-screening Procedures .................................................................................... 53 
6. 
STUDY PROCEDURES ................................................................................................ 54 
6.1. 
Tissue Screening ............................................................................................................. 54 
6.2. 
Screening ......................................................................................................................... 54 
6.3. 
Randomization ................................................................................................................ 56 


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6.4. 
Treatment Period ............................................................................................................. 56 
6.4.1. 
Cycle 1 to Cycle 4 and Subsequent Cycles ..................................................................... 56 
6.4.2. 
Every 6 Weeks (± 7 days) ............................................................................................... 59 
6.4.3. 
Fresh Tumor Biopsy During Treatment .......................................................................... 59 
6.4.4. 
Interstitial Lung Disease/Pneumonitis ............................................................................ 59 
6.5. 
End of Treatment ............................................................................................................ 60 
6.6. 
Follow-up ........................................................................................................................ 61 
7. 
EFFICACY ASSESSMENTS ......................................................................................... 63 
7.1. 
Assessments for Efficacy Endpoints ............................................................................... 63 
7.1.1. 
Primary Efficacy Endpoint .............................................................................................. 63 
7.1.2. 
Secondary Efficacy Endpoints ........................................................................................ 63 
7.1.3. 
Exploratory Efficacy Endpoints ...................................................................................... 63 
8. 
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS .......................... 64 
8.1. 
Pharmacokinetic (PK) Assessments ................................................................................ 64 
8.2. 
Biomarker Assessments .................................................................................................. 66 
8.2.1. 
Pharmacodynamic Assessments ..................................................................................... 66 
8.2.1.1. Pharmacodynamic Assessments in Blood Samples ........................................................ 66 
8.2.1.2. Pharmacodynamic Assessments in Tumor Specimens ................................................... 66 
8.2.1.3. Additional Exploratory Biomarker Assessments ............................................................ 67 
8.2.1.4. Disclosure of the Results of Additional Biomarker Assessments ................................... 67 
8.3. 
SARS-CoV-2 Serum samples collection ........................................................................ 67 
8.4. 
Pharmacogenomic Analysis ............................................................................................ 67 
8.4.1. 
Genomic or Genetic Analysis ......................................................................................... 67 
8.4.1.1. Disclosure of the Results of Genomic or Genetic Analysis ............................................ 67 
8.4.1.2. Storage and Disposal of Specimens for Genomic or Genetic Banking and 
Analysis ........................................................................................................................... 67 
8.5. 
Anonymization of Samples ............................................................................................. 68 
8.6. 
Sample Storage and Disposal .......................................................................................... 68 
8.7. 
Immunogenicity (Anti-drug Antibody) ........................................................................... 68 
9. 
SAFETY EVALUATION AND REPORTING ............................................................. 70 
9.1. 
Assessment of Safety Endpoint(s) .................................................................................. 70 
9.2. 
Adverse Event Collection and Reporting ........................................................................ 70 
9.3. 
Adverse Events of Special Interest ................................................................................. 71 
9.3.1. 
Interstitial Lung Disease/Pneumonitis ............................................................................ 71 


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9.3.1.1. Interstitial Lung Disease Adjudication Committee ......................................................... 72 
9.3.2. 
LVEF Decrease ............................................................................................................... 72 
9.4. 
Adverse Event ................................................................................................................. 72 
9.4.1. 
Definition of Adverse Event ........................................................................................... 72 
9.4.2. 
Serious Adverse Event .................................................................................................... 73 
9.4.3. 
Severity Assessment ....................................................................................................... 73 
9.4.4. 
Causality Assessment ...................................................................................................... 74 
9.4.5. 
Action Taken Regarding Study Drug(s) ......................................................................... 74 
9.4.6. 
Other Action Taken for Event ......................................................................................... 75 
9.4.7. 
Adverse Event Outcome ................................................................................................. 75 
9.5. 
Serious Adverse Events and Adverse Event of Special Interest 
Reporting-Procedure For Investigators ........................................................................... 75 
9.6. 
Notifying Regulatory Authorities, Investigators, and Institutional Review 
Board/Ethics Committee ................................................................................................. 77 
9.7. 
Exposure In Utero During Clinical Studies .................................................................... 77 
9.8. 
Clinical Laboratory Evaluations ..................................................................................... 77 
9.9. 
Vital Signs ....................................................................................................................... 78 
9.10. 
Electrocardiograms ......................................................................................................... 78 
9.11. 
Physical Examinations .................................................................................................... 79 
9.12. 
Other Examinations ......................................................................................................... 79 
10. 
OTHER ASSESSMENTS ............................................................................................... 80 
11. 
STATISTICAL METHODS ........................................................................................... 81 
11.1. 
General Statistical Considerations .................................................................................. 81 
11.2. 
Analysis Sets ................................................................................................................... 81 
11.2.1. Full Analysis Set/Safety Analysis Set ............................................................................. 81 
11.2.2. Pharmacokinetic Analysis Set ......................................................................................... 81 
11.3. 
Study Population Data .................................................................................................... 81 
11.4. 
Statistical Analyses ......................................................................................................... 82 
11.4.1. Efficacy Analyses ........................................................................................................... 82 
11.4.1.1. Primary Efficacy Analyses .............................................................................................. 82 
11.4.1.2. Secondary Efficacy Analyses .......................................................................................... 82 
11.4.1.3. Exploratory Efficacy Analyses ....................................................................................... 82 
11.4.2. Pharmacokinetic/Pharmacodynamic/Biomarker Analyses ............................................. 83 
11.4.2.1. Pharmacokinetic Analyses .............................................................................................. 83 


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11.4.2.2. Pharmacodynamic Analyses ........................................................................................... 84 
11.4.2.3. Biomarker Analyses ........................................................................................................ 84 
11.4.2.4. Pharmacogenomic Analyses ........................................................................................... 84 
11.4.3. Safety Analyses ............................................................................................................... 84 
11.4.3.1. Adverse Event Analyses ................................................................................................. 84 
11.4.3.2. Clinical Laboratory Evaluation Analyses ....................................................................... 84 
11.4.3.3. Vital Sign Analyses ......................................................................................................... 85 
11.4.3.4. Electrocardiogram Analyses ........................................................................................... 85 
11.4.3.5. Anti-Drug Antibodies (ADA) Analyses ......................................................................... 85 
11.4.3.6. Other Safety Analyses ..................................................................................................... 85 
11.4.4. Other Analyses ................................................................................................................ 85 
11.5. 
Interim Analyses ............................................................................................................. 85 
11.6. 
Sample Size Determination ............................................................................................. 85 
11.7. 
Statistical Analysis Process ............................................................................................. 86 
12. 
DATA INTEGRITY AND QUALITY ASSURANCE .................................................. 87 
12.1. 
Monitoring and Inspections ............................................................................................ 87 
12.2. 
Data Collection ............................................................................................................... 87 
12.3. 
Data Management ........................................................................................................... 88 
12.4. 
Study Documentation and Storage .................................................................................. 88 
12.5. 
Record Keeping ............................................................................................................... 89 
13. 
FINANCING AND INSURANCE ................................................................................. 91 
13.1. 
Finances .......................................................................................................................... 91 
13.2. 
Reimbursement, Indemnity, and Insurance ..................................................................... 91 
14. 
PUBLICATION POLICY ............................................................................................... 92 
15. 
ETHICS AND STUDY ADMINISTRATIVE INFORMATION .................................. 93 
15.1. 
Compliance Statement, Ethics, and Regulatory Compliance ......................................... 93 
15.2. 
Subject Confidentiality ................................................................................................... 93 
15.3. 
Informed Consent ............................................................................................................ 93 
15.4. 
Informed Consent for Pharmacogenomic Analysis ........................................................ 94 
15.5. 
Regulatory Compliance ................................................................................................... 94 
15.6. 
Protocol Deviations ......................................................................................................... 95 
15.7. 
Supply of New Information Affecting the Conduct of the Study ................................... 95 
15.8. 
Protocol Amendments ..................................................................................................... 96 
15.9. 
Study Termination ........................................................................................................... 96 


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15.10. 
Data and Safety Monitoring Board ................................................................................. 96 
15.11. 
Steering Committee ......................................................................................................... 96 
15.12. 
Address List .................................................................................................................... 96 
15.12.1. Sponsor ............................................................................................................................ 96 
15.12.2. Sponsor’s Responsible Medical Officer ......................................................................... 97 
15.12.3. Sponsor’s Clinical Study Leader ..................................................................................... 97 
15.12.4. Sponsor’s Clinical Operations Delivery Lead ................................................................ 97 
15.12.5. Sponsor’s Safety Contacts .............................................................................................. 97 
15.12.6. ARO ................................................................................................................................ 98 
15.12.7. CROs ............................................................................................................................... 98 
15.12.8. Vendor of Interactive Web Response System ................................................................. 98 
15.12.9. Central Laboratory .......................................................................................................... 98 
15.12.10. 
Central Imaging .......................................................................................................... 98 
15.12.11. 
Bioanalytical Laboratory (Pharmacokinetics and Anti-drug 
Antibodies) ...................................................................................................................... 99 
15.12.12. 
Sponsor’s Biostatistician ............................................................................................ 99 
15.12.13. 
Data Safety Monitoring Board ................................................................................... 99 
16. 
REFERENCES .............................................................................................................. 100 
17. 
APPENDICES .............................................................................................................. 102 
17.1. 
Cockcroft-Gault Equation ............................................................................................. 102 
17.2. 
Eastern Cooperative Oncology Group Performance Status (ECOG PS) ...................... 103 
17.3. 
Response Evaluation Criteria in Solid Tumors, Version 1.1 ........................................ 103 
17.3.1. Measurability of Tumor at Baseline .............................................................................. 103 
17.3.1.1. Definitions ..................................................................................................................... 103 
17.3.1.2. Specifications by Methods of Measurements ............................................................... 104 
17.3.2. Tumor Response Evaluation ......................................................................................... 105 
17.3.2.1. Assessment of Overall Tumor Burden and Measurable Disease .................................. 105 
17.3.2.2. Baseline Documentation of “Target” and “Non-target” Lesions .................................. 105 
17.3.2.3. Response Criteria .......................................................................................................... 106 
17.3.2.4. Evaluation of Best Overall Response ............................................................................ 108 
17.3.2.5. Frequency of Tumor Re-evaluation .............................................................................. 110 
17.4. 
New York Heart Association Functional Classification ............................................... 111 
17.5. 
Instructions Related to SARS-CoV-2 ........................................................................... 112 
17.5.1. Dose Modification Criteria for Suspected or Confirmed SARS-CoV-2 ....................... 112 


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17.5.2. Prior and Concomitant Medications- Prohibited Therapies/Products ........................... 113 
17.5.3. PK Assessment(s) if Chloroquine or Hydroxychloroquine is 
Administered ................................................................................................................. 113 
17.5.4. SARS-CoV-2 Assessment(s) ........................................................................................ 113 
17.5.5. Statistical Analysis - Assessment of the Impact of SARS-CoV-2 ................................ 113 
18. 
SCHEDULE OF EVENTS ........................................................................................... 114 
 
 
LIST OF TABLES 
Table 1.1: Mean (± Standard Deviation) Pharmacokinetic Parameters of Serum 
DS-8201a Following the First Dose ........................................................................... 26 
Table 1.2: Mean (± Standard Deviation) Pharmacokinetic Parameters of Serum 
Total Antibody Following the First Dose .................................................................. 26 
Table 1.3: Mean (± Standard Deviation) Pharmacokinetic Parameters of MAAA-
1181a Following the First Dose ................................................................................. 26 
Table 5.1: Dose Reduction Levels of DS-8201a ......................................................................... 42 
Table 5.2: Dose or schedule modification for DS-8201a ............................................................ 43 
Table 8.1: Pharmacokinetic Parameters ...................................................................................... 64 
Table 8.2: Blood Sampling for Pharmacokinetic Analysis ......................................................... 65 
Table 8.3: Schedule of PK Sample Collection for Subjects Administered 
Chloroquine or Hydroxychloroquine ......................................................................... 65 
Table 8.4: Extracellular Domain of Human Epidermal Growth Factor Receptor 2 
Sampling Time Points ................................................................................................ 66 
Table 8.5: Cell Free Deoxyribonucleic Acid Sampling Time Points .......................................... 66 
Table 17.1: Eastern Cooperative Oncology Group Performance Status Scale ........................... 103 
Table 17.2: Overall Response: Subjects with Target (± Non-target) Disease ............................. 109 
Table 17.3: New York Heart Association Functional Classification .......................................... 111 
Table 17.4: SARS-CoV-2 Dose Modification Criteria ............................................................... 112 
Table 18.1: Schedule of Events ................................................................................................... 114 
 


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LIST OF FIGURES 
Figure 3.1: Study Design Schema of DS8201-A-J203 ................................................................. 33 
 
 


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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 events of special interest 
ALT  
alanine aminotransferase 
AST  
aspartate aminotransferase (transaminase) 
AUC 
area under the plasma/serum concentration-time curve 
AUC0-21d 
area under the plasma/serum concentration-time curve up to Day 
21 
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 time 
BI 
before infusion  
BRAF 
v-raf murine sarcoma viral oncogene homolog B1 
BSEP 
bile salt export pump 
cfDNA 
cell free deoxyribonucleic acid 
CHO 
Chinese hamster ovary 
CI 
confidence interval 
CL 
total body clearance 
Cmax 
maximum plasma/serum concentration 
COVID-19 
coronavirus disease 2019 
CR  
complete response 
CrCl 
creatinine clearance  
CRF 
case report form 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DAR 
drug-to-antibody ratio  
CCI


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ABBREVIATION 
DEFINITION 
DCR 
disease control rate 
DLT 
dose limiting toxicity 
DoR 
duration of response 
DS1 
drug substance manufactured using MAAL-9001 produced using 
the CHO
 
DS2 
drug substance manufactured using MAAL-9001 produced using 
the CHO
  
EC 
Ethics Committee 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group performance status 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EGFR 
epidermal growth factor receptor 
EIU 
Exposure In Utero 
EOI 
end of infusion 
EOT 
end of treatment 
EU 
European Union 
FAS 
full analysis set 
F/U 
follow-up 
GCP 
Good Clinical Practice  
G-CSF 
granulocyte-colony stimulating factor 
HER2 
human epidermal growth factor receptor 2 
HER2ECD 
extracellular domain of HER2 
hERG 
human ether-a-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 
IHC 
immunohistochemistry 
ILD 
interstitial lung disease 
INN 
international non-proprietary name 
INR/PT and aPTT 
International normalized ratio/Prothrombin time and activated 
partial thromboplastin time 
CCI
C
CI


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ABBREVIATION 
DEFINITION 
IRB 
institutional review board 
ISH 
in situ hybridization  
IV 
intravenous(ly) 
IXRS 
interactive web response system 
KRAS 
human Kirsten rat sarcoma viral oncogene homologue 
LVEF 
left ventricular ejection fraction 
MAAA-1181a 
the drug component of DS-8201a – a derivative of exatecan, a 
topoisomerase I inhibitor, free form 
MAAL-9001 
the antibody component of DS-8201a – a humanized anti-HER2 
immunoglobulin G1 monoclonal antibody produced in-house with 
reference to the same amino acid sequence of trastuzumab 
MATE 
multidrug and toxin extrusion 
mCRC 
metastatic colorectal cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
mRNA 
messenger RNA 
MTD 
maximum tolerated dose 
MUGA 
multigated acquisition (scan) 
NCI 
National Cancer Institute 
NE 
not evaluable 
NSAID 
nonsteroidal anti-inflammatory drug 
OAT 
organic anion transporter 
OATP 
organic anion transporting polypeptide 
OCT 
organic cation transporter 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
pop-PK 
population pharmacokinetics 
pop-PK/PD 
population pharmacokinetics/pharmacodynamics 
PR 
partial response 
PT 
Preferred Term 
Q3W 
once every 3 weeks 
QTc 
corrected QT interval 


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ABBREVIATION 
DEFINITION 
QTcF 
corrected QT interval by Fridericiaʼs formula 
RAS 
rat sarcoma viral oncogenes homolog 
RECIST 
Response Evaluation Criteria in Solid Tumours 
RP2D 
recommended phase 2 dose 
RT-PCR 
real-time polymerase chain reaction 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SAVER 
Serious Adverse Event Report 
SD 
stable disease 
SLD 
sum of the longest diameters 
SMQ 
Standard MedDRA Query 
SOC 
system organ class 
SOP 
standard operating procedure 
SpO2 
peripheral oxygen saturation 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t1/2 
terminal elimination half-life 
TBL 
total bilirubin 
T-DM1 
trastuzumab emtansine 
TEAE 
treatment emergent adverse event 
Tmax 
time to reach maximum plasma/serum concentration 
ULN 
upper limit of normal 
Vss 
volume of distribution at the steady state 
 


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1. 
INTRODUCTION 
1.1. 
Background 
Colorectal cancer is the third most common cancer worldwide; there were approximately 
1.36 million new cases diagnosed and 690,000 deaths worldwide in 2012.1   Several 
standard therapies for advanced or metastatic colorectal cancer are listed in the guidelines 
2 ,3 ,4, however, the treatment benefit of third line or subsequent therapy is limited in 
patients who maintain their good performance status after receiving available treatments.   
Because of differences in examination methods and objective criteria, the reported 
frequency of Human epidermal growth factor receptor 2 (HER2) amplification and 
overexpression in colorectal cancer varies between studies.5  In the HERACLES study to 
assess the antitumor activity of trastuzumab and lapatinib in patients with HER2-positive 
FRORUHFWDOFDQFHUKDGHER2-positive tumors in human Kirsten rat sarcoma viral 
oncogene homologue (KRAS) wild-type colorectal cancer.6  In the report from the 
analysis of 3256 patients enrolled in the QUSAR, FOCUS, and PICCOLO studies, it was 
reported that HER2 overexpression in KRAS/v-raf murine sarcoma viral oncogene 
homolog B1 (BRAF) PXWDWHGFRORUHFWDOFDQFHUWXPRUZDV7  HER2 gene 
amplification is considered to be associated with resistance to anti-epidermal growth 
factor receptor (EGFR)-targeted therapy8  and HER2 amplification is a predictive marker 
of shorter progression-free survival (PFS) after anti-EGFR antibody cetuximab treatment 
in patients with metastatic colorectal cancer (mCRC) harboring wild-type rat sarcoma 
viral oncogenes homolog (RAS) and BRAF.9  Therefore, HER2 is considered to be an 
important target for mCRC, however no HER2-targeted therapies are approved for 
colorectal cancer. 
DS-8201a is an antibody-drug conjugate (ADC) targeting HER2.  In the ongoing Phase 1 
clinical study, DS8201-A-J101, in subjects with advanced solid tumors, DS-8201a was 
well tolerated at repeated doses of up to 8.0 mg/kg intravenously (IV) once every 3 weeks 
(Q3W).  
1.2. 
Investigational Product 
1.2.1. 
Description 
DS-8201a consists of an antibody component, MAAL-9001, covalently conjugated via a 
maleimide tetrapeptide linker, to a drug component, MAAA-1181a.  MAAL-9001 is an in-
house humanized immunoglobulin G1 monoclonal antibody with the same amino acid 
sequence as trastuzumab.  MAAA-1181a, an exatecan derivative, is a topoisomerase I 
inhibitor that is cell-membrane permeable, and more potent than SN-38 (active metabolite 
of irinotecan).  This ADC achieves a high drug-to-antibody ratio (DAR) (7 to 8) with 
homogeneous conjugation with MAAA-1181a.  DS-8201a is cleaved by lysosomal 
enzymes and releases MAAA-1181a in the cytoplasm after it binds to the HER2 receptor, 
and gets internalized in tumor cells. 
The DS-8201a Phase 1 clinical study, DS8201-A-J101, was initiated with the antibody 
component, MAAL-9001, produced using the Chinese hamster ovary (CHO)
 cell line 
(DS1).  To support J203 study, as well as commercial development, transition has been 
CCI




