Clinical trial NCT03383692
Conditions: Neoplasm Metastasis
Keywords: Unresectable or metastatic solid malignant tumors Solid malignant tumors Oncology HER2 Antibody drug conjugate ADC
Sponsor: Daiichi Sankyo Co., Ltd.
Start date: 2018-01-12; Completion date: 2023-09-11
Enrollment: 40 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
HER2-positive cancer is a cancer that tests positive for a protein called human epidermal growth factor receptor 2 (HER2). HER2 promotes the growth of certain cancer cells. This study will test an experimental drug called DS-8201a that has not been approved by the health authorities yet.

DS-8201a will be tested for safety in patients with advanced solid malignant tumors that test positive for HER2. It also will test how DS-8201a moves within the body (pharmacokinetics).

Detailed description:
The expected time from the first subject's enrollment until the last subject's enrollment is approximately 8.5 months. The screening period is 28 days and each cycle of treatment is 21 days.

The data for the primary analysis will cutoff after all subjects have either discontinued the study or completed at least 3 cycles, whichever comes first. After the primary analysis, the main study will be closed and transition to the extension period.

Depending on the preliminary results of Cohort 1, Sponsor may decide whether Cohort 2 will be opened or not.

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

Arms: arm 1: DS-8201a will be administered as an intravenous (IV) solution once every 3 weeks (Q3W) + Ritonavir twice daily (BID) on Day 17 of Cycle 2 until Day 21 of Cycle 3 arm 2: DS-8201a will be administered as an intravenous (IV) solution once every 3 weeks (Q3W) + Itraconazole BID on Day 17 of Cycle 2 followed by 200 mg daily (QD) until Day 21 of Cycle 3
Interventions: intervention 1: DS-8201a intervention 2: Ritonavir intervention 3: Itraconazole
Intervention descriptions: intervention 1: DS-8201a is provided as a sterile lyophilized powder of DS-8201a in a glass vial, which will be dissolved and administered as an intravenous (IV) solution intervention 2: Ritonavir is a OATP1B inhibitor; an antiretroviral tablet for oral administration intervention 3: Itraconazole is a CYP3A inhibitor; an antifungal tablet for oral administration

Protocol documents:
Prot_SAP_000.pdf: 
Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 1 
 
 
CLINICAL STUDY PROTOCOL 
 
A PHASE 1, MULTICENTER, OPEN-LABEL, 
SINGLE SEQUENCE CROSSOVER STUDY TO 
EVALUATE DRUG-DRUG INTERACTION 
POTENTIAL OF OATP1B/CYP3A INHIBITOR ON 
THE PHARMACOKINETICS OF DS-8201A IN 
SUBJECTS WITH HER2-EXPRESSING 
ADVANCED SOLID MALIGNANT TUMORS 
 
DS8201-A-A104 
 
VERSION 6.0, 03 JUL 2020 
VERSION 5.0, 26 APR 2019 
VERSION 4.0, 06 NOV 2018 
VERSION 3.0, 25 JAN 2018 
VERSION 2.0, 06 NOV 2017 
VERSION 1.0, 06 OCT 2017 
 
 
DAIICHI SANKYO 
 
 
CONFIDENTIALITY STATEMENT 
Information contained in this document is proprietary to Daiichi Sankyo.  The 
information is provided to you in confidence which is requested under an agreed upon 
and signed Confidentiality and Disclosure Agreement.  Do not give this document or 
any copy of it or reveal any proprietary information contained in it to any third party 
(other than those in your organization who are assisting you in this work and are 
bound by the Confidentiality and Disclosure Agreement) without the prior written 
permission of an authorized representative of Daiichi Sankyo. 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 2 
INVESTIGATOR AGREEMENT 
A PHASE 1, MULTICENTER, OPEN-LABEL, SINGLE SEQUENCE 
CROSSOVER STUDY TO EVALUATE DRUG-DRUG INTERACTION 
POTENTIAL OF OATP1B/CYP3A INHIBITOR ON THE PHARMACOKINETICS 
OF DS-8201A IN SUBJECTS WITH HER2-EXPRESSING ADVANCED SOLID 
MALIGNANT TUMORS 
Sponsor Approval: 
This clinical study protocol has been reviewed and approved by the Daiichi Sankyo Co., 
LTD representative listed below. 
 
Print Name 
Signature 
Clinical Study Lead 
Title 
Date (DD MMM YYYY) 
Investigator’s Signature: 
I have fully discussed the objectives of this study and the contents of this protocol with the 
Sponsor’s representative. 
I understand that information contained in or pertaining to this protocol is confidential and should 
not be disclosed, other than to those directly involved in the execution or the ethical review of the 
study, without written authorization from the Sponsor.  It is, however, permissible to provide 
information to a subject in order to obtain consent. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in accordance 
with the Declaration of Helsinki, International Council for Harmonisation guidelines on Good 
Clinical Practice (ICH E6), and applicable regional regulatory requirements. 
I agree to make available to Sponsor personnel, their representatives and relevant regulatory 
authorities, my subject’s 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


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 3 
PROTOCOL SYNOPSIS 
EudraCT: 
Not applicable. 
IND Number: 
Not applicable. 
Protocol Number: 
DS8201-A-A104 
Investigational Product: 
DS-8201a 
Active Ingredient(s)/INN: 
Trastuzumab deruxtecan 
Study Title: 
A Phase 1, multicenter, open-label, single sequence 
crossover study to evaluate drug-drug interaction potential 
of OATP1B/CYP3A inhibitor on the pharmacokinetics of 
DS-8201a in subjects with HER2-expressing advanced 
solid malignant tumors 
Study Phase: 
Phase 1 
Indication Under 
Investigation: 
DS-8201a will be assessed in subjects with human 
epidermal growth factor receptor 2 (HER2)-expressing 
advanced solid malignant tumors. 
Study Objectives: 
Primary Objectives 
 Cohort 1: To evaluate the effect of ritonavir (dual 
inhibitor of cytochlome P450 [CYP] 3A [strong] and 
organic anion transporting polypeptide [OATP] 1B) on 
DS-8201a and MAAA-1181a pharmacokinetics (PK) in 
subjects with HER2-expressing advanced solid 
malignant tumors 
 Cohort 2: To evaluate the effect of itraconazole (strong 
CYP3A inhibitor) on DS-8201a and MAAA-1181a PK 
in subjects with HER2-expressing advanced solid 
malignant tumors 
Key Secondary Objectives 
 To assess the safety of DS-8201a with/without ritonavir 
or itraconazole 
Other Secondary Objectives 
 To evaluate the efficacy of DS-8201a 
 To assess the incidence of anti-drug antibodies (ADA) 
against DS-8201a 
Exploratory Objectives 
 To assess the effect of genetic polymorphism 
(OATP1B1 and breast cancer resistance protein 
[BCRP]) on the exposure of MAAA-1181a 
Study Design: 
This is a Phase 1, multicenter, open-label, single sequence 
crossover study to evaluate drug-drug interaction potential 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 4 
of OATP1B/CYP3A inhibitor on DS-8201a in subjects 
with HER2-expressing advanced solid malignant tumors. 
The data for the primary analysis will cutoff after all 
subjects have either discontinued the study or completed at 
least 3 cycles, whichever comes first.  After the primary 
analysis, the main study will be closed and transition to the 
extension period. 
Depending on the preliminary results of Cohort 1, Sponsor 
may decide whether Cohort 2 will be opened or not. 
Study Duration: 
The subject's enrollment is expected for approximately 6 
months, with the data cutoff for the primary analysis 
projected to be completed within approximately 2.5 months 
thereafter.  Thus, the expected duration of the study is 
approximately 8.5 months. 
The screening period is up to 28 days.  Each cycle of 
treatment will be 21 days. The number of treatment cycles 
with DS-8201a is not fixed. 
Study Sites and Location: 
This study is planned to be conducted in Japan, Korea and 
Taiwan. 
Subject Eligibility Criteria: 
Key Inclusion Criteria 
1. Is male and female ≥20 years old. 
2. Has a pathologically documented unresectable or 
metastatic solid malignant tumors with HER2 
expression (determined by immunohistochemistry 
[IHC] 3+, IHC 2+, IHC 1+, and/or in situ 
hybridization [ISH] +, Next Generation Sequencing, 
or other analysis techniques as appropriate) that is 
refractory to or intolerable with at least 1 prior 
systemic chemotherapy regimen, or for which no 
standard treatment is available. 
3. Has presence of tumor lesion assessed by the 
Investigator based on Response Evaluation Criteria 
in Solid Tumors (RECIST) version 1.1.  Subjects 
with only non-target lesions can be eligible. 
4. Has a left ventricular ejection fraction (LVEF) 
≥50% by either ECHO or MUGA scan within 28 
days before enrollment. 
5. Is able to withhold potential concomitant treatments 
defined as: 
Treatment 
Treatment prohibited period 
CYP3A strong 
inhibitors and 
OATP1B 
inhibitors 
From 2 weeks prior to the first 
dose of the study drug until end 
of treatment (EOT) 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 5 
CYP3A 
weak/moderate 
inhibitors  
From 2 weeks prior to the first 
dose of the study drug until the 
beginning of Cycle 4 
CYP3A inducers 
From 4 weeks prior to the first 
dose of the study drug until the 
beginning of Cycle 4 
CYP3A 
substrates and 
OATP1B 
substrates 
From 2 weeks prior to the first 
dose of the study drug until the 
beginning of Cycle 4 
6. Has a study treatment expectancy of ≥2.5 months. 
Key Exclusion Criteria 
1. Has a contraindication for receiving ritonavir or 
itraconazole according to the prescribing 
information. 
2. Is NOT able to take ritonavir and itraconazole by 
oral intake. 
3. Has a medical history of myocardial infarction 
within 6 months before enrollment, symptomatic 
congestive heart failure (CHF) (New York Heart 
Association Class II-IV), or troponin levels 
consistent with myocardial infarction as defined 
according to the manufacturer within 28 days prior 
to enrollment. 
4. Has a corrected QT interval by Fridericia's formula 
(QTcF) prolongation to >470 ms (females) or 
>450 ms (males) based on average of the screening 
triplicate12-lead electrocardiogram (ECG). 
5. 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. 
6. Has human immunodeficiency virus (HIV) 
infection, or active hepatitis B or C infection. 
Dosage Form, Dose and 
Route of Administration: 
The study will consist of Cohort 1 and Cohort 2. 
DS-8201a in Cohort 1 and Cohort 2: 
DS-8201a for injection 100 mg is provided as a sterile 
lyophilized powder containing 100 mg of DS-8201a in a 
glass vial (Lyo-DP).  “DS-8201a” will be administered as 
an intravenous (IV) solution at 5.4 mg/kg once every 3 
weeks (Q3W).  The study treatment will be continued to 
derive clinical benefit in the absence of withdrawal of 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 6 
subject consent, progressive disease (PD), or unacceptable 
toxicity. 
Cohort 1: 
Ritonavir 200 mg twice a day [Bis In Die (BID)] on Day 17 
of Cycle 2 until Day 21 of Cycle 3. 
Cohort 2: 
Itraconazole 200 mg BID on Day 17 of Cycle 2 followed 
by 200 mg once a day [Quaque Die (QD)] until Day 21 of 
Cycle 3. 
Study Endpoints: 
Primary Endpoints 
 PK parameters (Cmax and AUC0-17d) of DS-8201a and 
MAAA-1181a (± ritonavir) 
 PK parameters (Cmax and AUC0-17d) of DS-8201a and 
MAAA-1181a (± itraconazole) 
Key Secondary Endpoints 
 Serious adverse events (SAEs) 
 Treatment emergent adverse events (TEAEs) 
 Discontinuation due to adverse events (AEs) 
 Discontinuation due to adverse events of special 
interest (AESIs) 
 Physical examination findings (including Eastern 
Cooperative Oncology Group Performance Status 
[ECOG PS]) 
 Vital sign measurements 
 Standard clinical laboratory parameters 
 12-lead ECG parameters 
 Echocardiogram (ECHO)/multiple-gated acquisition 
(MUGA) findings 
 Ophthalmologic findings 
 ADA 
Other Secondary Endpoints 
 Objective response rate (ORR) 
 Disease control rate (DCR) 
 Duration of Response (DoR) 
 Duration of stable disease (Duration of SD) 
 Clinical benefit ratio (CBR) 
 Time to response (TTR) 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 7 
 Progression free survival (PFS) 
 Best (minimum) percent change from baseline in the 
sum of diameters of target lesion 
Exploratory Endpoints 
 Genetic polymorphism (OATP1B1 and BCRP) 
Planned Sample Size: 
Approximately 32 subjects (16 in each cohort; 12 
completers for each cohort) are planned for this study. 
Statistical Analyses: 
PK Analyses 
As a primary analysis, geometric mean ratio of Cycle 3 as 
compared with Cycle 2 as a reference and its two-sided 
90% confidence intervals (CI) for PK parameters (Cmax 
and AUC0-17d) of DS-8201a and MAAA-1181a will be 
calculated to evaluate drug-drug interactions. 
Serum concentration-time data for DS-8201a, total anti-
HER2 antibody and MAAA-1181a will be listed, plotted, 
and summarized using descriptive statistics at each time 
point. 
PK parameters of DS-8201a, total anti-HER2 antibody and 
MAAA-1181a will be listed and summarized using 
descriptive statistics. 
Safety Analyses 
Safety endpoints will be based on AEs, physical 
examination findings, vital sign measurements, clinical 
laboratory measurements, ECG recordings, ADA, ECG 
parameter, ECHO or MUGA findings, and ophthalmologic 
findings.  AEs will be graded according to the National 
Cancer Institute Common Terminology Criteria for 
Adverse Event (NCI-CTCAE) version 4.03.  Safety 
analyses in general will be descriptive and will be 
presented in tabular format with the appropriate summary 
statistics. 
Efficacy Analyses 
Efficacy endpoints will include ORR (the sum of complete 
response [CR] and partial response [PR] rates); DCR (the 
sum of CR rate, PR rate, and SD rate for a minimum of 5 
weeks from the first dosing date), DoR, duration of SD, 
clinical benefit ratio (CBR), TTR, PFS and best (minimum) 
percent change from baseline in the sum of diameters of 
target lesion using RECIST version 1.1. 
Pharmacogenomic Analyses 
As an exploratory analysis, the frequency table for 
OATP1B1 (Haplotypes: *5, *15, *1b, Nucleotide changes: 
388A>G and 521T>C) and BCRP (Nucleotide change: 
421C>A) will be prepared.   


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 8 
TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT ................................................................... 2 
PROTOCOL SYNOPSIS ................................................................................. 3 
TABLE OF CONTENTS .................................................................................. 8 
LIST OF TABLES .......................................................................................... 15 
LIST OF FIGURES ........................................................................................ 16 
LIST OF ABBREVIATIONS ......................................................................... 17 
1. 
INTRODUCTION ............................................................................ 21 
1.1. 
Background....................................................................................... 21 
1.2. 
Data Summary .................................................................................. 21 
1.2.1. 
Physical, Chemical, Pharmaceutical Properties and Formulation .... 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 Study ................................................................................... 24 
1.2.3.1. Clinical Experience .......................................................................... 24 
1.2.3.2. Summary of Clinical Pharmacokinetics ........................................... 26 
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 
2.1.2.1. Key Secondary Objectives ............................................................... 30 
2.1.2.2. Other Secondary Objectives ............................................................. 30 
2.1.3. 
Exploratory Objectives ..................................................................... 30 
2.2. 
Study Hypotheses ............................................................................. 30 
2.3. 
Study Endpoints................................................................................ 30 
2.3.1. 
Primary Endpoints ............................................................................ 30 
2.3.2. 
Key Secondary Endpoints ................................................................ 30 
2.3.3. 
Other Secondary Endpoints .............................................................. 31 
2.3.4. 
Exploratory Endpoints ...................................................................... 31 
3. 
STUDY DESIGN ............................................................................. 32 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 9 
3.1. 
Overall Design .................................................................................. 32 
3.2. 
Discussion of Study Design.............................................................. 33 
3.2.1. 
Duration of the Study ....................................................................... 33 
3.2.2. 
Duration of Subject Participation ..................................................... 33 
4. 
STUDY POPULATION ................................................................... 34 
4.1. 
Inclusion Criteria .............................................................................. 34 
4.2. 
Exclusion Criteria ............................................................................. 37 
4.3. 
Subject Replacement ........................................................................ 38 
4.4. 
Subject Re-screening Procedures ..................................................... 39 
5. 
STUDY TREATMENT(S) ............................................................... 40 
5.1. 
Assigning Subjects to Treatment Group(s) /Sequences and Blinding
 
40 
5.1.1. 
Treatment Group(s) /Sequences ....................................................... 40 
5.1.2. 
Method of Treatment Group(s) /Sequences Allocation.................... 40 
5.1.3. 
Enrollment ........................................................................................ 40 
5.1.4. 
Blinding ............................................................................................ 41 
5.1.5. 
Emergency Unblinding Procedure ................................................... 41 
5.2. 
Study Drug(s) ................................................................................... 41 
5.2.1. 
Description ....................................................................................... 41 
5.2.2. 
Labeling and Packaging ................................................................... 41 
5.2.3. 
Preparation ........................................................................................ 41 
5.2.4. 
Administration .................................................................................. 42 
5.2.5. 
Storage .............................................................................................. 42 
5.2.6. 
Drug Accountability ......................................................................... 42 
5.3. 
Inhibitor Drugs ................................................................................. 43 
5.3.1. 
Description ....................................................................................... 43 
5.3.2. 
Labeling and Packaging ................................................................... 43 
5.3.3. 
Preparation ........................................................................................ 43 
5.3.3.1. Ritonavir ........................................................................................... 43 
5.3.3.2. Itraconazole ...................................................................................... 43 
5.3.4. 
Administration .................................................................................. 43 
5.3.4.1. Ritonavir ........................................................................................... 43 
5.3.4.2. Itraconazole ...................................................................................... 44 
5.3.5. 
Storage .............................................................................................. 44 
5.3.5.1. Ritonavir ........................................................................................... 44 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 10 
5.3.5.2. Itraconazole ...................................................................................... 44 
5.3.6. 
Drug Accountability ......................................................................... 44 
5.4. 
Dose Interruptions and Reductions .................................................. 44 
5.5. 
Method of Assessing Treatment Compliance ................................... 52 
5.5.1. 
Study Drug........................................................................................ 52 
5.5.2. 
Inhibitor Drugs ................................................................................. 53 
5.6. 
Prior and Concomitant Medications ................................................. 53 
5.6.1. 
Concomitant Medications ................................................................. 53 
5.6.2. 
Prohibited Concomitant Medications/Activities .............................. 53 
5.6.3. 
Dietary and Lifestyle Restrictions .................................................... 54 
5.7. 
Subject Withdrawal/Discontinuation................................................ 54 
5.7.1. 
Reasons for Withdrawal from Study Treatment ............................... 54 
5.7.2. 
Reasons for Withdrawal from Study Participation ........................... 55 
5.7.3. 
Withdrawal Procedures .................................................................... 55 
5.7.4. 
Subject Re-screening Procedures ..................................................... 55 
6. 
STUDY PROCEDURES .................................................................. 57 
6.1. 
Screening .......................................................................................... 57 
6.2. 
Randomization .................................................................................. 58 
6.3. 
Treatment Period .............................................................................. 58 
6.3.1. 
Tumor Assessment ........................................................................... 58 
6.3.2. 
Other Study Procedure in Treatment Period .................................... 58 
6.3.2.1. Cycle 1, Day 1 .................................................................................. 58 
6.3.2.2. Cycle 2, Day 1 .................................................................................. 60 
6.3.2.3. Cycle 2, Day 2 .................................................................................. 61 
6.3.2.4. Cycle 2, Day 4 .................................................................................. 61 
6.3.2.5. Cycle 2, Day 8 .................................................................................. 62 
6.3.2.6. Cycle 2, Day 12 ................................................................................ 62 
6.3.2.7. Cycle 2, Day 17 ................................................................................ 62 
6.3.2.8. Cycle 2, Day18 to Day 21 ................................................................ 62 
6.3.2.9. Cycle 2, Day 22 ................................................................................ 63 
6.3.2.10. Cycle 3, Day 1 .................................................................................. 63 
6.3.2.11. Cycle 3, Day 2 .................................................................................. 64 
6.3.2.12. Cycle 3, Day 4 .................................................................................. 64 
6.3.2.13. Cycle 3, Day 5 to Day 7 ................................................................... 64 
6.3.2.14. Cycle 3, Day 8 .................................................................................. 65 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 11 
6.3.2.15. Cycle 3, Day 9 to Day 11 ................................................................. 65 
6.3.2.16. Cycle 3, Day 12 ................................................................................ 65 
6.3.2.17. Cycle 3, Day 17 ................................................................................ 65 
6.3.2.18. Cycle 3, Day 13 to Day 21 ............................................................... 65 
6.3.2.19. Cycle 3, Day 22 ................................................................................ 66 
6.3.2.20. Cycle 4 and Subsequent Cycles, Day 1 ............................................ 66 
6.3.2.21. Cycle 5, Day 22 and Cycle 7, Day 22 .............................................. 67 
6.4. 
End of Treatment .............................................................................. 67 
6.5. 
Follow-up ......................................................................................... 68 
7. 
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS
 