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pharmacokinetics (PK) profiles, indicating that the majority of the administered DS-8201a 
circulates in plasma unchanged.  The plasma concentrations of MAAA-1181a, the drug 
that is release from DS-8201a, were quite low.  The Cmax of DS-8201a for DS2 was 
statistically comparable to that for DS1, but the AUClast of DS-8201a for DS2 was about 
22% lower than that for DS1.  No anti-DS-8201a antibodies were detected in any animals. 
The plasma protein binding ratios of MAAA-1181a (10 ng/mL to 100 ng/mL) were 90.3% 
to 92.5% in mice, 94.2% to 96.7% in rats, 86.5% to 89.1% in monkeys, and 96.8% to 
98.0% in humans. 
The in vitro release rates of MAAA-1181a from DS-8201a in mouse, rat, monkey, and 
human plasma for 3 weeks were 3.9% or less.  Cytochrome P450 (CYP) 3A4 was the 
primary CYP enzyme involved in the metabolism of MAAA-1181a.  No human-specific 
metabolites were detected in vitro. 
MAAA-1181a did not exhibit any potential to inhibit CYP1A2, CYP2B6, CYP2C8, 
CYP2C9, CYP2C19, CYP2D6, or CYP3A (50% inhibitory concentration [IC50] 
>50 μmol/L).  MAAA-1181a did not exhibit any potential to induce CYP3A4, CYP1A2, 
or CYP2B6 at concentrations of up to 30 μmol/L.  MAAA-1181a did not inhibit organic 
anion transporter (OAT) 3, organic cation transporter (OCT) 1, OCT2, organic anion 
transporting polypeptide (OATP) 1B3, multidrug and toxin extrusion (MATE) 1, MATE2-
K, P-glycoprotein, breast cancer resistance protein, and bile salt export pump (BSEP) 
(IC50 >30 μmol/L).  MAAA-1181a inhibited OAT1 and OATP1B1 with the IC50 values of 
12.7 and 14.4 μmol/L, respectively, although the values were much higher than the Cmax 
of MAAA-1181a in humans (9.25 ng/mL [0.019 μmol/L] at 8.0 mg/kg of DS-8201a).  In 
addition, OATPs appeared to contribute to the human hepatic uptake of MAAA-1181a. 
1.2.2.4. 
Toxicology 
In a study of intermittent intravenous dosing of DS-8201a in rats (Q3W dosing for 
6 weeks), no deaths or moribund animals were found at dose levels up to 197 mg/kg, the 
maximum dose.  The major observed findings were testicular and intestinal toxicity at 
dose levels of 20 mg/kg and greater, and lymphatic/hematopoietic, skin, incisor tooth 
toxicity, and renal toxicity at dose levels of 60 mg/kg and greater.  Except for the testicular 
and incisor tooth changes, these changes were all found to recover. 
In an intermittent intravenous dosing study of DS-8201a in cynomolgus monkeys (Q3W, 
6 weeks), one female was sacrificed moribund at 78.8 mg/kg, the highest dose level tested.  
The major toxicity findings in this moribund animal were observed in the intestine, 
hematopoietic system, skin, and kidney.  The cause of the moribundity appeared to be the 
deteriorated condition of the animal, which resulted from decreased body weight and food 
consumption, as well as bone marrow toxicity and intestinal toxicity.  The major findings 
of toxicity in the surviving animals were observed in the intestine at dose levels of 
10 mg/kg and greater, and in the lung, testes, and skin at dose levels of 30 mg/kg and 
greater.  In addition, hematopoietic system toxicity, renal toxicity, and electrocardiogram 
(ECG) abnormalities (shortened PR interval and corrected QT interval [QTc] 
prolongation) were found at 78.8 mg/kg.  Except for the pulmonary and skin toxicity 
(pigmentation), these findings tended to recover. 
Thus, as described above, the severely toxic dose in 10% of the animals (STD10) in a rat 
intermittent intravenous dosing study of DS-8201a was found to be greater than 


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197 mg/kg.  In the monkey study, due to observed moribundity at 78.8 mg/kg and 
evidence of critical pulmonary toxicity (eg, interstitial inflammation and/or alveolar 
edema) in the surviving animals, it was concluded that the highest non-severely toxic dose 
is 30 mg/kg.  
In an intermittent intravenous dose toxicity study of MAAA-1181a (once weekly dosing 
for 4 weeks), findings in the lymphatic/hematopoietic system, intestinal tract, and cornea 
of the eye were observed at 3 mg/kg and greater in rats but there was no deaths or 
moribundity up to 30 mg/kg.  Findings similar to those in rats were observed in 
cynomolgus monkeys at dose levels of 1 mg/kg and greater.  In addition, 1 female monkey 
died and 1 male monkey was sacrificed moribund at 12 mg/kg.  Although effects on the 
heart (focal myocardial cell degeneration/necrosis) were found in the moribund male 
along with the above-mentioned toxicities, there were no abnormal heart findings in the 
female that died, even though both animals exhibited worsening clinical conditions 
associated with sustained decreases in food consumption, bone marrow toxicity, and 
intestinal toxicity.  These changes were considered to be the cause of death and 
moribundity.  The common adverse findings in both DS-8201a and MAAA-1181a studies 
were intestinal and lymphatic/hematopoietic system toxicities.  For DS-8201a treatment, 
pulmonary, testicular, skin, and renal toxicities were observed while heart, liver, and 
corneal toxicities were found only when MAAA-1181a was administered.   
In a human cross-reactivity study of DS-8201a with a panel of human tissues, DS-8201a-
related cell membrane staining was found only in the placenta.  In a cross-reactivity study 
of DS-8201a with selected cynomolgus monkey tissues (eg, brain, liver, kidney, lung, 
heart, intestines, lymphoid organs, testes, and skin), neither membranous nor cytoplasmic 
staining was noted in any tissues.   
In an in vitro 3T3 NRU phototoxicity study, MAAA-1181a was found to be phototoxic to 
Balb/c 3T3 mouse fibroblasts.  However, in an in vivo single dose phototoxicity study of 
MAAA-1181a in pigmented rats, no phototoxic reaction was noted at 3 mg/kg, the highest 
dose tested. For additional nonclinical data supporting DS-8201a use in nonclinical studies, 
please refer to the current Investigator’s Brochure (IB). 
1.2.3. 
Clinical Experience 
DS8201-A-J101 is a Phase 1, 2-part, multicenter, non-randomized, open-label, multiple 
dose, first in human study of DS-8201a.  The Dose Escalation part (Part 1) was conducted 
to identify the maximum tolerated dose (MTD) or the recommended phase 2 dose (RP2D) 
of DS-8201a, and the Dose Expansion part (Part 2) is being conducted to confirm the 
safety, tolerability, and efficacy of DS-8201a at the MTD/RP2D.  DS-8201a is infused 
intravenously into each subject on Day 1 of each 21 day cycle.  Subjects may continue to 
receive DS-8201a Q3W at the discretion of the Investigators, until unacceptable toxicity, 
progressive disease, or withdrawal of consent. This study is on-going. 
Part 1 enrolled subjects with advanced breast cancer and gastric or gastroesophageal 
junction adenocarcinoma.  Upon completion of Part 1 with determination of MTD/RP2D, 
Part 2 was started.  Part 2 consists of multiple cohorts:  subjects with T-DM1-treated 
HER2 overexpressing breast cancer (Part 2a); trastuzumab-treated HER2 overexpressing 
gastric or gastroesophageal junction adenocarcinoma (Part 2b); HER2 low-expressing 
breast cancer (Part 2c); HER2 expressing other solid malignant tumor (Part 2d); and 
HER2 expressing breast cancer (Part 2e).   


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As of 8 June 2017, a total of 148 subjects, 24 in Part 1 and 124 in Part 2, have received 
DS-8201a in this study.  In Part 1, no dose limiting toxicities (DLTs) were reported and the 
MTD was not reached.  Two doses were chosen for expansion in Part 2: 5.4 mg/kg and 
6.4 mg/kg.  Overall efficacy results from all dose cohorts in Part 1 demonstrate an objective 
response rate (ORR) of 34.8% (8 of 23) and disease control rate (DCR) of 91.3% (21 of 23).  
Preliminary result from Part 2 demonstrates an ORR of 48.8% (41 of 84) and a DCR of 85.7% 
(72 of 84).  Among 148 subjects who have received DS-8201a across all parts and cohorts in 
the study, the adverse events (AEs) that occurred in more than 20% of subjects were nausea 
(65%), decreased appetite (53%), vomiting (34%), platelet count decreased (31%), anemia 
(28%), alopecia (26%), diarrhea (24%), constipation (24%), neutrophil count decreased (24%), 
white blood cell count decreased (24%), and malaise (22%).  The majority of the AEs were of 
Grade 1 or 2 severity; 52 of 148 subjects (35.1%) experienced Grade 3 AEs and 10 subjects 
(6.8%) experienced Grade 4 AEs as the worst grade experienced.  As of 10 April, 2 out of 5 
evaluable patients with colorectal cancer achieved partial responses (PRs) and 3 patients 
were stable diseases (SDs). 
Refer to the current IB for a summary of preliminary clinical study data. 
1.2.4. 
Summary of Clinical Pharmacokinetics 
Preliminary PK data are available from 24 subjects in DS8201-A-J101 study.  The study is 
on-going.   
PK parameters of DS-8201a, total antibody and MAAA-1181a at 5.4, 6.4, and 8.0 mg/kg 
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 tended to increase 
greater than dose-proportional.  Terminal elimination half-life (T1/2) also increased with 
dose, and flattened out in the 6.4 and 8.0 mg/kg cohorts.  Following a single intravenous 
administration of DS-8201a at 6.4 mg/kg, peak serum concentration (Cmax) of DS-8201a 
was achieved with a median Tmax of 2.16 hours and mean T1/2 of 7.33 days.  The volume 
of distribution at steady state for DS-8201a was approximately 45 mL/kg to 70 mL/kg 
(approximating plasma/serum volume), suggesting that DS-8201a is primarily limited to 
the vascular compartment. 
The total antibody profile is 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 time to reach Tmax (6 to 7 hours, median Tmax) compared to those for DS-
8201a.  The systemic exposure (Cmax and AUC 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.  The elimination (T1/2) appeared to be similar to that of DS-8201a.  This 
reflects the intrinsic stability of the linker when DS-8201a is in circulation systemically. 


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Table 1.1: 
Mean (± Standard Deviation) Pharmacokinetic Parameters of Serum 
DS-8201a Following the First Dose 
Dose 
(mg/kg) 
Cmax 
(μg/mL) 
Tmaxa 
(h) 
AUClast 
(μg·day/mL) 
AUCinf 
(μg·day/mL) 
T1/2 
(day) 
CL 
(mL/day/kg) 
Vss 
(mL/kg) 
5.4 
(N = 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 
(N = 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 
(N = 3) 
216 
(52.0) 
1.92 
(1.92, 
2.16) 
914 
(235) 
1020 
(279) 
6.97 
(0.357) 
8.17 
(1.93) 
69.7 
(13.1) 
AUClast = area under the plasma concentration-time curve up to the last quantifiable time, AUCinf = area 
under the plasma concentration-time curve up to infinity, CL: total body clearance, Cmax = maximum 
plasma concentration, N = number, T1/2 = terminal elimination half-life, Tmax = time to reach maximum 
plasma concentration, Vss: volume of distribution at steady state. 
Mean (standard deviation) 
Tmax reported as median (min, max). 
 
Table 1.2: 
Mean (± Standard Deviation) Pharmacokinetic Parameters of Serum 
Total Antibody Following the First Dose 
Dose 
(mg/kg) 
Cmax 
(μg/mL) 
Tmax a 
(h) 
AUClast 
(μg·day/mL) 
AUCinf 
(μg·day/mL) 
T1/2 
(day) 
5.4 (N = 6) 
116 (13.9) 
1.92 (1.92, 6.96) 
609 (151) 
682 (172) 
6.78 (2.39) 
6.4 (N = 6) 
146 (18.9) 
3.84 (2.16, 6.96) 
878 (97.1) 
1050 (149) 
8.25 (2.16) 
8.0 (N = 3) 
178 (18.5) 
2.16 (1.92, 6.72) 
1090 (213) 
1270 (296) 
7.35 (0.417) 
AUClast = area under the plasma concentration-time curve up to the last quantifiable time, AUCinf = area 
under the plasma concentration-time curve up to infinity, Cmax = maximum plasma concentration, N = 
number, T1/2 = terminal elimination half-life, Tmax = time to reach maximum plasma. concentration 
Mean (standard deviation) 
Tmax reported as median (min, max). 
 
Table 1.3: 
Mean (± Standard Deviation) Pharmacokinetic Parameters of MAAA-
1181a Following the First Dose  
Dose 
(mg/kg) 
Cmax 
(ng/mL) 
Tmax a 
(h) 
AUClast 
(ng·day/mL) 
AUCinf 
(ng·day/mL) 
T1/2 
(day) 
5.4 (N = 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 (N = 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 (N = 3) 
9.25 (3.18) 
6.72 (6.72, 6.96) 
39.4 (6.43) 
43.4 (9.16) 
6.36 (1.53) 
AUClast = area under the plasma concentration-time curve up to the last quantifiable time, AUCinf = area 
under the plasma concentration-time curve up to infinity, Cmax = maximum plasma concentration, N = 
number, T1/2 = terminal elimination half-life, Tmax = time to reach maximum plasma concentration. 
Mean (standard deviation), Tmax reported as median (min, max). 




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exploratory cohort for HER2 low expressed subjects will be opened after monitor the data 
of the 20 subjects with HER2-overexpressing colorectal cancer. 
1.4. 
Risks and Benefits for Study Subjects 
Preliminary data suggests that DS-8201a demonstrated anti-tumor activity with a small 
number of HER2-overexpressing colorectal cancer subjects (see Section 1.2.3). 
Overall, the reported AEs in the DS8201-A-J101 clinical study (see Section 1.2.3) are 
consistent with the safety profile of DS-8201a, expected based on data available from 
nonclinical toxicology studies as well as drugs of similar class.  Considering the frequency 
and biological plausibility of the AEs reported, the following AEs have been identified as 
adverse drug reactions associated with the use of DS-8201a: nausea, decreased appetite, 
vomiting, platelet count decreased, anaemia, alopecia, diarrhoea, neutrophil count 
decreased, white blood cell count decreased.  The majority of the treatment emergent 
adverse events (TEAEs) were of Grade 1 and Grade 2 severity.   Based on clinical data 
and safety information available from other sources as of 13 Dec 2017 and the 2 fatal 
cases confirmed by the ILD AC as ILD and caused by DS-8201a, ILD and pneumonitis 
are added as adverse drug reactions associated with the use of DS-8201a.  Subjects 
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, the intestinal toxicity, hematopoietic system toxicity, 
pulmonary toxicity, testicular toxicity, skin toxicity, and renal toxicity were found in 
association with the administration of DS-8201a.  In addition to these toxicities, similar to 
other products of the same class, the possibility of cardiotoxicity, hepatotoxicity, embryo-
fetal toxicity, or corneal toxicity occurring in subjects receiving DS-8201a cannot be 
excluded.    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 end 
of treatment, 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. 
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, the following events are considered to be adverse events of special interest 
(AESI): Interstitial lung disease (ILD)/pneumonitis, Cardiotoxicity (cardiac-related events 
including QT Prolongation and Left ventricular ejection fraction (LVEF) Decrease), and 
Infusion related reactions.   
ILD/pneumonitis should be ruled out if a subject develops an acute onset of new or 
worsening pulmonary or other related signs/symptoms such as dyspnea, cough or fever.  If 
the AE is suspected to be ILD/pneumonitis, study drug should be interrupted pending 
diagnostic evaluation, which should include high resolution CT and pulmonologist 
consultation.  As soon as ILD/pneumonitis is suspected, corticosteroid treatment should be 
started promptly as per clinical treatment guidelines. 
If the AE is confirmed to be ILD/pneumonitis, follow the management guidance as 
described in Section 5.4.  An ILD Adjudication Committee (AC) is being established for 
the program and will review all cases of potential ILD/pneumonitis on an ongoing basis.   


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LVEF will be measured by either echocardiogram (ECHO) or multigated acquisition 
(MUGA) scan.  All ECHOs/MUGAs will be evaluated by the Investigator or delegated 
physician for monitoring cardiac function.  Troponin will be measured at screening and 
after each infusion and as needed based on subject reported cardiac symptoms.  Triplicate 
ECGs will be performed and standard ECG parameters will be measured, including RR, 
PR, QT intervals, and QRS duration.   
As with any therapeutic antibodies, there is a possibility of infusion-related reactions, and 
immune responses causing allergic or anaphylactic reactions with administration of DS-
8201a.  Immune response causing allergic or anaphylactic reactions is considered to be an 
event of special interest for DS-8201a clinical program.  Subjects receiving DS-8201a 
should be monitored vital signs, physical examination, monitor signs and symptoms of 
infusion related reaction: chills, fever, hypotension, skin rash, etc. 
Additional safety assessments should be conducted as needed, at the investigator’s 
discretion.  Hepatotoxicity, embryo-fetal toxicity, visual disturbances/corneal toxicity, or 
phototoxicity occurring in subjects receiving DS-8201a also cannot be excluded.   
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 further clinical development of DS-8201a in 
this patient population.  For up to date assessments of risks and benefits to subjects, please 
refer to the current IB for DS-8201a. 


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2. 
STUDY OBJECTIVES AND HYPOTHESIS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objectives 
• To determine the ORR of DS-8201a in HER2-positive advanced metastatic 
colorectal cancer patients (Cohort A). 
2.1.2. 
Secondary Objectives 
• To evaluate duration of response (DoR), DCR, PFS, and overall survival (OS).  
ORR assessed by the investigator is also evaluated. 
• To evaluate the safety of DS-8201a  
• To determine the PK and anti-drug antibodies (ADA) of DS-8201a 
2.1.3. 
Exploratory Objectives 
• To evaluate time to response 
• To determine biomarker 
• To evaluate exposure-response relationships for efficacy and safety endpoints 
2.2. 
Study Hypotheses 
DS-8201a confers an ORR benefit in HER2-expressing advanced colorectal cancer 
patients 
2.3. 
Study Endpoints 
2.3.1. 
Primary Endpoint 
ORR assessed by the independent radiologic facility review based on Response Evaluation 
Criteria in Solid Tumors (RECIST) version 1.1 in Cohort A. 
2.3.2. 
Secondary Endpoints 
• Efficacy Endpoints (based on central review unless otherwise stated): 
− ORR based on RECIST version 1.1 in Cohorts B and C 
− DoR 
− DCR 
− ORR assessed by the investigator based on RECIST version 1.1.  
− PFS 
− OS 
• Safety Endpoints will include: 


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− Serious adverse events (SAEs)  
− TEAEs  
− Physical examination findings (including Eastern Cooperative Oncology 
Group performance status [ECOG PS])  
− Vital sign measurements  
− Standard clinical laboratory parameters 
− ECG parameters 
− ECHO/MUGA findings 
− Ophthalmologic findings 
− ADA 
• PK Endpoints (DS-8201a, total anti-HER2 antibody and MAAA-1181a): 
− PK parameters: Cmax, Tmax, AUClast and AUC0-21d 
− Serum concentrations. 
2.3.3. 
Exploratory Endpoints 
• Exploratory efficacy endpoints: 
− Time to response 
− Best percent change in the sum of the longest diameters (SLD) of 
measurable tumors 
• Serum extracellular domain of HER2 (HER2ECD) 
• Biomarker analysis using cell free deoxyribonucleic acid (cfDNA) 
• Analysis of biopsies for mechanisms of  resistance to DS-8201a 
• Markers of prior COVID-19 infection 


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3. 
STUDY DESIGN 
3.1. 
Overall Design 
3.1.1. 
Overview 
This is a multicenter, open-label, 3-cohort, Phase 2 study to investigate the safety and 
efficacy of DS-8201a in HER2-expressing advanced colorectal cancer subjects.  
Cohort A is a single arm study and will enroll approximately 50 subjects with HER2-
positive (immnohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization [ISH] +), 
advanced colorectal cancer.  Sponsor monitors the data after at least 20 subjects completed 
tumor assessment at 12 weeks in Cohort A.  Cohorts B and C will be opened depending on 
the assessment of benefit and risk observed in the program, and Sponsor will inform to the 
study sites when Cohorts B and C are opened. 
Cohort B will enroll approximately 20 subjects with HER2 IHC 2+/ISH – advanced 
colorectal cancer.  
Cohort C will enroll approximately 20 subjects with HER2 IHC 1+ advanced colorectal 
cancer.  
DS-8201a will be administered as a sterile IV solution at a dose of the 6.4 mg/kg every 3 
weeks. 
After obtaining a signed informed consent form (ICF)  for tissue screening from a subject, 
the tumor samples will be submitted to central laboratory to examine HER2 status for 
screening.  The subject whose ICF for study entry will be registered to interactive web 
response system (IXRS). 
The study treatment will be continued according to the dosing criteria to derive clinical 
benefit in the absence of withdrawal of subject consent, progressive disease (PD), or 
unacceptable toxicity.  If the study treatment is delayed more than 4 weeks from the 
planned date of administration, the subject will be withdrawn from the study (see Section 
5.4). 


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Figure 3.1: 
Study Design Schema of DS8201-A-J203 
 
 
 
3.1.2. 
Duration of the Study 
Enrollment is planned to occur over approximately 18 months, and treatment and follow-
up (F/U) is projected to be completed approximately 6 months thereafter.  Thus, the 
anticipated duration of the study is at least 24 months. 
Sponsor may terminate the study at any time and study termination may also be requested 
by (a) competent authority(ies).  
3.1.3. 
Duration of Subject Participation 
Each cycle of treatment of DS-8201a will be 21 days. The number of treatment cycles in 
this study is not fixed.  Upon commencing study treatment, subjects may continue 
receiving the study drug until the occurrence of any of the events defined in Section 5.7.  
After discontinuation from study treatment, all subjects, regardless of whether they 
discontinued prior to or subsequent to disease progression, may be contacted every 3 
months until death or until F/U data collection is no longer needed (at the sponsor’s 
discretion), to obtain information about subsequent treatment(s) and survival status. 
3.2. 
Discussion of Study Design 
It is estimated that approximately 90 subjects will be enrolled in the study in North 
America, Japan, and European Union (EU).  
3.3. 
Selection of Dose and Usage 
The dose selection was based on the preliminary clinical data from Study DS8201-A-J101.  
DS-8201a was administered at 0.8 mg/kg to 8.0 mg/kg Q3W in the Phase 1 study and the 
MTD was not reached up to 8.0 mg/kg.  In the 8.0 mg/kg cohort, 2 of 3 subjects 
HER2 = human epidermal growth factor receptor 2, IHC = immunohistochemistry, ISH = in situ 
hybridization, IXRS = interactive web/voice response system 
Cohort B and C are opened after Sponsor’s notification to the study sites. 


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discontinued due to adverse events.  In the Part 2d, 11 colorectal cancer subjects received 
6.4 mg/kg of DS-8201a and 2 of them had PR.  On the basis of the efficacy, tolerability 
and PK profile established in the Phase 1 study and non-clinical studies, the dose of 
6.4 mg/kg Q3W will be used in this study. 


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4. 
STUDY POPULATION 
Subjects must sign and date the informed consent form 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. Age ≥20 years old in Japan, ≥18 years old in other countries. 
2. Pathologically documented unresectable, recurrent, or metastatic colorectal 
adenocarcinoma.  Until sponsor’s notification to the study sites, subject must be a 
RAS/BRAF wild-type cancer. 
3. Received at least 2 prior regimens of standard treatment 
− The following therapies must be included in prior lines of therapy; 
a. Fluoropyrimidine, irinotecan, and oxaliplatin 
b. In subjects with RAS wild-type, anti-EGFR antibody.  
4. Is willing and able to provide an adequate archival tumor sample available for 
tissue screening to confirm HER2 status by Central Laboratory.  If any anti-HER2 
therapies (including pan-human epidermal growth factor receptor agents and study 
drugs) were received, tumor samples used should come from post anti-HER2 
therapy. 
5. Appropriate HER2 expression assessed by Central Laboratory per Cohort setting 
Cohort A: HER2 IHC 3+ or IHC 2+/ISH +.  
Cohort B: HER2 IHC 2+/ISH –. 
Cohort C: HER2 IHC 1+. 
6. Presence of at least 1 measurable lesion assessed by the investigator based on 
RECIST version 1.1. 
7. Has ECOG PS of 0 to 1. 
8. Has LVEF ≥50% within 28 days before enrollment (study drug treatment). 
9. Has adequate organ function within 14 days before enrollment (study drug 
treatment), defined as: 
Parameter 
Laboratory value 
Adequate bone marrow function 
Platelet count 
≥100,000/mm3  
(Platelet transfusion is not allowed within 1 
week prior to screening assessment) 
Hemoglobin 
≥9.0 g/dL  
(Red blood cell transfusion is not allowed 
within 1 week prior to screening assessment) 


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Parameter 
Laboratory value 
Absolute neutrophil count 
≥1500/mm3  
(G-CSF administration is not allowed within 1 
week prior to screening assessment) 
Adequate renal function 
Creatinine 
Creatinine clearance ≥30 mL/min as calculated 
using the Cockcroft-Gault equation (Section 
17.1) 
Adequate hepatic function 
Alanine aminotransferase (ALT), 
Aspartate aminotransferase (AST) 
 ≤5 × upper limit of normal (ULN) 
Total bilirubin  
≤1.5 × ULN if no liver metastases or < 3 x ULN 
in the presence of documented Gilbert’s 
Syndrome (unconjugated hyperbilirubinemia) 
or liver metastases at baseline 
Adequate blood clotting function 
International normalized 
ratio/Prothrombin time and activated 
partial thromboplastin time 
≤1.5 × ULN 
 
10. Has adequate treatment washout period before enrollment (study treatment), 
defined as: 
Treatment 
Washout Period 
Major surgery 
>4 weeks 
Radiation therapy 
>4 weeks (if palliative stereotactic radiation 
therapy without abdominal, >2 weeks) 
Chemotherapy (including antibody 
drug therapy, retinoid therapy) 
>3 weeks (>2 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, 
weekly paclitaxel; 
>4 weeks: Abs (eg, bevacizumab, cetuximab 
and panitumumab, ramucirumab); 
>6 weeks for nitrosureas or mitomycin C 
Immunotherapy 
>4 weeks 
Cytochrome P450 (CYP) 3A4 strong 
inhibitor, OATP inhibitor 
>3 elimination half-lives of the inhibitor 
11. 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 months for 


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males after the last dose of study drug.  Methods considered as highly effective 
methods of contraception include:  
• Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation: 
− Oral 
− Intravaginal 
− Transdermal 
• Progestogen-only hormonal contraception associated with inhibition of 
ovulation: 
− Oral 
− Injectable 
− Implantable 
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Vasectomized partner 
• Complete and true sexual abstinence defined as abstinence when it is in line 
with the preferred and usual lifestyle of the subject.  Subjects in this study 
should refrain from heterosexual intercourse during and upon completion of the 
study and for at least 7 months for females and 4 months for males after the last 
dose of study drug.  Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods), declaration of abstinence for the 
duration of exposure to study drug, and withdrawal are not acceptable methods 
of contraception. 
Non-child-bearing 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 HRT to allow 
confirmation of post-menopausal status prior to study enrollment.  For most forms 
of HRT, at least 2 to 4 weeks will elapse between the cessation of therapy and the 
blood draw; this interval depends on the type and dosage of HRT.  Following 
confirmation of their post-menopausal status, they can resume use of HRT during 
the study without use of a contraceptive method. 
12. Male subjects must not freeze or donate sperm starting at Screening and 
throughout the study period, and at least 4  months after the final study drug 


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administration. Preservation of sperm should be considered prior to enrolment in 
this study. 
13. 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. 
14. Must have provided informed consent for study participation (see Section 15.3) 
before performance of any study-specific procedures or tests. 
15. Subjects should be able and willing to comply with protocol visits and procedures. 
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 (study 
treatment), symptomatic congestive heart failure (New York Heart Association 
Class II to IV, Section 17.4), troponin levels consistent with myocardial infarction 
as defined according to the manufacturer 28 days prior to enrollment (study 
treatment). 
2. Has a corrected QT interval (QTcF) prolongation to >470 ms (females) or >450 ms 
(males) based on average of the screening triplicate 12-lead ECG.  The QT 
intervals will be corrected for heart rate by Fridericia’s formula (QTcF = QT/[RR]). 
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 clinically significant corneal disease in the opinion of the investigator. 
5. Has 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. 
6. Has multiple primary malignancies within 3 years, except adequately resected non-
melanoma skin cancer, curatively treated in-situ disease, other solid tumors 
curatively treated. 
7. Has history of severe hypersensitivity reactions to either the drug substances or 
inactive ingredients in the drug product. 
8. Has an uncontrolled infection requiring IV injection of antibiotics, antivirals, or 
antifungals. 
9. Has substance abuse or any other medical conditions that would increase the safety 
risk to the subject or interfere with participation of the subject or evaluation of the 
clinical study in the opinion of the Investigator. 


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10. Has known human immunodeficiency virus (HIV) infection, or active hepatitis B 
or C infection.  Subjects should be tested for HIV prior to enrollment (study 
treatment) if required by local regulations or institutional review board 
(IRB)/ethics committee (EC). 
11. Has unresolved toxicities from previous anticancer therapy, defined as toxicities 
(other than alopecia) not yet resolved to Grade ≤ 1 or baseline.  Subjects with 
chronic Grade 2 toxicities may be eligible per the discretion of the Investigator 
after consultation with the Sponsor Medical Monitor or designee (eg, Grade 2 
chemotherapy-induced neuropathy). 
12. Is pregnant or breastfeeding, or planning to become pregnant. 
13. Prior treatment with an ADC which consists of an exatecan derivative that is a 
topoisomerase I inhibitor. 
14. Social, familial, or geographical factors that would interfere with study 
participation or F/U 
15. Has a concomitant medical condition that would increase the risk of toxicity, in the 
opinion of the investigator. 
 


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5. 
STUDY TREATMENTS 
5.1. 
Assigning Subjects to Treatments and Blinding 
5.1.1. 
 Treatment Groups/Sequences 
There will be subjects allocated to 3 different cohorts according to the HER2 status. 
Cohort A will be opened from the beginning and Cohorts B and C will be opened after the 
decision of the sponsor during the study.  All subjects will receive DS-8201a treatment of 
the 6.4 mg/kg Q3W. 
5.1.2. 
Method of Treatment Allocation 
Subjects are registered in IXRS and they are allocated to each cohort according to the 
centrally confirmed HER2 status.  
Cohort A  
HER2-overexpressing (IHC 3+ or IHC 2+/ISH +)  
Cohort B 
HER2 IHC 2+/ISH –  
Cohort C 
HER2 IHC 1+  
5.1.3. 
Blinding 
This study is an open-label study and no blinding will be performed.  
5.1.4. 
Emergency Unblinding Procedure 
Not applicable. 
 
5.2. 
Study Drug 
5.2.1. 
Description 
The DS-8201a drug product containing 100 mg of DS-8201a is provided as a lyophilized 
powder containing 100 mg of DS-8201a in a glass vial.  Each glass vial should be 
reconstituted to a concentration of 20 mg/mL.  Each vial is designed for single use only 
and is not to be used to treat more than 1 subject.   
5.2.2. 
Labeling and Packaging 
DS-8201a will be supplied by the sponsor.  This will be clinical labeled in compliance 
with the regulatory requirements and packaged.  The labeling or the packaging will clearly 
display the name of the investigational product, the investigational product manufacturing 
code, storage conditions and other required information in accordance with local 
regulations. 


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5.2.3. 
Preparation 
The drug for IV infusion is prepared by dilution of the required volume of the drug 
product 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 instructions provided by the sponsor. 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 instruction for detailed 
information about preparation and administration of DS-8201a. 
5.2.4. 
Administration 
The study drug will be administered every 3 weeks at the 6.4 mg/kg.  The initial dose of 
DS-8201a will be infused intravenously into each subject for approximately 90 minutes. If 
there is no infusion-related reaction after the initial dose, the second and thereafter dose of 
DS-8201a will be infused intravenously into each subject for approximately 30 minutes. 
The subject’s weight at screening (baseline) will be used to calculate the initial dose.  If 
during the course of the treatment, the subject’s weight changes by more than 10% of the 
baseline weight, the subject’s dose will be recalculated based on the subject’s updated 
weight. 
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 
contract research organization (CRO) should be contacted. 
5.2.6. 
Drug Accountability 
When a study drug shipment is received, the investigator or designee will check the 
amount and condition of the drug check the appropriateness of the label, drug expiration 
date and sign the Receipt of Shipment Form provided by 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. 
Drug Accountability Record will be provided for the study drug.  The record must be kept 
current and should contain the dates and quantities of study drug received, subject’s 
information (the site subject identifier and the subject number) for whom the study drug 
was dispensed, the drug number, the date and quantity of study drug dispensed and 
remaining, as well as the initials or seal of the dispenser. 
At the end of the study, as per local laws and/or directed by Sponsor, all unused DS-8201a 
will be returned or destroyed as per local laws or site policy and only after the study 
monitor has completed a final inventory.  As applicable, the study site must file a copy of 
the appropriate institution policy within their investigator site file and provide a copy to 
the Sponsor.  Please see pharmacy manual for details.  


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All investigational product inventory forms must be made available for inspection by a 
Sponsor authorized representative or designee and regulatory agency inspectors.  
5.3. 
Control Treatment 
Not Applicable. 
5.4. 
Dose Modifications for Managing Adverse Events 
The investigator will evaluate which toxicities are attributable to DS-8201a and adjust the 
dose of DS-8201a as recommended below.  All dose modifications (interruption, reduction 
and/or discontinuation) should be based on the worst preceding toxicity (Common 
Terminology Criteria for Adverse Events [CTCAE] version 5.0).  Specific criteria for 
interruption, reinitiating, dose reduction and/or discontinuation of DS-8201a are listed in 
Section 5.4.  All interruptions or modifications must be recorded on the case report form 
(CRF).  Appropriate clinical experts should be consulted as deemed necessary.  
For Grade 3 or Grade 4 events, monitoring (including local laboratory tests when 
appropriate) should be performed at intervals no greater than 7 days until AE is 
determined to be resolving or subject is discontinued at end of treatment. 
Prophylactic or supportive treatment for expected toxicities, including management of 
study-drug induced adverse events will be as per the treating physician’s discretion and 
institutional guidelines.  
Dose Reduction Guidelines: 
NOTE: There will be no dose modifications for Grade 1 or Grade 2 AEs unless specified 
in Table 5.2. 
Two dose reductions will be permitted.  The adjustment for a reduced dosing of DS-8201a 
is as shown in Table 5.1. 
Table 5.1: 
Dose Reduction Levels of DS-8201a 
Starting Dose 
Dose Level −1 
Dose Level −2 
6.4 mg/kg 
5.4 mg/kg 
4.4 mg/kg 
Once the dose of DS-8201a has been reduced because of toxicity, all subsequent cycles 
should be administered at that lower dose level unless further dose reduction is required.  
More than 2 dose reductions are not allowed and the subject will be withdrawn from the 
study treatment if further toxicity meeting the requirement for dose reduction occurs. DS-
8201a dose increases are not allowed in the study.  
Dose Interruption and Modification/Toxicity Management Guidelines: 
A dose can be delayed for up to 28 days (49 days from the last infusion date) from the 
planned date of administration.  If a subject is assessed as requiring a dose delay of longer 
than 28 days, 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 SARS-CoV-2 infection events must be recorded in the eCRF.  
Please refer to Appendix 17.5 for additional information on dose modification. 


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Table 5.2: 
Dose or schedule modification for DS-8201a 
Worst toxicity CTCAE v5.0 
Grade (unless otherwise 
specified) 
Dose or schedule modification for DS-8201a 
No toxicity 
Maintain dose and schedule 
Infusion-Related Reaction 
Grade 1 (Mild transient 
reaction; infusion interruption 
not indicated; intervention not 
indicated) 
• 
If infusion related reaction (such as fever and chills, with and without 
nausea/vomiting, pain, headache, dizziness, dyspnea, hypotension) is 
observed during administration, the infusion rate should be reduced by 
50% and subjects should be closely monitored.  
• 
If no other reactions appear, the subsequent infusion rate could be 
resumed at the initial planned rate.  
Grade 2 (Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment (eg, 
antihistamines, NSAIDs, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs) 
• 
Administration of DS-8201a should be interrupted and symptomatic 
treatment started (eg, antihistamines, NSAIDs, narcotics, IV fluids). 
• 
If the event resolves or improves to grade 1, infusion can be re-started 
at a 50% reduced infusion rate. 
• 
Subsequent administrations should be conducted at the reduced rate. 
Grade 3 or 4 (Prolonged or 
life-threatening consequences, 
urgent intervention indicated) 
• 
Administration of DS-8201a should be discontinued immediately and 
permanently. 
• 
Urgent intervention indicated.  Antihistamines, steroids, epinephrine, 
bronchodilators, vasopressors, intravenous fluid therapy, oxygen 
inhalation etc., should be administered. 
Hematologic Toxicity 
Neutrophil Count Decreased and/or White Blood Cell Count Decreased 
Grade 3  
Delay dose until resolved to ≤ Grade 2, then maintain dose 
Grade 4  
Delay dose until resolved to ≤ Grade 2: 
• 
Reduce dose 1 level 
Febrile Neutropenia (absolute 
neutrophil count <1 × 109/L, 
fever >38.3°C or a sustained 
temperature of ≥38°C for more 
than one hour) 
Delay dose until resolved: 
• 
Reduce dose by 1 level 
Lymphocyte Count 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 
 


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Table 5.2: 
Dose or schedule modification for DS-8201a (Continued) 
Worst toxicity CTCAE v5.0 
Grade (unless otherwise 
specified) 
Dose or schedule modification for DS-8201a 
Anaemia 
Grade 3 (Hemoglobin (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 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 
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% to 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> 500 ms on 2 
separate ECGs) 
Delay dose until resolved to ≤Grade 1 (corrected QTc ≤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 > 500 or > 
60 ms change from baseline 
and Torsade de pointes or 
polymorphic ventricular 
tachycardia or signs/symptoms 
of serious arrhythmia) 
Discontinue subject from study treatment 


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Table 5.2: 
Dose or schedule modification for DS-8201a (Continued) 
Worst toxicity CTCAE v5.0 
Grade (unless otherwise 
specified) 
Dose or schedule modification for DS-8201a 
Troponin 
Grade 1 (Levels above the 
upper limit of normal and 
below the level of myocardial 
infarction as defined by the 
manufacturer) 
If troponin levels are above the upper limit of normal at baseline and 
below the level of myocardial infarction as defined by the manufacturer 
(CTCAE Grade 1) at baseline, no repeat testing is required after the first 
end of infusion 3-hour troponin test if the troponin level is not Grade 3. 
For new diagnosed Grade 1, repeat troponin testing at 3 ± 1 hours (~ 6 
hours post-infusion) after initial troponin test.  
If repeat troponin level at 3 ± 1 hours (~ 6 hours post-infusion) rises 
significantly per institutional guidelines,   
• 
Perform ECG in triplicate 
• 
Repeat troponin testing at 6 ± 1 hour (~9 hours post-infusion) after 
initial troponin test 
• 
Follow institutional guidelines for management of detectable troponin 
testing. 
If repeat troponin level at 3 ± 1 hours (~ 6 hours post-infusion) does not 
rise significantly per institutional guidelines, 
• 
Repeat troponin testing at 6 ±1 hours (~9 hours post-infusion) or at 24 
± 2 hours (~27 hours post-infusion) 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 ± 1 hours (~9 hours post-infusion) and 12 ± 1 
hours (~15 hours post-infusion) after initial troponin test.   
Follow institutional guidelines for management of detectable troponin 
testing.  If acute myocardial infarction 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 
 


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Table 5.2: 
Dose or schedule modification for DS-8201a (Continued) 
Worst toxicity CTCAE v5.0 
Grade (unless otherwise 
specified) 
Dose or schedule modification for DS-8201a 
Pulmonary Toxicity 
If a subject develops radiographic changes potentially consistent with 
ILD/pnumonitis 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” in the 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 
• 
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. 
Other tests could be considered, as needed. 
If the AE is confirmed to be ILD/pneumonitis, follow the ILD/pneumonitis 
management guidance as outlined below. 
All events of ILD/pnumonitis regardless of severity or seriousness will be 
followed until resolution including after drug discontinuation. 
Grade 1 
The administration of DS-8201a must be interrupted for any 
ILD/pnumonitis 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, DS-8201a can be restarted only if the event is fully 
resolved to Grade 0: 
• 
If resolved in ≤ 28 days from day of onset, maintain dose 
• 
If resolved in > 28 days from day of onset, reduce dose 1 level 
However, if the event Grade 1 ILD/pnumonitis occurs beyond cycle day 
22 and has not resolved within 49 days from the last infusion, the drug 
should be discontinued. 
* If subject is asymptomatic, then subject should still be considered as 
Grade 1 even if steroid treatment is given 