69 
7.1. 
Pharmacokinetic Assessment(s) ....................................................... 69 
7.2. 
Pharmacodynamic Assessment(s) .................................................... 71 
7.3. 
Biomarker and Exploratory Assessment(s) ...................................... 71 
7.3.1. 
Human Epidermal Growth Factor Receptor 2 Status Assessed by 
Central Laboratory............................................................................ 71 
7.3.2. 
Troponin-T Assessed by Central Laboratory ................................... 71 
7.4. 
Immunogenicity ................................................................................ 72 
7.4.1. 
Anti-drug Antibody .......................................................................... 72 
7.5. 
Pharmacogenomic Analysis ............................................................. 73 
7.6. 
Blood Sampling ................................................................................ 73 
7.7. 
Tumor Sampling ............................................................................... 73 
8. 
SAFETY EVALUATION AND REPORTING ............................... 74 
8.1. 
Assessment of Safety Endpoint Event(s) ......................................... 74 
8.2. 
Adverse Event Collection and Reporting ......................................... 74 
8.3. 
Adverse Events of Special Interest ................................................... 75 
8.3.1. 
Interstitial Lung Disease/Pneumonitis .............................................. 75 
8.3.1.1. Interstitial Lung Disease Adjudication Committee .......................... 76 
8.3.2. 
LVEF decrease ................................................................................. 76 
8.4. 
Adverse Event .................................................................................. 77 
8.4.1. 
Definition of Adverse Event ............................................................. 77 
8.4.2. 
Serious Adverse Event ..................................................................... 77 
8.4.3. 
Severity Assessment ......................................................................... 78 
8.4.4. 
Causality Assessment ....................................................................... 78 
8.4.5. 
Action Taken Regarding Study Drug(s) ........................................... 78 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 12 
8.4.6. 
Other Action Taken for Event .......................................................... 79 
8.4.7. 
Adverse Event Outcome ................................................................... 79 
8.5. 
Serious Adverse Events Reporting–Procedure For Investigators .... 79 
8.6. 
Notifying Regulatory Authorities, Investigators, and Institutional 
Review Board/Ethics Committee ..................................................... 81 
8.7. 
Exposure in Utero During Clinical Studies ...................................... 81 
8.8. 
Clinical Laboratory Evaluations ....................................................... 81 
8.9. 
Vital Signs ........................................................................................ 82 
8.10. 
Electrocardiograms ........................................................................... 82 
8.11. 
Physical Examinations...................................................................... 82 
8.12. 
Other Examinations .......................................................................... 83 
9. 
EFFICACY ASSESSMENTS .......................................................... 84 
9.1. 
Assessments for Efficacy Endpoint(s) .............................................. 84 
9.2. 
Appropriateness of Selected Efficacy Assessment(s) ...................... 84 
10. 
OTHER ASSESSMENTS ................................................................ 85 
11. 
STATISTICAL METHODS ............................................................ 86 
11.1. 
General Statistical Considerations .................................................... 86 
11.2. 
Analysis Sets .................................................................................... 86 
11.2.1. Enrolled Analysis Set ....................................................................... 86 
11.2.2. Efficacy Analysis Set ....................................................................... 86 
11.2.3. Safety Analysis Set ........................................................................... 86 
11.2.4. Pharmacokinetic Analysis Set .......................................................... 87 
11.2.5. Biomarker Analysis Set .................................................................... 87 
11.3. 
Study Population Data ...................................................................... 87 
11.4. 
Statistical Analysis ........................................................................... 87 
11.4.1. Pharmacokinetic Analyses ................................................................ 87 
11.4.2. Safety Analyses ................................................................................ 87 
11.4.2.1. Adverse Event Analyses ................................................................... 87 
11.4.2.2. Clinical Laboratory Evaluation Analyses ......................................... 88 
11.4.2.3. Vital Sign Analyses .......................................................................... 88 
11.4.2.4. Electrocardiogram Analyses ............................................................. 88 
11.4.2.5. Anti-Drug Antibodies Analyses ....................................................... 88 
11.4.2.6. Other Safety Analyses ...................................................................... 88 
11.4.3. Efficacy Analyses ............................................................................. 89 
11.4.4. Pharmacodynamic Analyses ............................................................. 89 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 13 
11.4.5. Biomarker Analyses ......................................................................... 89 
11.4.6. Pharmacogenomic Analyses ............................................................. 89 
11.5. 
Interim Analyses ............................................................................... 90 
11.6. 
Data Monitoring Committee............................................................. 90 
11.7. 
Sample Size Determination .............................................................. 90 
11.8. 
Statistical Analysis Process .............................................................. 90 
12. 
DATA INTEGRITY AND QUALITY ASSURANCE ................... 91 
12.1. 
Monitoring and Inspections .............................................................. 91 
12.2. 
Data Collection ................................................................................. 91 
12.3. 
Electronic Data Capture System ....................................................... 92 
12.4. 
Data Management ............................................................................. 92 
12.5. 
Study Documentation and Storage ................................................... 93 
12.6. 
Record Keeping ................................................................................ 93 
13. 
FINANCING AND INSURANCE................................................... 95 
13.1. 
Finances ............................................................................................ 95 
13.2. 
Reimbursement, Indemnity, and Insurance ...................................... 95 
14. 
PUBLICATION POLICY ................................................................ 96 
15. 
ETHICS AND STUDY ADMINISTRATIVE INFORMATION .... 97 
15.1. 
Compliance Statement, Ethics and Regulatory Compliance ............ 97 
15.2. 
Subject Confidentiality ..................................................................... 97 
15.3. 
Informed Consent ............................................................................. 97 
15.4. 
Regulatory Compliance .................................................................... 98 
15.5. 
Protocol Deviations .......................................................................... 99 
15.6. 
Supply of New Information Affecting the Conduct of the Study .... 99 
15.7. 
Protocol Amendments ...................................................................... 99 
15.8. 
Study Termination .......................................................................... 100 
15.9. 
Data and Safety Monitoring Board ................................................. 100 
15.10. 
Address List .................................................................................... 100 
15.10.1. Sponsor ........................................................................................... 100 
15.10.1.1. Sponsor’s Responsible Medical Officer .................................... 100 
15.10.1.2. Sponsor’s Clinical Study Leader ............................................... 100 
15.10.1.3. Sponsor’s Safety Contacts ......................................................... 100 
15.10.2. Academic Research Organization (ARO) ...................................... 101 
15.10.3. Contract Research Organizations (CRO) ....................................... 101 
15.10.4. Interactive Web/Voice Response System Vendor .......................... 101 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 14 
15.10.5. EDC Vendor ................................................................................... 101 
15.10.6. Central Laboratory.......................................................................... 101 
15.10.7. Bioanalytical Laboratory (Pharmacokinetics and Anti-Drug 
Antibodies) ..................................................................................... 101 
15.10.8. Genetic Polymorphism Central Laboratory.................................... 102 
15.10.9. Sponsor’s Biostatistician ................................................................ 102 
15.10.10. 
Data Safety Monitoring Board................................................... 102 
15.10.11. 
SARS-CoV-2 Assessment (RT-PCR test) ................................. 102 
16. 
REFERENCES ............................................................................... 103 
17. 
APPENDICES ................................................................................ 105 
17.1. 
Cockcroft-Gault Equation .............................................................. 105 
17.2. 
Eastern Cooperative Oncology Group Performance Status (ECOG 
PS) .................................................................................................. 106 
17.3. 
Response Evaluation Criteria in Solid Tumors, Version 1.1.......... 106 
17.3.1. Measurability of Tumor at Baseline ............................................... 106 
17.3.1.1. Definitions ...................................................................................... 106 
17.3.1.2. Specifications by Methods of Measurements ................................. 107 
17.3.2. Tumor Response Evaluation........................................................... 108 
17.3.2.1. Assessment of Overall Tumor Burden and Measurable Disease ... 108 
17.3.2.2. Baseline Documentation of “Target” and “Non-target” Lesions ... 108 
17.3.2.3. Response Criteria............................................................................ 109 
17.3.2.4. Evaluation of Best Overall Response ............................................. 111 
17.3.2.5. Frequency of Tumor Re-evaluation................................................ 113 
17.4. 
New York Heart Association Functional Classification ................ 114 
17.5. 
Schedule of Events ......................................................................... 115 
17.6. 
Instructions Related to Severe Acute Respiratory Syndrome 
Coronavirus 2 (SARS-CoV-2) ....................................................... 119 
 
 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 15 
LIST OF TABLES 
Table 1.1: Confirmed Objective Response Rate from DS8201-A-J101 Part 1 
(dose escalation) and Part 2 (dose expansion) as of 8 Jun 2017 . 26 
Table 1.2: Pharmacokinetic Parameters of DS-8201a in Cycle 1 ................. 27 
Table 1.3: Pharmacokinetic Parameters of Total Antibody in Cycle 1 ........ 27 
Table 1.4: Pharmacokinetic Parameters of MAAA-1181a in Cycle 1.......... 27 
Table 5.1: Content and Dosage Form of Inhibitor Drugs ............................. 43 
Table 5.2: Dose Reduction Levels of DS-8201a .......................................... 45 
Table 5.3: Management Guidelines for DS-8201a ....................................... 45 
Table 7.1: Pharmacokinetic Parameters ........................................................ 69 
Table 7.2: Pharmacokinetic Sampling Time Points ...................................... 70 
Table 7.3: Troponin Sampling Time Points .................................................. 72 
Table 7.4: Anti-Drug Antibodies Sampling Time Points ............................. 72 
Table 11.1: Relation between the Geometric Mean Ratio and its 90% 
Confidence Intervals (Number of Subjects = 12) ........................ 90 
Table 17.1: Eastern Cooperative Oncology Group Performance Status Scale
 ................................................................................................... 106 
Table 17.2: Overall Response: Subjects with Target (± Non-target) Disease
 ................................................................................................... 111 
Table 17.3: Overall Response: Subjects with Non-target Disease Only ...... 112 
Table 17.4: Schedule of Events .................................................................... 115 
Table 17.5: SARS-CoV-2 Dose Modification Criteria ................................. 119 
Table 17.6: Schedule of PK Sample Collection for Subjects Administered 
Chloroquine or Hydroxychloroquine ......................................... 120 
  


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 16 
LIST OF FIGURES 
Figure 3.1: Study Design Schema of DS8201-A-A104 ................................. 32 
Figure 5.1: Process for Subject Number Assignment and Enrollment .......... 41 
 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 17 
LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
AC 
Adjudication Committee 
ADA 
anti-drug antibodies 
ADC 
antibody-drug conjugate 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
BCRP 
breast cancer resistance protein 
BI 
before infusion 
BID 
twice a day [Bis In Die] 
CART 
Cell-free and Concentrated Ascites Reinfusion Therapy 
CBR 
clinical benefit ratio 
CHF 
congestive heart failure 
CI 
confidence interval 
CR 
complete response 
CRF 
case report form 
CRO 
contract research organization 
CT 
computed tomography 
CV 
coefficient of variation 
CYP 
cytochrome P450 
DCR 
disease control rate 
DLCO 
diffusing capacity of the lungs for carbon monoxide 
DNA 
deoxyribonucleic acid 
DoR 
duration of response 
EC 
Ethics Committee 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EIU 
exposure in utero 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 18 
ABBREVIATION 
DEFINITION 
EOI 
end of infusion 
EOT 
end of treatment  
FDA 
Food and Drug Administration 
F/U 
follow-up 
GCP 
Good Clinical Practice 
GEJ 
gastroesophageal junction 
Hb 
hemoglobin 
HER2 
human epidermal growth factor receptor 2 
hERG 
human ether-a-go-go-related gene 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ICMJE 
International Council of Medical Journal Editors 
IEC 
Independent Ethics Committee 
IgG1 
immunoglobulin G1 
IHC 
immunohistochemistry 
ILD 
interstitial lung disease 
IND 
investigational new drug 
INN 
international non-proprietary name 
IRB 
Institutional Review Board 
ISH 
in situ hybridization 
IV 
Intravenous(ly) 
IXRS 
interactive web/voice response system 
LVEF 
left ventricular ejection fraction 
MAAA-1181a 
the drug component of DS-8201a – a derivative of exatecan, a 
topoisomerase I inhibitor 
MAAL-9001 
the antibody component of DS-8201a – a humanized IgG1 monoclonal 
antibody produced in-house with reference to the same amino acid 
sequence of trastuzumab 
MATE 
multidrug and toxin extrusion 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MUGA 
multiple-gated acquisition 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 19 
ABBREVIATION 
DEFINITION 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Event 
NE 
not evaluable 
NSAIDs 
nonsteroidal anti-inflammatory drugs 
OAT 
organic anion transporter 
OATP 
organic anion transporting polypeptide 
OCT 
organic cation transporter 
ORR 
objective response rate 
PD 
progressive disease 
PFS 
progression free survival 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
PR 
partial response 
PT 
prothrombin time or Preferred Term 
QD 
once a day [Quaque Die] 
QW 
once weekly 
Q3W 
once every 3 weeks 
QTc 
corrected QT (interval) 
QTcF 
corrected QT interval by Fridericia's formula 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended Phase 2 dose 
RT-PCR 
reverse transcription polymerase chain reaction 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2, ie COVID-19 
SAVER 
serious adverse event report 
SCR 
screening 
SD 
stable disease 
SMQ 
Standardised MedDRA Query 
SOC 
System Organ Class 
SOP 
standard operating procedure 
SpO2 
peripheral oxygen saturation 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TBL 
total bilirubin 
T-DM1 
trastuzumab emtansine 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 20 
ABBREVIATION 
DEFINITION 
TEAE 
treatment emergent adverse event 
TKI 
tyrosine kinase inhibitors 
TTR 
time to response 
ULN 
upper limit of normal 
 
List of Pharmacokinetic Parameters 
ABBREVIATION 
DEFINITION 
AUC 
area under the plasma/serum concentration-time curve 
AUC0-17d 
area under the plasma/serum concentration-time curve from the time of 
dosing to 17 day 
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 
AUCtau 
area under the plasma/serum concentration-time curve during dosing 
interval 
CL 
total body clearance  
CLss 
total body clearance at steady state 
Cmax 
maximum serum concentration  
CrCl 
creatinine clearance rate 
IC50 
50% inhibitory concentration 
Kel 
elimination rate constant associated with the terminal phase 
Tmax 
time to reach maximum plasma/serum concentration 
T1/2 
terminal elimination half-life 
Vss  
volume of distribution at steady state 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 21 
1. 
INTRODUCTION 
1.1. 
Background 
Human epidermal growth factor receptor 2 (HER2) is a member of the HER 
superfamily that initiates signal transduction via the PI3K/AKT and RAS/MAPK 
pathways.1,2  In human advanced solid tumors, expression of HER2 protein has been 
reported in various tumor tissues and a variety of cultured tumor cell lines including 
breast cancer,3 gastric cancer,4,5 pancreatic cancer,6 lung cancer,7 colorectal cancer,8 
and ovarian cancer.9  There are also many reports demonstrating an association 
between expression of HER2 protein and clinical poor prognosis. In normal human 
tissue, low expression of HER2 protein has been reported on cell membranes of 
epithelial cells in the gastro-intestinal, respiratory, reproductive, and urinary tract as 
well as in the skin, breast and placenta.10 
As an antibody targeting HER2, trastuzumab has been approved in the United States 
for the indication of HER2 overexpressing breast cancer and HER2-overexpressing 
metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma,11 in Europe 
for HER2 positive metastatic breast cancer and HER2 positive metastatic 
adenocarcinoma of the stomach or GEJ,12 and in Japan for HER2-overexpressing 
breast cancer and HER2-overexpressing unresectable and advanced/recurrent gastric 
or GEJ adenocarcinoma.13  Trastuzumab emtansine (T-DM1) is an antibody-drug 
conjugate (ADC) targeting HER2 that has been approved in the United States for the 
indication of HER2-positive metastatic breast cancer,14 in Europe for the indication of 
HER2-positive unresectable locally advanced or metastatic breast cancer,15 and in 
Japan for HER2-positive unresectable or recurrent breast cancer.16 
DS-8201a is an ADC targeting HER2.  DS-8201a is currently under investigation in a 
two-part Phase 1 study (DS8201-A-J101): Part 1 is the dose escalation study in 
subjects with either advanced breast cancer or gastric/GEJ adenocarcinoma.  Part 2 is 
the expansion phase and focuses on HER2-expressing breast and gastric/GEJ 
adenocarcinoma, as well as other HER2-expressing solid tumors. 
1.2. 
Data Summary 
1.2.1. 
Physical, Chemical, Pharmaceutical Properties and Formulation 
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 (IgG1) monoclonal antibody 
having the same amino acid sequence as trastuzumab.  MAAA-1181a, an exatecan 
derivative,17, 18, 19 is a topoisomerase I inhibitor, cell-membrane permeable, and more 
potent than SN-38 (active metabolite of irinotecan).  This ADC achieves a high drug-
to-antibody ratio (7 to 8) with homogeneous conjugation with MAAA-1181a.20  DS-
8201a is cleaved by lysosomal enzymes and releases MAAA-1181a in the cytoplasm 
after it binds to HER2 receptor and gets internalized in tumor cells. 
 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 22 
1.2.2. 
Nonclinical Studies 
1.2.2.1. 
Pharmacology 
DS-8201a inhibits tumor growth by mainly topoisomerase I inhibition-derived DNA 
damage and apoptosis by the MAAA-1181a that is released from DS-8201a after 
internalization in cancer cells via HER2.  In vitro nonclinical pharmacology studies 
have confirmed that DS-8201a exhibits HER2 expression-dependent cell growth 
inhibition, and in vivo studies using tumor-bearing mouse models suggest that the 
administration of DS-8201a results in the regression of a broad array of HER2-
expressing tumors, including multiple models unresponsive to T-DM1.  In addition, in 
vivo studies in tumor-bearing mouse models have confirmed that DS-8201a has 
antitumor activity even against HER2 low-expressing tumors which are insensitive to 
T-DM1.  DS-8201a is therefore expected to be effective against HER2 low-
expressing tumors which are insensitive to T-DM1, and is also expected to be 
effective against T-DM1 insensitive tumors with HER2 high-expressing and HER2 
low-expressing tumors for which T-DM1 has not been approved. Moreover, DS-
8201a demonstrated potent efficacy in mice inoculated with a mixture of HER2-
positive and -negative cells while T-DM1 did not, due to more potent bystander 
killing and higher cell membrane permeability of the conjugated toxin.  The effect 
therefore supports the efficacy of DS-8201a against tumors with HER2 heterogeneity. 
1.2.2.2. 
Safety Pharmacology 
In a safety pharmacology study in monkeys treated with single intravenous doses of 
DS-8201a, no effects on the cardiovascular system, the respiratory system, or the 
central nervous system were observed under the study condition.  In addition, in 
human ether-a-go-go-related gene (hERG) studies of MAAA-1181a, the drug 
component, MAAA-1181a did not inhibit the hERG channel current. 
1.2.2.3. 
Pharmacokinetics and Drug Metabolism 
The plasma DS-8201a concentrations decreased exponentially following a single 
intravenous administration of DS-8201a at 0.1 mg/kg to 3.0 mg/kg to cynomolgus 
monkeys.  The Vss was close to the plasma volume.  The CL decreased as the dose 
increased, and the pharmacokinetics (PK) were found to be non-linear.  Both DS-
8201a and the total antibody, bound and unbound antibody combined, exhibited 
similar plasma concentration-time profiles at all dose levels, as well as similar AUC.  
All individual plasma concentrations of MAAA-1181a, the released drug from DS-
8201a, were below the lower limit of quantification (0.100 ng/mL) at 0.1 and 
0.3 mg/kg.  A low-plasma level of MAAA-1181a was detected at limited time points 
at 1.0 and 3.0 mg/kg.  No anti-DS-8201a antibody was detected in any animals. 
The mean plasma protein binding ratios of MAAA-1181a at 10 ng/mL to 100 ng/mL 
were from 90.3% to 92.5% in mice, 94.2% to 96.7% in rats, 86.5% to 89.1% in 
monkeys, and 96.8% to 98.0% in humans.   
The release rates of MAAA-1181a from DS-8201a increased gradually throughout the 
incubation period in mouse, rat, and monkey plasma with the release rates from 1.2% 
to 3.9% on Day 21.  On the other hand, the release rate reached a plateau on Day 14 
in human plasma with the release rates from 2.2% to 2.4%.  These results indicate that 
most DS-8201a is stable in plasma. 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 23 
No major differences were found among the metabolite profiles of DS-8201a in rat, 
monkey, and human hepatocytes.  MAAA-1181a was metabolized by cytochrome 
P450 (CYP) enzymes; CYP3A4 was the primary CYP enzyme in the metabolism, 
CYP3A5 and CYP2D6 were also involved in the metabolism. 
MAAA-1181a did not 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 induce to 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 (P-gp), breast cancer resistance protein 
(BCRP), and bile salt export pump (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, MAAA-1181a 
was found to be a substrate of OATP1B1 and 1B3. 
1.2.2.4. 
Toxicology 
In a study of intermittent intravenous dosing of DS-8201a in rats (once every 3 weeks 
[Q3W] dosing for 6 weeks), no deaths or moribund animals were found at dose levels 
up to 197 mg/kg, the maximum dose.  The major observed findings included testicular 
and intestinal toxicity at dose levels of 20 mg/kg and greater, and 
lymphatic/hematopoietic, skin, and incisor tooth, and renal toxicity at dose levels of 
60 mg/kg and greater.  Except for the testicular and incisor tooth changes, these 
changes were all found to recover. 
In an intermittent 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 included decreased 
body weight and food consumption, as well as bone marrow toxicity and intestinal 
toxicity.  The major findings of toxicity in the surviving animals were observed in the 
intestine at dose levels of 10 mg/kg and greater, and in the lung, testes, and skin at 
dose levels of 30 mg/kg and greater.  In addition, hematopoietic system toxicity, renal 
toxicity, and electrocardiogram (ECG) abnormalities (shortened PR interval and 
corrected QT interval [QTc] prolongation) were found at 78.8 mg/kg.  Except for the 
pulmonary and skin toxicity (pigmentation), these findings tended to recover. 
Thus, as described above, the severely toxic dose in 10% of the animals in a rat 
intermittent intravenous dosing study of DS-8201a was found to be greater than 
197 mg/kg.  In the monkey study, due to observed moribundity at 78.8 mg/kg and 
evidence of critical pulmonary toxicity (eg, interstitial inflammation and/or alveolar 
edema) in the surviving animals, it was concluded that the highest non-severely toxic 
dose is 30 mg/kg. 
In an intermittent intravenous dose toxicity study of MAAA-1181a (once weekly 
[QW] dosing for 4 weeks), findings in the lymphatic/hematopoietic system, intestinal 
tract, and the cornea of the eye were observed at 3 mg/kg and greater in rats and there 
was no death or moribundity at up to 30 mg/kg.  Findings similar to those in rats were 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 24 
observed in cynomolgus monkeys at dose levels of 1 mg/kg and greater.  In addition, 
1 female monkey died and 1 male monkey was sacrificed moribund at 12 mg/kg.  
Although effects on the heart (focal myocardial cell degeneration/necrosis) were 
found in the moribund male along with the above mentioned toxicities, there were no 
abnormal heart findings in the female that died even though both animals exhibited 
worsening clinical conditions associated with sustained decreases in food 
consumption, bone marrow toxicity, and intestinal toxicity.  These changes were 
considered to be the cause of the death and moribundity.  The common adverse 
findings with both DS-8201a and MAAA-1181a studies were intestinal and 
lymphatic/hematopoietic system toxicities.  For DS-8201a treatment, pulmonary, 
testicular, skin and renal toxicities were observed while heart, liver, and corneal 
toxicities were found only when MAAA-1181a was administered.   
In a human cross-reactivity study of DS-8201a with a panel of human tissues, DS-
8201a-related cell membrane staining was found only in the placenta.  In a cross-
reactivity study of DS-8201a with selected cynomolgus monkey tissues (eg, brain, 
liver, kidney, lung, heart, intestines, lymphoid organs, testis, and skin), neither 
membranous nor cytoplasmic staining was noted in any tissues.   
In an in vitro 3T3 neutral red uptake 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 Study 
1.2.3.1. 
Clinical Experience 
The DS-8201a first-in-human study (DS8201-A-J101) is an open-label, dose finding 
study to assess the safety and tolerability of DS-8201a in subjects with advanced solid 
tumors.  The study is being conducted in 2 parts; dose escalation (Part 1) and dose 
expansion (Part 2): Part 1 was a dose escalation phase in subjects with either 
advanced breast cancer or gastric/ GEJ adenocarcinoma.  Part 2 is the expansion 
phase and focuses on HER2 expressing breast (previously treated T-DM1 HER2 
positive breast cancer) and gastric/GEJ junction adenocarcinoma, as well as other 
HER2 expressing solid cancers.   
Preliminary results from Part 1 indicate that DS-8201a has a favorable safety and PK 
profile and robust antitumor activity in breast cancer subjects, with tumors that were 
previously treated with T-DM1.  Adverse events of special interest detailed in the 
Phase 1 study (DS8201-A-J101) included infusion reactions, cardiac events, and 
pneumonitis.  Periodic cardiac assessments are performed including echocardiogram 
(ECHO) or multigated acquisition (MUGA) performed at every 2 cycles (42 days) 
and 12-lead triplicate ECGs performed at least every cycle (21 days).  
As of 08 Jun 2017, a total of 148 subjects, 24 in Part 1 and 124 in Part 2, have 
received DS-8201a in this study.  In Part 1, no dose limiting toxicities were reported 
and the MTD was not reached.  Two doses were chosen for expansion in Part 2: 5.4 
and 6.4 mg/kg.   


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 25 
For 148 subjects who have received DS-8201a in the on-going study, the most 
common adverse events (AEs) (>20%) of any grades were nausea (65%), decreased 
appetite (53%), vomiting (34%), platelet count decreased (31%), anemia (28%), 
alopecia (26%), diarrhea (24%), constipation (24%), neutrophil count decreased 
(24%), white blood cell count decreased (24%), and malaise (22%).  The majority of 
the AEs were of Grade 1 or 2 severity; 52 (35.1%) of 148 subjects experienced Grade 
3 AEs and 10 subjects (6.8%) experienced Grade 4 AEs as the worst grade 
experienced.  A total of 3 subjects died due to an AE; 1 due to mechanical ileus, 1 due 
to extradural hematoma/traumatic intracranial haemorrhage occurring more than 28 
days after last dose of study drug, and 1 due to disease progression reported as an AE.  
All these fatal events were considered not related to study drug by the Investigators. 
As of 08 Jun 2017, 13 (8.7%) of 148 subjects experienced treatment emergent adverse 
events (TEAEs) relating to cardiotoxicity in the on-going study.  Of these 13 subjects, 
9 experienced QT prolongation (7 Grade 1 and 2 Grade 2, all non-serious), all 
considered related to the study therapy. Two subjects experienced ejection fraction 
decreased (Grade 2, non-serious, related), 1 subject experienced Grade 2 tachycardia 
and 1 subject experienced heart rate decreased (related).  No action was taken 
regarding the study drug therapy and no subjects discontinued study therapy.   
Irrespective of the Investigator/Sponsor causality, of the 148 treated subjects, there 
were 3 subjects (where one received 8.0 mg/kg and the other 2 received 6.4 mg/kg) 
who had experienced one serious and 2 non-serious pneumonitis (one was Grade 1 
and the other as Grade 2).  There were also 2 subjects who experienced interstitial 
lung disease (ILD) (1 serious and Grade 3 in severity, and the other non-serious; with 
Grade 1 severity).   
Of the 148 subjects, a total of 2 subjects (1.4%) experienced infusion related reactions 
(both Grade 1, non-serious) and 1 subject experienced infusion site extravasation 
(Grade 1, non-serious).  Study drug administration was interrupted for 1 of 3 reported 
events.  The outcome was reported as resolved in all subjects. 
The preliminary results from Parts 1 and 2 indicate that DS 8201a has a robust 
antitumor activity as summarized in Table 1.1.  Overall efficacy results from all 
cohorts in Part 1 demonstrated an objective response rate (ORR) of 34.8% and disease 
control rate (DCR) of 91.3%.  Subjects in the higher dose levels (≥5.4 mg/kg, 15 
subjects) showed ORR of 53.3%.  Overall efficacy results from all cohorts in Part 2 
demonstrated an ORR of 48.8% and DCR of 85.7%.  Breast cancer cohorts with 
HER2 positive and low expression, Part 2a and 2c, showed ORR of 61.5% and 
50.0%, and DCR of 96.2% and 90.0% respectively.  The HER2 positive gastric 
cancer cohort showed ORR of 48.4% and DCR of 80.6%. 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 26 
Table 1.1: 
Confirmed Objective Response Rate from DS8201-A-J101 Part 1 
(dose escalation) and Part 2 (dose expansion) as of 8 Jun 2017 
CR = complete response, DCR = disease control rate, HER2 = human epidermal growth factor receptor 
2, ORR = objective response rate, PR = partial response, SD = stable disease 
a. Analysis set: efficacy evaluable subjects for confirmed overall response, at least 2 post-baseline 
scans 
1.2.3.2. 
Summary of Clinical Pharmacokinetics 
PK was evaluated in 24 Japanese subjects who received DS-8201a.  Following a 
single intravenous administration, PK parameters at 5.4, 6.4, and 8.0 mg/kg are shown 
in Table 1.2, Table 1.3 and Table 1.4.  The maximum serum concentration (Cmax) of 
DS-8201a at 6.4 mg/kg was achieved with median time to reach Cmax (Tmax) of 
0.09 d (2.16 h).  Cmax and AUClast at 6.4 mg/kg were 181 μg/mL and 901 μg·d/mL, 
respectively.  The systemic exposure at 6.4 mg/kg in subjects in Cycle 1 exceeded the 
systemic efficacious exposure observed during non-clinical pharmacology evaluation.  
Mean T1/2 of DS-8201a was 7.33 d at 6.4 mg/kg.  The Vss for DS-8201a is 
58.6 mL/kg, which is similar to the serum volume. 
PK parameters of total antibody were close to that of DS-8201a. 
Cmax and AUClast of MAAA-1181a were 6.80 ng/mL and 31.0 ng d/mL at 
6.4 mg/kg, respectively, which were quite low.  The T1/2 of MAAA-1181a was similar 
to that of DS-8201a. 
Study (n=107) a 
CR 
PR 
ORR 
(CR+PR) 
SD 
DCR 
(CR+PR+SD
) 
Part 1 
- 
34.8% 
(8/23) 
34.8% 
(8/23) 
56.5% 
(13/23) 
91%  
(21/23) 
Part 1 dose cohorts 
≥5.4 mg/kg 
- 
53.3% 
(8/15) 
53.3% 
(8/15) 
46.7% 
(7/15) 
100%  
(15/15) 
Part 2 Cohorts 
1.2% 
(1/84) 
47.6% 
(40/84) 
48.8% 
(41/84) 
36.9% 
(31/84) 
85.7%  
(72/84) 
2a (HER2-positive 
breast) 
3.8% 
(1/26) 
57.7% 
(15/26) 
61.5% 
(16/26) 
34.6% 
(9/26) 
96.2%  
(25/26) 
2b (HER2-positive 
gastric) 
- 
48.4% 
(15/31) 
48.4% 
(15/31) 
32.3% 
(10/31) 
80.6%  
(25/31) 
2c (HER2 low 
expressing breast) 
- 
50.0% 
(5/10) 
50.0% 
(5/10) 
40.0% 
(4/10) 
90.0%  
(9/10) 
2d (Other HER2 
expressing solid 
cancers) 
- 
29.4% 
(5/17) 
29.4% 
(5/17) 
47.1% 
(8/17) 
76.5%  
(13/17) 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 27 
Table 1.2: 
Pharmacokinetic Parameters of DS-8201a in Cycle 1 
Dose 
(mg/kg) 
Cmax 
(μg/mL) 
Tmax 
(h) 
AUClast 
(μg•d/mL) 
AUCinf 
(μg•d/mL) 
T1/2 
(d) 
CL 
(mL/d/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 
(0.36) 
8.17 
(1.93) 
69.7 
(13.1) 
N = number, Mean (standard deviation), Tmax: median (max, min). 
 
Table 1.3: 
Pharmacokinetic Parameters of Total Antibody in Cycle 1 
Dose 
(mg/kg) 
Cmax 
(μg/mL) 
Tmax 
(h) 
AUClast 
(μg•d/mL) 
AUCinf 
(μg•d/mL) 
T1/2 
(d) 
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) 
N = number, Mean (standard deviation), Tmax: median (max, min) 
 
Table 1.4: 
Pharmacokinetic Parameters of MAAA-1181a in Cycle 1 
Dose 
(mg/kg) 
Cmax 
(ng/mL) 
Tmax 
(h) 
AUClast 
(ng•d/mL) 
AUCinf 
(ng•d/mL) 
T1/2 
(d) 
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) 
N = number; Mean (standard deviation), Tmax: median (max, min) 
1.3. 
Study Rationale 
DS-8201a is an ADC that targets HER2.  A humanized IgG1 monoclonal antibody 
with reference to the amino acid sequence of trastuzumab is used as the antibody 
component and a derivative of exatecan, a topoisomerase I inhibitor, is used as the 
drug component.   
Typically drug-drug interactions involving antibodies are not common.  This is a 
clinical pharmacology study to evaluate drug-drug interaction potential of CYP3A 
and OATP1B inhibitor on DS-8201a and MAAA-1181a in subjects with HER2-
expressing advanced solid malignant tumors.  In vitro studies indicated that MAAA-
1181a was principally metabolized by CYP3A4 and that MAAA-1181a was 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 28 
transported by OATP1B which are polymorphic.  In vivo nonclinical data in rats 
indicate, however, that MAAA-1181a was primarily excreted unchanged with a small 
metabolic contribution.   Therefore, this study was designed to evaluate the effect of 
ritonavir and itraconazole on DS-8201a and MAAA-1181a PK.  Ritonavir is selected 
as a dual inhibitor for the CYP3A and OATP1B and itraconazole is selected as an 
inhibitor for the CYP3A. 
In this study, the effect of ritonavir and itraconazole on the exposure of DS-8201a and 
MAAA-1181a will be assessed.  Ritonavir tablet and itraconazole have been approved 
in Japan, Korea and Taiwan. As ritonavir is recommended in the US Food and Drug 
Administration (FDA) 2012 draft guidance as a strong CYP3A inhibitor and OATP1B 
inhibitor, ritonavir is selected.21  Ritonavir is expected to be safely administered as 
recommended dosage of up to 600 mg twice daily (BID) for adult subjects.  Since 
itraconazole is a known and FDA-recommended probe inhibitor of CYP3A, 
itraconazole is considered appropriate to evaluate the inhibition of CYP3A.21  
Itraconazole is not exceeding the maximum recommended dose and duration and is 
well recognized as alternative to ketoconazole (another strong CYP3A inhibitor). 
Based on the preclinical data, MAAA-1181a exposure may increase when OATP1B 
inhibitors are administered concomitantly when dosed as MAAA-1181a.  The clinical 
relevance of this inhibition is not known when DS-8201a is administered as an intact 
molecule. Nevertheless, the lower dose of 5.4 mg/kg with acceptable potential benefit 
to subjects was selected to allow for safety in case there is increased exposure due to 
the drug-drug interaction. 
1.4. 
Risks and Benefits for Study Subjects 
As of 13 Dec 2017, three clinical studies have subjects dosed with DS-8201a: 
DS8201-A-J101 (see Section 1.2.3) DS8201-A-U201, and DS8201-A-J202. 
Overall, the reported AEs were consistent with the safety profile of DS-8201a 
expected based on the nonclinical toxicology data.  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 is 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 specific intervals 
described within the protocol and at the end of treatment (EOT), when an additional 
exam will also be performed.  In addition, at the discretion of the Investigator, 
ophthalmologic testing can be performed at any time during the study. 
As of 08 Jun 2017, 13 (8.7%) of 148 subjects experienced TEAEs relating to 
cardiotoxicity in the Phase 1 study (DS8201-A-J101, see Section 1.2.3.1).  Similar to 
other products of the same class, the possibility of cardiotoxicity, relative to the 
potential for QT prolongation were found in association with the administration of 
DS-8201a and cannot be excluded.  Left ventricular ejection fraction (LVEF) will be 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 29 
measured by either ECHO or MUGA scan.  All ECHO or MUGA, will be evaluated 
by the Investigator or delegated physician for monitoring cardiac function.  
Pulmonary toxicity was observed in association with the administration of DS-8201a 
and cannot be excluded.  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 
Adjudication Committee (AC) as ILD and caused by DS-8201a, ILD and pneumonitis 
are added as adverse drug reactions associated with the use of DS-8201a. 
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.  


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 30 
2. 
STUDY OBJECTIVES AND HYPOTHESIS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objectives 
 Cohort 1: To evaluate the effect of ritonavir (dual inhibitor of CYP3A 
(strong) and OATP1B) on DS-8201a and MAAA-1181a PK in subjects 
with HER2-expressing advanced solid malignant tumors. 
 Cohort 2: To evaluate the effect of itraconazole (strong CYP3A inhibitor) 
on DS-8201a and MAAA-1181a PK in subjects with HER2-expressing 
advanced solid malignant tumors. 
2.1.2. 
Secondary Objectives 
2.1.2.1. 
Key Secondary Objectives 
 To assess the safety of DS-8201a with/without ritonavir or itraconazole. 
2.1.2.2. 
Other Secondary Objectives 
 To evaluate the efficacy of DS-8201a 
 To assess the incidence of anti-drug antibodies (ADA) against DS-8201a  
2.1.3. 
Exploratory Objectives 
 To assess the effect of genetic polymorphism (OATP1B1 and BCRP) on 
the exposure of  MAAA-1181a  
2.2. 
Study Hypotheses 
There is no hypothesis to be tested. This study is aimed at estimating the magnitude of 
DS-8201a and MAAA-1181a pharmacokinetic changes when administered with 
known inhibitors of OATP1B and CYP3A4.   
2.3. 
Study Endpoints 
2.3.1. 
Primary Endpoints 
 PK parameters (Cmax and AUC0-17d) of DS-8201a and MAAA-1181a (± 
ritonavir)  
 PK parameters (Cmax and AUC0-17d) of DS-8201a and MAAA-1181a (± 
itraconazole) 
2.3.2. 
Key Secondary Endpoints 
Key secondary endpoints are the following safety endpoints. 
 Serious adverse events (SAEs) 
 TEAEs 
 Discontinuation due to AE 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 31 
 Discontinuation due to adverse events of special interest (AESIs) 
 Physical examination findings (including Eastern Cooperative Oncology 
Group Performance Status [ECOG PS]) 
 Vital sign measurements 
 Standard clinical laboratory parameters 
 12-lead ECG parameters 
 ECHO or MUGA findings 
 Ophthalmologic findings 
 ADA 
2.3.3. 
Other Secondary Endpoints 
Other secondary endpoints are the following efficacy endpoints. 
 ORR 
 DCR 
 Duration of response (DoR) 
 Duration of stable disease (Duration of SD) 
 Clinical benefit ratio (CBR) 
 Time to response (TTR) 
 Progression free survival (PFS) 
 Best (minimum) percent change from baseline in the sum of diameters of 
target lesion 
2.3.4. 
Exploratory Endpoints 
 Genetic polymorphism (OATP1B1 and BCRP) 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 32 
3. 
STUDY DESIGN 
3.1. 
Overall Design 
This is a Phase 1, multicenter, open-label, single sequence crossover study of DS-
8201a designed to evaluate drug-drug interaction potential of ritonavir 
(OATP1B/CYP3A inhibitor) and itraconazole (CYP3A inhibitor) on DS-8201a and 
MAAA-1181a in subjects with HER2-expressing advanced solid malignant tumors.  
The study comprises Cohort 1 and Cohort 2 as shown in Figure 3.1.  Depending on 
the preliminary results of Cohort 1, Sponsor may decide whether Cohort 2 will be 
opened or not.  The primary analysis will be conducted after all subjects have either 
discontinued the study or completed at least 3 cycles of the study drug. 
Cohort 1 
Cohort 1 is a non-randomized cohort to evaluate the effect of ritonavir (dual inhibitor 
of CYP3A (strong) and OATP1B) on DS-8201a and MAAA-1181a PK. 
Cohort 2 
Cohort 2 is a non-randomized cohort to evaluate the effect of itraconazole (strong 
CYP3A inhibitor) on DS-8201a and MAAA-1181a PK. 
 
Figure 3.1: 
Study Design Schema of DS8201-A-A104 
 
HER2 = human epidermal growth factor receptor 2 
 
Approximately 32 subjects (16 subjects in each cohort; 12 completers for each cohort) 
are planned for this study. 
DS-8201a will be administered as an intravenous infusion solution at 5.4 mg/kg 
Q3W.  The study treatment will be continued according to the dosing criteria (See 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 33 
Section 5.4) 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 28 days from the planned date of administration, the subject will be 
withdrawn from the study. 
The data cutoff for the primary analysis will occur after all subjects have either 
discontinued the study or completed at least 3 cycles, whichever comes first.  After 
the primary analysis, the main study will be closed and transition to the extension 
period. 
3.2. 
Discussion of Study Design 
DS-8201a was administered in 0.8 mg/kg to 8.0 mg/kg tri-weekly in the prior Phase 1 
study (DS8201-A-J101) and the MTD was not reached up to 8.0 mg/kg.  On the basis 
of efficacy, tolerability and PK profile established in the Phase 1 study, 7.4, 6.4 and 
5.4 mg/kg have been considered as the recommended the Phase 2 study dose. In this 
study, 5.4 mg/kg which is lowest dose for the candidate recommended Phase 2 dose 
have been considered as the dosage for this study because there is a possibility that a 
drug–drug interactions (DDIs) may increase a risk of AEs and increase efficacy of 
DS-8201a and may accordingly impact on subject’s quality of life. 
 