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Table 5.2: 
Dose or schedule modification for DS-8201a (Continued) 
Worst toxicity CTCAE v5.0 
Grade (unless otherwise 
specified) 
Dose or schedule modification for DS-8201a 
Grade 2 
Permanently discontinue subject from study treatment. 
• 
Promptly start and treat with systemic steroids (e.g., at least 1 
mg/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,  
• 
Re-consider additional work-up for alternative etiologies 
as described above. 
• 
Consider other immuno-suppressants and/or treat per 
local practice.  
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 
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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Table 5.2: 
Dose or schedule modification for DS-8201a (Continued) 
Worst toxicity CTCAE v5.0 
Grade (unless otherwise 
specified) 
Dose or schedule modification for DS-8201a 
Hepatic Toxicity 
Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) with simultaneous Total 
bilirubin (TBL) 
AST/ALT ≥3.0 x ULN with 
simultaneous TBL ≥2.0 x 
ULN 
Delay study medication until drug-induced liver injury can be ruled out.  
If drug-induced liver injury is ruled out, the subject should be treated 
accordingly, and resumption of study drug may occur after discussion 
between the Investigator and Sponsor.  
If drug-induced liver injury cannot be ruled out from diagnostic workup, 
permanently discontinue study treatment. 
Monitor AST/ALT and TBL twice weekly until resolution or return to 
baseline. 
AST or ALT 
Grade 2 (>3.0 to 5.0 × ULN if 
baseline was normal; >3.0 - 
5.0 x baseline if baseline was 
abnormal) 
No action for Grade 2 AST/ALT  
Grade 3 (>5.0 to 20.0 × ULN 
if baseline was normal; >5.0 - 
20.0 x baseline if baseline was 
abnormal) 
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 x ULN 
if baseline was normal; >8.0 to 
20.0 x baseline if baseline was 
abnormal) 
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 if 
baseline was normal; >20.0 x 
baseline if baseline was 
abnormal) 
Discontinue subject from study treatment 
TBL 
Grade 2 (>1.5 to 3.0 × ULN if 
baseline was normal; >1.5 - 
3.0 x baseline if baseline was 
abnormal) 
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 
 


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Table 5.2: 
Dose or schedule modification for DS-8201a (Continued) 
Worst toxicity CTCAE v5.0 
Grade (unless otherwise 
specified) 
Dose or schedule modification for DS-8201a 
Grade 3 (>3.0 to 10.0 × ULN 
if baseline was normal; >3.0 to 
10.0 x baseline if baseline was 
abnormal) 
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 if 
baseline was normal; >10.0 x 
baseline if baseline was 
abnormal) 
Discontinue subject from study treatment 
Blood Alkaline Phosphatase Increased 
Grade 3 (>5.0 to 20.0 x ULN 
if baseline was normal; >5.0 to 
20.0 x baseline if baseline was 
abnormal) 
or  
Grade 4 (>20.0 x ULN if 
baseline was normal; >20.0 x 
baseline if baseline was 
abnormal) 
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 
Diarrhoea/Colitis 
Grade 3 
Delay dose until resolved to ≤ Grade 1 
• 
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 
 


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Table 5.2: 
Dose or schedule modification for DS-8201a (Continued) 
Worst toxicity CTCAE v5.0 
Grade (unless otherwise 
specified) 
Dose or schedule modification for DS-8201a 
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 
AE = adverse event, ALP = alkaline phosphatase, ALT = L-alanine aminotransferase, AST = L-aspartate 
aminotransferase, CT = computed tomography, CTCAE: Common Terminology Criteria for Adverse Events, 
ECG = electrocardiogram, ILD = interstitial lung disease, IV = intravenous, LVEF = left ventricular ejection 
fraction, NSAIDs = nonsteroidal anti-inflammatory drugs, QTc = corrected QT, 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 proceeding toxicity. 
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 
DS-8201a will be administered IV only to subjects participating in the study and under the 
supervision of clinical study personnel at the study site.  Therefore, treatment compliance 
will be guaranteed as long as the subject attends each visit for administration of the study 
treatment.  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 informed consent form for study 
participation the F/U 40 days visit (± 7 days) after the last administration of DS-8201a will 
be recorded.  Prophylactic treatment for the study treatment and all concomitant 
medications will be recorded in the eCRF. 
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 
will be prohibited during the treatment period. The Sponsor must be notified if a subject 
receives any of these during the study.  : 
1. Other anticancer therapy, including cytotoxic, targeted agents, immunotherapy, 
antibody, retinoid, or anti-cancer hormonal treatment [concurrent use of hormones 
for noncancer-related conditions (e.g. insulin for diabetes and hormone 
replacement therapy) is acceptable]. 
2. Other investigational therapeutic agents. 


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3. Radiotherapy (except for palliative radiation to known metastatic sites as long as it 
does not affect assessment of response and it does not interrupt treatment for more 
than the maximum time specified in dose modification section). 
4. Radiotherapy to the thorax. 
5. Concomitant use of chronic systemic (IV or oral) corticosteroids or other 
immunosuppressive medications except for managing adverse events; (Inhaled 
steroids or intra articular steroid injections are permitted in this study.) Subjects 
with bronchopulmonary disorders who require intermittent use of bronchodilators 
(such as albuterol) will not be excluded from this study.  
6. Concomitant treatment with chloroquine or hydroxychloroquine is not allowed 
during the study treatment. Refer to appendix 17.5 for further details. 
 
Permitted Therapies/Products 
1. Hematopoietic growth factor may be used for prophylaxis or treatment based on 
the clinical judgment of the investigator. 
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 AE will be otherwise 
as per investigator’s discretion and the institutional guidelines. 
4. Based on the currently available clinical safety data, it is recommended that 
subjects receive prophylactic anti-emetic agents prior to infusion of DS8201a 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 
 
Restricted Products 
1. Use of e-cigarettes and vaping is strongly discouraged but not prohibited.   
 
5.7. 
Subject Withdrawal/Discontinuation 
5.7.1. 
Reasons for Discontinuation of Study Treatment 
Subjects may be withdrawn from study treatment after signing the informed consent for 
the following reasons:  
• Progressive disease per RECIST version 1.1 assessed by the investigator; 
• Clinical progression (definitive clinical signs of disease progression, but a 
recent radiographic assessment did not meet the criteria for Progressive 
Disease according to RECIST version 1.1); 


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• Adverse event; 
• Withdrawal of consent by subject; 
• Physician Decision; 
• Death; 
• Pregnancy; 
• Study terminated by Sponsor; 
• Lost to F/U; 
• Others, specify. 
All subjects who are withdrawn from the study treatment should complete protocol-
specified withdrawal procedures (Section 5.7.3) and F/U procedures (Section 6.6). 
Record the reason for any subject who discontinues study treatment.  Discontinued 
subjects will be followed for survival, either through direct contacts or by collecting public 
records (eg, death certificates) as allowed by local laws. 
5.7.2. 
Reasons for Discontinuation of Study Participation 
Subjects may be withdrawn from study after study treatment for the following reasons: 
• Subject withdraws consent to participate in study procedures; 
• Subject dies; 
• Study is terminated by the sponsor; 
• Subject is lost to F/U; 
• Others, specify. 
5.7.3. 
Withdrawal Procedures 
If a subject is withdrawn 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 
the last treatment and the reason for withdrawal. 
If the subject is withdrawn due to an adverse event, the investigator will follow the subject 
until the adverse event has resolved or stabilized, post cancer treatment, or lost to F/U. 
All subjects who are withdrawn from the study should complete protocol-specified 
withdrawal procedures.  Protocol-specified withdrawal procedures will be obtained during 
the end of treatment visit (+ 7 days) and the F/U 40 days visit (+ 7 days) conducted after 
the last administration of DS-8201a (Section 6.5 and Section 6.6). 
5.7.4. 
Subject Replacement 
Subjects that have been enrolled and administered study medication will not be replaced.  
It is allowable to replace a subject that was enrolled but was not administered any study 
medication. 


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5.7.5. 
Subject Re-screening Procedures 
Re-screening is permitted for any subject who failed to meet the eligibility criteria in the 
initial screening.  The limit of re-screening is 1 time.  The site subject identifier and 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 in the Screening Log.  No data from the initial evaluation will be entered into the 
clinical database for a subject who is rescreened. 


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6. 
STUDY PROCEDURES 
A study visit schedule in tabular format is provided in Section 18. Obtain a signed and 
dated ICF before any study-related procedures or assessments are conducted.  A separate 
tissue screening ICF may be used to obtain consent to send the sample to the central 
laboratory. 
After obtaining informed consent, the investigator or designee assign a site subject 
identifier. 
Informed consent for pharmacogenomics study will be obtained separately. 
6.1. 
Tissue Screening 
To determine eligibility, subjects must meet tumor biomarker criteria.   
Note: A separate tissue screening ICF may be used to obtain consent to send the sample to 
the central laboratory.  Subjects may continue on prior therapy while tissue testing takes 
place.   
Please refer to the study laboratory manual for required tumor sample specifications and 
shipping instructions.  
The following procedures will be conducted: 
• Obtain a signed and dated written consent from the subject to collect tissue 
and/or perform a biopsy as needed. 
• Obtain adequate archival or recent tumor tissue sample for HER2 testing.  
Approximately 10 slides or adequate paraffin-embedded tissue blocks of 
formalin-fixed tissue specimens can be submitted for this analysis.   
• Send the sample to the Central Laboratory to confirm HER2 status 
• If a tumor biopsy is needed, record any SAEs directly related to tissue 
screening procedure (ie, tumor biopsy). 
• For subjects who sign only the Informed Consent Form for tissue screening, 
report only serious adverse events (SAEs) directly related to tissue screening 
procedure (ie, tumor biopsy). Unless documentation of other AEs is required 
by local law, only SAEs directly related to tumor biopsy will be recorded 
during tissue screening. 
6.2. 
Screening 
Obtain a signed and dated ICF before any study-related procedures or assessments are 
conducted.  After eligibility is met, the subject will be registered to IXRS as eligible and 
assigned to the cohort.  Subject who is ineligible after obtaining ICF for study entry should 
also be registered as ineligible in the IXRS. 
The following activities and/or assessments will be performed during the screening period: 
• Obtain fresh tumor biopsy specimen from a subject.  Tumor tissue will be sent 
to the central laboratory for an exploratory biomarker analysis.  Fresh biopsy is 


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not needed if a sample that was obtained after the most recent anti-cancer 
therapy is already available.   Further details will be provided in the laboratory 
manual. 
Within 28 days before enrollment (study treatment)   
• Perform a HIV antibody test.  It is tested as required by local regulations or 
IRB/ECs. 
• Perform hepatitis B surface antigen test, and hepatitis C antibody test.   
• Ophthalmologic assessments.  The assessments will include visual acuity 
testing, slit lamp examination, and fundoscopy.  
• Perform an ECHO or MUGA (note: the same test must be used for the subject 
throughout the study).  
• Perform tumor assessment by computed tomography (CT) or magnetic 
resonance imaging (MRI) scans of the chest, abdomen, pelvis, and any other 
sites of disease.  A CT or MRI of the brain is to be included for all subjects.   
NOTE: To assess objective response or future progression, it is necessary to 
estimate the overall tumor burden at baseline and use it as comparator for 
subsequent measurement.  Therefore, all lesions (target and non-target) have to 
be assessed at Screening according to RECIST version 1.1 (Section 17.3). 
The following activities and/or assessments will be performed during the screening period 
within 14 days before enrollment (study treatment) except as indicated: 
• Obtain demographics (eg, birth date, sex, race, ethnicity),  medical and surgical 
history, including all previous, now resolved, significant medical conditions, 
date of diagnosis, extent of disease, disease staging,  Primary tumor site 
(rectum, sigmoid, descending, transverse, ascending, cecum), previous cancer 
therapies (including prior radiation therapy), historical RAS (KRAS/ 
neuroblastoma RAS viral oncogene homolog) status, BRAF status, 
microsatellite instability status, historical HER2 status and oncology surgical 
history. 
• Perform a complete physical examination (see Section 9.11) including weight 
and height. 
• Assess AEs throughout the screening period (from the time the subject signed 
the ICF for study entry). 
• Record concomitant medications (from the time the subject signed the ICF)  
• Obtain vital signs (systolic and diastolic blood pressure, pulse rate, body 
temperature) and peripheral oxygen saturation (SpO2). 
• Assess functional status using the ECOG PS Scale (Section 17.2). 
• Obtain blood samples for hematology and blood chemistry tests (includes 
calculated creatinine clearance.  See Section 17.1), coagulation (prothrombin 
time and activated partial thromboplastin time), troponins (preferably high-
sensitivity troponin-T) and HER2ECD. The test used to test troponin should 


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remain the same throughout the course of a subject’s time on study.  An 
additional sample should be submitted for central lab troponin-T testing. 
• Perform urinalysis test 
• Perform a 12-lead ECG in triplicate.  See Section 11.4.3.4 for corrected QTc.  
Average of the triplicates should be checked for screening. 
*: ECGs will be taken in close succession, a few minutes apart, after the 
subject has been in a supine/semi-recumbent position. 
• Review inclusion/exclusion criteria. 
Within 72 hours prior to enrollment (study treatment) 
• Obtain a serum or urine sample for pregnancy testing in women of childbearing 
potential.  Test must be confirmed within 72 hours prior to enrollment (study 
treatment).  For postmenopausal subjects (no childbearing potential, as 
indicated by an elapse of at least 12 months after the last menstruation) or 
subjects who have no possibility of pregnancy due to sterilization surgery, etc., 
no pregnancy test will be required.  Subjects who have been amenorrheic for 
12 months or longer for medical reasons other than sterilization surgery (eg, 
effect of medication) will be regarded as women of child-bearing potential and 
required to undergo the pregnancy test.  A positive urine pregnancy will be 
confirmed using blood test. 
6.3. 
Randomization 
Not applicable. 
The subjects who consented to study entry should be registered to IXRS. 
6.4. 
Treatment Period 
Treatment will be started as soon as a subject is registered to IXRS. 
6.4.1. 
Cycle 1 to Cycle 4 and Subsequent Cycles 
Treatment and procedures performed on Day 1 of Cycle 1 and beyond are specified in 
Section 18.  Procedures are to be performed within 3 days of the Day 1 visit of each cycle 
unless otherwise specified.   
Physical examination, weight, ECOG PS assessment, 12-lead ECG, hematology, blood 
chemistry, and vital signs (including SpO2) evaluations do not need to be repeated at the 
Cycle 1, Day 1 visit if performed within 3 days before the first dose of study drug. 
Before Dosing: 
• Record concomitant medications and AEs at every visit.  Safety will be 
monitored by assessment as well as by collection of the AEs at every visit.  For 
details on AE collection and reporting, refer to Section 9.4 . 
• Obtain a blood sample for pharmacogenetic assessment on Day 1 of Cycle 1.  
(This sample is not required for study participation and will be collected from 


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subjects who have provided consent by signing the pharmacogenetics sample 
banking consent form.)  
• Blood samples for cfDNA analysis will be collected before treatment on Day 1 
of Cycle 1 and Cycle 4. 
• Physical examination (Section 9.11) will be performed on the scheduled day 
even if study treatment is being withheld.  More frequent examinations may be 
performed at the discretion of the investigator and if medically indicated.  
Weight is recorded. 
• Ophthalmologic assessments to include visual acuity testing, slit lamp 
examination and fundoscopy will be performed at Day 1 of Cycle 2 (within 3 
days before administration) and every 4 cycles (± 7 days) thereafter (eg, Day 1 
Cycles 2, 6, 10, 14...).  
• Vital signs (systolic and diastolic blood pressure, pulse rate, body temperature) 
and SpO2 will be performed as per the Schedule of Events.  More frequent 
examinations may be performed at the discretion of the investigator and if 
medically indicated. 
• ECOG PS will be assessed as per the Schedule of Events. 
• Blood samples for hematology and blood chemistry assessments will be 
collected as per the Schedule of Events.  Refer to Section 9.8 for a list of 
parameters to be evaluated.  
• Triplicate 12-lead ECG will be performed at every cycle.  ECGs should be 
performed before PK blood draws at respective time points.  ECGs will be 
taken in close succession, a few minutes apart, after the subject has been in a 
supine/semi-recumbent position. 
• Perform an ECHO or MUGA scan assessment (note: the same test must be 
used for the subject throughout the study) every 4 cycles (± 7 days) starting 
with Cycle 5 (eg, Cycles 5, 9, 13…). 
• Blood samples for HER2ECD assessment will be collected on Cycle 3 Day 1 
and every other cycle thereafter (eg, Cycles 3, 5, 7, 9...). A portion of this 
blood sample from each subject who provides consent will be used for future 
central lab analysis for SARS-CoV-2 testing at Cycle 5 Day 1 and every 4 
cycles thereafter (Cycles 5, 9, 13, etc). 
• Obtain a serum or urine sample for pregnancy testing in women of childbearing 
potential.  Test must be confirmed within 72 hours prior to drug administration.  
A positive urine pregnancy will be confirmed using blood test. 
− 8 to 0 hours of infusion 
• Blood samples for PK assessments will be obtained before infusion (− 8 to 0 
hours) on Day 1 of each cycle through Cycle 4; then at Day 1 of Cycle 6. 
• Blood samples for ADA will be obtained before infusion (− 8 to 0 hours) on 
Day 1 of Cycle 1, 2 and 4, and then every 4 cycles. 
 


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Dosing and Post Infusion Assessments: 
• Administer DS-8201a IV infusion approximately 90 minutes for the initial dose 
and, if no infusion related reaction after the initial dose, infuse subsequent 
doses over approximately 30 minutes.  Record start and stop times.  DS-8201a 
is to be administered every 3 weeks ± 3 days. 
• Collect blood samples within 15 minutes after end of infusion (EOI) for PK 
analysis for on Day 1 of each cycle through Cycle 4; then at Day 1 of Cycle 6.  
• Obtain blood sample for PK assessments at the following time points 
− Cycle 1 Day 1 
• 4 hours after the start of drug administration (± 15 minutes) 
• 7 hours after the start of drug administration (± 2 hours) 
− Cycle 1 Day 8 (± 1 day) and Day 15 (± 1 day) 
− Cycle 3 Day 1: 
• 4 hours after the start of drug administration (± 15 minutes) 
• 7 hours after the start of drug administration (± 2 hours) 
− If the schedule on Day 1 of Cycles 2 is delayed for 3 days or more, or if the 
subject cannot continue onto the next cycle, PK blood sample will be 
collected on Day 22 of Cycle 1 as per the Schedule of Event 
• Vital signs (systolic and diastolic blood pressure, pulse rate, body temperature 
and SpO2) will be performed as per the Schedule of Events.  More frequent 
examinations may be performed at the discretion of the investigator and if 
medically indicated. 
− Cycle 1 Day 8 (± 1 day) and Day 15 (± 1 day) 
• Collect blood samples for troponin (preferably high-sensitivity troponin-T) 2 to 
3 hours after end of infusion.  The test used to test troponin should remain the 
same throughout the course of a subject’s time on study.  An additional sample 
should be submitted for central lab troponin-T testing.  
− If troponin levels are consistent with myocardial infarction as defined 
according to manufacturer (CTCAE Grade 3), perform ECG testing in 
triplicate, repeat troponin testing 6 ±1 hours (~9 hours post-infusion) and 
12 ±1 hours (~15 hours post-infusion) after initial troponin test was drawn, 
and follow institutional guidelines.       
− 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), 
repeat troponin testing at 3 ±1 hours (~ 6 hours post-infusion) after initial 
troponin test was drawn.  
If repeat troponin level at 3 ± 1 hours (~6 hours post-infusion) rises 
significantly per institutional guidelines, perform ECG testing in triplicate, 
and repeat troponin testing at 6 ±1 hours (~9 hours post-infusion) and 
follow institutional guidelines. 


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If repeat troponin level does not rise significantly per institutional 
guidelines, repeat troponin testing at 6 ±1 hours (~9 hours post-infusion) or 
at 24 ±2 hours (~27 hours post-infusion) after initial troponin test. 
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. 
• Blood samples for hematology and blood chemistry assessments will be 
collected at Cycle 1 Day 8 (± 1 day) and Day 15 (± 1 day) as per the Schedule 
of Events.  Refer to Section 9.8 for a list of parameters to be evaluated. 
6.4.2. 
Every 6 Weeks (± 7 days) 
• Tumor assessments, based on sites of disease identified at Screening and any 
additional newly suspected sites of progressive disease, will be conducted 
every 6 weeks (± 7 days) from Cycle 1 Day 1, independent of treatment cycle.  
CT or MRI scans of the suspected sites of disease in the chest, abdomen and 
pelvis are mandatory.  Computerized tomography and/or MRI (spiral CT or 
MRI with ≤5 mm cuts) of chest, abdomen, and pelvis should be used for tumor 
assessment unless another modality of disease assessment is necessary for the 
lesions.  The same assessment modality should be used throughout the study 
for all assessments for each subject unless prior approval is obtained from 
sponsor or its designee.  Unscheduled tumor assessments may be performed if 
progression is suspected.  
• A CT or MRI of the brain is mandatory for all subjects included with baseline 
stable brain metastases.  Subjects without brain metastases do not need 
additional brain scans for tumor assessment unless clinically indicated. 
Imaging results will be reviewed by an independent radiologic facility.  Copies of CT or 
MRI images should be provided after the images are taken.  
6.4.3. 
Fresh Tumor Biopsy During Treatment 
Obtain fresh tumor biopsy specimen from a subject at day 43 (± 7 days) if available.  
Tumor tissue will be sent to the central laboratory for an exploratory biomarker analysis.  
Further details will be provided in the laboratory manual.  If the tumor is not taken, 
document the reason why the fresh tumor sample is unavailable. 
6.4.4. 
Interstitial Lung Disease/Pneumonitis  
For suspected 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 


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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. 
Other tests could be considered, as needed. 
All events of ILD/pnumonitis regardless of severity or seriousness will be followed until 
resolution including after drug discontinuation. 
6.5. 
End of Treatment 
The end of treatment (EOT) is defined as the date the investigator decides to discontinue 
study treatment (+ 7 days).  The following procedures will be performed as specified in 
the Schedule of Events.  However, if the EOT assessments have been performed within 40 
(+ 7) days of their last treatment, they can be considered to be the EOT data and there is 
no need to repeat them, otherwise these assessments need to be repeated.  
• Physical examination.   
• Weight will be recorded.  
• Ophthalmologic assessments to include visual acuity testing, slit lamp 
examination, and fundoscopy. 
• Vital signs (systolic and diastolic blood pressure, pulse rate, body temperature) 
and SpO2. 
• ECOG PS. 
• AEs and concomitant medications will be recorded. 
• Blood samples for hematology and blood chemistry assessments will be 
collected.  Refer to Section 9.8 for a list of parameters to be evaluated.  
• Blood sample for cfDNA analysis will be collected. 
• Blood sample for HER2ECD assessment. A portion of this blood sample from 
each subject who provides consent will be used for future central lab analysis 
for SARS-CoV-2 testing. 
• Triplicate 12-lead ECG.  
• ECHO or MUGA (note: the same test must be used for the subject throughout 
the study). 
• Serum or urine sample for pregnancy testing in women of childbearing 
potential.   
• Evaluations of tumor assessments should include all sites of disease identified 
at screening and any other locations if progressive disease is suspected (eg, 
MRI of the brain should also be imaged, if brain metastases are suspected) per 
RECIST 1.1) (Section 17.3).  If investigator makes a clinical diagnosis that 


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there has been progression, imaging examinations should be performed as 
promptly as possible, and effort should be made to obtain an image based 
assessment of PD.  An MRI of the brain is mandatory for all subjects included 
with baseline stable brain metastases.  Subjects without brain metastases do not 
need brain scan for tumor assessment unless clinically indicated. 
• Collect blood samples for troponin (preferably high-sensitivity troponin-T).  
The test used to test troponin should remain the same throughout the course of 
a subject’s time on study.  An additional sample should be submitted for 
central lab troponin-T testing. 
• Obtain fresh tumor specimen from a subject at the end of treatment if available.  
Tumor tissue will be sent to the central laboratory for an exploratory biomarker 
analysis.  Further details will be provided in the laboratory manual.  If the 
tumor is not taken, document the reason why the fresh tumor sample is 
unavailable. 
6.6. 
Follow-up 
Forty days (+ 7 days) after last study drug administration or before starting new anticancer 
treatment, whichever comes first, the following procedures will be performed as specified 
in the Schedule of Events.  If EOT is >40 (+ 7) days after last treatment, then the EOT 
assessments can also function as the F/U visit.  
• Vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, 
body temperature and SpO2).  
• Physical examination.   
• Weight will be recorded.  
• ECOG PS.  
• Hematology and blood chemistry assessments will be performed.  
• Serum or urine sample for pregnancy testing in women of childbearing 
potential.   
• Collect blood samples for high sensitivity troponin (preferably troponin-T).  
The test used to test troponin should remain the same throughout the course of 
a subject’s time on study.  An additional sample should be submitted for 
central lab troponin-T testing. 
• AEs and concomitant medications will be recorded. 
• For subjects with positive ADA at the F/U visit, additional serum ADA 
samples may be collected every 3 months (± 7 days) up to 1 year from the last 
dose of study drug, or until the ADA becomes negative, or until the ADA titer 
becomes less than baseline (applicable when pre-existing ADA is observed), or 
until the subject starts another therapy for cancer, or withdraws consent from 
the study, whichever occurs first.  
Subjects will also be assessed every 3 months (± 14 days), from the date of F/U visit, for 
survival and subsequent anticancer therapy until death, withdrawal of consent, loss to F/U, 


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or study closure; whichever occurs first.  This information may be collected in a visit or 
via phone contact, or (as necessary for survival status, in the case of withdrawal of consent 
or loss to F/U) from public records as allowed by law. 
Further follow-up may be required for ongoing AEs (see Section 9.4). 
A study visit schedule in tabular format is provided below in Section 18.  
 
 


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7. 
EFFICACY ASSESSMENTS 
7.1. 
Assessments for Efficacy Endpoints 
7.1.1. 
Primary Efficacy Endpoint 
Efficacy assessments will be based on tumor assessments to be performed at screening and 
every 6 weeks while the subject remains on study drug.  The primary efficacy endpoint is 
ORR assessed by independent central imaging facility review based on RECIST version 
1.1 in Cohort A.  Refer to Section 17.3 for details regarding RECIST for radiological 
tumor assessments. 
7.1.2. 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints include DoR, DCR, PFS, OS, and ORR assessed by the 
investigator based on RECIST version 1.1. 
7.1.3. 
Exploratory Efficacy Endpoints 
Exploratory efficacy endpoints include, time to response, best percent change in the SLD 
of measurable tumors, serum HER2ECD, and other biomarker analysis. 


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8. 
PHARMACOKINETIC/PHARMACODYNAMIC 
ASSESSMENTS 
8.1. 
Pharmacokinetic (PK) Assessments 
The serum PK parameters listed in Table 8.1 of DS-8201a, total anti-HER2 antibody and 
MAAA-1181a for each subject will be estimated using standard noncompartmental 
methods.  The details of PK analysis will be specified in the Statistical Analysis Plan. 
Table 8.1: 
Pharmacokinetic Parameters 
 
PK parameters 
DS-8201a, total anti-HER2 antibody and 
MAAA-1181a 
Cmax, Tmax, AUClast and AUC21d, if 
appropriate, AUCinf, t1/2, CL, and Vss 
AUC21d = area under the plasma concentration-time curve up to Day 21, AUClast = area under the plasma 
concentration-time curve up to the last quantifiable time, AUCinf = area under the plasma concentration-
time curve up to infinity, CL: total body clearance, Cmax = maximum plasma concentration, t1/2 = terminal 
elimination half-life, Tmax = time to reach maximum plasma concentration, Vss: volume of distribution at 
steady state. 
Blood samples for DS-8201a PK analyses will be obtained at the time points specified in 
the Schedule of Events and in Table 8.2. 
At each time point, blood will be collected for DS-8201a analysis.  The actual time of 
study drug administration and the exact time of blood sampling for DS-8201a PK analysis 
must be recorded on the eCRF.  
.  
Instructions for the handling of blood samples and shipping of serum samples for 
DS-8201a PK analyses are included in a separate document (ie, laboratory manual).  The 
DS-8201a PK samples will be shipped to a central laboratory for forwarding to a Sponsor 
designated bioanalytical laboratory. 


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Table 8.2: 
Blood Sampling for Pharmacokinetic Analysis  
Cycle 
Day 
Sampling Time Point (Acceptable Range) 
Cycle 1 
Day 1 
BI (– 8 to 0 hours)  
EOI: Within 15 minutes after EOI 
4 hours after the start of drug administration (± 15 minutes) 
7 hours after the start of drug administration (± 2 hours) 
Day 8 
7 days after the start of drug administration (± 1 day) 
Day 15 
14 days after the start of drug administration (± 1 day) 
(Day 22) 
If the schedule on Day 1 of the next cycle is delayed for 3 days 
or more, including if the subject cannot continue onto the next 
cycle, collect blood sample 21 days after the start of drug 
administration (± 2 days).  If the next schedule is not delayed, 
sampling at this point is not necessary 
Cycle 2 
Day 1 
BI (– 8 to 0 hours) 
EOI: Within 15 minutes after EOI 
Cycle 3 
Day 1 
BI (– 8 to 0 hours)  
EOI: Within 15 minutes after EOI 
4 hours after the start of drug administration (± 15 minutes) 
7 hours after the start of drug administration (± 2 hours) 
Cycle 4 
Day 1 
BI (– 8 to 0 hours)  
EOI: Within 15 minutes after EOI 
Cycle 6 
Day 1 
BI (– 8 to 0 hours)  
EOI: Within 15 minutes after EOI 
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 8.3. 
The chloroquine or hydroxychloroquine administration time and the exact time of blood 
sampling for DS-8201a PK analysis must be recorded in the CRF. 
Table 8.3: 
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. 
 


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8.2. 
Biomarker Assessments 
In this study, biomarker analyses will be used to investigate the effect of the DS-8201a at 
the molecular and cellular level as well as to determine how changes in the markers may 
relate to exposure and clinical outcomes.  The sample collection information as required 
should be recorded on the eCRF page(s) and central laboratory requisition form(s).  
Detailed instructions for the collection, handling, and shipping of biomarker samples are 
outlined in the laboratory manual.  Biomarker samples will be shipped to a central 
laboratory. 
8.2.1. 
Pharmacodynamic Assessments 
8.2.1.1. 
Pharmacodynamic Assessments in Blood Samples 
Pharmacodynamic biomarkers will be analyzed with the intent of monitoring the anti-
tumor impact of treatment with DS-8201a.  The pharmacodynamic biomarkers are 
HER2ECD and cfDNA.  Blood samples will be collected for HER2ECD analysis at the 
time points specified in Table 8.4, and cfDNA analysis at the time points specified in 
Table 8.5.  
Table 8.4: 
Extracellular Domain of Human Epidermal Growth Factor Receptor 2 
Sampling Time Points 
Cycle 
Sampling Time Point (Acceptable Range) 
Screening 
Latest data within 14 days before Day 1 on Cycle 1 
Every 2 cycles from Cycle 3 (eg, 
Cycle 3, 5, 7, 9, 11...) 
Within 3 days before administration 
EOT 
The date when the investigator decides on 
discontinuation of the study treatment (+7 days).   
EOT = end of treatment. 
 
Table 8.5: 
Cell Free Deoxyribonucleic Acid Sampling Time Points 
Cycle 
Sampling Time Point (Acceptable Range) 
Cycle 1 Day 1 
Within 3 days before administration 
Cycle 4 Day 1 
Within 3 days before administration 
EOT 
The date when the investigator decides on 
discontinuation of the study treatment (+ 7 days).   
cfDNA = cell free deoxyribonucleic acid, EOT = end of treatment. 
8.2.1.2. 
Pharmacodynamic Assessments in Tumor Specimens 
Collection of tumor specimens is critical to assess the pharmacodynamic effect of DS-
8201a.  Timing of sample collection is screening, at Day 43 and EOT.  Tumor specimens 
will be used to assess the HER2 status using IHC and/or ISH, and mRNA expression 
profile using NGS technology and or other methods.   


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8.2.1.3. 
Additional Exploratory Biomarker Assessments 
During the study, in addition to the biomarkers specified above, exploratory biomarker 
research may be conducted on any samples. These studies would extend the search for 
other potential biomarkers relevant to the effects of DS-8201a, and/or the resistance to the 
treatment.  This may include the development of ways to detect, monitor or treat cancer.  
These additional investigations would be dependent upon clinical outcome, reagent and 
sample availability.  If the patient agrees, the remaining samples (tumor tissues, blood and 
plasma) may be stored for up to 15 years. 
8.2.1.4. 
Disclosure of the Results of Additional Biomarker Assessments 
Because the nature and value of future additional biomarker assessments is unknown at 
this time, any results obtained from research involving samples will not be disclosed to the 
subject or investigators now or in the future. 
8.3. 
SARS-CoV-2 Serum samples collection 
Portion of HER2ECD blood sample from each subject who provides consent will be used 
for future central lab analysis for SARS-CoV-2 testing. Samples will be sent to the central 
laboratory and stored until the tests will become available.  
 
8.4. 
Pharmacogenomic Analysis 
8.4.1. 
Genomic or Genetic Analysis 
A single blood sample for pharmacogenomics analysis will be collected from each subject, 
who consented to this test, on Day 1 of Cycle 1.  Participation in this part of the study is 
optional for all subjects. 
The following procedures will be used for the long-term preservation (banking) of DNA 
specimens extracted from subjectsʼ blood samples.  Pharmacogenomic samples may be 
analyzed for genes involved in absorption, distribution, metabolism, elimination, safety, 
and efficacy of DS-8201a.  Additionally, samples may be analyzed for genes involved in 
DS-8201a related signaling pathways, or to examine diseases or physiologic processes 
related to DS-8201a.  DNA samples will not be immortalized or sold to anyone.  This 
information may be useful in increasing the knowledge of differences among individuals 
in the way they respond to the study drug. 
Specimen shipping and handling details will be included in the laboratory manual. 
8.4.1.1. 
Disclosure of the Results of Genomic or Genetic Analysis 
Because the nature and value of future pharmacogenomic research cannot be known at this 
time, any results obtained from research involving pharmacogenomic samples will not be 
disclosed to the subject or investigators now or in the future. 
8.4.1.2. 
Storage and Disposal of Specimens for Genomic or Genetic Banking and 
Analysis 
Samples will be retained until exhausted or until the Sponsor requests disposition.  


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If the subject withdraws consent, the banked blood samples will be promptly managed 
regarding proper disposition.  However, the data will not be discarded if genetic analysis 
has been completed before the subject withdraws consent. 
8.5. 
Anonymization of Samples 
The samples should be submitted to the courier without any personal information such as 
name that can be used to identify individuals.  The samples should be identified by  a 
unique “site subject identifier.”  The correspondence list which can link the site subject 
identifier and the personal information should be kept strictly at the study center and the 
linkage between the site subject identifier and personal information should not be 
informed the courier or the central laboratory.  The samples and any other components 
from the cells collected for the additional biomarker assessment and pharmacogenomic 
analysis will be stored in the central laboratory up to 15 years. 
If the subject withdraws consent, samples should be disposed of by the following 
procedure depending on the location of the tumor samples.  Obtained data will not be 
discarded if the assessments have already been performed before consent was withdrawn.  
If samples are temporarily stored at the study center, the investigator will identify the 
samples of the relevant subject and dispose of them.  If samples are stored at the central 
laboratory, the investigator will notify the sponsor about the identification number of the 
subject who withdrew consent.  The sponsor will instruct the central laboratory to dispose 
of the relevant samples.  Eventually, after the end of the sample storage period, the central 
laboratory will dispose of all samples as instructed by the sponsor. 
8.6. 
Sample Storage and Disposal 
The samples and any other components from the cells collected for the additional 
biomarker assessment and pharmacogenomic analysis will be stored up to 15 years . 
If the subject withdraws consent, samples should be disposed of by the following 
procedure depending on the location of the tumor samples.  Obtained data will not be 
discarded if the assessments have already been performed before consent was withdrawn.  
If samples are temporarily stored at the study site 
• The investigator will identify the samples of the relevant subject and dispose of 
them.  
If samples are stored at the central laboratory  
• The investigator will notify the sponsor about the identification number of the 
subject who withdrew consent.  The sponsor will instruct the central laboratory 
to dispose of the relevant samples.   
Eventually, after the end of the sample storage period, the central laboratory will dispose 
of all samples as instructed by the sponsor. 
8.7. 
Immunogenicity (Anti-drug Antibody) 
Blood samples for ADA analyses will be collected at the time points specified in Section 6.  
A blood sample will be drawn at each time point.  Serum concentrations of DS-8201a 


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and/or total anti-HER2 antibody may be measured using the same ADA samples for 
purpose of ADA assessment.  
Instructions for the handling and shipping of ADA serum samples are included in a 
separate document (ie, laboratory manual).  The ADA samples will be shipped to a central 
laboratory for forwarding to a Sponsor designated bioanalytical laboratory. 
The immunogenicity testing will be performed using validated ADA assay following 
tiered assay steps including screening, confirmatory as well as titer determination.  
Samples confirmed positive will be banked until availability of the neutralizing anti-drug 
antibody assay. 


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9. 
SAFETY EVALUATION AND REPORTING 
9.1. 
Assessment of Safety Endpoint(s) 
Safety parameters will include SAEs, TEAEs, ECHO/MUGA findings; ophthalmologic 
findings, physical examination findings (including ECOG PS), vital sign measurements, 
standard clinical laboratory parameters (blood chemistry and hematology), ADA, and 
ECG parameters.  Adverse events will be categorized using the Medical Dictionary for 
Regulatory Activities (MedDRA).  Adverse events and abnormal laboratory test results, if 
applicable, will be graded using National Cancer Institute (NCI)-CTCAE version 5.0. 
9.2. 
Adverse Event Collection and Reporting 
All clinical AEs (see Section 9.4.1 for definitions) occurring after the subject signs the 
Informed Consent Form for study participation and up to 40 (+ 7) days after the last dose 
(ie, the F/U period), whether observed by the Investigator or reported by the subject, will 
be recorded on the Adverse Event CRF page.  For subjects who sign only the Informed 
Consent Form for tissue screening, report only serious adverse events (SAEs) directly 
related to tissue screening procedure (ie, tumor biopsy). Unless documentation of other 
AEs is required by local law, only SAEs directly related to tumor biopsy will be recorded 
during tissue screening.  Medical conditions (including laboratory values/vital signs that 
are out of range) that were diagnosed or known to exist prior to Informed Consent will be 
recorded as part of medical history.   
All AEs, SAEs, and events of special interest are to be reported according to the 
procedures in Section 9.5.   
All clinical laboratory results, vital signs, and ECG results or findings should be appraised 
by the Investigator to determine their clinical significance.  Isolated abnormal laboratory 
results, vital sign findings, or ECG findings (ie, not part of a reported diagnosis) should be 
reported as AEs if they are symptomatic, lead to study drug discontinuation, dose 
reduction, require corrective treatment, or constitute an AE in the Investigator’s clinical 
judgment. 
At each visit, the Investigator will determine whether any AEs have occurred by 
evaluating the subject.  Adverse events may be directly observed, reported spontaneously 
by the subject or by questioning the subject at each study visit.  Subjects should be 
questioned in a general way, without asking about the occurrence of any specific 
symptoms.  The Investigator must assess all AEs to determine seriousness, severity, and 
causality, in accordance with the definitions in Section 9.4.  The Investigator’s assessment 
must be clearly documented in the site’s source documentation with the Investigator’s 
signature.   
Always report the diagnosis as the AE or SAE term.  When a diagnosis is unavailable, 
report the primary sign or symptom as the AE or SAE term with additional details 
included in the narrative until the diagnosis becomes available.  If the signs and symptoms 
are distinct and do not suggest a common diagnosis, report them as individual entries of 
AE or SAE.   