3.2.1. 
Duration of the Study 
The subject's enrollment is expected for approximately 6 months, with the data cutoff 
for the primary analysis projected to be completed within approximately 2.5 months 
thereafter.  Thus, the expected duration of the study is approximately 8.5 months. 
Sponsor may terminate the study at any time and study termination may also be 
requested by (a) competent authority(ies). 
3.2.2. 
Duration of Subject Participation 
The screening period is up to 28 days.  Each cycle of treatment will be 21 days. The 
number of treatment cycles with DS-8201a is not fixed.  Subjects who continue to 
derive clinical benefit from the study drug in the absence of withdrawal of consent, 
PD, or unacceptable toxicity may continue the study drug.  Upon commencing study 
treatment, subjects may continue receiving study drug until the occurrence of any of 
the events defined in Section 5.7.1. 
After discontinuation from study treatment, all subjects, regardless of whether they 
discontinued prior to or subsequent to disease progression, may be contacted until 
follow-up (F/U) data collection is no longer of scientific value or otherwise needed (at 
the Sponsor’s discretion), to obtain information. 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 34 
4. 
STUDY POPULATION 
Each subject will sign an informed consent form (ICF) provided by the site.  A 
subject is considered enrolled in the study upon the Investigator or designee obtaining 
written informed consent from the subject (see Section 15.3) at the time of Screening 
and upon determination that all inclusion and exclusion criteria have been satisfied. 
Investigators will maintain a confidential screening log of all potential study 
candidates that includes limited subject information (initials, age, gender) and 
outcome of screening process (ie, enrollment in the study, reason for ineligibility, 
refused to participate). 
Investigators will be expected to maintain an Enrollment Log of all subjects enrolled 
in the study indicating their assigned study number. 
Investigators will maintain a confidential subject identification code list.  This 
confidential list of the names of all subjects, allocated study numbers on enrolling in 
the study, allows the Investigator to reveal the identity of any subject when necessary. 
4.1. 
Inclusion Criteria 
Subjects must satisfy all of the following criteria to be included in the study: 
1. Is male or female ≥ 20 years old. 
2. Has a pathologically documented unresectable or metastatic solid malignant 
tumors with HER2 expression (determined by immunohistochemistry [IHC]/in 
situ hybridization [ISH] [IHC 3+, IHC 2+, IHC 1+, and/or ISH +], Next 
Generation Sequencing, or other analysis techniques as appropriate) that is 
refractory to or intolerable with at least 1 prior systemic chemotherapy 
regimen, or for which no standard treatment is available. 
3. Has presence of tumor lesion assessed by the Investigator based on Response 
Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Subjects with only 
non-target lesions can be eligible. 
4. Has a LVEF ≥ 50% by either ECHO or MUGA scan within 28 days before 
enrollment. 
5. Has an Eastern Cooperative Oncology Group Performance Status (ECOG PS) 
0 or 1. 
6. Has adequate organ function within 14 days before enrollment, defined as: 
Item 
Laboratory value 
Adequate bone marrow function 
Platelet count 
100,000/mm3 (Platelet transfusion is not 
allowed within 1 week prior to screening 
assessment) 
Hemoglobin (Hb) 
≥9.0 g/dL (Red blood cell transfusion is 
not allowed within 1 week prior to 
screening assessment) 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 35 
Item 
Laboratory value 
Absolute neutrophil count 
(ANC) 
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  (see Section 17.1) 
Adequate hepatic function 
Aspartate aminotransferase 
(AST)/ Alanine 
aminotransferase (ALT) 
≤5  upper limit of normal (ULN) 
Total bilirubin (TBL); except 
gastric cancer indication 
≤1.5 × ULN or < 3 × ULN in the presence 
of documented Gilbert’s Syndrome or 
liver metastases at baseline 
Serum Albumin; Only gastric 
cancer indication 
≥2.5 g/dL 
Adequate blood clotting function 
International normalized ratio 
/Prothrombin time and activated 
partial thromboplastin time 
≤1.5 × ULN 
7. Has adequate treatment washout period before enrollment, 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, hormonal 
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; >6 weeks for nitrosureas or 
mitomycin C; > 1 week for tyrosine kinase 
inhibitors (TKIs) approved for the treatment 
of non-small cell lung cancer - baseline CT 
scan must be completed after discontinuation 
of TKI) 
Immunotherapy 
4 weeks 
Cytochrome P450 (CYP) 
3A4 strong inhibitor, OATP 
inhibitor 
>3 elimination half-lives of the inhibitor 
8. Is able to withhold potential concomitant treatments defined as: 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 36 
Treatment 
Treatment prohibited period 
CYP3A strong inhibitors 
and OATP1B inhibitors 
From 2 weeks prior to the first dose of the 
study drug until EOT 
CYP3A weak/moderate 
inhibitors  
From 2 weeks prior to the first dose of the 
study drug until the beginning of Cycle 4 
CYP3A inducers 
From 4 weeks prior to the first dose of the 
study drug until the beginning of Cycle 4 
CYP3A substrates and 
OATP1B substrates 
From 2 weeks prior to the first dose of the 
study drug until the beginning of Cycle 4 
9. Is able to provide written informed consent.  Subject must be fully informed 
about their illness and the investigational nature of the study protocol 
(including foreseeable risks and possible toxicities) and must sign and date an 
Institutional Review Board (IRB) approved ICF before performance of any 
study-specific procedures or examinations. 
10. Has a life expectancy of ≥3 months. 
11. Has a study treatment expectancy of ≥2.5 months. 
12. Is able and willing to comply with protocol visits and procedures. 
13. 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 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 
 Intravaginal 
 Transdermal 
 Intrauterine device (IUD) 
 Intrauterine hormone-releasing system (IUS) 
 Bilateral tubal occlusion 
 Vasectomized partner 
 Complete sexual abstinence defined as refraining from heterosexual 
intercourse during and upon completion of the study and for at least 7 
months for females and 4 months for males after the last dose of study 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 37 
drug. Periodic abstinence (calendar, symptothermal, post-ovulation 
methods) is not an acceptable method 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 [FSH] >40 mIU/mL and 
estradiol <40 pg/mL [<147 pmol/L] is confirmatory). Females on hormone 
replacement therapy (HRT) and whose menopausal status is in doubt will be 
required to use one of the contraception methods outlined for women of 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. 
14. 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 
administration. Preservation of sperm should be considered prior to enrolment 
in this study. 
15. Female subjects must not donate, or retrieve for their own use, ova from the 
time of Screening and throughout the study treatment period, and for at least 7 
months after the final study drug administration. 
4.2. 
Exclusion Criteria 
Subjects who meet any of the following criteria will be disqualified from entering the 
study: 
1. Has a contraindication for receiving ritonavir or itraconazole according to the 
prescribing information. 
2.  Is NOT able to take ritonavir and itraconazole by oral intake. 
3. Has a medical history of myocardial infarction within 6 months before 
enrollment, symptomatic congestive heart failure (CHF) (New York Heart 
Association Class II-IV, Section 17.4), or troponin levels consistent with 
myocardial infarction as defined according to the manufacturer 28 days prior 
to enrollment. 
4. Has a QTc 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]). 
5. 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. 
6. Has known human immunodeficiency virus (HIV) infection, or active 
hepatitis B or C infection.  Subjects should be tested for HIV prior to 
randomization/enrollment if required by local regulations or IRB/Ethics 
Committee (EC). 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 38 
7. Has clinically significant corneal disease in the opinion of the Investigator. 
8. Has a pleural effusion, ascites or pericardial effusion that requires drainage, 
peritoneal shunt, or Cell-free and Concentrated Ascites Reinfusion Therapy 
(CART). (Drainage and CART are not allowed within 2 weeks prior to 
screening assessment). 
9. 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. 
10. Has multiple primary malignancies within 3 years, except adequately resected 
non-melanoma skin cancer, curatively treated in-situ disease, other solid 
tumors curatively treated, or contralateral breast cancer. 
11. Has a history of severe hypersensitivity reactions to other monoclonal 
antibodies or has a history of hypersensitivity reactions to either the drug 
substances or inactive ingredients in the drug product. 
12. Has an uncontrolled infection requiring intravenous (IV) injection of 
antibiotics, antivirals, or antifungals. 
13. 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. 
14. 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). 
15. Is pregnant or breastfeeding, or planning to become pregnant. 
16. Prior treatment with an ADC which consists of an exatecan derivative that is a 
topoisomerase I inhibitor. 
17. Has social, familial, or geographical factors that would interfere with study 
participation or F/U. 
18. Has a concomitant medical condition that would increase the risk of toxicity, 
in the opinion of the Investigator. 
4.3. 
Subject Replacement 
Subjects that have been enrolled and received study drug will not be replaced.  It is 
allowable to replace a subject that was enrolled but did not receive study drug. 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 39 
4.4. 
Subject Re-screening Procedures 
Re-screening is permitted for any subject who failed to meet eligibility criteria upon 
initial screening.  The limit of re-screening is 1 time.  The site subject identifier and 
the unique Subject Number must remain the same at the time of re-screening.  The 
initial screening information and the reason why the subject is ineligible for the initial 
evaluation will be recorded on the Screening Log.  No data from the initial evaluation 
will be entered into the clinical database for a subject who is rescreened. 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 40 
5. 
STUDY TREATMENT(S) 
5.1. 
Assigning Subjects to Treatment Group(s) /Sequences and 
Blinding 
5.1.1. 
Treatment Group(s) /Sequences 
There are two cohort groups.  Study treatment of DS-8201a and procedure is the same 
among all subjects enrolled in this study. 
5.1.2. 
Method of Treatment Group(s) /Sequences Allocation 
Each subject will be provided with information about the study, will have all 
questions answered to their satisfaction, and will sign and date an ICF.  This will be 
completed before any study-specific procedures are performed.  Additional 
information about informed consent procedures is provided in Section 15.3. 
Investigators will maintain a confidential screening log of all potential study 
candidates that includes limited information of the subjects (initials, age, gender), date 
and outcome of screening process (eg, enroll in the study, reason for ineligibility, 
refused to participate). 
Investigators will be expected to maintain an Enrollment Log of all subjects enrolled 
in the study indicating their assigned Subject Number. 
At the beginning of study, Investigator will allocate subjects for Cohort 1.  Once 
Cohort 2 will be opened, Investigator will allocate subjects for Cohort 2. 
Investigators will maintain a confidential subject identification code list.  This 
confidential list of names of all subjects allocated to Subject Numbers on enrolling in 
the study, allows the Investigator to reveal the identity of any subject when necessary. 
5.1.3. 
Enrollment 
A subject is considered to be enrolled in the study upon the Investigator’s or 
designee’s obtaining written informed consent from the subject (See Section 15.3) 
and upon determination of all inclusion and exclusion criteria having been satisfied. 
Investigators will assess the eligibility of a subject based on the inclusion and 
exclusion criteria after obtaining written informed consent from the subject.  After 
assessment by Investigators, subject enrollment will be conducted in the interactive 
web/voice response system (IXRS) regardless of eligibility.  The date of enrollment is 
defined as the date that subject is successfully registered as eligible in the IXRS.  The 
date of screen failure is defined as the date that subject is successfully registered as 
ineligible in the IXRS (see Figure 5.1). 




Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 42 
operating procedures (SOPs) of the study site.  Refer to the pharmacy manual for 
detailed information about preparation and administration of DS-8201a. 
5.2.4. 
Administration 
The study drug will be administered as a 5.4 mg/kg. The initial dose of DS-8201a will 
be infused for approximately 90 minutes.  If there is no infusion related reaction, after 
the initial dose, the dose of DS-8201a in Cycle 2 and Cycle 3 will be infused for 30 
minutes.  After Cycle 4, the dose will be infused for approximately 30 minutes. 
From Cycle 1 to Cycle 4, DS-8201a is to be administered every 3 weeks + 2 days. 
After Cycle 5, DS-8201a is to be administered every 3 weeks ± 2 days. 
The subject’s weight at screening will be used to calculate the initial dose.  If during 
the course of treatment the subject’s weight would be changed 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 drug shipment is received, the Investigator or designee will check the amount 
and condition of the drug, check for appropriate local language in the label, drug 
expiration date, and sign the Receipt of Shipment Form provided by the Sponsor.  The 
Receipt of Shipment Form should be signed and the original Form will be retained at 
the site.  In addition, the Investigator or designee shall contact Sponsor as soon as 
possible if there is a problem with the shipment. 
A Drug Accountability Record will be provided for the study drug.  The record must 
be kept current and should contain the dates and quantities of study drug received, 
subject’s information (the site subject identifier and the subject number), for whom 
the study drug was dispensed, 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 law and/or as directed by the Sponsor, all unused 
DS-8201a will be returned or destroyed as per local laws or site policy and only after 
the study monitor has completed a final inventory.  As applicable, the study site must 
file a copy of the appropriate institution policy within their investigator site file and 
provide a copy to the Sponsor.  Please see pharmacy manual for details.  
All study drug inventory forms must be made available for inspection by a Sponsor 
authorized representative or designee and regulatory agency inspectors.   


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 43 
5.3. 
Inhibitor Drugs 
5.3.1. 
Description 
Commercially available ritonavir and itraconazole will be supplied as inhibitor drugs 
by Sponsor. (See Table 5.1). 
Table 5.1: 
Content and Dosage Form of Inhibitor Drugs 
Drug Name 
Content and Dosage Form 
Ritonavir tablet 100 mg 
White to pale yellow-white film-coated 
ovaloid tablets 100 mg ritonavir.   
Itraconazole Capsule 100 mg 
Itraconazole Capsules are available 
containing 100 mg of itraconazole.   
Ritonavir tablet and itraconazole capsule have been approved in Japan, Korea and 
Taiwan.  Ritonavir is selected as a dual inhibitor for the CYP3A and OATP1B 
inhibitor due to no suitable specific OATP inhibitors used by multiple doses for 
cancer subjects.   Itraconazole is considered appropriate to evaluate the effect of 
inhibition to CYP3A. 
5.3.2. 
Labeling and Packaging 
The outer box of the commercial product of Ritonavir tablet 100 mg and Itraconazole 
Capsules 100 mg will be labeled with the description of “For Clinical Trial Use Only” 
and other information based on each county regulation. 
5.3.3. 
Preparation 
5.3.3.1. 
Ritonavir 
Ritonavir tablet 100 mg will be provided by Sponsor.  Specific instructions on 
preparation and dispensation will be provided in the pharmacy manual and package 
insert. 
5.3.3.2. 
Itraconazole 
Itraconazole capsule 100 mg will be provided by Sponsor.  Specific instructions on 
preparation and dispensation will be provided in the pharmacy manual and package 
insert. 
5.3.4. 
Administration 
5.3.4.1. 
Ritonavir 
The ritonavir will be administrated with sufficient water (eg, 240 mL) orally under 
fed condition in principle as 200 mg twice a day [Bis In Die (BID)] on Day 17 of 
Cycle 2 until Day 21 of Cycle 3.  The timing of the dosing for the ritonavir on Day 17 
of Cycle 2 and Day 1 of Cycle 3 will be after PK sampling and immediately before 
DS-8201a dosing, respectively.   


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 44 
5.3.4.2. 
Itraconazole 
The itraconazole will be administrated with sufficient water (eg, 240 mL) orally under 
fed condition as 200 mg BID on Day 17 followed by 200 mg once a day [Quaque Die 
(QD)] until Day 21 of Cycle 3.  The timing of the dosing for the itraconazole on Day 
17 of Cycle 2 and Day 1 of Cycle 3 will be after PK sampling and immediately before 
DS-8201a dosing, respectively. 
5.3.5. 
Storage 
5.3.5.1. 
Ritonavir 
Ritonavir will be stored at controlled room temperature. 
If storage conditions are not maintained per specified requirements, the Sponsor or 
CRO should be contacted. 
5.3.5.2. 
Itraconazole 
Itraconazole will be stored at controlled room temperature.  Protect from moisture. 
If storage conditions are not maintained per specified requirements, the Sponsor or 
CRO should be contacted. 
5.3.6. 
Drug Accountability 
The same process will be applied for the drug accountability on Section 5.2.6.  Please 
see pharmacy manual for details. 
5.4. 
Dose Interruptions and Reductions 
The Investigator will evaluate which toxicities are attributed to the study drug and 
adjust the dose of the drug as recommended below.  All dose modifications 
(interruption, reduction and/or discontinuation) should be based on the worst 
preceding toxicity (National Cancer Institute Common Terminology Criteria for 
Adverse Event [NCI-CTCAE] version 4.03).  Specific criteria for interruption, re-
initiation, dose reduction and/or discontinuation of DS-8201a are listed in Table 5.3.  
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 discontinuation of study treatment is decided. 
Prophylactic or supportive treatment for expected toxicities, including management of 
study-drug induced AEs will be as per the treating physician’s discretion and 
institutional guidelines. 
 
Dose Reduction Guidelines: 
Note: There will be no dose modifications for Grade 1 or Grade 2 AEs unless 
specified in Table 5.3. 
Two dose reductions will be permitted.  The adjustment for a reduced dosing of DS-
8201a is as shown in Table 5.2. 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 45 
Table 5.2: 
Dose Reduction Levels of DS-8201a 
Starting Dose 
Dose Level -1 
Dose Level -2 
5.4 mg/kg 
4.4 mg/kg 
3.2 mg/kg 
Once the dose of DS-8201a has been reduced because of toxicity, all subsequent 
cycles should be administered at that lower dose level unless further dose reduction is 
required.  More than 2 dose reductions are not allowed and the subject will be 
withdrawn from the study treatment if further toxicity meeting the requirement for 
dose reduction occurs. 
 
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 Cycle 2 Day 1 or/and Cycle 3 Day 1 is delayed for 
3 days or longer, the subject will be excluded from Primary analysis.  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 severe acute respiratory syndrome coronavirus 2 (SARS-
CoV-2) infection events must be recorded in the eCRF. Please refer to Section 17.6 
for additional information on dose modification. 
 
Table 5.3: 
Management Guidelines for DS-8201a 
Worst toxicity NCI-
CTCAE version 4.03 
Grade (unless otherwise 
specified) 
Management Guidelines for DS-8201a 
No toxicity 
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. 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 46 
Worst toxicity NCI-
CTCAE version 4.03 
Grade (unless otherwise 
specified) 
Management Guidelines for DS-8201a 
Grade 2  
(Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment (eg, 
antihistamines, NSAIDs, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hours) 
 
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, IV 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. 
 
Maintain dose 
Grade 4 
Delay dose until resolved to ≤Grade 2. 
 
Reduce dose 1 level 
Febrile Neutropenia 
Grade 3 
(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 1 level 
Grade 4 
Discontinue subject from study treatment. 
Lymphocyte Count Decreased 
Grade 1 to 3 
No dose modification. 
Grade 4 
(<0.2 × 109/L) 
Delay dose until resolved to ≤Grade 2: 
 
If resolved in ≤14 days from day of onset, maintain dose 
 
If resolved in >14 days from day of onset, reduce dose 1 level 
Anaemia 
Grade 3 
(Hb <8.0 g/dL; 
transfusion indicated) 
Delay dose until resolved to ≤Grade 2. 
 
Maintain dose 
Grade 4  
Delay dose until resolved to ≤Grade 2. 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 47 
Worst toxicity NCI-
CTCAE version 4.03 
Grade (unless otherwise 
specified) 
Management Guidelines for DS-8201a 
(Life threatening 
consequences; urgent 
intervention indicated) 
 
Reduce dose by 1 level 
Platelet Count Decreased 
Grade 3 
(<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  
(<25 ×109/L) 
Delay dose until resolved to ≤Grade 1. 
 
Reduce dose 1 level 
Cardiac Toxicity 
Symptomatic CHF 
Discontinue subject from study treatment. 
Decrease in LVEF 10% to 
20% (absolute value), but 
LVEF >45% 
Continue treatment with DS-8201a. 
LVEF 40% to ≤45% and 
decrease is <10% (absolute 
value) from baseline 
Continue treatment with DS-8201a. 
Repeat LVEF assessment within 3 weeks. 
LVEF 40% to ≤45% and 
decrease is 10-20% (absolute 
value) from baseline 
Interrupt DS-8201a dosing. 
Repeat LVEF assessment within 3 weeks. 
If LVEF has not recovered to within 10% (absolute value) from 
baseline, discontinue subject from study treatment. 
If LVEF recovers to within 10% from baseline, resume study drug 
treatment. 
LVEF <40% or >20% 
(absolute value) drop from 
baseline 
Interrupt DS-8201a dosing. 
Repeat LVEF assessment within 3 weeks. 
If LVEF <40% or >20% drop from baseline is confirmed, discontinue 
subject from study treatment. 
Electrocardiogram QT prolonged 
Grade 3 
(QTc>500 ms on 2 separate 
ECGs) 
Delay dose until resolved to ≤ Grade 1 (QTc ≤480 ms). 
 
Determine if another medication the subject was taking 
may be responsible and can be adjusted 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. 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 48 
Worst toxicity NCI-
CTCAE version 4.03 
Grade (unless otherwise 
specified) 
Management Guidelines for DS-8201a 
Troponin 
Grade 1 
(Levels above the ULN and 
below the level of 
myocardial infarction as 
defined by the manufacturer) 
If troponin levels are above the upper limit of normal at baseline and 
below the level of myocardial infarction as defined by the 
manufacturer (CTCAE Grade 1), no repeat testing is required if the 
troponin level is not Grade 3. 
For new diagnosed Grade 1, repeat troponin testing at 3 hours (± 1 
hour) after initial troponin test. 
 
 If levels at 3 hours (± 1 hour) rise significantly per institutional 
guidelines,  
 
Perform ECG in triplicate 
 
Repeat troponin testing at 6 hours (± 1 hour) 
 
Follow institutional guidelines for management of 
detectable troponin testing. 
 If levels at 3 hours (± 1 hour) does not rise significantly per 
institutional guidelines,  
 
Repeat troponin testing at 6 hours (± 1 hour) or at 24 hours 
(± 2 hours) after initial troponin test  
 
Continue treatment with DS-8201a. 
 
Grade 3  
(Levels consistent with 
myocardial infarction as 
defined by the manufacturer) 
Perform ECG in triplicate. 
Repeat troponin testing at 6 hours (± 1 hour) and 12 hours (± 1 hour) 
after initial troponin test.  
Follow institutional guidelines for management of detectable troponin 
testing.  If 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 
Pulmonary Toxicity 
 
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, 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 of the study protocol. 
If the AE is suspected to be ILD/pneumonitis, treatment with study 
drug should be interrupted pending further evaluations.  
Evaluations should include: 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 49 
Worst toxicity NCI-
CTCAE version 4.03 
Grade (unless otherwise 
specified) 
Management Guidelines for DS-8201a 
 
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/pneumonitis 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/pneumonitis 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-8201acan 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/pneumonitis 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. 
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,  


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 50 
Worst toxicity NCI-
CTCAE version 4.03 
Grade (unless otherwise 
specified) 
Management Guidelines for DS-8201a 
• 
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. 
 
Reduce dose 1 level 
Grade 4 
(>6.0 × ULN) 
Discontinue subject from study treatment. 
Hepatic Toxicity 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) with simultaneous 
Total bilirubin (TBL) 
AST/ALT ≥3.0 × ULN 
with simultaneous TBL 
>2.0 × ULN 
Delay study medication until drug-induced liver injury can be ruled 
out.  
If drug-induced liver injury is ruled out, the subject should be treated 
accordingly, and resumption of study drug may occur after discussion 
between the Investigator and Sponsor.  
If drug-induced liver injury cannot be ruled out from diagnostic 
workup, permanently discontinue study treatment. 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 51 
Worst toxicity NCI-
CTCAE version 4.03 
Grade (unless otherwise 
specified) 
Management Guidelines for DS-8201a 
Monitor AST/ALT and TBL twice weekly until resolution or return to 
baseline. 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
Grade 2 
(>3.0 to 5.0 × ULN) 
No action for Grade 2 AST/ALT. 
Grade 3 
(>5.0 to 20.0 × ULN) 
In subjects without liver 
metastases and subjects 
with liver metastases and 
baseline level ≤3 × ULN 
Repeat testing within 3 days. 
Delay dose until resolved to ≤Grade 1, if baseline ≤ 3 x ULN, 
otherwise delay dose until resolved to ≤ baseline, then: 
 
If resolved in ≤7 days from day of onset, maintain dose 
 
If resolved in >7 days from day of onset, reduce dose 1 level 
Grade 3 
(>8.0 to 20.0 × ULN) 
In subjects with liver 
metastases, if the baseline 
level was >3 × ULN 
Repeat testing within 3 days. Delay dose until resolved to ≤ baseline 
level, then: 
 
If resolved in ≤7 days from day of onset, maintain dose 
 
If resolved in >7 days from day of onset, reduce dose 1 level 
Grade 4  
(>20 × ULN) 
Discontinue subject from study treatment. 
TBL increased 
Grade 2 
(>1.5 to 3.0 × ULN) 
If no documented Gilbert’s syndrome or liver metastases at baseline, 
delay dose until resolved to ≤Grade 1: 
 
If resolved in ≤7 days from day of onset, maintain dose 
 
If resolved in >7 days from day of onset, reduce dose 1 level 
If documented Gilbert’s syndrome or liver metastases at baseline, 
continue study treatment 
Grade 3 
(>3.0 to 10.0 × ULN) 
If no documented Gilbert’s syndrome or liver metastases at baseline, 
repeat testing 3 days.  Delay dose until resolved to ≤Grade 1: 
 
If resolved in ≤7 days from day of onset, reduce dose 1 level 
 
If resolved in >7 days from day of onset, discontinue DS-8201a 
If documented Gilbert’s syndrome or liver metastases at baseline, 
repeat testing within 3 days. Delay dose until resolved to < Grade 2: 
 
If resolved in ≤ 7 days from day of onset, reduce dose 1 level 
 
If resolved in > 7 days from day of onset, discontinue DS-8201a 
Grade 4 
(>10.0 × ULN) 
Discontinue subject from study treatment. 
Blood Alkaline Phosphatase (ALP) increased 
Grade 3 to 4 
(>5.0 × ULN) 
No modification unless determined by the Investigator to be clinically 
significant or life-threatening. 
Gastrointestinal 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 52 
Worst toxicity NCI-
CTCAE version 4.03 
Grade (unless otherwise 
specified) 
Management Guidelines for DS-8201a 
Nausea 
Grade 3  
Delay dose until resolved to ≤Grade 1:  
 
If resolved in ≤7 days from day of onset, maintain dose 
 
If resolved in >7 days from day of onset, reduce dose 1 level 
Diarrhea/Colitis 
Grade 3 
Delay dose until resolved to ≤Grade 1: 
 
If resolved in ≤3 days from day of onset, maintain dose 
 
If resolved in >3 days from day of onset, reduce dose 1 level 
Grade 4 
Discontinue subject from study treatment. 
Other Laboratory Adverse Events 
Grade 3 
Delay dose until resolved to ≤Grade 1 or baseline level:  
 