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For events that are serious due to hospitalization, the reason for hospitalization must be 
reported as the serious adverse event (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 Informed Consent Form) procedures or treatments 
requiring hospitalization for pre-existing conditions that do not worsen in severity should 
not be reported as SAEs (see Section 9.4.2 for Definitions).   
For deaths, the underlying or immediate cause of death should always be reported as an 
SAE.  Disease progression is a study endpoint and consequently, should not be reported as 
an AE/SAE.  However, when a subject dies from PD with no other immediate causes, 
“disease progression” should be reported as an SAE.  
Any serious, untoward event that may occur subsequent to the reporting period that the 
Investigator assesses as related to study drug should also be reported and managed as an 
SAE. 
9.3. 
Adverse Events of Special Interest 
Additional relevant information regarding the AESI’s except infusion-related reactions 
specified below for the DS-8201a clinical program will be collected through the targeted 
questionnaires, in-built within the eCRF in the study clinical database. 
For broad surveillance of LVEF decrease, relevant AEs under the MedDRA SMQs of 
Cardiac Failure and Miocardial Infraction (MI) are included for enhanced data collection; 
additional data for these AEs are collected via TQs of heart failure and MI. 
For broad surveillance of ILD, selected 42 Preferred Terms (PT) [all from the ILD 
Standard MedDRA Query (SMQ)] plus 2 PTs of acute respiratory failure and respiratory 
failure are included for enhanced data collections. 
9.3.1. 
Interstitial Lung Disease/Pneumonitis  
Clinical Summary:  
ILD/pneumonitis is considered an important identified risk based on a comprehensive 
cumulative review of the available safety data from the DS8201-A-J101 clinical study as 
well as the results of potential ILD/pneumonitis cases reviewed by the independent ILD 
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:  
ILD/pneumonitis should be ruled out if a subject develops radiographic changes 
potentially consistent with ILD/pneumonitis or develops an acute onset of new or 
worsening pulmonary or other related signs/symptoms such as dyspnea, cough or fever.   
If the AE is confirmed to have an etiology other than ILD/pneumonitis, follow the 
management guidance outlined in Section 5.4. 
If the AE is suspected to be ILD/pneumonitis, treatment with study drug should be 
interrupted pending further evaluations. Evaluations should include high resolution CT, 
pulmonologist consultation (infectious disease consultation as clinically indicated), blood 
culture and CBC (other blood tests could be considered as needed), bronchoscopy and 


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bronchoalveolar lavage if clinically indicated and feasible should be considered, 
pulmonary function tests and pulse oximetry (SpO2), arterial blood gases if clinically 
indicated, and 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 management guidance in 
Section 5.4.  
All events of ILD/pneumonitis regardless of severity or seriousness will be followed until 
resolution including after drug discontinuation. 
9.3.1.1. 
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 PT [all from the 
ILD Standard MedDRA Query (SMQ)] plus 2 PTs of acute respiratory failure and 
respiratory failure.   
9.3.2. 
LVEF Decrease 
Clinical Summary:  
LVEF decrease 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. 
Management Guidance: 
LVEF will be measured by either ECHO or MUGA scan.  All ECHOs/MUGAs, will be 
evaluated by the investigator or delegated physician for monitoring cardiac function.  
Troponin will be measured at screening and after each infusion and EOTas needed based 
on subject reported cardiac signs or symptoms suggesting congestive heart failure, 
myocardial infarction, or other causes of cardiac myocyte necrosis.  If ECG is abnormal, 
follow institutional guidelines.  
Triplicate ECGs will be performed and standard ECG parameters will be measured, 
including RR, PR, QT intervals, and QRS duration.  All ECGs must be evaluated by 
investigator or delegated physician for the presence of abnormalities.  Whether or not 
measurement is performed, date performed, results, and findings for each parameter will 
be recorded in the eCRF. 
9.4. 
Adverse Event 
9.4.1. 
Definition of Adverse Event 
An adverse event is any untoward medical occurrence in a subject administered a 
pharmaceutical product and that does not necessarily have to have a causal relationship 


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with this treatment.  An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product, whether 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). 
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 adverse events. 
9.4.2. 
Serious Adverse Event 
A serious adverse event is any untoward medical occurrence that at any dose: 
• Results in death, 
• Is life-threatening, 
• Requires 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 Informed Consent Form) procedures or 
treatments requiring hospitalizations for pre-existing conditions that do not 
worsen in severity are not SAEs. 
9.4.3. 
Severity Assessment 
All AEs will be graded (1 to 5; see below) according to the latest NCI-CTCAE version 
5.0: 
• Grade 1 Mild AE 


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


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• Drug Interrupted: The study drug was temporarily stopped. 
9.4.6. 
Other Action Taken for Event 
• None. 
− No treatment was required. 
• Medication required. 
− Prescription and/or OTC medication was required to treat the adverse event. 
• Hospitalization or prolongation of hospitalization required. 
− Hospitalization was required or prolonged due to the AE, whether or not 
medication was required. 
• Other. 
9.4.7. 
Adverse Event Outcome 
• Recovered/Resolved 
− The subject fully recovered from the adverse event with no residual effect 
observed. 
• Recovering/Resolving 
− The adverse event improved but has not fully resolved. 
• Not Recovered/Not Resolved 
− The adverse event itself is still present and observable. 
• Recovered/Resolved with Sequelae 
− The residual effects of the adverse event are still present and observable. 
− Include sequelae/residual effects. 
• Fatal 
− Fatal should be used when death is a direct outcome of the adverse event. 
• Unknown 
9.5. 
Serious Adverse Events and Adverse Event of Special Interest 
Reporting-Procedure For Investigators 
All AEs, SAEs, events of special interest, and medication errors including overdose will 
be reported in the CRF. 
Serious events that are also efficacy endpoints (eg, PD) 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. 


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The following types of events should be reported by the Investigator in electronic data 
capture (EDC) within 24 hours of becoming aware: 
• SAEs (see Section 9.4.2 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). 
• 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 
total bilirubin (TBL) >2 × ULN that may occur either at different time points 
or simultaneously during the study.  A targeted questionnaire is built as an 
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 DS8201a dosage, clinical 
course, associated AEs, and outcome must be captured in the Narrative 
form of the CRF within EDC. 
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.  
In the event that eCRF is unavailable, report SAEs by faxing the paper Serious Adverse 
Event Report (SAVER) Form to CRO using the provided fax transmittal form and the 
appropriate fax number provided for your country.  Once eCRF becomes available, please 
enter SAEs reported on the SAVER Form into eCRF as soon as possible.  Please refer to 
eCRF Completion Guide for additional instructions.   
See Section 15.12.4 for contact information for SAE reporting.  Please call the local SAE 
Hotline (see Study Manual) or your study monitor for any questions on SAE reporting.   


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9.6. 
Notifying Regulatory Authorities, Investigators, and 
Institutional Review Board/Ethics Committee 
Daiichi Sankyo and/or CRO will inform Investigators, IRBs/ECs, and regulatory 
authorities of any Suspected Unexpected Serious Adverse Reactions (SUSARs) occurring 
in other study sites or other  studies of the investigational drug, as appropriate per local 
reporting requirements.  Daiichi Sankyo and/or CRO will comply with any additional 
local safety reporting requirements. 
In the US, upon receipt of the Sponsor’s notification of SUSARs that occurred with the 
study drug, unless delegated to the Sponsor, it is the Investigator’s responsibility to inform 
the IRB per Sponsor’s instruction. 
In the European Economic Area states, it is the Sponsor’s responsibility to report SUSARs 
to all ECs. 
9.7. 
Exposure In Utero During Clinical Studies 
Daiichi Sankyo must be notified of any subject who becomes pregnant while receiving or 
within 7 months of discontinuing the study drug.  
Although pregnancy is not technically an adverse event, all pregnancies must be followed 
to conclusion to determine their outcome.  This information is important for both drug 
safety and public health concerns.  It is the responsibility of the Investigator, or designee, 
to report any pregnancy in a female subject using the Exposure In Utero (EIU) Reporting 
form.  Please contact your study monitor to receive the EIU Reporting Form upon learning 
of a pregnancy.  The Investigator should make every effort to follow the subject until 
completion of the pregnancy and complete the EIU Reporting Form with complete 
pregnancy outcome information, including normal delivery and induced abortion.  The 
adverse pregnancy outcome, either serious or non-serious, should be reported in 
accordance with study procedures.  If the outcome of the pregnancy meets the criteria for 
immediate classification as a SAE (ie, post-partum complications, spontaneous 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 9.5.  
9.8. 
Clinical Laboratory Evaluations 
The following items will be measured.  For clinical laboratory parameters, the reference 
range of the institution that performs the measurements will be used. 
Information will be entered in the case report form on whether measured, date of 
measurement, and measurement results for the following items.   
1. Hematology tests 
• Red blood cell count, hemoglobin, hematocrit, platelet count, white blood cell 
count, differential white blood cell count (neutrophils, lymphocytes, monocytes, 
eosinophils, basophils). 
2. Blood chemistry tests 


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• Total protein, albumin, alkaline phosphatase, ALT, AST, TBL, blood urea 
nitrogen/urea, calcium, chloride, serum creatinine, lactate dehydrogenase 
(LDH), potassium, sodium, magnesium).   
• A coagulation test will be performed (prothrombin time and activated partial 
thromboplastin time) and creatinine clearance (mL/min) will be calculated 
using the Cockcroft-Gault equation (Section 17.1). 
3. Urinalysis test 
• Protein, glucose, blood, microscopy assessments (if indicated), and specific 
gravity 
In addition, the following parameters will be analyzed at the visits indicated in the 
Schedule of Events, Section 6.  
• Pregnancy test (serum or urine) for all female subjects of childbearing potential 
must be performed during the Screening Period before each treatment cycle, 
EOT and F/U visit.  A positive urine pregnancy test result must be confirmed 
immediately using a serum test.  Test must be confirmed negative within 72 
hours prior to drug administration. 
• Troponin (preferably troponin-T) test must be performed at the visits indicated 
in Section 18.  Additional troponin testing should be performed if subject 
reports cardiac symptoms.  Same assay should be used for the subject 
throughout their study participation. 
All clinical laboratory values must be appraised by the investigator as to clinical 
significance and used to take appropriate clinical management measures.  All abnormal 
clinical 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, it will be reported in the eCRF and other relevant procedures must be followed (see 
Section 9.5).  Abnormal laboratory values (NCI-CTCAE grade 3 or 4) occurring during 
the clinical study will be followed until repeat test results return to normal (or baseline), 
stabilize, or are no longer clinically significant. 
9.9. 
Vital Signs 
Vital sign measurements will include systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature.  Additionally, SpO2 will be measured at Screening, 
before administration on Day 1 of each cycle, EOT and F/U. 
9.10. 
Electrocardiograms 
Standard supine/semi-recumbent 12-lead ECGs in triplicate (taken in close succession, 3 
minutes apart) will be performed as described in the Schedule of Events.  Standard ECG 
parameters will be measured, including RR, PR, QT intervals, and QRS duration.  All 
ECGs must be evaluated by investigator or delegated physician for the presence of 
abnormalities. 


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9.11. 
Physical Examinations 
Physical examination findings including ECOG PS will be used to evaluate 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. 
9.12. 
Other Examinations 
ECOG PS 
Cardiac Assessments 
• Either ECHO or MUGA, will be performed as described in the Schedule of 
Events (Section 6).  LVEF will be measured. 
Ophthalmic Assessments 
• Will include visual acuity testing, slit lamp examination, and fundoscopy. 
Pulmonary Assessments 
• Will include CT or MRI of the chest, SpO2 and will be performed as described 
in schedule of events.  For more details please refer to Section 6 of the protocol. 
• An ILD Adjudication Committee (AC) will review all cases of (potential) ILD 
on an ongoing basis.  Description of the ILD AC is available in Section 9.3.1 . 


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10. 
OTHER ASSESSMENTS 
Not applicable. 
 


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11. 
STATISTICAL METHODS  
11.1. 
General Statistical Considerations 
The primary analysis will be performed after all subjects have either discontinued the 
study or at least completed tumor assessment at 18 weeks (ie, at least 3 post-treatment 
tumor assessments) in Cohort A.  A data cut-off date for database lock will be identified 
for the primary analysis.  After the primary analysis, the data will be followed until 
completion. 
Summary statistics will be presented by cohort.  Continuous variables will be summarized 
by the number of observations, mean, standard deviation, median, minimum, and 
maximum values (as well as geometric means and geometric coefficient of variation for 
Cmax and AUC PK parameters), unless otherwise specified.  Categorical variables will be 
summarized using frequency counts and percentages, unless otherwise specified. 
Assessment of change from baseline to post-treatment or the ratio of post-treatment to 
baseline will include only those subjects with both baseline and post-treatment 
measurements.  The last non-missing value of a variable taken before the first dose of the 
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. 
Efficacy analyses will be performed on the full analysis set (FAS).  Safety analyses will be 
performed using the Safety Analysis Set.  Analysis of PK parameters will be based on the 
PK Analysis Set.  All other exploratory analyses will be performed based on the FAS and 
the availability of assessments. 
11.2. 
Analysis Sets 
11.2.1. 
Full Analysis Set/Safety Analysis Set 
FAS/Safety Analysis Set will include all subjects who received at least 1 dose of the study 
drug. 
11.2.2. 
Pharmacokinetic Analysis Set 
The PK Analysis Set will include all subjects who received at least 1 dose of the study 
drug and had measurable serum concentrations of DS-8201a. 
11.3. 
Study Population Data 
Subject disposition will be summarized.  The total number of subjects for each defined 
analysis population will also be tabulated.  The demographic and baseline characteristics 
will be summarized descriptively by cohort and overall for the FAS.  Study drug exposure, 
treatment duration, and compliance with study therapy as well as prior and concomitant 
medications will be summarized descriptively by cohort and overall for the Safety 
Analysis Set. 
 


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11.4. 
Statistical Analyses 
11.4.1. 
Efficacy Analyses 
11.4.1.1. Primary Efficacy Analyses 
The primary endpoint is ORR (the proportion of subjects who achieved a best overall 
response of complete response [CR] or PR) assessed by independent radiologic facility 
review in Cohort A.  Confirmation of CR/PR is required for this study. 
The point estimate of ORR and its 2-sided exact 95% CI using Clopper-Pearson method 
will be provided by cohort.  In addition, ORR at the fixed time points (eg, 6, 12, 18, and 
24 weeks) along with their 2-sided exact 95% CIs using Clopper-Pearson method will be 
provided by cohort. 
11.4.1.2. Secondary Efficacy Analyses 
The secondary efficacy endpoints include ORR in Cohort B and Cohort C, DoR, DCR, 
PFS, OS, and ORR assessed by the investigator.   
Duration of response is defined as the time from the date of the first documentation of an 
objective response (CR or PR) to the date of the first documentation of PD.  Duration of 
response will be measured for responding subjects (CR or PR) only.  Detailed censoring 
rules for duration of response will be specified in the statistical analysis plan (SAP). 
PFS is defined as the time from the date of the first dose to the earlier of the dates of the 
first objective documentation of radiographic PD via independent radiologic facility 
review or death due to any cause.  Detailed censoring rules for PFS will be specified in the 
SAP.  
OS is defined as the time from the date of first dose to the date of death from any cause.  If 
the death of a subject is not reported before the data cut-off for OS analysis, OS will be 
censored at the last contact date at which a subject was known to be alive. 
DoR, PFS, and OS will be summarized using Kaplan-Meier method with median event 
time and 2-sided 95% CI for the median using Brookmeyer and Crowley method by 
cohort. 
DCR will be analyzed in the same manner as ORR analysis.  ORR assessed by the 
investigator will be analyzed in the same manner as the primary endpoint.  Any additional 
analysis plans will be specified in the SAP. 
11.4.1.3. Exploratory Efficacy Analyses 
The exploratory efficacy analyses include subgroup analyses of the primary and secondary 
endpoints and analyses of exploratory efficacy endpoints.  
11.4.1.3.1. 
Subgroup Analyses 
Subgroup analyses for ORR, PFS, and OS will be performed in Cohort A.  Subgroup 
analyses will include: 
• Lines of prior systemic therapy (2, 3, ≥4) 
• Age (<65, ≥65 yrs.) 


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• Sex (female, male) 
• ECOG PS (0, 1) 
• HER2 status (Cohort A: HER2 3+ or HER2 2+/ISH+) 
• Primary tumor site (Rectum, Colon) 
• Histological subtype (Intestinal or Diffuse or Others) 
• Number of metastatic sites (<2, ≥2) 
• Prior treatment with irinotecan or other topoisomerase I inhibitors (Yes or No) 
• Prior treatment with HER2 targeted regimen 
• Prior treatment with any anti EGFR antibody or any VEGF antibody   
• Prior treatment with regorafenib or TAS-102  
• Prior treatment with anti-PD-1 inhibitor 
• Presence of non-liver metastasis  at baseline (Yes or No) 
• Renal impairment at baseline (within normal range, and mild/moderate 
impairment) 
 
In each subgroup defined above, the analysis will be carried out using the same type of 
methodology as described for the overall analysis of the corresponding endpoint. 
11.4.1.3.2. 
Analyses of Exploratory Efficacy Endpoints 
Time to response, and best percent change in the SLD of measurable tumors will be 
evaluated and considered as exploratory efficacy endpoints.  
Time to response will be summarized using Kaplan-Meier methods with median event 
time and 2-sided 95% CI for the median using Brookmeyer and Crowley method by 
cohort. 
Descriptive statistics for the best (minimum) percent change from baseline in the SLD will 
be provided by cohort.  Waterfall plots of the best (minimum) percent change in the SLD 
for each subject will be presented by cohort with vertical lines representing the sorted 
values of percent changes.  Spider plots of the percent change in the SLD for each subject 
will be also presented by cohort. 
11.4.2. 
Pharmacokinetic/Pharmacodynamic/Biomarker Analyses 
11.4.2.1. Pharmacokinetic Analyses 
Serum concentrations for DS-8201a, total anti-HER2 antibody and MAAA-1181a will be 
listed, plotted, and summarized using descriptive statistics by cohort at each time point.  
PK parameters will be listed and summarized using descriptive statistics by cohort. 
The population PK (pop-PK) analysis to evaluate the effect of intrinsic and extrinsic 
factors of DS-8201a, and, if appropriate, total anti-HER2 antibody and MAAA-1181a will 
be characterized, including available PK data from the Phase 1 study.  After establishment 


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of the pop-PK model, a pop-PK/PD model will be developed to evaluate the relationship 
between exposure and efficacy and toxicity.  The pop-PK and population 
pharmacokinetics/pharmacodynamics (pop-PK/PD) modeling analyses may be reported 
separately from the clinical study report. 
11.4.2.2. Pharmacodynamic Analyses 
Not applicable. 
11.4.2.3. Biomarker Analyses 
Biomarkers will be listed and summarized using descriptive statistics. 
11.4.2.4. Pharmacogenomic Analyses 
Not applicable. 
11.4.3. 
Safety Analyses 
Safety analysis will be performed using the Safety Analysis Set.  Safety analyses in 
general will be descriptive and will be presented in tabular format with the appropriate 
summary statistics. 
11.4.3.1. Adverse Event Analyses 
A TEAE is defined as an AE that emerges during the treatment period (from date of first 
dose until the F/U visit after the last dose of the study drug), 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 related to the pre-
treatment state, when the AE is continuous.  TEAEs will be coded using MedDRA and 
assigned grades based on version 5.0 of the NCI-CTCAE.  The number and percentage of 
subjects reporting TEAEs will be tabulated by system organ class (SOC), preferred term 
(PT), relationship to the study treatment, and the worst CTCAE grade.  Similarly, the 
number and percentage of subjects reporting treatment-emergent SAEs will be tabulated 
by cohort, as well as TEAEs leading to discontinuation of the study treatments. 
A by-subject AE (including treatment-emergent) data listing including but not limited to 
the verbatim terms, SOC, PT, CTCAE grade, and relationship to study treatment will be 
provided.  Deaths, other SAEs, and other significant AEs, including those leading to 
discontinuation of the study treatments, will be listed. 
11.4.3.2. Clinical Laboratory Evaluation Analyses 
Descriptive statistics will be provided by cohort for the clinical laboratory test results and 
changes from baseline by scheduled time of evaluation, as well as for the change from 
baseline.  In addition, the change from baseline will be summarized for the maximum 
post-treatment value, and minimum post-treatment value. 
Abnormal clinical laboratory results will be graded according to NCI-CTCAE version 5.0, 
if applicable, and the grade will be presented in a by-subject data listing.  A shift table, 
presenting 2-way frequency tabulation for baseline and the worst post-treatment value 
according to NCI-CTCAE grade, will be provided by cohort for clinical laboratory tests. 


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All clinical laboratory test results and abnormal clinical laboratory test results deemed of 
clinical significance or of Grade 3 or 4 will be listed. 
11.4.3.3. Vital Sign Analyses 
Descriptive statistics will be provided by cohort for the vital sign measurements and 
changes from baseline by scheduled time of evaluation, as well as for the change from 
baseline by scheduled time of evaluation, including the EOT visit and the maximum and 
minimum post-treatment values.  All vital sign data will also be listed. 
11.4.3.4. Electrocardiogram Analyses 
Descriptive statistics will be provided by cohort for ECG parameters and changes from 
baseline by scheduled time of evaluation, including the maximum post-treatment values 
and the values at the EOT Visit.  In addition, the number and percentage of subjects with 
ECG interval values meeting the criteria (eg, QTc ≤450 ms, >450 to ≤480 ms, >480 ms to 
≤500 ms, and >500 ms) will be tabulated by cohort.  The QT intervals will be corrected 
for heart rate by Fridericia’s formula (QTcF = QT/[RR]1/3).  ECG data will also be listed. 
11.4.3.5. Anti-Drug Antibodies (ADA) Analyses 
A shift table, presenting the 2-way frequency tabulation for baseline and all schedule times, 
including the EOT Visit, will be provided by cohort for the incidence of ADA. 
11.4.3.6. Other Safety Analyses 
All other safety endpoints (eg, physical examination findings including ECOG PS, 
ECHO/MUGA, and ophthalmologic findings) will be listed. 
11.4.4. 
Other Analyses 
Not Applicable. 
11.5. 
Interim Analyses 
No formal interim analyses are planned.   
11.6. 
Sample Size Determination 
A total of 90 (Cohort A: 50, Cohort B: 20, and Cohort C: 20) will be enrolled. 
Cohort A 
The sample size of 48 subjects provides a 90% probability of achieving a lower limit of 
95% CI for the ORR that exceeds 15% (threshold) under the expected ORR of 35%, and 
enables a statistical comparison with a historical control on PFS (eg, provides a power of 
about 80% to detect the difference in PFS under the assumption that median PFS will be 
prolonged from 2 months to 3 months compared to historical PFS in patients treated with 
regorafenib21 or TAS-10222).  Considering drop out, 50 subjects will be enrolled. 
Cohorts B and C 
With this sample size, the probability that more than 4 responders out of 20 subjects 
(ORR >20%) are observed will be less than 5% under the threshold ORR of 10%, but 
more than 75% under the expected ORR of 30%.  