If resolved in ≤7 days from day of onset, maintain dose 
 
If resolved in >7 days from day of onset, reduce dose 1 level 
Grade 4 
Discontinue subject from study treatment. 
Other Non-laboratory AEs 
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, CHF= congestive heart failure, CT = computed tomography, ECG = 
electrocardiogram, ILD = interstitial lung disease, IV = intravenous, LVEF = left ventricular ejection 
fraction, NCI-CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events, 
NSAIDs = nonsteroidal anti-inflammatory drugs, QTc = corrected QT, ULN = upper limit of normal. 
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 
5.5.1. 
Study Drug 
All drugs used for the study treatment will be administered by the Investigator or 
other designated study personnel.  Therefore, treatment compliance will be 
guaranteed as long as the subject attends each visit for the administration of study 
treatment.  Start and stop date/time of injection, amount of drug administered, and 
reason for dose reduction/interruption (if applicable) will be recorded in medical 
record by clinical study personnel.  These data will be recorded on the electronic case 
report form (eCRF). 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 53 
5.5.2. 
Inhibitor Drugs 
Ritonavir and itraconazole will be administrated to subjects from Day 17 of Cycle 2 
until Day 21 of Cycle 3.  The appropriate study personnel will document and maintain 
records of ritonavir and itraconazole administrated to each subject and any returns at 
each study visit.  Subjects will complete a dosing diary to record the number of tablet 
or capsules/date/time the dose was taken. 
At each site visit, subjects will be assessed for compliance with study drug 
administration, ie, actual tablet or capsules taken/expected tablets or capsules taken.  
The subject must also return all bottles (used/unused) at each dispensing visit.  
Returned tablets or capsules must be recorded in the Drug Accountability log. 
Further details can be found in the Study Reference Manual. 
5.6. 
Prior and Concomitant Medications 
5.6.1. 
Concomitant Medications 
Medications used from the time the subject signs the ICF for study participation the 
40-Day F/U 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. 
5.6.2. 
Prohibited Concomitant Medications/Activities 
With the exception of medications that are under investigation in the study (e.g. 
standard of care, comparators, or combination therapies, the following medications, 
treatment and procedures will be prohibited. The Sponsor must be notified if a subject 
receives any of these during the study. 
1. CYP3A strong inhibitors and OATP1B inhibitors beginning 2 weeks prior to 
the first dose of the study drug until Cycle 4listed in Supplement. 
2. CYP3A weak/moderate inhibitors beginning 2 weeks prior to the first dose of 
the study drug until the beginning of Cycle 4 listed in Supplement. 
3. CYP3A inducers beginning 4 weeks prior to the first dose of the study drug 
until the beginning of Cycle 4 listed in Supplement. 
4. CYP3A substrates and OATP1B substrates beginning 2 weeks prior to the first 
dose of the study drug until the beginning of Cycle 4 listed in Supplement. 
5. Foods or beverages containing grapefruit prior to the first dose of the study 
drug until the beginning of Cycle 4. 
6. 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]. 
7. Other investigational therapeutic agents. 
8. Radiotherapy (except for palliative radiation to known metastatic sites as long 
as it does not affect assessment of response or interrupt treatment for more 
than the maximum time specified in dose modification section). 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 54 
9. Radiotherapy to the thorax. 
10. Concomitant use of chronic systemic (IV or oral) corticosteroids or other 
immunosuppressive medications except for managing AEs; (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. 
11. Concomitant treatment with chloroquine or hydroxychloroquine is not allowed 
during the study treatment. Refer to Section 17.6 for further details. 
Permitted Therapies/Products 
 Hematopoietic growth factory may be used for prophylaxis or treatment based 
on the clinical judgment of the Investigator. 
 Concomitant use of dietary supplements, medications not prescribed by the 
Investigator, and alternative/complementary treatments is discouraged, but not 
prohibited. 
 Prophylactic or supportive treatment of study-drug induced AE will be 
otherwise as per Investigator’s discretion and the institutional guidelines. 
 Based on the currently available clinical safety data, it is recommended that 
subjects receive prophylactic anti-emetic agents prior to infusion of T-DXd 
and on subsequent days. Antiemetics such as 5-hydroxytryptamine receptor 
(5-HT3) antagonists or Neurokinin-1 (NK1) receptor antagonists and/or 
steroids (e.g. dexamethasone) should be considered and administered in 
accordance with the prescribing information or institutional guidelines. 
Restricted Products 
 Use of e-cigarettes and vaping is strongly discouraged but not prohibited. 
5.6.3. 
Dietary and Lifestyle Restrictions 
Not applicable. 
5.7. 
Subject Withdrawal/Discontinuation 
5.7.1. 
Reasons for Withdrawal from Study Treatment 
Subjects may be withdrawn from the study treatment after signing ICF for the 
following reasons: 
 PD per criteria set forth in RECIST version 1.1  
 Clinical progression (definitive clinical signs of disease progression, but a 
recent radiographic assessment did not meet the criteria for PD according 
to RECIST version 1.1) 
 AE 
 Withdrawal of consent to study treatment 
 Physician Decision 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 55 
 Death 
 Pregnancy 
 Study terminated by the Sponsor 
 Lost to F/U 
 Other, specify 
If there is evidence that the subject is receiving benefit from treatment even though 
the subject has met a criterion for discontinuation as listed above, the subject may 
remain on study treatment after discussion with the Sponsor Medical Monitor or 
designee.   
All subjects who are withdrawn from study treatment should complete protocol-
specified withdrawal procedures (see Section 6.4) and F/U procedures (see Section 
6.5). 
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 Withdrawal from Study Participation 
Subjects may be withdrawn from the study after signing ICF for the following 
reasons:  
 Withdrawal of consent to participate in study procedures 
 Death 
 Lost to F/U 
 Study terminated by the Sponsor 
 Other, 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 last treatment and the reason for withdrawal. 
If the subject is withdrawn due to an AE, the Investigator will follow the subject until 
the AE has resolved or stabilized. 
All subjects who are withdrawn from the study should complete protocol-specified 
withdrawal procedures.  Protocol-specified withdrawal procedures will be performed 
during the EOT visit (+ 7 days, Section 6.4) and the 40-Day F/U visit (+ 7 days, 
Section 6.5). 
5.7.4. 
Subject Re-screening Procedures 
Re-screening is permitted for any subject who failed to meet eligibility criteria upon 
initial screening.  The limit of re-screening is 1 time.  The unique Subject Number 
must remain the same at the time of re-screening.  The initial screening information 
and the reason why the subject is ineligible for the initial evaluation will be recorded 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 56 
on the Screening Log.  No data from the initial evaluation will be entered into the 
clinical database for a subject who is rescreened. 
 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 57 
6. 
STUDY PROCEDURES 
A study visit schedule in tabular format is provided in Section 17.5.  Obtain a signed 
and dated ICF before any study-related procedures or assessments are conducted.   
After obtaining informed consent, the Investigator or designee assign a site subject 
identifier and enter subject’s background data in the IXRS. 
6.1. 
Screening 
Obtain of a signed and dated ICF before any study-related procedures or assessments 
are conducted.  In this study, enrollment will be performed regardless of eligibility 
(see Section 5.1.2). 
The following activities and/or assessments will be performed during the screening 
period: 
Before enrollment 
 Assign a Site Subject Identifier. 
 Assign a unique Subject Number by IXRS. 
 Record demographic (eg, birth date, sex, race, ethnicity), primary cancer 
history, significant medical history information and prior treatment history 
information for cancer. 
 Record historical HER2 status.   
 Review Inclusion/Exclusion Criteria. 
 Assess subjects for AEs. 
Within 28 days before enrollment 
 Perform a HIV antibody test if 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 either ECHO or MUGA (LVEF). 
 Perform tumor assessment by CT or magnetic resonance imaging (MRI) 
scans of the brain, chest, abdomen, pelvis, and any other sites of disease 
(Section 17.3). 
Within 14 days before enrollment 
 Perform a 12-lead ECG in triplicate (Section 8.10).   
*: ECGs will be taken in close succession, a few minutes apart, after the 
subject has been in a supine/semi-recumbent position. 
 Perform a complete physical examination and record weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure and 
pulse rate and body temperature). 
 Assess functional status using the ECOG PS Scale (Section 17.2). 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 58 
 Obtain blood samples for safety laboratories (Section 8.8 and Section 
17.1), prothrombin time (PT) and activated partial thromboplastin time 
(aPTT), troponin (preferably high-sensitivity troponin-T) testing by study 
site, and troponin-T testing by central lab (Section 7.3.2). 
 Perform urinalysis test. 
 Review Inclusion/Exclusion Criteria. 
Within 72 hours before enrollment 
 Obtain a serum or urine sample for pregnancy testing in women of 
childbearing potential.  Test must be confirmed within 72 hours prior to 
enrollment. 
For postmenopausal subjects (no childbearing potential, as indicated by an 
elapse of at least 12 months after the last menstruation) or female subjects 
who have no possibility of pregnancy due to sterilization surgery, etc., no 
pregnancy test will be required.  Female subjects who have been 
amenorrheic for 12 months or longer for medical reasons other than 
sterilization surgery (eg, effect of medication) will be regarded as women 
of child-bearing potential and required to undergo the pregnancy test. 
Before the first dose of study drug administration 
 Perform a complete physical examination and record height. 
 Six tumor slides for assessment of HER2 by IHC/in situ hybridization 
(ISH) will be submitted as optional.  The detailed procedures for preparing 
and submitting tumor samples will be provided in Section 7.7. 
6.2. 
Randomization 
Not applicable. 
6.3. 
Treatment Period 
Treatment will be started sooner after a subject is registered to IXRS. 
6.3.1. 
Tumor Assessment 
The same imaging tumor assessment as at the time of screening by CT or MRI scans 
will be performed every 6 weeks (± 7 days) in the first 24 weeks after Day 1 of Cycle 
1 and thereafter every 12 weeks (± 7 days) regardless of delay in dosing.  The 
assessment will be conducted before Day 1 of each Cycle as possible.  CT or MRI 
scans of the chest, abdomen and pelvis are mandatory.  However, if there is no brain 
metastasis at the time of screening, CT or MRI should only be done when symptoms 
associated with brain metastasis occur.  If no clinical symptoms are observed, brain 
CT or MRI is not mandatory (Section 17.3). 
6.3.2. 
Other Study Procedure in Treatment Period 
6.3.2.1. 
Cycle 1, Day 1 
Before Infusion 
The following procedures will be completed at pre-dose on Day 1. 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 59 
 Record concomitant medications. 
 Assess subjects for AEs. 
 Obtain blood samples for genetic polymorphism (Section 7.5). 
Latest data within 3 days before administration 
Physical examination, weight, ECOG PS Scale assessment, hematology, blood 
chemistry and vital signs evaluations do NOT need to be repeated if performed 
within 3 days before the first dose of study drug. 
 Perform a complete physical examination and record weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure and 
pulse rate, body temperature and peripheral oxygen saturation [SpO2]). 
 Assess functional status using the ECOG PS Scale (Section 17.2). 
 Obtain blood samples for safety laboratories (Section 8.8). 
 Perform a 12-lead ECG in triplicate (Section 8.10). 
Within 8 hours before administration 
 Obtain PK blood sample (Section 7.1). 
 Obtain blood sample for ADA (Section 7.4.1). 
Administration and after Infusion 
 Administer DS-8201a per Section 5.2.4. 
The following procedures will be completed at post-dose on Day 1: 
 Obtain vital sign measurements (systolic and diastolic blood pressure and 
pulse rate and body temperature). 
 Obtain PK blood samples at the following time points: within 15 minutes 
after end of infusion (EOI) (Section 7.1). 
 Collect blood samples for troponin (preferably high-sensitivity troponin-T) 
2 to 3 hours after EOI. An additional sample should be submitted for 
central lab troponin-T testing (Section 7.3.2). 
 If troponin levels are consistent with myocardial infarction as defined 
according to manufacturer (NCI-CTCAE Grade 3), perform ECG 
testing in triplicate, repeat troponin testing 6 hours (± 1 hour) and 12 
hours (± 1 hour) after initial troponin test was drawn, and follow 
institutional guidelines. 
 If troponin levels are above the ULN and below the level of 
myocardial infarction as defined by the manufacturer (NCI-CTCAE 
Grade 1), repeat troponin testing at 3 hours (± 1 hour) after initial 
troponin test was drawn. If troponin level at 3 hours (6 hours post-
infusion): 
1. Significantly increases per institutional guidelines, then repeat 
troponin testing at 6 hours (± 1 hour) and follow institutional 
guidelines. 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 60 
2. Otherwise, repeat troponin testing at 6 hours (± 1 hour) or at 24 
hours (± 2 hours) after initial troponin test. 
 If troponin levels are above the ULN at baseline and below the level of 
myocardial infarction as defined by the manufacturer (CTCAE Grade 
1), no repeat testing is required after the first EOI 3 hour troponin test 
if the troponin level is not Grade 3. 
 Record concomitant medications. 
 Assess subjects for AEs. 
6.3.2.2. 
Cycle 2, Day 1 
Before Infusion 
The following procedures will be completed at pre-dose on Day 1. 
 Record concomitant medications.   
 Assess subjects for AEs. 
Latest data within 3 days before administration 
 Ophthalmologic assessments.   
The assessments will include visual acuity testing, slit lamp examination, 
and fundoscopy.  If the planned date of study drug administration is 
delayed after examination of ophthalmologic assessments, and there are no 
abnormal findings on the examination, ophthalmologic assessments may 
not be repeated at the Investigator’s judgment. 
 Perform a complete physical examination and record weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure and 
pulse rate, body temperature and SpO2). 
 Assess functional status using the ECOG PS Scale (Section 17.2). 
 Obtain blood samples for safety laboratories (Section 8.8). 
 Perform a 12-lead ECG in triplicate (Section 8.10) 
Within 8 hours before administration 
 Obtain PK blood samples (Section 7.1). 
 Obtain a blood sample for ADA (Section 7.4.1). 
Administration and after Infusion 
 Administer DS-8201a per Section 5.2.4. 
The following procedures will be completed at post-dose on Day 1. 
 Obtain vital sign measurements (systolic and diastolic blood pressure and 
pulse rate and body temperature). 
 Obtain PK blood samples within 15 minutes after EOI, 2, 4 and 7 hours (± 
15 minutes) after the start of administration (Section 7.1). 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 61 
 Collect blood samples for troponin (preferably high-sensitivity troponin-T) 
2 to 3 hours after EOI. An additional sample should be submitted for 
central lab troponin-T testing (Section 7.3.2). 
 If troponin levels are consistent with myocardial infarction as defined 
according to manufacturer (NCI-CTCAE Grade 3), perform ECG 
testing in triplicate, repeat troponin testing 6 hours (± 1 hour) and 12 
hours (± 1 hour) after initial troponin test was drawn, and follow 
institutional guidelines. 
 If troponin levels are above the ULN and below the level of 
myocardial infarction as defined by the manufacturer (NCI-CTCAE 
Grade 1), repeat troponin testing at 3 hours (± 1 hour) after initial 
troponin test was drawn. If troponin level at 3 hours (6 hours post-
infusion): 
1. Significantly increases per institutional guidelines, then repeat 
troponin testing at 6 hours (± 1 hour) and follow institutional 
guidelines. 
2. Otherwise, repeat troponin testing at 6 hours (± 1 hour) or at 24 
hours (± 2 hours) after initial troponin test. 
 If troponin levels are above the ULN at baseline and below the level of 
myocardial infarction as defined by the manufacturer (CTCAE Grade 
1), no repeat testing is required after the first EOI 3 hour troponin test 
if the troponin level is not Grade 3. 
 Record concomitant medications. 
 Assess subjects for AEs. 
6.3.2.3. 
Cycle 2, Day 2 
The following procedures will be performed on Day 2. 
 Obtain vital sign measurements (systolic and diastolic blood pressure and 
pulse rate and body temperature). 
 Obtain PK blood samples at the 24 hours (± 2 hours) after the start of Day 
1 administration (Section 7.1). 
 Obtain blood samples for safety laboratories (Section 8.8). 
 Record concomitant medications. 
 Assess subjects for AEs. 
6.3.2.4. 
Cycle 2, Day 4 
The following procedures will be performed on Day 4. 
 Obtain vital sign measurements (systolic and diastolic blood pressure and 
pulse rate and body temperature). 
 Obtain PK blood samples at the 72 hours (± 2 hours) after the start of Day 
1 administration (Section 7.1). 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 62 
 Record concomitant medications. 
 Assess subjects for AEs. 
6.3.2.5. 
Cycle 2, Day 8 
The following procedures will be performed on Day 8 (± 1 day).   
 Obtain vital sign measurements (systolic and diastolic blood pressure and 
pulse rate and body temperature). 
 Obtain PK blood samples at 7 days after the start of administration 
(Section 7.1). 
 Obtain blood samples for safety laboratories (Section 8.8). 
 Record concomitant medications. 
 Assess subjects for AEs. 
6.3.2.6. 
Cycle 2, Day 12 
The following procedures will be performed on Day 12 (± 1 day). 
 Obtain vital sign measurements (systolic and diastolic blood pressure and 
pulse rate and body temperature). 
 Obtain PK blood samples at 11 days after the start of administration 
(Section 7.1). 
 Obtain blood samples for safety laboratories (Section 8.8). 
 Record concomitant medications. 
 Assess subjects for AEs. 
6.3.2.7. 
Cycle 2, Day 17 
The following procedures will be performed on Day 17 (± 1 day). 
 Obtain vital sign measurements (systolic and diastolic blood pressure and 
pulse rate and body temperature). 
 Obtain PK blood samples at 16 days after the start of administration 
(Section 7.1). 
 Obtain blood samples for safety laboratories (Section 8.8). 
 Administer Ritonavir or Itraconazol per Section 5.3.4. 
 Record concomitant medications. 
 Assess subjects for AEs. 
6.3.2.8. 
Cycle 2, Day18 to Day 21 
 Administer Ritonavir or Itraconazol per Section 5.3.4. 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 63 
6.3.2.9. 
Cycle 2, 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, the following procedures will 
be performed on Day 22 (± 2 days). 
 Obtain PK blood samples during the Cycle 2, Day 22 (Section 7.1). 
 Administer Ritonavir or Itraconazol per Section 5.3.4. 
 Record concomitant medications. 
 Assess subjects for AEs. 
6.3.2.10. Cycle 3, Day 1 
Before Infusion 
The following procedures will be completed at pre-dose on Day 1.   
 Record concomitant medications. 
 Assess subjects for AEs. 
Latest data within 3 days before administration 
 Perform a complete physical examination and record weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure and 
pulse rate, body temperature and SpO2). 
 Assess functional status using the ECOG PS Scale (Section 17.2). 
 Obtain blood samples for safety laboratories (Section 8.8). 
 Perform a 12-lead ECG in triplicate (Section 8.10). 
Within 8 hours before administration 
 Obtain PK blood sample (Section 7.1).  
Administration and after Infusion 
 Administer DS-8201a per Section 5.2.4. 
 Administer Ritonavir or Itraconazol per Section 5.3.4. 
The following procedures will be completed at post-dose on Day 1: 
 Obtain vital sign measurements (systolic and diastolic blood pressure and 
pulse rate and body temperature). 
 Obtain PK blood samples within 15 minutes after EOI, 2, 4 and 7 hours (± 
15 minutes) after the start of administration (Section 7.1). 
 Collect blood samples for troponin (preferably high-sensitivity troponin-T) 
2 to 3 hours after EOI. An additional sample should be submitted for 
central lab troponin-T testing (Section 7.3.2). 
 If troponin levels are consistent with myocardial infarction as defined 
according to manufacturer (NCI-CTCAE Grade 3), perform ECG 
testing in triplicate, repeat troponin testing 6 hours (± 1 hour) and 12 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 64 
hours (± 1 hour) after initial troponin test was drawn, and follow 
institutional guidelines.   
 If troponin levels are above the ULN and below the level of 
myocardial infarction as defined by the manufacturer (NCI-CTCAE 
Grade 1), repeat troponin testing at 3 hours (± 1 hour) after initial 
troponin test was drawn. If troponin level at 3 hours (6 hours post-
infusion): 
1. Significantly increases per institutional guidelines, then repeat 
troponin testing at 6 hours (± 1 hour) and follow institutional 
guidelines. 
2. Otherwise, repeat troponin testing at 6 hours (± 1 hour) or at 24 
hours (± 2 hours) after initial troponin test. 
 If troponin levels are above the ULN at baseline and below the level of 
myocardial infarction as defined by the manufacturer (CTCAE Grade 
1), no repeat testing is required after the first EOI 3 hour troponin test 
if the troponin level is not Grade 3. 
 Record concomitant medications. 
 Assess subjects for AEs. 
6.3.2.11. Cycle 3, Day 2 
The following procedures will be performed on Day 2. 
 Obtain vital sign measurements (systolic and diastolic blood pressure and 
pulse rate and body temperature). 
 Obtain PK blood samples at the 24 hours (± 2 hours) after the start of Day 
1 administration (Section 7.1). 
 Obtain blood samples for safety laboratories (Section 8.8). 
 Administer Ritonavir or Itraconazol per Section 5.3.4. 
6.3.2.12. Cycle 3, Day 4 
The following procedures will be performed on Day 4. 
 Obtain vital sign measurements (systolic and diastolic blood pressure and 
pulse rate and body temperature). 
 Obtain PK blood samples at the 72 hours (± 2 hours) after the start of Day 
1 administration (Section 7.1). 
 Administer Ritonavir or Itraconazol per Section 5.3.4. 
 Record concomitant medications. 
 Assess subjects for AEs. 
6.3.2.13. Cycle 3, Day 5 to Day 7 
 Administer Ritonavir or Itraconazol per Section 5.3.4. 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 65 
6.3.2.14. Cycle 3, Day 8 
The following procedures will be performed on Day 8 (± 1 day).   
 Obtain vital sign measurements (systolic and diastolic blood pressure and 
pulse rate and body temperature). 
 Obtain PK blood samples 7 days after the start of administration (Section 
7.1). 
 Obtain blood samples for safety laboratories (Section 8.8). 
 Administer Ritonavir or Itraconazol per Section 5.3.4. 
 Record concomitant medications. 
 Assess subjects for AEs. 
6.3.2.15. Cycle 3, Day 9 to Day 11 
 Administer Ritonavir or Itraconazol per Section 5.3.4. 
6.3.2.16. Cycle 3, Day 12 
The following procedures will be performed on Day 12 (± 1 day). 
 Obtain vital sign measurements (systolic and diastolic blood pressure and 
pulse rate and body temperature). 
 Obtain PK blood samples at 11 days after the start of administration 
(Section 7.1). 
  Obtain blood samples for safety laboratories (Section 8.8). 
 Administer Ritonavir or Itraconazol per Section 5.3.4. 
 Record concomitant medications. 
 Assess subjects for AEs. 
6.3.2.17. Cycle 3, Day 17 
The following procedures will be performed on Day 17 (± 1 day). 
 Obtain vital sign measurements (systolic and diastolic blood pressure and 
pulse rate and body temperature). 
 Obtain PK blood samples at 16 days after the start of administration 
(Section 7.1). 
 Obtain blood samples for safety laboratories (Section 8.8). 
 Administer Ritonavir or Itraconazol per Section 5.3.4. 
 Record concomitant medications. 
 Assess subjects for AEs. 
6.3.2.18. Cycle 3, Day 13 to Day 21 
 Administer Ritonavir or Itraconazol per Section 5.3.4. 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 66 
6.3.2.19. Cycle 3, 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, the following procedures will 
be performed on Day 22 (± 2 days). 
 Obtain PK blood samples on Day 22 (Section 7.1). 
 Administer Ritonavir or Itraconazol per Section 5.3.4. 
 Record concomitant medications. 
 Assess subjects for AEs. 
6.3.2.20. Cycle 4 and Subsequent Cycles, Day 1 
Before Infusion 
The following procedures will be completed at pre-dose on Day 1. 
 Record concomitant medications. 
 Assess subjects for AEs. 
Latest data within 3 days before administration 
 Perform a complete physical examination and record weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure and 
pulse rate, body temperature and SpO2). 
 Assess functional status using the ECOG PS Scale (Section 17.2 ). 
 Obtain blood samples for safety laboratories (Section 8.8). 
 Perform a 12-lead ECG in triplicate (Section 8.10). 
Within 8 hours before administration 
<At Day 1 in Cycle 4, 6 and 8> 
 Obtain PK blood sample (Section 7.1).   
If blood sample is collected on Day 22 of Cycle 3, 5 and/or 7, the blood 
sample will be collected at BI on Day 1 of Cycle 4, 6 and/or 8 if possible. 
<At Day 1 of Cycle 1, 2 and 4, and then every 2 cycles to the EOT (eg, Day 1 in 
Cycle 4, 6, 8, 10, 12...EOT)> 
 Obtain a blood sample for ADA (Section 7.4.1).  
Others 
<At Day 1 of Cycle 5 and then every 4 cycles (± 7 days) (eg, Cycle 5, 9, 13…)> 
 Perform either ECHO or MUGA (LVEF). 
If the planned date of study drug administration is delayed after 
examination of ECHO or MUGA, and there are no abnormal findings on 
the examination, ECHO or MUGA may not be repeated at the 
Investigator’s judgment. 
 