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The probability value for the sample size is derived based on binomial distribution using 
SAS® Version 9.3. 
11.7. 
Statistical Analysis Process 
The clinical study will be analyzed by DS or its agent/CRO followed by this protocol, and 
the SAP which will demonstrate all methodologies and displays/shells for statistical 
analyses.   
The SAP will provide the statistical methods and definitions for the analysis of efficacy 
and safety data, and will describe the approaches to be taken to summarize other clinical 
study information such as subject disposition, demographic and baseline characteristics, 
study drug exposure, and prior and concomitant medications.  The SAP will also include a 
description of how missing, unused, and spurious data will be addressed.   
To preserve the integrity of the statistical analysis and clinical study conclusions, the SAP 
will be finalized prior to database lock.   
All statistical analyses will be performed using SAS® Version 9.3 or higher (SAS Institute, 
Cary, NC 27513). 


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12. 
DATA INTEGRITY AND QUALITY ASSURANCE 
The investigator/investigational site will permit study related monitoring, audits, IRB/EC 
review and regulatory inspections by providing direct access to source data/documents.  
Direct access includes permission to examine, analyze, verify, and reproduce any records 
and reports that are important to the evaluation of a clinical study. 
12.1. 
Monitoring and Inspections 
The Sponsor, CRO monitor, and regulatory authority inspectors are responsible for 
contacting and visiting the Investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the study (eg, 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 study 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 study 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, sub-investigator, or study site staff will enter the data in the CRF in 
accordance with the CCGs that are provided by the sponsor to CRF completion should be 
kept current to enable the monitor to review the subject’s status throughout the course of 
the study.  CRF will be completed, reviewed, and e-signed by the Investigator according 
to the study data flow.  
Any clinical data entered in the CRF will be subjected to these data management 
procedures and will be included in the final study datasets according to CDISC standards. 


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DS or a designee will supply eCRFs.  An eCRF must be completed for each subject who 
signs an ICF for study entry and undergoes any screening procedure.  If a subject is not 
treated, the reason must be recorded on the eCRF.  All data collected during the study will 
be recorded in this individual, subject-specific eCRF.  Instructions will be provided for the 
completion of the eCRF and any corrections made will be automatically documented via 
the EDC software’s “audit trail.” 
Completion of the eCRF should be kept current to enable the monitor to review the 
subject’s status throughout the course of the study.  All information and other material to 
be used by subjects and investigative staff must use vocabulary and language that are 
clearly understood.  The eCRF will be completed, reviewed and signed off or e-signed by 
the Investigator.  The Investigator will sign and date the indicated places on the eCRF via 
the EDC system’s electronic signature.  These signatures will indicate that the Investigator 
inspected or reviewed the data on the eCRF, the data queries, and the site notifications, 
and agrees with the content.  The information should be entered into the eCRF within 5 
days of the visit and should be completed, reviewed, and signed off by the investigator 
within 2 weeks of the last subject visit.  Query resolution should be completed within 48 
hours. 
12.3. 
Data Management 
Each subject will be identified in the database by a unique subject identifier as defined by 
the sponsor. 
To ensure the quality of clinical data across all subjects and study sites, a Clinical Data 
Management review will be performed on subject data according to specifications given to 
Sponsor or Designee.  Data will be vetted both electronically and manually for CRFs and 
the data will be electronically vetted by programmed data rules within the application.  
Queries generated by rules and raised by reviewers will be generated within the EDC 
application.  During this review, subject data will be checked for consistency, 
completeness and any apparent discrepancies.  
Data received from external sources such as central labs will be reconciled to the clinical 
database. 
Serious Adverse Events in the clinical database will be reconciled with the safety database. 
All Adverse Events will be coded using MedDRA.  
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 CRFs 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. 


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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, IRB/EC 
correspondence and approvals, approved and signed informed consent forms, 
Investigator’s Agreement, clinical supplies receipts, distribution and return records), and 
other sponsor 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 (essential) documentation, 
suitable for inspection at any time by representatives from the Sponsor and/or applicable 
regulatory authorities.  Essential documents contained in the Trial Master File include: 
• Subject files containing completed CRFs, informed consent forms, and 
supporting copies of source documentation (if kept). 
• Study files containing the protocol with all amendments, Investigator’s 
Brochure, copies of relevant essential documents required prior to commencing 
a clinical study, and all correspondence to and from the IRB/EC and the 
Sponsor. 
• Records related to the study drug(s) including acknowledgment of receipt at 
study site, accountability records and final reconciliation and applicable 
correspondence. 
In addition, all original source documents supporting entries in the CRFs must be 
maintained and be readily available. 
All essential documentation will be retained by the institution for at least 5 years after 
completion of the study or for a longer period, where so required by other applicable 
regulations or requirements.  It is the responsibility of the Sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained.  
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 Sponsor 
and the Investigator.  Should the Investigator wish to assign the study records to another 


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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 the CRO.  This agreement will include the financial 
information agreed upon by the parties. 
13.2. 
Reimbursement, Indemnity, and Insurance 
The Sponsor provides insurance for study subjects to make available compensation in case 
of study-related injury. 
Reimbursement, indemnity and insurance shall be addressed in a separate agreement on 
terms agreed upon by the parties. 


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14. 
PUBLICATION POLICY 
A study site may not publish results of a study until after a coordinated multicenter 
publication has been submitted for publication or until 1 year after the study has ended, 
whichever occurs first.  Therefore, the study site will have the opportunity to publish the 
results of the study, provided that Daiichi Sankyo has had the opportunity to review and 
comment on the study site’s proposed publication prior to its being submitted for 
publication with the prior advice of DS Legal Affairs (intellectual property council) and 
with proper regard to the protection of subjects’ identities. 


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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, ICH consolidated Guideline E6 for GCP 
(CPMP/ICH/135/95), and applicable regulatory requirement(s) including the following: 
• US Food and Drug Administration GCP Regulations: Code of Federal 
Regulations (CFR) Title 21, parts 11, 50, 54, 56, and 312 as appropriate and/or; 
• Japanese Ministry of Health, Labor and Welfare Ordinance No. 28 of 27 March, 
1997 and/or; 
• Directive 2001/20/EC of the European Parliament and of the Council on the 
approximation of the laws, regulations and administrative provisions of the 
Member States relating to the implementation of good clinical practice in the 
conduct of clinical trials on medicinal product for human use; 
• Other applicable local regulations. 
15.2. 
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. 
For EU study sites, the Sponsor will observe the rules laid down in the European Data 
Protection Directive 95/46/EC on the protection of individuals with regard to the 
processing of personal data and the free movement of such data.   
The Investigator must ensure that the subject’s anonymity is maintained.  On the CRFs or 
other documents submitted to the Sponsor or the CRO, subjects should be identified by a 
unique subject identifier as designated by the Sponsor.  Documents that are not for 
submission to the Sponsor or the CRO (eg, signed ICF) should be kept in strict confidence 
by the Investigator. 
In compliance with ICH GCP Guidelines, it is required that the Investigator and institution 
permit authorized representatives of the company, of the regulatory agency(s), and the 
IRB/EC direct access to review the subject’s original medical records for verification of 
study-related procedures and data.  The Investigator is obligated to inform the subject that 
his/her study-related records will be reviewed by the above named representatives without 
violating the confidentiality of the subject. 
15.3. 
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. 


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In obtaining and documenting informed consent, the Investigator should comply with the 
applicable regulatory requirements, and should adhere to GCP and to the ethical principles 
that have their origin in the Declaration of Helsinki.  The consent form and any revision(s) 
should be approved by the EC or IRB prior to being provided to potential subjects. 
The subject’s written informed consent should be documented in the subject’s medical 
records.  The ICF should be signed and personally dated by the subject and by the person 
who conducted the informed consent discussion (not necessarily the Investigator).  The 
original signed ICF should be retained in accordance with institutional policy, and a copy 
of the signed consent form should be provided to the subject.  The date and time (if 
applicable) that informed consent was given should be recorded on the CRF. 
Suggested model text for the ICF for the study and any applicable subparts (genomic, PK, 
etc.) are provided in the Sponsor’s ICF template for the Investigator to prepare the 
documents to be used at his or her study site.  Updates to applicable forms will be 
communicated via letter from the Sponsor. 
For study sites in the US, an additional consent is required for the Health Insurance 
Portability and Accountability Act (HIPAA).  Also, a separate special consent will be 
required for Pharmacogenomic testing for this protocol. 
15.4. 
Informed Consent for Pharmacogenomic Analysis 
Before obtaining samples for pharmacogenomic analysis, the investigator is responsible 
for obtaining freely given consent, in writing, from the subject, after giving an explanation 
of the pharmacogenomic analysis in intelligible terms.  Before obtaining the informed 
consent, the investigator should provide the subjects with adequate time to have the 
opportunity to inquire about the details of the study, and should answer all questions 
properly.  This analysis is an optional analysis for whom agreed to join clinical study, and 
another written informed consent document is prepared, separately from informed consent 
for clinical study. 
15.5. 
Regulatory Compliance 
The study protocol, subject information and consent form, the Investigator Brochure, 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 EC or IRB for ethical review and approval 
according to local regulations, prior to the study start.  The written approval should 
identify all documents reviewed by name and version. 
Changes in the conduct of the study or planned analysis will be documented in a protocol 
amendment and/or the SAP. 
The Investigator and/or Sponsor must submit and, where necessary, obtain approval from 
the EC or IRB for all subsequent protocol amendments and changes to the ICF.  The 
Investigator should notify the EC or IRB of deviations from the protocol or SAEs 
occurring at the study site and other AE reports received from the Sponsor/CRO, in 
accordance with local procedures. 


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As required by local regulations, the Sponsor’s local Regulatory Affairs group or 
representative to whom this responsibility has been delegated will ensure all legal aspects 
are covered, and approval from the appropriate regulatory bodies obtained, prior to study 
initiation, and that implementation of changes to the initial protocol and other relevant 
study documents happen only after approval by the relevant regulatory bodies.  
In the event of any prohibition or restriction imposed (eg, clinical hold) by an applicable 
Regulatory Authority(ies) in any area of the world, or if the Investigator is aware of any 
new information which might influence the evaluation of the benefits and risks of the 
investigational drug, the Sponsor should be informed immediately.   
In addition, the Investigator will inform the Sponsor immediately of any urgent safety 
measures taken by the Investigator to protect the study subjects against any immediate 
hazard, and of any suspected/actual serious GCP non-compliance that the Investigator 
becomes aware of. 
15.6. 
Protocol Deviations 
The Investigator should conduct the study in compliance with the protocol agreed to by 
Sponsor and, if required, by the regulatory authority(ies), and which was given 
approval/favorable opinion by the IRBs/ECs. 
A deviation to any protocol procedure or waiver to any stated criteria will not be allowed 
in this study except where necessary to eliminate immediate hazard(s) to the subject.  
Sponsor must be notified of all intended or unintended deviations to the protocol (eg, 
inclusion/exclusion criteria, dosing, missed study visits) on an expedited basis. 
The Investigator, or person designated by the Investigator, should document and explain 
any deviation from the approved protocol. 
If a subject was ineligible or received the incorrect dose or study treatment, and had at 
least 1 administration of study drug, data should be collected for safety purposes. 
If applicable, the Investigator should notify the IRB/EC of deviations from the protocol in 
accordance with local procedures. 
15.7. 
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/ECs, 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/EC.  The 
Investigator should obtain written informed consent to continue participation with the 
revised written information even if subjects were already informed of the relevant 


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information.  The Investigator or other responsible personnel who provided explanations 
and the subject should sign and date the revised ICF. 
15.8. 
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 site s 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.  Sponsor approval of local amendments will be clearly 
documented. 
A protocol amendment may be implemented after it has been approved by the IRB/EC and 
by regulatory authorities where appropriate, unless immediate implementation of the 
change is necessary for subject safety. 
15.9. 
Study Termination 
The Sponsor has the right to terminate the study at any time and study termination may 
also be requested by (a) competent authority (ies). 
15.10. 
Data and Safety Monitoring Board 
Not applicable. 
15.11. 
Steering Committee 
A steering committee will be established for this study.  Details on the membership, 
responsibilities, and working procedures of the committee will be described in its own 
charter. 
15.12. 
Address List 
A list of key study personnel (including personnel at the sponsor, CRO, laboratories, and 
other vendors) and their contact information (address, telephone, fax, email) will be kept 
on file and regularly updated as necessary. 
15.12.1. 
Sponsor 
Japan 
Daiichi Sankyo Company, Limited  
3-5-1, Nihonbashi-honcho, Chuo-ku, Tokyo 103-8426, Japan 
US 
Daiichi Sankyo, Inc.  








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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/Pages/fact_sheets_population.aspx. 
2. Watanabe T, Muro K, Ajioka Y, et al; Japanese Society for Cancer of the Colon 
and Rectum. Japanese Society for Cancer of the Colon and Rectum (JSCCR) 
Guidelines 2016 for treatment of colorectal cancer. Int J Clin Oncol. 2017 Mar 27. 
Epub  
3. NCCN Clinical Practice Guidelines in Oncology, Colon Cancer, Rectal Cancer 
Version 2. Available from: 
https://www.nccn.org/professionals/physician_gls/f_guidelines.asp. 
4. Van Cutsem E, Cervantes A, Adam R, et al. ESMO consensus guidelines for the 
management of patients with metastatic colorectal cancer. Ann Oncol. 
2016;27(8):1386-422. 
5. Takegawa N, Yonesaka K. HER2 as an Emerging Oncotarget for Colorectal 
Cancer Treatment After Failure of Anti-Epidermal Growth Factor Receptor 
Therapy. Clin Colorectal Cancer. 2017;S1533-0028(16)30247-7. 
6. Sartore-Bianchi A, Trusolino L, Martino C, et al. Dual-targeted therapy with 
trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, 
HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, 
multicentre, open-label, phase 2 trial. Lancet Oncol. 2016;17(6):738-46. 
7. Richman SD, Southward K, Chambers P, et al. HER2 overexpression and 
amplification as a potential therapeutic target in colorectal cancer: analysis of 3256 
patients enrolled in the QUASAR, FOCUS and PICCOLO colorectal cancer trials. 
J Pathol. 2016;238(4):562-70. 
8. V Martin, L Landi, et al. HER2 gene copy number status may influence clinical 
efficacy to anti-EGFR monoclonal antibodies in metastatic colorectal cancer 
patients. Br J Cancer. 2013;108(3):668-75. 
9. Jeong JH, Kim J, Hong YS, et al. HER2 Amplification and Cetuximab Efficacy in 
Patients With Metastatic Colorectal Cancer Harboring Wild-type RAS and BRAF. 
Clin Colorectal Cancer. 2017;S1533-0028(17)30032-4. 
10. Ogitani Y, Hagihara K, Oitate M, et al. Bystander killing effect of DS-8201a, a 
novel anti-human epidermal growth factor receptor 2 antibody-drug conjugate, in 
tumors with human epidermal growth factor receptor 2 heterogeneity. Cancer Sci. 
2016;107(7):1039-46. 
11. Ogitani Y, Aida T, Hagihara K, et al. DS-8201a, A Novel HER2-Targeting ADC 
with a Novel DNA Topoisomerase I Inhibitor, Demonstrates a Promising 
Antitumor Efficacy with Differentiation from T-DM1. Clin Cancer Res. 
2016;22(20):5097-108. 


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12. 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. 
13. 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. 
14. 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. 
15. 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. 
16. Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a 
novel therapeutic target. Ann Oncol. 2008;19(9):1523-9. 
17. 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. 
18. 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. 
19. 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. 
20. 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. 
21. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for 
previously treated metastatic colorectal cancer (CORRECT): an international, 
multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 
2013;381(9863):303-12. 
22. Mayer RJ, Van Cutsem E, Falcone, et al. Randomized trial of TAS-102 for 
refractory metastatic colorectal cancer. N Engl J Med. 2015;372(20):1909-19. 


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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 kilograms (1 kilogram = 2.2 pounds): 
Conventional - serum creatinine in mg/dL: 
Male: 
CrCl (mL/min) = 
72
 
 
mg/dL)
(in 
 
creatinine
 
serum
kg)
(in 
 weight 
 
years)]
(in 
 
age
 - 
[140
×
×
 
Female: 
CrCl (mL/min) = 
72
 
 
mg/dL)
(in 
 
creatinine
 
serum
kg)
(in 
 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
×
×
µ
 
 
Female: 
CrCl (mL/min) = 
0.0113
 
 
72
 
 
mol/L)
(in 
 
creatinine
 
serum
kg)
(in 
 weight 
  
years)]
(in 
 
age
 - 
[140
×
×
×
µ
 
× 0.85 
 
Source: Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum 
creatinine. Nephron 1976;16:31-41. 


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17.2. 
Eastern Cooperative Oncology Group Performance Status 
(ECOG PS) 
Table 17.1: 
Eastern Cooperative Oncology Group Performance Status Scale 
0 
Normal activity.  Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous activity, but ambulatory 
and able to carry out work of a light or sedentary nature (eg, light housework, office 
work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but unable to carry 
out any work activities.  Up and about more than 50% of waking hours. 
3 
In bed >50% of the time.  Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally confined 
to bed or chair. 
5 
Dead. 
Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
Response Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-55. 
17.3. 
Response Evaluation Criteria in Solid Tumors, Version 1.1 
17.3.1. 
Measurability of Tumor at Baseline 
17.3.1.1. Definitions 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable 
as follows: 
17.3.1.1.1. Measurable 
• Tumor lesions: Must be accurately measured in at least 1 dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size 
of:  
− 10 mm by CT scan (CT scan slice thickness no greater than 5 mm)  
− 10 mm caliper measurement by clinical exam (lesions which cannot be 
accurately measured with calipers should be recorded as non-measurable)  
− 20 mm by chest X-ray  
• Measurable malignant lymph nodes: To be considered pathologically enlarged 
and measurable, a lymph node must be ≥15 mm in short axis when assessed by 
CT scan (CT scan slice thickness recommended to be no greater than 5 mm).  
At baseline (ie, screening for this study) and in F/U (ie, all measurements past 
screening for this study), only the short axis will be measured and followed.  
See also notes below on “Baseline documentation of target and non-target 
lesions” for information on lymph node measurement.  


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17.3.1.1.2. Non-Measurable 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph 
nodes with ≥10 to <15 mm short axis), as well as truly non-measurable lesions.  Lesions 
considered truly non-measurable include: leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or 
lung, and abdominal masses/abdominal organomegaly identified by physical exam that is 
not measurable by reproducible imaging techniques. 
17.3.1.1.3. Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment. 
17.3.1.1.3.1. Bone Lesions 
• Bone scan, positron emission tomography 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. 
17.3.1.1.3.2. Cystic Lesions 
• Lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-
measurable) since they are, by definition, simple cysts.  
• “Cystic lesions” thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described 
above.  However, if noncystic lesions are present in the same subject, these are 
preferred for selection as target lesions.  
17.3.1.1.3.3. Lesions with Prior Local Treatment 
• Tumor lesions situated in a previously irradiated area, or in an area subjected to 
other loco-regional therapy, are not considered measurable unless there has been 
demonstrated progression in the lesion. 
17.3.1.2. Specifications by Methods of Measurements 
17.3.1.2.1. Measurement of Lesions 
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and NEVER more than 28 days before enrollment(study treatment). 