 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 67 
Administration and after Infusion 
 Administer DS-8201a per Section 5.2.4. 
The following procedures will be completed at post-dose on Day 1. 
 Record concomitant medications. 
 Assess subjects for AEs. 
<At Day 1 of Cycle 4 and every 2 cycles until Cycle 8 at the maximum (eg, Day 1 
of Cycle 4, 6, 8)> 
 Obtain PK blood sample at the end of administration within 30 minutes 
after EOI (Section 7.1). 
6.3.2.21. Cycle 5, Day 22 and Cycle 7, 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, the following procedures will 
be performed on Day 22 (± 2 days). 
 Obtain PK blood samples on Day 22 (Section 7.1). 
 Record concomitant medications. 
 Assess subjects for AEs. 
6.4. 
End of Treatment 
The EOT is defined as the date the Investigator decides to discontinue study 
treatment.  The following assessments will be performed at EOT visit (+ 7 days).  
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. 
 Ophthalmologic assessments.  The assessments will include visual acuity 
testing, slit lamp examination, and fundoscopy. 
 Perform a complete physical examination and record weight. 
 Obtain vital sign measurements (systolic and diastolic blood pressure and 
pulse rate, body temperature and SpO2). 
 Assess functional status using the ECOG PS Scale (Section 17.2). 
 Perform a 12-lead ECG in triplicate (Section 8.10). 
 Obtain blood samples for safety laboratories (Section 8.8), ADA (Section 
7.4.1), and troponin (preferably high-sensitivity troponin-T) testing by 
study site (Section 7.3.2). 
 Obtain a serum or urine sample for pregnancy testing in women of 
childbearing potential.  For postmenopausal subjects (no childbearing 
potential, as indicated by an elapse of at least 12 months after the last 
menstruation) or female subjects who have no possibility of pregnancy due 
to sterilization surgery, etc., no pregnancy test will be required.  Female 
subjects who have been amenorrheic for 12 months or longer for medical 
reasons other than sterilization surgery (eg, effect of medication) will be 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 68 
regarded as women of child-bearing potential and required to undergo the 
pregnancy test. 
 Perform either ECHO or MUGA (LVEF). 
 Perform same imaging tumor assessment as at the time of screening by CT 
or MRI scans.  CT or MRI scans of the chest, abdomen and pelvis are 
mandatory.  However, if there is no brain metastasis at the time of 
screening, CT or MRI should only be done when symptoms associated 
with brain metastasis occur.  If no clinical symptoms are observed, brain 
CT or MRI is not mandatory (Section 17.3).  If progression is identified in 
a prior examination, only the chest is examined by CT to monitor the 
pulmonary status. 
 Record concomitant medications. 
 Assess subjects for AEs. 
 Record reason for treatment discontinuation. 
6.5. 
Follow-up 
Forty days (+ 7 days) after last study drug administration or before starting new 
anticancer treatment, whichever comes first, the following procedures will be 
performed.  If EOT is >40 (+ 7) days after last treatment, then the EOT assessments 
can also function as the F/U visit. 
 Obtain vital sign measurements (systolic and diastolic blood pressure and 
pulse rate and body temperature and SpO2). 
 Perform a complete physical examination and record weight.  
 Assess functional status using the ECOG PS Scale (Section 17.2). 
 Obtain blood samples for safety laboratories (Section 8.8) and ADA 
(Section 7.4.1) For subjects with positive ADA at 40-Day F/U visit, 
additional serum ADA samples may be collected every 3 months (± 1 
month) up to 1 year from the last dose of study drug, or if the ADA 
becomes negative, or if ADA titer becomes less than baseline (applicable 
when pre-existing ADA is observed), or if the subject starts another 
therapy for cancer, or withdraws consent from the study, whichever occurs 
first. 
 Obtain a serum or urine sample for pregnancy testing in women of 
childbearing potential.  For postmenopausal subjects (no childbearing 
potential, as indicated by an elapse of at least 12 months after the last 
menstruation) or female subjects who have no possibility of pregnancy due 
to sterilization surgery, etc., no pregnancy test will be required.  Female 
subjects who have been amenorrheic for 12 months or longer for medical 
reasons other than sterilization surgery (eg, effect of medication) will be 
regarded as women of child-bearing potential and required to undergo the 
pregnancy test. 
 Record concomitant medications. 
 Assess subjects for AEs. 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 69 
7. 
PHARMACOKINETIC/PHARMACODYNAMIC 
ASSESSMENTS 
7.1. 
Pharmacokinetic Assessment(s) 
Serum PK parameters of DS-8201a, total anti-HER2 antibody and MAAA-1181a for 
each subject will be estimated using standard noncompartmental methods. 
Table 7.1: 
Pharmacokinetic Parameters 
Analyte 
PK parameters 
DS-8201a 
Cmax, Tmax, AUC0-17d, AUCtau, Kel, T1/2, CLss, Vz and 
Vss 
Total anti-HER2 antibody 
and MAAA-1181a 
Cmax, Tmax, AUC0-17d, AUCtau, Kel and T1/2 
HER2 = human epidermal growth factor receptor 2 
Blood samples of approximately 4 mL for PKs analyses will be collected at the time 
points specified in Table 7.2.  The actual time of study drug administration and the 
exact time of blood sampling must be recorded in source document and the eCRF. 
 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 70 
Table 7.2: 
Pharmacokinetic Sampling Time Points 
Cycle 
Day 
Sampling Time Point (Acceptable Range) 
Cycle 1 
Day 1 
BI (Within 8 hours before administration) 
EOI (Within 15 minutes after EOI) 
Cycle 2 
Day 1 
BI (Within 8 hours before administration) 
EOI (Within 15 minutes after EOI) 
2, 4 and 7 hours after the start of administration:  ± 15 
minutes  
Day 2 
24 hours after the start of administration (± 2 hours) 
Day 4 
72 hours after the start of administration (± 2 hours) 
Day 8 
7 days after the start of administration (± 1 day) 
 
Day 12 
11 days after the start of administration (± 1 day) 
Day 17 
16 days after the start of 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 on 21 days after 
the start of administration (± 2 days) 
Cycle 3 
Day 1 
BI (Within 8 hours before administration) 
EOI (Within 15 minutes after EOI) 
2, 4 and 7 hours after the start of administration:  ± 15 
minutes 
Day 2 
24 hours after the start of administration (± 2 hours) 
Day 4 
72 hours after the start of administration (± 2 hours) 
Day 8 
7 days after the start of administration (± 1 day) 
Day 12 
11 days after the start of administration (± 1 day) 
Day 17 
16 days after the start of 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 on 21 days after 
the start of administration (± 2 days) 
Cycle 4, 6, 8 
Day 1 
BI (Within 8 hours before administration)  
If blood sample is collected on Day 22 of Cycle 3, 5 
and/or 7, the blood sample will be collected at BI on Day 
1 of next Cycle if possible. 
EOI (Within 30 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 17.6. 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 71 
7.2. 
Pharmacodynamic Assessment(s) 
Not applicable. 
7.3. 
Biomarker and Exploratory Assessment(s) 
7.3.1. 
Human Epidermal Growth Factor Receptor 2 Status Assessed by 
Central Laboratory 
HER2 status in pre-treatment tumor sample will be assessed by central laboratory.  
The status will be assessed by IHC and/or ISH. 
7.3.2. 
Troponin-T Assessed by Central Laboratory 
Blood samples of approximately 3.0 mL for troponin-T testing by central lab will be 
collected at the time points specified in Table 7.3.  Troponin (preferably high-
sensitivity troponin-T) testing will be conducted also by study site at the time points 
specified in Table 7.3. 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 72 
Table 7.3: 
Troponin Sampling Time Points 
Cycle 
Day 
Sampling Time Point (Acceptable Range) 
Screening 
- 
Within 14 days before enrollment 
EOT 
- 
The date Investigator decides the 
discontinuation of the study treatment 
(+ 7 days).   
ECG= electrocardiogram, EOI = end of infusion, EOT= end of treatment, F/U = follow-up, NCI-
CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Event, ULN = upper 
limit of normal. 
Instructions for the handling and shipping of plasma samples are included in a 
separate document (eg, laboratory manual). 
7.4. 
Immunogenicity 
7.4.1. 
Anti-drug Antibody 
Blood samples for ADA analyses of approximately 4 mL will be collected at the time 
points specified in Table 7.4.  Serum concentrations of DS-8201a and/or total 
anti-HER2 antibody may be measured using the same ADA samples for the purpose 
of ADA assessment. 
Instructions for the handling and shipping of serum samples are included in a separate 
document (eg, laboratory manual). 
Table 7.4: 
Anti-Drug Antibodies Sampling Time Points 
Cycle 
Day 
Sampling Time Point (Acceptable Range) 
Cycle 1 
Day 1 
BI (Within 8 hours before administration)  
Cycle 2 
Day 1 
BI (Within 8 hours before administration) 
After Cycle 4 at every 2 
cycles (eg, Cycle 4, 6, 8, 10, 
12, and so on) 
Day 1 
BI (Within 8 hours before administration) 
EOT 
- 
The date Investigator decides the 
discontinuation of the study drug (+ 7 days).   
F/U* 
- 
40 days (+ 7 days) after the last study drug 
administration or until starting new 
anticancer treatment, whichever comes first. 
ADA = anti-drug antibodies, BI = before infusion, EOT = end of treatment, F/U = follow-up. 
*: For subjects with positive ADA at F/U visit, additional serum ADA samples may be collected every 
3 months (± 1 month) up to 1 year from the last dose of study drug, or if the ADA becomes negative, 
or if ADA titer becomes less than baseline (applicable when pre-existing ADA is observed), or if the 
subject starts another therapy for cancer, or withdraws consent from the study, whichever occurs 
first. 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 73 
7.5. 
Pharmacogenomic Analysis 
Blood samples of approximately 10 mL for genetic polymorphism of OATP1B1 
(Haplotypes: *5, *15, *1b, Nucleotide changes: 388A>G and 521T>C) and BCRP 
(Nucleotide change: 421C>A) testing by central lab will be collected at BI on Day 1 
of Cycle 1. 
7.6. 
Blood Sampling 
Blood samples for PK, Troponin-T and ADA will be collected into blood sampling 
tubes supplied by the Sponsor.  The collected blood will be centrifuged to separate the 
serum or plasma.  The serum or plasma samples will be shipped to a central 
laboratory. 
The detail instructions for the handling of blood samples and shipping of serum or 
plasma samples are included in a separate document (eg, laboratory manual). 
7.7. 
Tumor Sampling 
Six slides of tumor tissue sections (4 μm thick) which are obtained before the first 
study drug administration for Biomarker (eg, HER2 by IHC and ISH) will be 
submitted to a central laboratory for exploratory assessment of the biomarker as 
optional.   
Archived tumor samples including tissue samples from surgery, endoscopy or needle 
biopsy already collected and formalin-fixed paraffin-embedded will be used.  If the 
both of surgery and biopsy samples are available for one subject, it is recommended 
to submit the most recent samples to the central laboratory.   
 
Paraffin-embedded tissue blocks of formalin-fixed tissue specimens will be prepared 
by the standard procedure at the study center and the unstained slides with tissue 
sections (4 μm thick) will be submitted to the courier assigned by the Sponsor. 
The detail instructions for the handling of tumor samples and shipping of tumor 
samples are included in a separate document (eg, laboratory manual). 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 74 
8. 
SAFETY EVALUATION AND REPORTING 
8.1. 
Assessment of Safety Endpoint Event(s) 
Safety endpoints will include SAEs, TEAEs, physical examination findings (including 
ECOG PS), vital sign measurements, standard clinical laboratory parameters, ECG 
parameters, ECHO or MUGA findings, and ophthalmologic assessments.  TEAEs will 
be graded according to the NCI-CTCAE version 4.03. 
8.2. 
Adverse Event Collection and Reporting 
All clinical AEs (see Section 8.4.1 for definitions) occurring after the subject signs the 
ICF and up to the 40-Days (+ 7) after last treatment (ie, the F/U period), whether 
observed by the Investigator or reported by the subject, will be recorded on the AE 
case report form (CRF) page.  All SAEs occurring after the subject signs the ICF for 
study participation and up to 40-Days (+ 7) after last treatment will be recorded on 
CRF.  Medical conditions (including clinical laboratory values/vital signs that are out 
of range) that were diagnosed or known to exist prior to informed consent will be 
recorded as part of medical history. 
All AEs and SAEs are to be reported according to the procedures in Section 8.5. 
All clinical laboratory results, vital 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.  AEs 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 8.4.  The Investigator’s 
assessment must be clearly documented in the site’s source documentation with the 
Investigator’s signature. 
Always report the diagnosis as the AE or SAE term.  When a diagnosis is unavailable, 
report the primary sign or symptom as the AE or SAE term with additional details 
included in the narrative until the diagnosis becomes available.  If the signs and 
symptoms are distinct and do not suggest a common diagnosis, report them as 
individual entries of AE or SAE. 
For events that are serious due to hospitalization, the reason for hospitalization must 
be reported as the SAE (diagnosis or symptom requiring hospitalization).  A 
procedure is not an AE or SAE, but the reason for the procedure may be an AE or 
SAE.  Pre-planned (prior to signing the ICF) procedures or treatments requiring 
hospitalization for pre-existing conditions that do not worsen in severity should not be 
reported as SAEs (see Section 8.4.2 for Definitions). 
For deaths, the underlying or immediate cause of death should always be reported as 
an SAE.  Progression of an underlying disease (tumor) will be handled as follows: 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 75 
 Disease progression (enlargement of measurable/non-measurable lesions, 
appearance of new lesions) will not be handled as an AE. However when a 
subject dies and no proximal cause of death other than disease progression 
can be determined, "disease progression" should be reported as an SAE 
with a fatal outcome.  If a fatal event is identified due to disease 
progression, the event should be captured. 
An increase in the value of a tumor marker will not be regarded as an AE/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. 
8.3. 
Adverse Events of Special Interest 
For the DS-8201a clinical program, based on the available pre-clinical data, review of 
the cumulative literature, reported toxicities for the same class of agents and 
biological plausibility, interstitial lung disease and LVEF decrease are considered to 
be adverse events of special interest (AESI).  
Additional relevant information regarding the AESIs for the DS-8201a clinical 
program regardless of seriousness is to be collected through the targeted 
questionnaires built within the applicable eCRFs in the clinical study database.  In the 
event that eCRF is unavailable, report AESIs on a paper form.  Once eCRF becomes 
available, please enter AESIs reported on the paper form into eCRF as soon as 
possible. 
8.3.1. 
Interstitial Lung Disease/Pneumonitis  
Clinical Summary:  
Interstitial lung disease/pneumonitis is considered an important identified risk based 
on a comprehensive cumulative review of the available safety data from the clinical 
development program as well as the results of potential interstitial lung disease 
(ILD)/pneumonitis cases reviewed by the independent ILD Adjudication Committee 
(AC), available data from recent epidemiology/literature, biological plausibility, and 
safety information from drugs of similar class.  Refer to the current IB for a summary 
of preliminary clinical study data. 
Management Guidance:  
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 the designated “Other Non-Laboratory Adverse 
Events” dose modification section of the study protocol. (See 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 bronchoalveolar lavage if clinically indicated and feasible should 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 76 
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 
outlined in the designated “Pulmonary Toxicity” dose modification section of the 
study protocol (See Section 5.4). All events of ILD/pneumonitis regardless of severity 
or seriousness will be followed until resolution including after drug discontinuation. 
 