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17.3.1.2.2. Method of Assessment 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during F/U.  Imaging based evaluation 
should always be performed rather than clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment.  This guideline has defined measurability of lesions on 
CT scan based on the assumption that CT slice thickness is 5 mm or less.  When CT scans 
have slice thickness greater than 5 mm, the minimum size for a measurable lesion should 
be twice the slice thickness.  MRI is also acceptable in certain situations (eg, for body 
scans). 
17.3.2. 
Tumor Response Evaluation 
17.3.2.1. Assessment of Overall Tumor Burden and Measurable Disease 
To assess objective response or future progression, it is necessary to estimate the overall 
tumor burden at baseline and use this as a comparator for subsequent measurements. 
In this study, only subjects with measurable disease at baseline should be included. 
17.3.2.2. Baseline Documentation of “Target” and “Non-target” Lesions 
When more than 1 measurable lesion is present at baseline, all lesions up to a maximum of 
5 lesions total (representative of all involved organs) should be identified as target lesions 
and will be recorded and measured at baseline (this means in instances where subjects 
have only 1 or 2 organ sites involved a maximum of 2 and 4 lesions respectively will be 
recorded). 
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be 
selected. 
Lymph nodes merit special mention since they are normal anatomical structures which 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes which are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of ≥15 mm by CT scan.  Only the short axis of these nodes will 
contribute to the baseline sum.  The short axis of the node is the diameter normally used 
by radiologists to judge if a node is involved by solid tumor.  Nodal size is normally 
reported as 2 dimensions in the plane in which the image is obtained (for CT scan this is 
almost always the axial plane; for MRI the plane of acquisition may be axial, sagittal, or 
coronal).  The smaller of these measures is the short axis.  For example, an abdominal 
node which is reported as being 20 mm × 30 mm has a short axis of 20 mm and qualifies 
as a malignant, measurable node.  In this example, 20 mm should be recorded as the node 
measurement.  All other pathological nodes (those with short axis ≥10 mm but <15 mm) 
should be considered non-target lesions.  Nodes that have a short axis <10 mm are 
considered non-pathological and should not be recorded or followed. 


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A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters.  If lymph 
nodes are to be included in the sum, then as noted above, only the short axis is added into 
the sum.  The baseline sum diameters will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be 
identified as non-target lesions and should also be recorded at baseline.  Measurements are 
not required and these lesions should be followed as “present,” “absent,” or in rare cases 
“unequivocal progression.”  In addition, it is possible to record multiple non-target lesions 
involving the same organ as a single item on the case record form (eg, “multiple enlarged 
pelvic lymph nodes” or “multiple liver metastases”). 
17.3.2.3. Response Criteria 
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions. 
17.3.2.3.1. Evaluation of Target Lesions 
CR: Disappearance of all target lesions.  Any pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to <10 mm. 
PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference 
the baseline sum diameters. 
PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference 
the smallest sum on study (this includes the baseline sum if that is the smallest on study).  
In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.  (Note: the appearance of 1 or more new lesions is also 
considered progression.)  
SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum diameters while on study. 
17.3.2.3.2. Special Notes on the Assessment of Target Lesions 
Lymph nodes: Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10 mm on study.  This means that when 
lymph nodes are included as target lesions, the “sum” of lesions may not be zero even if 
CR criteria are met, since a normal lymph node is defined as having a short axis of 
<10 mm.  For PR, SD, and PD, the actual short axis measurement of the nodes is to be 
included in the sum of target lesions. 
Target lesions that become “too small to measure”: While on study, all lesions (nodal 
and non-nodal) recorded at baseline should have their actual measurements recorded at 
each subsequent evaluation, even when very small (eg, 2 mm).  However, sometimes 
lesions or lymph nodes which are recorded as target lesions at baseline become so faint on 
CT scan that the radiologist may not feel comfortable assigning an exact measure and may 
report them as being “too small to measure.”  When this occurs, it is important that a value 
be recorded on the eCRF.  If it is the opinion of the radiologist that the lesion has likely 
disappeared, the measurement should be recorded as 0 mm.  If the lesion is believed to be 


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present and is faintly seen but too small to measure, a default value of 5 mm should be 
assigned.  (Note: It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat such as in 
the retroperitoneum; however, if a lymph node is believed to be present and is faintly seen 
but too small to measure, a default value of 5 mm should be assigned in this circumstance 
as well.)  This default value is derived from the 5 mm CT slice thickness (but should not 
be changed with varying CT slice thickness).  The measurement of these lesions is 
potentially non-reproducible, therefore providing this default value will prevent false 
responses or progressions based upon measurement error.  To reiterate, however, if the 
radiologist is able to provide an actual measure, that should be recorded, even if it is below 
5 mm. 
Lesions that split or coalesce on treatment: When non-nodal lesions “fragment,” the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum.  Similarly, as lesions coalesce, a plane between them may be maintained 
that would aid in obtaining maximal diameter measurements of each individual lesion.  If 
the lesions have truly coalesced such that they are no longer separable, the vector of the 
longest diameter in this instance should be the maximal longest diameter for the 
“coalesced lesion.” 
17.3.2.3.3. Evaluation of Non-target Lesions 
This section provides the definitions of the criteria used to determine the tumor response 
for the group of non-target lesions.  While some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only qualitatively 
at the time points specified in the protocol. 
CR: Disappearance of all non-target lesions and normalization of tumor marker level.  All 
lymph nodes must be non-pathological in size (<10 mm short axis). 
Non-CR/Non-PD: Persistence of 1 or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
PD: Unequivocal progression (see comments below) of existing non-target lesions (Note: 
the appearance of 1 or more new lesions is also considered progression). 
17.3.2.3.4. Special Notes on Assessment of Progression of Non-target Disease 
The concept of progression of non-target disease requires additional explanation as 
follows: 
When the subject also has measurable disease: In this setting, to achieve “unequivocal 
progression” on the basis of the non-target disease, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of SD or PR in 
target disease, the overall tumor burden has increased sufficiently to merit discontinuation 
of therapy.  A modest “increase” in the size of 1 or more non-target lesions is usually not 
sufficient to qualify for unequivocal progression status.  The designation of overall 
progression solely on the basis of change in non-target disease in the face of SD or PR of 
target disease will therefore be extremely rare. 
When the subject has only non-measurable disease: The same general concepts apply here 
as noted above, however, in this instance there is no measurable disease assessment to 


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factor into the interpretation of an increase in non-measurable disease burden.  Because 
worsening in non-target disease cannot be easily quantified (by definition: if all lesions are 
truly non-measurable) a useful test that can be applied when assessing subjects for 
unequivocal progression is to consider if the increase in overall disease burden based on 
the change in non-measurable disease is comparable in magnitude to the increase that 
would be required to declare PD for measurable disease (ie, an increase in tumor burden 
representing an additional 73% increase in “volume“ [which is equivalent to a 20% 
increase diameter in a measurable lesion]).  If ‘unequivocal progression’ is seen, the 
subject should be considered to have had overall PD at that point.  While it would be ideal 
to have objective criteria to apply to non-measurable disease, the very nature of that 
disease makes it impossible to do so, therefore the increase must be substantial. 
17.3.2.3.5. New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: ie, not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some 
“new” bone lesions may be simply healing or flare of preexisting lesions).  This is 
particularly important when the subject’s baseline lesions show PR or CR.  For example, 
necrosis of a liver lesion may be reported on a CT scan report as a “new” cystic lesion, 
which it is not. 
A lesion identified on a 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 
brain ordered which reveals metastases.  The subject’s brain metastases are considered to 
be evidence of PD even if he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
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. 
17.3.2.4. Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the study 
treatment until the EOT.  Confirmatory measurement for CR, PR, or SD is required in the 
study. 
The subject’s best overall response assignment will depend on the findings of both target 
and non-target disease and will also take into consideration the appearance of new lesions. 
17.3.2.4.1. Time Point Response 
It is assumed that at each protocol-specified time point, a response assessment occurs.  
Table 17.2 provides a summary of the overall response status calculation at each time 
point for subjects who have measurable disease at baseline. 
When subjects have non-measurable (therefore non-target) disease only, see Table 17.2. 


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Table 17.2: 
Overall Response: Subjects with Target (± Non-target) Disease 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all Evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, NE = not 
evaluable. 
17.3.2.4.2. Missing Assessments and Inevaluable Designation 
When no imaging/measurement is performed 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 3 measured 
lesions and at F/U only 2 lesions were assessed, but those gave a sum of 80 mm, the 
subject will have achieved PD status, regardless of the contribution of the missing lesion. 
17.3.2.4.3. Best Overall Response: All Time Points 
The best overall response is determined once all the data for the subject is known. 
Best response determination in this study requires confirmation of CR or PR:  Best 
response is defined as the lesser of the two best responses across 2 consecutive scans (eg, 
a subject who has PR at first assessment, SD at second assessment, and PD on last 
assessment; this would report as a best overall response of SD).  When SD is believed to 
be best response, it must also meet the protocol specified minimum time from baseline, 6 
weeks (± 7 days).  If the minimum time is not met when SD is otherwise the best time 
point response, the subject’s best response depends on the subsequent assessments.  For 
example, a subject who has SD at first assessment, PD at second and does not meet 
minimum duration for SD, will have a best response of PD.  The same subject lost to F/U 
after the first SD assessment would be considered inevaluable. 
17.3.2.4.4. Special Notes on Response Assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to 
“normal” size (<10 mm), they may still have a measurement reported on scans.  This 
measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes.  As noted earlier, 
this means that subjects with CR may not have a total sum of “zero” on the eCRF. 


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Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document objective 
progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response: it is a reason for stopping study therapy.  The 
objective response status of such subjects is to be determined by evaluation of target and 
non-target disease. 
For equivocal findings of progression (eg, very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
17.3.2.5.  
Frequency of Tumor Re-evaluation 
In this study, tumor measurement will be conducted every 6 weeks (± 7 days) while the 
subject remains on study until progression of disease, withdrawal of consent, death, or loss 
to F/U.  Scan dates should not be adjusted or rescheduled due to dose interruption of any 
type. 
Baseline tumor assessments must be performed within 28 days of enrollment (study 
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 chest, abdomen, and 
pelvis at screening period.  A CT or MRI of the brain is mandatory for all subjects 
included with baseline stable brain metastases.  Any additional suspected sites of disease 
should also be imaged.  Every effort should be made to use the same assessment modality 
for all assessments for each subject.  F/U evaluations should include all sites of disease 
identified at screening and any other locations if progressive disease is suspected (eg, CT 
or MRI of the brain if brain metastases are suspected) should also be imaged.  All 
evaluations should meet the standard of care for imaging of lesions in the respective 
organ(s) and should conform to the image acquisition guidelines according to institutional 
standards. 
All target and non-target sites are evaluated at each time point of tumor assessment. 
 


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17.4. 
New York Heart Association Functional Classification 
Table 17.3: 
New York Heart Association Functional Classification 
Functional Capacity 
Objective Assessment 
Class I. Patients with cardiac disease but 
without resulting limitation of physical 
activity.  Ordinary physical activity does not 
cause undue fatigue, palpitation, dyspnea, or 
anginal pain. 
A. No objective evidence of cardiovascular 
disease. 
Class II. Patients with cardiac disease 
resulting in slight limitation of physical 
activity.  They are comfortable at rest. 
Ordinary physical activity results in fatigue, 
palpitation, dyspnea, or anginal pain. 
B. Objective evidence of minimal 
cardiovascular disease. 
Class III. Patients with cardiac disease 
resulting in marked limitation of physical 
activity.  They are comfortable at rest.  Less 
than ordinary activity causes fatigue, 
palpitation, dyspnea, or anginal pain. 
C. Objective evidence of moderately severe 
cardiovascular disease. 
Class IV. Patients with cardiac disease 
resulting in inability to carry on any physical 
activity without discomfort.  Symptoms of 
heart failure or the anginal syndrome may be 
present even at rest.  If any physical activity is 
undertaken, discomfort is increased. 
D. Objective evidence of severe cardiovascular 
disease. 
Source: American Heart Association, Inc. Classification of Functional Capacity and Objective Assessment. 
Available from: 
http://my.americanheart.org/professional/StatementsGuidelines/ByPublicationDate/PreviousYears/Classifica
tion-of-Functional-Capacity-and-Objective-Assessment_UCM_423811_Article.jsp 
 
 


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17.5. 
Instructions Related to 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. 
 
17.5.1. 
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 study protocol. 
− 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 
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 
Grade 4 
Discontinue study drug 
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. 
If an event is suspected to be drug-related ILD/pneumonitis, manage per protocol 
ILD/pneumonitis management guideline. 


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17.5.2. 
Prior and Concomitant Medications- Prohibited Therapies/Products 
• 
Chloroquine or hydroxychloroquine; 
− Concomitant treatment is not allowed during the study treatment (Section 5.6). 
− 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. 
 
17.5.3. 
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 8.3). 
The chloroquine or hydroxychloroquine administration time and the exact time of blood 
sample collection for PK analysis must be recorded on the eCRF. 
 
17.5.4. 
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 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. 
 
17.5.5. 
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. 


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18. 
SCHEDULE OF EVENTS 
Table 18.1: 
Schedule of Events 
 
Tissue 
Screen 
S 
C 
R 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 and 
subsequent 
cycles Day 1 
EOT a 
F/U b 
q3 mo 
F/U (± 
14 
days) 
Day 1 
Day 8 
Day 15 
Day 22 
Day 1 
Day 1 
BI 
EOI 
(± 1 day) 
(± 1 day) 
(± 2 days) 
BI 
EOI 
BI 
EOI 
BI 
EOI 
Informed Consent 
●c 
● 
 
 
 
 
 
 
 
 
 
 
Tumor 
sample 
for 
tissue 
screening 
● 
 
 
 
 
 
 
 
 
 
 
 
Review 
inclusion/exclusion 
criteria, and Registration to 
IXRS 
● 
 
 
 
 
 
 
 
 
 
 
HIV antibody Test 
(as 
required 
by 
local 
regulations) 
Hepatitis 
B 
Surface 
Antigen/Hepatitis C Antibody 
 
●q 
 
 
 
 
 
 
 
 
 
 
Administer DS-8201a 
 
 
● 
 
 
 
● 
● 
● 
 
 
 
Medical history/Demographic 
 
●d 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Sign 
 
●d 
●e 
● 
● 
● 
 
●e 
● 
●e 
● 
●e 
 
● 
● 
 
Physical Examination 
 
●d 
●e 
 
 
 
 
●e 
 
●e 
 
●e 
 
● 
● 
 
SpO2 
 
●d 
●e 
 
 
 
 
●e 
 
●e 
 
●e 
 
● 
● 
 
Height 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight, ECOG PS 
 
●d 
●e 
 
 
 
 
●e 
 
●e 
 
●e 
 
● 
● 
 
 


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Table 18.1: 
Schedule of Events (Continued) 
 
Tissue 
Screen 
S 
C 
R 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 and 
subsequent cycles 
Day 1 
EOT a 
F/U b 
q3 mo 
F/U (± 
14 
days) 
Day 1 
Day 8 
Day 15 
Day 22 
Day 1 
Day 1 
BI 
EOI 
(± 1 day) 
(± 1 day) 
(± 2 days) 
BI 
EOI 
BI 
EOI 
BI 
EOI 
Clinical Laboratory Tests 
 
●d 
●e 
 
● 
● 
 
●e 
 
●e 
 
●e 
 
● 
● 
 
Troponinf 
 
●d 
 
●f 
 
 
 
 
●f 
 
●f 
 
●f 
●f 
●f 
 
Blood Samples for cfDNAg 
 
 
●e 
 
 
 
 
 
 
 
 
●e,g 
 
● 
 
 
Pharmacogenomics 
Blood 
Sample 
 
 
● h 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK Blood Sample x 
 
 
●i 
●j,k 
● 
● 
(●l) 
●i 
●j 
●i 
●j,k 
●i 
●j 
 
 
 
ADA Blood Sample 
 
 
●m 
 
 
 
 
●m 
 
 
 
●m 
 
 
● 
●n 
Blood Sample for HER2ECD 
(y) 
 
●d 
 
 
 
 
 
 
 
●e,o 
 
●e,o 
 
● 
 
 
Urinalysis 
 
●d 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECHO or MUGA (LVEF)  
 
●q 
 
 
 
 
 
 
 
 
 
●r 
 
● 
 
 
12-lead ECG in triplicates 
 
●d 
●e 
 
 
 
 
●e,p 
 
●e,p 
 
●e,p 
 
● 
 
 
Ophthalmologic Assessmentst 
 
●q 
 
 
 
 
 
●e 
 
 
 
●t 
 
● 
 
 
Pregnancy Test 
 
●u 
 
 
 
 
●u 
 
●u 
 
●u 
 
● 
● 
 
Tumor Assessment 
 
●q,v 
●v Every 6 weeks ( ± 7 days) until PD or starting new anticancer treatment regardless of Post Treatment Follow-up 
period 
● 
 
 
Fresh tumor sample 
 
●w 
 
 
 
 
 
 
●At day 43 (± 7 days) 
 
 
● 
 
 
Concomitant Medications/ AEs 
 
● 
 
Survival F/U 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
● 
ADA = anti-drug antibody, AE = adverse event, BI = before infusion, cfDNA  = cell free deoxyribonucleic acid, COVID-19 = coronavirus disease 2019, CT = 
computed tomography, ECG = electrocardiogram, ECOG PS = Eastern Cooperative Oncology Group performance status, ECHO = echocardiogram, EOI = end of 
infusion, EOT = end of treatment, F/U: follow-up, HER2ECD = extracellular domain of HER2, ICF = informed consent form, IXRS = interactive web/voice response 
system, MUGA = multigated acquisition, MRI = magnetic resonance imaging, LVEF = left ventricular ejection fraction, PD = progressive disease, PK = 
pharmacokinetic, SpO2 = peripheral oxygen saturation, q3 mo = once every 3 months, SCR = screening 


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a. The date when the investigator decides to discontinue study treatment (+ 7 days) 
b. 40 days (+ 7 days) after the last study drug administration or before starting new anticancer treatment, whichever comes first 
c. Three types of informed consent are prepared by the sponsor.  If the site use the ICF for “tissue screening,” it should be obtained before obtaining tumor or 
submitting tumor to the central laboratory. 
d. Within 14 days before Day 1 on Cycle 1 
e. Within 3 days before administration 
f. Troponin (preferably high-sensitivitytroponin-T) should be collected at screening and Day 1 of every Cycles, EOT and F/U at 2 to 3 hours after end of infusion as per 
the table above.  If elevated, or detected, refer to Section 6.4.1.  The test used to test troponin should remain the same throughout the course of a subject’s time on 
study.  An additional sample should be submitted for central lab troponin-T testing 
g. Samples will be collected at BI on Day 1 of Cycle 1, Cycle 4 and EOT for cfDNA. 
h. Participation in this part of the study is optional for all subjects. 
i. − 8 to 0 hours BI on Day 1 of each cycle until Cycle 4 and in Cycle 6. 
j. Within 15 minutes of EOI on Day 1 of each cycle until Cycle 4 and in Cycle 6. 
k. 4 h (± 15 minutes) and 7 h (± 2 hours) after the start of administration  
l. If treatment of the next cycle is delayed for 3 days or longer, or the subject is discontinued, collect PK blood on this day (± 2 days) 
m. − 8 to 0 hours BI on Day 1 of Cycles 1, 2 and 4, and then every 4 cycles  
n. For subjects with positive ADA at the F/U visit, additional serum ADA samples may be collected every 3 months (± 14 days) up to 1 year after the last dose of the 
study drug, or until the ADA becomes negative, or until the ADA titer becomes less than the baseline (applicable when pre-existing ADA was observed), or until the 
subject starts another therapy for cancer, or withdraws consent from the study, whichever occurs first. 
o. Every 2 cycles from Cycle 3 (eg, Day 1 of Cycles 3, 5, 7, 9...).  
p. Before administration at every cycles 
q. Within 28 days before Day1 on Cycle1. 
r. ECHO or MUGA scan assessments will be performed at Screening and BI on Day 1 of Cycle 5 and then every 4 cycles (± 7 days) (eg, Cycles 5, 9, 13…) 
s. ECGs will be taken in close succession, while in a supine/semi-recumbent position 
t. Ophthalmologic assessments including visual acuity testing, slit lamp examination and fundoscopy 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 Cycles 2, 6, 10, 14...). 
u. Within 72 hours prior to enrollment (study treatment)  
v. A CT or MRI of the brain is to be included for all subjects at SCR. Subjects without brain metastases do not need additional brain scans for tumor assessment unless 
clinically indicated.  Scans of the chest, abdomen, pelvis, and any other sites of disease are requested.  
w. Obtain fresh tumor biopsy specimen from a subject.  Fresh biopsy is not needed if a sample that was obtained after the most recent anti-cancer therapy is already 
available. 
x. In case of administration of chloroquine/hydroxychloroquine, perform PK sampling according to the following schedule: pre-dose on Day 1 of 
chloroquine/hydroxychloroquine administration, pre-dose on Day 3 or Day 4 (±4 hours), end of chloroquine/hydroxychloroquine treatment (±4 hours), and after 
washout period (14 days) pre-dose on the day of restarting study treatment (±8 hours)  (Table 8.3). 
y. A portion of HER2ECD blood sample from each subject who provides consent will be used for future central lab analysis for SARS-CoV-2 testing. SARS-CoV-2 
testing will be conducted every 4 cycles from Cycle 5 (Cycles 5, 9, 13, etc) and EOT. 
 


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For suspected ILD/pneumonitis, treatment with study drug should be interrupted pending evaluation.  
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. 
Other tests could be considered, as needed.