8.3.1.1. 
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, 
chronic obstructive pulmonary disease (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 MedDRA preferred terms (PT) from 
the current ILD Standard MedDRA Query (SMQ). For broad surveillance of 
ILD/pneumonitis, selected 42 Preferred Terms [all from the ILD Standard MedDRA 
Query (SMQ)] plus 2 PTs of acute respiratory failure and respiratory failure are 
included for enhanced data collections. 
8.3.2. 
LVEF decrease 
Clinical Summary:  
LVEF decrease in association with DS-8201a is considered to be 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 as needed based 
on subject reported cardiac symptoms. Triplicate ECGs will be performed and 
standard ECG parameters will be measured, including RR, PR, QT intervals, and 
QRS duration.  All ECGs must be evaluated by Investigator or delegated physician 
for the presence of abnormalities.  Whether or not measurement is performed, date 
performed, results, and findings for each parameter will be recorded in the eCRF. For 
broad surveillance of LVEF decrease, relevant AEs under the MedDRA SMQs of 
Cardiac Failure is included for enhanced data collection; additional data for these AEs 
are collected via TQs of heart failure. 
 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 77 
8.4. 
Adverse Event 
8.4.1. 
Definition of Adverse Event 
An AE is any untoward medical occurrence in a subject administered a 
pharmaceutical product and that does not necessarily have to have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, 
or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product (International Counsil 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 AEs. 
8.4.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death, 
 Is life-threatening, 
 Requires inpatient hospitalization or prolongation of existing 
hospitalization, 
 Results in persistent or significant disability/incapacity, 
 Is a congenital anomaly/birth defect, or 
 Is an important medical event. 
Note: The term “life-threatening” in the definition of “serious” refers to an event in 
which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it were more severe (ICH E2A 
Guideline.  Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting, Oct 1994). 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the subject or may require intervention to prevent one of the other 
outcomes listed in the definition above.  Examples include allergic bronchospasm, 
convulsions, and blood dyscrasias or development of drug dependency or drug abuse. 
Note:  
 Procedures are not AEs or SAEs, but the reason for the procedure may be 
an AE or SAE. 
 Pre-planned (prior to signing the ICF) procedures or treatments requiring 
hospitalizations for pre-existing conditions that do not worsen in severity 
are not SAEs. 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 78 
8.4.3. 
Severity Assessment 
All AEs will be graded (1 to 5; see below) according to the NCI-CTCAE version 
4.03: 
 Grade 1 Mild AE 
 Grade 2 Moderate AE 
 Grade 3 Severe AE 
 Grade 4 Life-threatening consequences; urgent intervention indicated 
 Grade 5 Death related to AE 
Severity vs. Seriousness: Severity is used to describe the intensity of a specific event 
while the event itself, however, may be of relatively minor medical significance (such 
as severe headache).  This is not the same as "seriousness," which is based on 
subject/event outcome at the time of the event.  For example, the NCI-CTCAE Grade 
4 (life-threatening consequences; urgent intervention indicated) is assessed based on 
unique clinical descriptions of severity for each AE, and these criteria may be 
different from those used for the assessment of AE seriousness.  An AE assessed as 
grade 4 based on the NCI-CTCAE grades may or may not be assessed as serious 
based on the seriousness criteria. 
8.4.4. 
Causality Assessment 
The Investigator should assess causal relationship between an AE and the study drug 
on the basis of his/her clinical judgment and the following definitions.  The causality 
assessment must be made based on the available information and can be updated as 
new information becomes available. 
 Related: 
 The AE follows a reasonable temporal sequence from study drug 
administration, and cannot be reasonably explained by the subject’s 
clinical state or other factors (eg, disease under study, concurrent 
diseases, and concomitant medications). 
or 
 The AE follows a reasonable temporal sequence from study drug 
administration, and is a known reaction to the drug under study or its 
chemical group, or is predicted by known pharmacology. 
 Unrelated: 
 The AE does not follow a reasonable sequence from study drug 
administration, or can be reasonably explained by the subject’s clinical 
state or other factors (eg, disease under study, concurrent diseases, and 
concomitant medications). 
8.4.5. 
Action Taken Regarding Study Drug(s) 
 Dose Not Changed: No change in study drug dosage was made. 
 Drug Withdrawn: The study product was permanently stopped. 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 79 
 Dose Reduced: The dosage of study product was reduced. 
 Drug Interrupted: The study product was temporarily stopped. 
 Not Applicable. 
8.4.6. 
Other Action Taken for Event 
 None. 
 No treatment was required. 
 Medication required. 
 Prescription and/or over the counter medication was required to treat 
the AE. 
 Hospitalization or prolongation of hospitalization required. 
 Hospitalization was required or prolonged due to the AE, whether or 
not medication was required. 
 Other. 
8.4.7. 
Adverse Event Outcome 
 Recovered/Resolved 
 The subject fully recovered from the AE with no residual effect 
observed. 
 Recovering/Resolving 
 The AE improved but has not fully resolved. 
 Recovered/Resolved with Sequelae 
 The residual effects of the AE are still present and observable. 
 Include sequelae/residual effects 
 Not Recovered/Not Resolved 
 The AE itself is still present and observable. 
 Fatal 
 Fatal should be used when death is a direct outcome of the AE. 
 Unknown 
8.5. 
Serious Adverse Events Reporting–Procedure For 
Investigators 
All AEs, SAEs, AESIs, and medication errors including overdose will be reported in 
the eCRF. 
Serious events that are also efficacy endpoints (eg, PD) and/or safety endpoints will 
be exempted from SAE processing and expedited reporting.  Disease progression 
should not be reported as an AE/SAE.  However, when a subject dies from PD with 
no other immediate causes, “disease progression” should be reported as a SAE and 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 80 
captured on designated eCRF.  These events are clinically anticipated events in the 
target treatment population, and will be periodically reviewed by the Daiichi Sankyo 
safety teams to ensure prompt identification of any clinically concerning safety issues. 
The following types of events should be reported by the Investigator in electronic data 
capture (EDC) within 24 hours of awareness: 
 SAEs (see Section 8.4.2 for definition) 
 All potential ILD/pneumonitis cases should be reported within 24 hours; 
including both serious and non-serious potential ILD/pneumonitis cases 
(potential ILD/pneumonitis 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 TBL >2 × ULN that may occur either at different time points or 
simultaneously during the study conduct.  A targeted questionnaire is in-
built within the eCRF to collect relevant additional information for these 
potential cases. 
 Overdose, defined as the accidental or intentional administration of any 
dose of a product that is considered both excessive and medically 
important. An “excessive and medically important” overdose includes any 
overdose in which either a serious adverse event, a non-serious adverse 
event, or no adverse event occurs and is considered by the Investigator as 
clinically relevant, i.e. poses an actual or potential risk to the subject.  
- 
Overdose is always serious. By definition an overdose is 
medically important, which meets the seriousness criterion of 
important medical event. An overdose can occur with or 
without an AE. AEs can either be serious or non-serious. 
Details of the overdose including DS-8201a 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 the CRO using the provided fax cover sheet and the appropriate 
fax number provided for your country.  Once eCRF becomes available, please enter 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 81 
SAEs reported on the SAVER Form into eCRF as soon as possible.  Please refer to 
eCRF Completion Guide for additional instructions. 
See Section 15.10.1.3 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.   
8.6. 
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 study drug, as appropriate per 
local reporting requirements.  Daiichi Sankyo and/or CRO will comply with any 
additional local safety reporting requirements. 
8.7. 
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 AE, all pregnancies must be followed to 
conclusion to determine their outcome.  This information is important for both drug 
safety and public health concerns.  It is the responsibility of the Investigator, or 
designee, to report any pregnancy in a female subject using the exposure in utero 
(EIU) Reporting form.  Please contact your study monitor to receive the EIU 
Reporting Form upon learning of a pregnancy.  The Investigator should make every 
effort to follow the subject until completion of the pregnancy and complete the EIU 
Reporting Form with complete pregnancy outcome information, including normal 
delivery and induced abortion.  The adverse pregnancy outcome, either serious or 
non-serious, should be reported in accordance with study procedures.  If the outcome 
of the pregnancy meets the criteria for immediate classification as a SAE (ie, post-
partum complications, spontaneous or induced abortion, stillbirth, neonatal death, or 
congenital anomaly, including that in an aborted fetus), the Investigator should follow 
the procedures for reporting SAEs outlined in Section 8.5. 
8.8. 
Clinical Laboratory Evaluations 
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 CRF on whether measured, date of measurement, 
and measurement results for the following items.   
Laboratory tests 
Parameters 
Hematology 
Red blood cell count, hemoglobin, hematocrit, platelet count, 
white blood cell count, differential white blood cell count 
(neutrophils, lymphocytes, monocytes, eosinophils, basophils) 
Blood Chemistry 
Total protein, albumin, ALP, ALT, AST, TBL, blood urea 
nitrogen/urea, calcium, chloride, serum creatinine, LDH, 
potassium, sodium, and magnesium 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 82 
Laboratory tests 
Parameters 
Urinalysis 
Protein, glucose, blood, microscopy assessments (if indicated), 
and specific gravity 
A coagulation test will be performed (PT and aPTT) and creatinine clearance 
(mL/min) will be calculated using the modified Cockcroft-Gault equation. 
In addition, the following parameters will be analyzed at the visits indicated in 
Section 17.5. 
 PT and aPTT must be performed during the Screening Period. 
 Pregnancy test (serum or urine) for all female subjects of childbearing 
potential must be performed during the Screening Period.  A positive urine 
pregnancy test result must be confirmed immediately using a serum test. 
 HIV antibody test must be performed during the Screening Period if 
required by local regulations or IRB/EC. 
 Troponin (preferably high-sensitivity troponin-T) test must be performed 
at the visits indicated in Section 17.5.  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 clinical 
laboratory value constitutes an SAE, a SAE information should be reported according 
to the procedures in Section 8.5.  Abnormal clinical laboratory values (NCI-CTCAE 
Grade 3 or 4) occurring during the clinical study will be followed until repeat test 
results return to normal (or baseline), stabilize, or are no longer clinically significant. 
8.9. 
Vital Signs 
Vital sign measurements will include systolic and diastolic blood pressure, pulse rate, 
and body temperature.  Additionally, SpO2 will be measured before administration on 
Day 1 of each cycle, at EOT, and at 40D F/U. 
8.10. 
Electrocardiograms 
Standard supine 12-lead ECGs in triplicate will be performed as described in the 
Schedule of Events (Table 17.4). 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. 
8.11. 
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. 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 83 
8.12. 
Other Examinations 
Either ECHO or MUGA, and ophthalmologic assessments will be performed as 
described in the schedule of events.  LVEF will be measured by either ECHO or 
MUGA.  Ophthalmologic assessments will include visual acuity testing, slit lamp 
examination, and fundoscopy.  All ECHO or MUGA, and the ophthalmologic 
assessments must be evaluated by the Investigator or delegated physician.  Additional 
safety assessments should be conducted as needed, at the Investigator’s discretion. 
ECOG PS 
Cardiac Assessments 
 Either ECHO or MUGA scan will be performed as described in the 
schedule of events.  LVEF will be measured by either ECHO or MUGA 
scan. 
Ophthalmic Assessments 
 Ophthalmic assessments will include visual acuity testing, slit lamp 
examination and fundoscopy. 
Pulmonary Assessments 
 Pulmonary assessment will include CT or MRI of the chest, SpO2 and will 
be performed as described in schedule of events.  For more details please 
refer to Section 6 of the protocol. 
 An ILD AC will review all cases of ILD on an ongoing basis.  Description 
of the ILD AC is available in Section 8.3.1. 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 84 
9. 
EFFICACY ASSESSMENTS 
9.1. 
Assessments for Efficacy Endpoint(s) 
Efficacy assessments will be based on tumor assessments to be performed at 
screening and every 6 weeks in the first 24 weeks after Day 1 of Cycle 1 and 
thereafter every 12 weeks while the subject remains on study drug.  The clinical 
activity of DS-8201a will be assessed by evaluating tumor response.  Tumor response 
will be evaluated using RECIST version 1.1 (Section 17.3). 
CT or MRI (spiral CT or MRI with 5 mm cuts) of brain, chest, abdomen, and pelvis 
should be used for tumor assessment unless another modality of disease assessment is 
necessary for the lesions at screening period.  Every effort should be made to use the 
same assessment modality for all assessments for each subject.  However, if there is 
no brain metastasis at the time of screening, CT or MRI should only be done when 
symptoms associated with brain metastasis occur during study period.  If no clinical 
symptoms are observed, brain CT or MRI is not mandatory during study period. 
The following efficacy variables will be assessed. 
 ORR (the sum of complete response [CR] rate and partial response [PR] 
rate) 
 DCR (the sum of CR rate, PR rate, and SD rate) 
 DoR 
 Duration of SD 
 CBR 
 TTR 
 PFS 
 Best (minimum) percent change from baseline in the sum of diameters of 
target lesion 
9.2. 
Appropriateness of Selected Efficacy Assessment(s) 
The efficacy assessments were selected for this study because RECIST is used widely 
and generally recognized as standard tumor response criteria. 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 85 
10. 
OTHER ASSESSMENTS 
Not applicable. 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 86 
11. 
STATISTICAL METHODS  
11.1. 
General Statistical Considerations 
The data cutoff for the primary analysis will occur after all subjects have either 
discontinued the study or completed at least 3 cycles, whichever comes first.  After 
the primary analysis, the main study will be closed and the data will be followed until 
completion.   
Descriptive statistics will be provided for selected demographic, safety, and PK data 
by time as appropriate.  Descriptive statistics on continuous data will include means, 
medians, standard deviations, and ranges (as well as geometric means and geometric 
coefficient of variation for Cmax and AUC PK parameters), while categorical data 
will be summarized using frequency counts and percentages.  The dose adjusted 
Cmax and AUC may be calculated and used for statistical analysis if the number of 
subjects with dose reductions exceeds 4 subjects per cohort.  Graphical summaries of 
the data may be presented. 
Assessments of change from baseline to post-treatment or the ratio of post-treatment 
to baseline will include only those subjects with both baseline and post-treatment 
measurements.  The last nonmissing value of a variable taken before the first dose of 
study drug will be used as the baseline value, unless otherwise specified.  In general, 
missing or dropout data will not be imputed for the purpose of data analysis, unless 
otherwise specified.   
Safety analyses will be performed based on the safety analysis set.  Analysis of PK 
parameters will be based on the PK analysis sets and biomarker analyses will be 
based on the biomarker analysis sets.  Efficacy endpoints will be analyzed based on 
the efficacy analysis set.   
A detailed statistical analysis plan (SAP) describing the methodology to be used in the 
final analysis will be prepared and finalized before database lock.  Statistical methods 
described within this document may be changed based on advances in research. 
 
11.2. 
Analysis Sets 
11.2.1. 
Enrolled Analysis Set 
The enrolled analysis set will include all subjects who signed an ICF and were 
enrolled in the study. 
11.2.2. 
Efficacy Analysis Set 
The efficacy analysis set will include all subjects enrolled in the study who received 
at least one dose of DS-8201a and who had pre- and post-treatment efficacy data. 
11.2.3. 
Safety Analysis Set 
The safety analysis set will include all subjects enrolled in the study who received at 
least one dose of DS-8201a. 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 87 
11.2.4. 
Pharmacokinetic Analysis Set 
The PK analysis set will include all subjects in the enrolled analysis set who received 
DS-8201a at 5.4 mg/kg in both Cycle 2 and Cycle 3 and assessed any primary 
endpoints for both Cycle 2 and Cycle 3, as PK analysis is the primary endpoint. 
11.2.5. 
Biomarker Analysis Set 
The biomarker analysis set will include all subjects in the enrolled analysis set who 
received at least one dose of DS-8201a and who had the baseline assessment and 
where applicable, at least one post-baseline assessment for biomarkers. 
11.3. 
Study Population Data 
Disposition and reasons for ending the treatment and discontinuing from the study 
will be summarized and listed for subjects in the enrolled analysis set. 
Demographic and baseline characteristics such as age, sex, race, baseline ECOG PS, 
histology, cancer stage, best response to prior chemotherapy, lines of prior regimens, 
and prior treatment type will be summarized for efficacy analysis set, and safety 
analysis set.  If 2 analysis sets are identical to each other, the table will be presented 
only once. 
11.4. 
Statistical Analysis 
11.4.1. 
Pharmacokinetic Analyses 
The PK analyses will be performed on the PK Analysis Set.  A detailed SAP, 
describing the methods to be used in the final analysis, will be prepared after 
completion of the final protocol.  PK parameters for each subject will be estimated 
using non-compartmental methods.   
Serum concentration-time data for DS-8201a, total anti-HER2 antibody and MAAA-
1181a will be listed, plotted, and summarized using descriptive statistics at each time 
point. 
PK parameters of DS-8201a, total anti-HER2 antibody and MAAA-1181a will be 
listed and summarized using descriptive statistics. 
As a primary analysis, geometric mean ratio of Cycle 3 as compared with Cycle 2 as a 
reference and its two-sided 90% confidence intervals (CI) for PK parameters (Cmax 
and AUC0-17d) of DS-8201 and MAAA-1181a will be calculated to evaluate drug-drug 
interactions. 
11.4.2. 
Safety Analyses 
Safety analyses in general will be descriptive and will be presented in tabular format 
with the appropriate summary statistics.  Safety analyses in general will be descriptive 
and will be presented in tabular format with the appropriate summary statistics. 
11.4.2.1. Adverse Event Analyses 
 A TEAE is defined as an AE that occurs, having been absent before the first dose of 
study drug, or has worsened in severity or seriousness after the initiating the study 
drug until 47 days after last dose of the study drug.  SAEs with an onset or worsening 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 88 
48 days or more after the last dose of study drug, if considered related to the study 
treatment, are also TEAEs. 
The number and percentage of subjects reporting TEAEs will be tabulated by the 
worst NCI-CTCAE grade, System Organ Class (SOC), and Preferred Term (PT). 
Similarly, the number and percentage of subjects reporting treatment-emergent SAEs 
will be tabulated, as well as TEAEs/SAEs considered related to DS-8201a.   
A by-subject AE (including TEAE) data listing will be provided including, but not 
limited to, verbatim term, PT, SOC, NCI-CTCAE grade, and relationship to study 
drug. 
Deaths, other SAEs, and other significant AEs, including those leading to permanent 
discontinuation from DS-8201a, will be listed. 
11.4.2.2. Clinical Laboratory Evaluation Analyses 
Descriptive statistics will be provided for selected clinical laboratory test results 
(hematology and chemistry) and changes from baseline by scheduled time of 
evaluation, including the EOT visit, maximum post-treatment value, and minimum 
post-treatment value.   
Abnormal laboratory results will be graded according to the NCI-CTCAE version 
4.03, if applicable.  A shift table, presenting the 2-way frequency tabulation for 
baseline and the worst post-treatment value according to the NCI-CTCAE grade, will 
be provided for selected clinical laboratory tests.  Abnormal clinical laboratory test 
results that are deemed of clinical significance or of Grade 3 or 4 will be listed. 
11.4.2.3. Vital Sign Analyses 
Descriptive statistics will be provided for the vital signs measurements and changes 
from baseline by scheduled time of evaluation, including the EOT visit and the 
maximum and minimum post-treatment values. 
11.4.2.4. Electrocardiogram Analyses 
Descriptive statistics will be provided by cohort/treatment group for ECG parameters 
and changes from baseline by scheduled time of evaluation, including the EOT visit 
and the maximum post-treatment value.  In addition, the number and percentage of 
subjects with ECG interval values meeting the criteria will be tabulated (eg, QTc 
≤450 ms, >450 ms to ≤480 ms, >480 ms to ≤500 ms, and >500 ms).  The QT intervals 
will be corrected for heart rate by Fridericia’s formula (QTcF = QT/[RR]1/3).  ECG 
data will also be listed. 
11.4.2.5. Anti-Drug Antibodies Analyses 
A shift table, presenting the 2-way frequency tabulation for baseline and each 
schedules time, including the EOT visit, will be provided for incidence of ADA. 
11.4.2.6. Other Safety Analyses 
All other safety endpoints (eg, physical examination findings including ECOG PS, 
ECHO or MUGA findings, and ophthalmologic findings) will be listed. 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 89 
11.4.3. 
Efficacy Analyses 
Efficacy endpoints will include ORR (the sum of CR and PR rates); DCR (the sum of 
CR rate, PR rate, and SD rate for a minimum of 5 weeks from the first dosing date), 
CBR (the proportion of subjects who achieved a best overall response of CR or PR or 
more than 6 months SD), DoR, duration of SD, TTR, PFS and best (minimum) 
percent change from baseline in the sum of diameters of target lesion using RECIST 
version 1.1. 
The efficacy endpoints will be listed and summarized.  For ORR, DCR and CBR, 
point estimates and 95% exact binomial CIs will be provided.  Time to event variables 
including DoR, duration of SD, TTR and PFS will be summarized descriptively using 
the Kaplan-Meier method.   
DoR is defined as the time from the date of the first documentation of objective 
response (CR or PR) to the date of the first objective documentation of radiographic 
PD.  DoR will be measured for responding subjects (CR or PR) only.  Duration of SD 
is defined for subjects whose best response is SD as the time from the date of the first 
dose to the date of the first documentation of PD.  TTR is defined as the time from the 
date of the first dose to the date of the first documentation of objective response (CR 
or PR).  Detailed censoring rules for DoR, duration of SD, and TTR will be specified 
in the 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 or death due to any cause.  
Censoring rules for the PFS analysis will be specified in the SAP.   
Descriptive statistics for the best (minimum) percent change from baseline in the sum 
of the diameters will be provided by cohort.  Waterfall plots of the best (minimum) 
percent change in the sum of the diameters 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 sum of the diameters for each subject will be also 
presented by cohort. 
11.4.4. 
Pharmacodynamic Analyses 
Not applicable. 
 
11.4.5. 
Biomarker Analyses 
Exploratory analyses for biomarkers will be listed and summarized using descriptive 
statistics. 
11.4.6. 
Pharmacogenomic Analyses 
As an exploratory analysis, the frequency table for OATP1B1 (Haplotypes: *5, *15, 
*1b, Nucleotide changes: 388A>G and 521T>C) and BCRP (Nucleotide change: 
421C>A) will be prepared.  Because of the sample size and the frequency of these 
genetic polymorphisms, data from this study may be combined with data from other 
studies to allow for the PGx-PK association analysis. 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 90 
11.5. 
Interim Analyses 
No formal interim analysis is planned. 
11.6. 
Data Monitoring Committee 
Not applicable. 
11.7. 
Sample Size Determination  
A total of 32 subjects (16 subjects per each cohort) will be enrolled in this study. The 
sample size is not determined based on statistical considerations, but practical 
considerations. 
Based on the results from previous study, the intra-individual variability (intra-
individual coefficient of variation) in this study is estimated to be around 30 to 40%.  
Under the above assumption, the relation between the geometric mean ratio and its 
90% confidence intervals were shown in Table 11.1 when the number of subjects is 
12.  Considering the dropout rate of approximately 30%, 16 subjects will be enrolled 
into each cohort. 
Table 11.1: 
Relation between the Geometric Mean Ratio and its 90% 
Confidence Intervals (Number of Subjects = 12) 
Geometric 
mean ratio 
Intra-subject coefficient 
of variation 
Confidence interval for 
ratio 
Imprecision 
(%) 
1 
0.2 
(0.864, 1.158) 
13.64 
0.3 
(0.803, 1.246) 
19.74 
0.4 
(0.746, 1.341) 
25.42 
2.0 
0.2 
(1.727, 2.316) 
13. 64 
0.3 
(1.605, 2.492) 
19.74 
0.4 
(1.492, 2.682) 
25.42 
11.8. 
Statistical Analysis Process 
The clinical study will be analyzed by the Sponsor or its agent/CRO followed by this 
protocol, and 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 the 
efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other clinical study information such as subject disposition, 
demographic and baseline characteristics, study drug exposure, and prior and 
concomitant medications.  The SAP will also include a description of how missing, 
unused, and spurious data will be addressed. 
To preserve the integrity of the statistical analysis and clinical study conclusions, the 
SAP will be finalized prior to database lock.   
All statistical analyses will be performed using SAS® Version 9.3 or higher (SAS 
Institute, Cary, NC 27513). 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 91 
12. 
DATA INTEGRITY AND QUALITY ASSURANCE 
The Investigator/investigational site will permit study-related monitoring, audits, IRB/ 
Ethics Committee (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 
Daiichi Sankyo or a designee will supply eCRFs.  An eCRF must be completed for 
each subject who signs an ICF 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 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 92 
are clearly understood.  The eCRF will be completed, reviewed and 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. 
12.3. 
Electronic Data Capture System 
The EDC system used for completing eCRF in this study is shown below. 
Name of EDC system 
Medidata Rave® 
EDC system developer 
Medidata Solutions Inc. 
Entry method 
Web-based data entry 
Input terminal 
Desktop/laptop computer at the study site 
Incompatible operating 
systems 
None 
Recommended browsers 
The Medidata Rave® supports any browser which is HTML 5 and 
CSS2 compliant.  Browsers must have JavaScript enabled. 
Screen Resolution 
The minimum screen resolution required to properly display 
Medidata Rave applications is 1024 × 764. 
Connection Speed 
128kbps is the minimum connection speed recommended for using 
Medidata Rave. 
Other 
Adobe Flash Player: ver. 10 or above is required 
12.4. 
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 CRO.  Data will be vetted both electronically and 
manually for CRFs and the data will be electronically vetted by programmed data 
rules within the application.  Queries generated by rules and raised by reviewers will 
be generated within the EDC application.  During this review, subject data will be 
checked for consistency, completeness and any apparent discrepancies.  CRFs queries 
will be raised and resolved within the EDC application. 
Data received from external sources such as central labs will be reconciled to the 
clinical database. 
SAEs in the clinical database will be reconciled with the safety database. 
All AEs will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA).  All concomitant medications and prior cancer therapies will be coded 
using World Health Organization Drug Dictionary. 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 93 
12.5. 
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. 
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 ICFs, 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. 
12.6. 
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, ICFs, and supporting copies of 
source documentation (if kept). 
 Study files containing the protocol with all amendments, IB, copies of 
relevant essential documents required prior to commencing a clinical 
study, and all correspondence to and from the IRB/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. 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 94 
All study related essential documentation will be retained by the Investigator until at 
least 3 years after the last approval of a marketing application in an ICH region and 
until there are no pending or contemplated marketing applications in an ICH region or 
at least 3 years have lapsed since the formal discontinuation of clinical development 
of the investigational drug.  These documents should be retained for a longer period, 
however, if required by the applicable regulatory requirements or by an agreement 
with the Sponsor.  It is the responsibility of the Sponsor to inform the 
Investigator/institution as to when these documents no longer need to be retained. 
Subject's medical files should be retained in accordance with applicable legislation 
and in accordance with the maximum period of time permitted by the hospital, 
institution or private practice. 
No study document should be destroyed without prior written agreement between 
Sponsor and the Investigator.  Should the Investigator wish to assign the study records 
to another party or move them to another location, he/she must notify Sponsor in 
writing of the new responsible person and/or the new location. 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 95 
13. 
FINANCING AND INSURANCE 
13.1. 
Finances 
Prior to starting the study, the Principal Investigator and/or institution will sign a 
clinical study agreement with the Sponsor or a CRO.  This agreement will include the 
financial information agreed upon by the parties. 
13.2. 
Reimbursement, Indemnity, and Insurance 
The Sponsor 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. 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 96 
14. 
PUBLICATION POLICY 
Daiichi Sankyo is committed to meeting the highest standards of publication and 
public disclosure of information arising from clinical trials Sponsored by the 
company.  Daiichi Sankyo will comply with US, EU, and Japanese policies for public 
disclosure of the clinical trial protocol and clinical trial results, and for sharing of 
clinical trial data.  Daiichi Sankyo follows the principles set forward in “Good 
Publication Practice for Communicating Company-Sponsored Medical Research 
(GPP3)” published by the International Society for Medical Publication Professionals 
(ISMPP), and publications will adhere to the “Recommendations for the Conduct, 
Reporting, Editing, and Publication of Scholarly Work in Medical Journals” 
established by the International Committee of Medical Journal Editors (ICMJE).   
In order to ensure that Daiichi Sankyo are in compliance with the public disclosure 
policies and the ICMJE recommendations, and to protect proprietary information 
generated during the study, all publications (manuscripts, abstracts, or other public 
disclosure) based on data generated in this study must be accepted, reviewed, and 
approved in writing by the Sponsor prior to submission. 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 97 
15. 
ETHICS AND STUDY ADMINISTRATIVE 
INFORMATION 
15.1. 
Compliance Statement, Ethics and Regulatory Compliance 
This study will be conducted in compliance with the protocol, the ethical principles 
that have their origin in the Declaration of Helsinki, The ICH consolidated Guideline 
E6 for GCP (CPMP/ICH/135/95), and applicable regulatory requirement(s) including 
the following: 
 US FDA GCP Regulations: Code of Federal Regulations (CFR) Title 21, 
parts 11, 50, 54, 56 and 312, as appropriate. 
 Japanese Ministry of Health, Labor and Welfare Ordinance No. 28 of 27 
March, 1997. 
 The Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, 
Medical Devices, Regenerative and Cellular Therapy Products, Gene 
Therapy Products, and Cosmetics of 25 November, 2014. 
 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. 
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. 
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 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 98 
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. 
If the subject cannot read, then according to ICH GCP Guideline, Section 4.8.9, an 
impartial witness should be present during the entire informed consent discussion.  
This witness should sign the ICF after the subject has consented to the subject’s 
participation and, if possible, signed the ICF.  By signing the ICF, the witness attests 
that the information in the ICF and any other written information was adequately 
explained to and apparently understood by the subject and that informed consent was 
freely given by the subject.   
For studies conducted outside the US, a separate special consent for 
Pharmacogenomic testing will be obtained from subjects in accordance with health 
authorities in their particular region/country. 
15.4. 
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. 
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.  If changes to the initial protocol and other relevant study 
documents are made, this representative will also ensure that any revised documents 
required for submission are submitted to regulatory authorities and implementation of 
these changes happen only after approval by the relevant regulatory bodies, as 
required. 
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 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 99 
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. 
15.5. 
Protocol Deviations 
The Investigator should conduct the study in compliance with the protocol agreed to 
by Sponsor and, if required, by the regulatory authority(ies), and which was given 
approval/favorable opinion by the IRBs/ECs. 
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 or EC of deviations from the 
protocol in accordance with local procedures. 
15.6. 
Supply of New Information Affecting the Conduct of the 
Study 
When new information becomes available that may adversely affect the safety of 
subjects or the conduct of the study, the Sponsor will inform all Investigators 
involved in the clinical study, ECs/IRBs, and regulatory authorities of such 
information, and when needed, will amend the protocol and/or subject information. 
The Investigator should immediately inform the subject whenever new information 
becomes available that may be relevant to the subject’s consent or may influence the 
subject’s willingness to continue participation in the study.  The communication 
should be documented on medical records, for example, and it should be confirmed 
whether the subject is willing to remain in the study. 
If the subject information is revised, it must be re-approved by the EC/IRB.  The 
Investigator should obtain written informed consent to continue participation with the 
revised written information even if subjects were already informed of the relevant 
information.  The Investigator or other responsible personnel who provided 
explanations and the subject should sign and date the revised ICF. 
15.7. 
Protocol Amendments 
Any amendments to the study protocol that seem to be appropriate as the study 
progresses will be communicated to the Investigator by Daiichi Sankyo or the CRO.  
Also, the Sponsor will ensure the timely submission of amendments to regulatory 
authorities. 








Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 103 
16. 
REFERENCES 
1. 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. 
2. 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. 
3. 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. 
4. 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. 
5. Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a 
novel therapeutic target. Ann Oncol. 2008;19(9):1523-9. 
6. 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. 
7. 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. 
8. 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. 
9. 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. 
10. Press MF, Cordon-Cardo C, Slamon DJ. Expression of the HER-2/neu proto-
oncogene in normal human adult and fetal tissues. Oncogene. 1990;5(7):953-
62. 
11. Food and Drug Administration (United States) [Internet]. Herceptin: Full 
prescribing information. Revised 2015 Apr [cited 2017 Sep 15]. Available 
from:http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/103792s5327
lbl.pdf 
12. European public assessment reports (Europe) [Internet]. Herceptin: EPAR - 
Product Information. Updated 2015 Apr 21 [cited 2017 Sep 15]. Available 
from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/000278/WC500074922.pdf 
13. Pharmaceuticals and Medical Devices Agency (Japan) [Internet]. Herceptin: 
Package insert. Revised 2015 Dec [cited 2017 Sep 15]. Available from: 
http://www.info.pmda.go.jp/go/pack/4291406D3021_1_02/ 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 104 
14. Food and Drug Administration (United States) [Internet]. Kadcyla: Full 
prescribing information. Revised 2014 Jul [cited 2017 Sep 15]. Available 
from: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125427s033lbl.pdf 
15. European public assessment reports (Europe) [Internet]. Kadcyla: EPAR - 
Product information. Updated 2014 Dec 3 [cited 2017 Sep 15]. Available 
from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/002389/WC500158593.pdf 
16. Pharmaceuticals and Medical Devices Agency (Japan) [Internet]. Kadcyla: 
Package insert. Revised 2017 Jan [cited 2017 Sep 15]. Available from: 
http://www.info.pmda.go.jp/go/pack/4291426D1026_1_04/ 
17. Abou-Alfa GK, Letourneau R, Harker G, et al. Randomized phase III study of 
exatecan and gemcitabine compared with gemcitabine alone in untreated 
advanced pancreatic cancer. J Clin Oncol. 2006;24(27):4441-7. 
18. Cheverton P, Friess H, Andras C, et al. Phase III results of exatecan (DX-
8951f) versus gemcitabine (Gem) in chemotherapy-naive patients with 
advanced pancreatic cancer (APC) [abstract]. J Clin Oncol. 2004;22(Suppl 
14):4005. 
19. De Jager R, Cheverton P, Tamanoi K, et al. DX-8951f: summary of phase I 
clinical trials. Ann N Y Acad Sci. 2000;922:260-73. 
20. 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):5097-5108. 
21. Center for Drug Evaluation and Research (CDER). Guidance for industry: 
Drug interaction studies - study design, data analysis, implications for dosing, 
and labeling recommendations. (February, 2012) 
 
 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 105 
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) = 
 
Female: 
CrCl (mL/min) = 
72
 x 
mg/dL)
(in 
 
creatinine
 
serum
kg)
(in 
 x weight 
years)]
(in 
 
age
 - 
[140
  0.85 
 
International System of Units (SI) – serum creatinine in μmol/L: 
Male: 
CrCl (mL/min) = 
 
Female: 
CrCl (mL/min) = 
0.0113
 x 
72
 x 
mol/L)
(in 
 
creatinine
 
serum
kg)
(in 
 x weight 
years)]
(in 
 
age
 - 
[140

  0.85 
Source: Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31-
41. 
 
72
 x 
mg/dL)
(in 
 
creatinine
 
serum
kg)
(in 
 x weight 
years)]
(in 
 
age
 - 
[140
0.0113
 x 
72
 x 
mol/L)
(in 
 
creatinine
 
serum
kg)
(in 
 x weight 
years)]
(in 
 
age
 - 
[140



Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 106 
17.2. 
Eastern Cooperative Oncology Group Performance Status (ECOG 
PS) 
Table 17.1: 
Eastern Cooperative Oncology Group Performance Status Scale 
GRADE 
DESCRIPTION 
0 
Normal activity.  Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous activity, but ambulatory 
and able to carry out work of a light or sedentary nature (eg, light house work, office 
work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but unable to carry 
out any work activities.  Up and about more than 50% of waking hours. 
3 
In bed >50% of the time.  Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally 
confined to bed or chair. 
5 
Dead. 
Source: Oken MM, Creech RH, Tormey DC, et al. Toxicity and Response Criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol. 1982;5(6):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 and 
in F/U, only the short axis will be measured and followed.  See also notes below on 
“Baseline documentation of target and non-target lesions” for information on lymph 
node measurement. 
17.3.1.1.2. Non-measurable 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes 
with ≥10 mm to <15 mm short axis), as well as truly non-measurable lesions.  Lesions 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 107 
considered truly non-measurable include: leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, and abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques. 
17.3.1.1.3. Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment. 
17.3.1.1.3.1. Bone Lesions 
 Bone scan, positron emission tomography (PET) scan or plain films are not 
considered adequate imaging techniques to measure bone lesions.  However, these 
techniques can be used to confirm the presence or disappearance of bone lesions. 
 Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as CT 
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 of the first dose of study drug administration. 
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. 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 108 
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.   
17.3.2.2. Baseline Documentation of “Target” and “Non-target” Lesions 
When more than 1 measurable lesion is present at baseline, all lesions up to a maximum of 5 
lesions total (representative of all involved organs) should be identified as target lesions and will 
be recorded and measured at baseline (this means in instances where subjects have only 1 or 2 
organ sites involved a maximum of 2 and 4 lesions respectively will be recorded). 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements.  It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor.  As noted above, pathological nodes which are 
defined as measurable and may be identified as target lesions must meet the criterion of a short 
axis of ≥15 mm by CT scan.  Only the short axis of these nodes will contribute to the baseline 
sum.  The short axis of the node is the diameter normally used by radiologists to judge if a node 
is involved by solid tumor.  Nodal size is normally reported as 2 dimensions in the plane in 
which the image is obtained (for CT scan this is almost always the axial plane; for MRI the plane 
of acquisition may be axial, sagittal, or coronal).  The smaller of these measures is the short axis.  
For example, an abdominal node which is reported as being 20 mm × 30 mm has a short axis of 
20 mm and qualifies as a malignant, measurable node.  In this example, 20 mm should be 
recorded as the node measurement.  All other pathological nodes (those with short axis ≥ 10 mm 
but <15 mm) should be considered non-target lesions.  Nodes that have a short axis <10 mm are 
considered non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum.  The baseline 
sum diameters will be used as reference to further characterise 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”). 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 109 
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 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 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 110 
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 quality for 
unequivocal progression status.  The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare.   
When the subject has only non-measurable disease: The same general concepts apply here as 
noted above, however, in this instance there is no measurable disease assessment to factor into 
the interpretation of an increase in non-measurable disease burden.  Because worsening in non-
target disease cannot be easily quantified (by definition: if all lesions are truly non-measurable) a 
useful test that can be applied when assessing subjects for unequivocal progression is to consider 
if the increase in overall disease burden based on the change in non-measurable disease is 
comparable in magnitude to the increase that would be required to declare PD for measurable 
disease (ie, an increase in tumor burden representing an additional 73% increase in ‘volume’ 
[which is equivalent to a 20% increase diameter in a measurable lesion]).  If ‘unequivocal 
progression’ is seen, the subject should be considered to have had overall PD at that point.  
While it would be ideal to have objective criteria to apply to non-measurable disease, the very 
nature of that disease makes it impossible to do so, therefore the increase must be substantial. 
17.3.2.3.5. New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: ie, not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some “new” 
bone lesions may be simply healing or flare of preexisting lesions).  This is particularly 
important when the subject’s baseline lesions show PR or CR.  For example, necrosis of a liver 
lesion may be reported on a CT scan report as a “new” cystic lesion, which it is not. 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 111 
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.  No 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, Table 17.3 is to be used. 
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 = inevaluable. 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 112 
Table 17.3: 
Overall Response: Subjects with Non-target Disease Only 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PDa 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR = complete response, PD = progressive disease, NE = inevaluable. 
a ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as 
endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be measured is not 
advised. 
17.3.2.4.2. Missing Assessments and In-evaluable Designation 
When no imaging/measurement is performed at all at a particular timepoint, the subject is not 
evaluable (NE) at that timepoint.  If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered NE at that timepoint, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not change 
the assigned time point response.  This would be most likely to happen in the case of PD.  For 
example, if a subject had a baseline sum of 50 mm with 3 measured lesions and at 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 where confirmation of CR or PR IS NOT required: 
Best response in this study is defined as the best response across all time points (eg, a subject 
who has SD at first assessment, PR at second assessment, and PD on last assessment has a best 
overall response of PR).  When SD is believed to be best response, it must also meet the protocol 
specified minimum time from baseline, 6 weeks (± 1 week).  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. 
17.3.2.4.4. Special Notes on Response Assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to “normal” 
size (<10 mm), they may still have a measurement reported on scans.  This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 
based on increase in size of the nodes.  As noted earlier, this means that subjects with CR may 
not have a total sum of “zero” on the eCRF. 
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document objective progression 
even after discontinuation of treatment.  Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping study therapy.  The objective response status of 
such subjects is to be determined by evaluation of target and non-target disease. 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 113 
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 in the first 24 weeks after 
Day 1 of Cycle 1 and thereafter every 12 weeks 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 the first dose of study drug 
administration. 
All efforts should be made to ensure consistency between the baseline measurements and all 
subsequent measurements in reference to utilization of scanning method, equipment, technique 
(including slice thickness and field of view), and radiographic interpreter. 
The radiographic evaluation must include CT or MRI scanning of the brain, chest, abdomen, and 
pelvis at screening period.  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.  However, if there is no brain metastasis at the time of screening, CT or MRI should 
only be done when symptoms associated with brain metastasis occur during study period.  If no 
clinical symptoms are observed, brain CT or MRI is not mandatory during study period.  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. 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
 
 
Proprietary and Confidential 
Page 114 
17.4. 
New York Heart Association Functional Classification 
Functional Capacity 
Objective Assessment 
Class I. 
Patients with cardiac disease but without resulting limitation of 
physical activity.  Ordinary physical activity does not cause 
undue fatigue, palpitation, dyspnea, or anginal pain. 
A. 
No objective evidence of 
cardiovascular disease. 
Class II. 
Patients with cardiac disease resulting in slight limitation of 
physical activity.  They are comfortable at rest. Ordinary 
physical activity results in fatigue, palpitation, dyspnea, or 
anginal pain. 
B. 
Objective evidence of minimal 
cardiovascular disease. 
Class III. 
Patients with cardiac disease resulting in marked limitation of 
physical activity.  They are comfortable at rest.  Less than 
ordinary activity causes fatigue, palpitation, dyspnea, or anginal 
pain. 
C. 
Objective evidence of moderately 
severe cardiovascular disease. 
Class IV. 
Patients with cardiac disease resulting in inability to carry on 
any physical activity without discomfort.  Symptoms of heart 
failure or the anginal syndrome may be present even at rest.  If 
any physical activity is undertaken, discomfort is increased. 
D. 
Objective evidence of severe 
cardiovascular disease. 
Source: American Heart Association, Inc. Classification of Functional Capacity and Objective Assessment. 
Available from: 
http://my.americanheart.org/professional/StatementsGuidelines/ByPublicationDate/PreviousYears/Classification-of-
Functional-Capacity-and-Objective-Assessment_UCM_423811_Article.jsp 
 
 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
Proprietary and Confidential 
Page 115 
17.5. 
Schedule of Events 
Table 17.4: 
Schedule of Events 
 
SCR 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
and 
subsequent 
cycles 
EOTa 
40D 
F/Ub 
Day 
1 
1 
2 
4 
8 
12 
17 
22 
1 
2 
4 
8 
12 
17 
22 
1 
[Allowance (±)] 
BI 
EOI 
BI EOI 
[1] 
[1] 
[1] 
[2] 
BI EOI 
[1] 
[1] 
[1] 
[2] 
BI 
EOI 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic 
information 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV Antibody Test 
(as required by 
local regulations or 
IRB/ECs) 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B Surface 
Antigen / Hepatitis 
C Antibody 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xc 
Xc 
Urinalysis test 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IHC/ISH  
(tumor sample, as 
optional) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
Proprietary and Confidential 
Page 116 
Table 17.4: 
Schedule of Events (Continued 1) 
 
SCR 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
and 
subsequent 
cycles 
EOTa 
40D 
F/Ub 
Day 
1 
1 
2 
4 
8 
12 
17 
22 
1 
2 
4 
8 
12 
17 
22 
1 
[Allowance (±)] 
BI 
EOI 
BI EOI 
[1] 
[1] 
[1] 
[2] 
BI EOI 
[1] 
[1] 
[1] 
[2] 
BI 
EOI 
Administer DS-
8201a 
 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Administer 
Ritonavir or 
Itraconazole 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight, ECOG PS 
Xd 
Xe 
 
Xe 
 
 
 
 
 
 
 
Xe 
 
 
 
 
 
 
 
Xe 
 
X 
X 
Vital sign 
Xd 
Xe 
X 
Xe 
X 
X 
X 
X 
X 
X 
 
Xe 
X 
X 
X 
X 
X 
X 
 
Xe 
 
X 
X 
Physical 
examination 
Xd 
Xe 
 
Xe 
 
 
 
 
 
 
 
Xe 
 
 
 
 
 
 
 
Xe 
 
X 
X 
SpO2 
 
Xe 
 
Xe 
 
 
 
 
 
 
 
Xe 
 
 
 
 
 
 
 
Xe 
 
X 
X 
Ophthalmologic 
assessmentso 
Xf 
 
 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Tumor assessment 
Xf 
Every 6 weeks (± 7 days) in the first 24 weeks after Day 1 of Cycle 1, and thereafter every 12 weeks (± 7 days) 
X 
 
Laboratory tests 
Xd 
Xe 
 
Xe 
 
X 
 
X 
X 
X 
 
Xe 
 
X 
 
X 
X 
X 
 
Xe 
 
X 
X 
ADAu 
 
Xg 
 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xg,h 
 
X 
Xi 
Troponinr 
Xd 
 
Xp 
 
Xp 
 
 
 
 
 
 
 
Xp 
 
 
 
 
 
 
 
 
X 
 
12-lead ECG in 
triplicate 
Xd 
Xe 
 
Xe 
 
 
 
 
 
 
 
Xe 
 
 
 
 
 
 
 
Xe 
 
X 
 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
Proprietary and Confidential 
Page 117 
Table 17.4: 
Schedule of Events (Continued 2) 
 
SCR 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
and 
subsequent 
cycles 
EOTa 
40D 
F/Ub 
Day 
1 
1 
2 
4 
8 
12 
17 
22 
1 
2 
4 
8 
12 
17 
22 
1 
[Allowance (±)] 
BI 
EOI 
BI EOI 
[1] [1] [1] 
[2] 
BI EOI 
[1] [1] 
[1] 
[2] 
BI 
EOI 
Genetic 
polymorphism 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK 
 
Xg 
Xs 
Xg 
Xl 
Xm 
Xm 
X 
X 
X 
(X)k Xg 
Xl 
Xm 
Xm 
X 
X 
X 
(X)k 
Xg, n 
Xj,n 
 
 
ECHO or MUGA 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xq 
 
X 
 
AEs 
Xt 
Concomitant 
medications 
 
X 
40D F/U = 40-Day follow-up (+ 7 days), ADA = anti-drug antibodies, AE = adverse event, BI = before infusion, EC = ethics committee, ECG = electrocardiogram, 
ECHO = echocardiogram, ECOG PS = Eastern Cooperative Oncology Group Performance Status, EOI = end of infusion, EOT = end of treatment, 
IHC = immunohistochemistry, IRB = institutional review board, ISH = in situ hybridization, MUGA = multiple-gated acquisition, PK = pharmacokinetics, SCR = screening, 
SpO2 = peripheral oxygen saturation. 
a. 
The date Investigator decides the discontinuation of the 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. 
Within 72 hours before enrollment for all female subjects of childbearing potential; a positive urine pregnancy test result must immediately be confirmed using a serum 
test. 
d. Latest data within 14 days before enrollment. 
e. 
Latest data within 3 days BI. 
f. 
Latest data within 28 days before enrollment. 
g. Within 8 hours BI. 
h. Every 2 cycles until the EOT (eg, Cycle 4, 6, 8, 10, 12...). 
i. 
For subjects with positive ADA at F/U visit, additional serum ADA samples may be collected every 3 months (± 1 month) up to 1 year from the last dose of study drug, 
or if the ADA becomes negative, or if ADA titer becomes less than baseline (applicable when pre-existing ADA is observed), or if the subject starts another therapy for 
cancer, or withdraws consent from the study, whichever occurs first. 
j. 
Within 30 minutes after EOI. 
k. 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 for PK 
analysis. 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
Proprietary and Confidential 
Page 118 
l. 
Within 15 minutes after EOI, and 2, 4 and 7 hours after the start of administration (± 15 minutes). 
m. 24 and 72 hours after the start of administration (± 2 hours). 
n. Every 2 cycles until Cycle 8 (eg, Cycle 4, 6, 8).  If blood sample is collected on Day 22 of Cycle 3, 5 and/or 7, the blood sample will be collected at BI on Day 1 of next 
Cycle if possible. 
o. Ophthalmologic assessments including visual acuity testing, slit lamp examination and fundoscopy will be performed at screening and EOT and as clinically indicated. 
p. 2 to 3 hours after EOI. 
q. Every 4 cycles from Cycle 5 to the EOT (eg, Day 1 in Cycle 5, 9, 13...). 
r. 
Troponin (preferably high-sensitivity troponin-T) should be collected at screening and  EOT as per the table above.  If troponin level with more than NCI-CTCAE Grade 
1 will be detected, please refer to Section 6.3.2.  The test used to test troponin should remain the same throughout the course of a subject’s time on study.  
s. 
Within 15 minutes after EOI. 
t. 
For suspected ILD/pneumonitis, treatment with study drug should be interrupted pending evaluations. 
Evaluations should include: 
• 
High resolution CT  
• 
Pulmonologist consultation (Infectious Disease consultation as clinically indicated)  
• 
Blood culture and CBC. Other blood tests could be considered as needed 
• 
Consider bronchoscopy and bronchoalveolar lavage if clinically indicated and feasible 
• 
Pulmonary function tests and pulse oximetry (SpO2) 
• 
Arterial blood gases if clinically indicated 
• 
One blood sample collection for PK analysis as soon as ILD/pneumonitis is suspected, if feasible. 
Other tests could be considered, as needed. 
u. A portion of ADA blood sample will be used for future central lab analysis for SARS-CoV-2 testing once protocol version 6.0 is applied for a subject. SARS-CoV-2 
testing will be conducted every 4 cycles from Cycle 4 (Cycle 4, Cycle 8 etc.). 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
Proprietary and Confidential 
Page 119 
17.6. 
Instructions Related to Severe Acute Respiratory Syndrome 
Coronavirus 2 (SARS-CoV-2) 
Due to the potential impact of SARS-CoV-2, ie COVID-19, on subject safety, the Sponsor 
recommends the following dose modification and management plan for subjects with 
confirmed or suspected SARS-CoV-2 while being treated with DS-8201a. Dose 
modifications will be based on the worst CTCAE grade. Use CTCAE version 5.0 general 
grading criteria to evaluate SARS-CoV-2. All dose modifications (discontinuation, 
interruptions or reductions) must be recorded on the AE and drug administration eCRFs. 
Dose Modification Criteria for Suspected or Confirmed SARS-CoV-2 
If SARS-CoV-2 infection is suspected, interrupt DS-8201a and rule out SARS-CoV-2 per 
local guidance. 
 If SARS-CoV-2 is ruled out, follow dose modification and management guidance 
as outlined in Table 5.3. 
 If SARS-CoV-2 is confirmed or is still suspected after evaluation follow dose 
modification as outlined in Table 17.5 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 17.5: 
SARS-CoV-2 Dose Modification Criteria 
SARS-CoV-2 Worst Toxicity NCI-CTCAE 
Version 5.0 Grade (unless otherwise specified) 
Schedule Modification for DS-8201a 
Grade 1 
Resume study drug at the same dosea 
Grade 2 
Resume study drug at the same dose if chest CT 
findings are completely resolveda 
Reduce by 1 dose level if chest CT findings are 
nearly resolved 
Grade 3 
Reduce by 1 dose level if chest CT findings are 
completely resolved 
Discontinue study drug if chest CT findings are 
not completely resolved 
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 17.5, 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 (Table 5.3). 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
Proprietary and Confidential 
Page 120 
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. 
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 17.6). 
The chloroquine or hydroxychloroquine administration time and the exact time of blood 
sample collection for PK analysis must be recorded on the eCRF. 
 
Table 17.6: 
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 treatment (within 
8 hrs) 
CQ = chloroquine; HCQ = hydroxychloroquine.  
a Washout period of no less than 14 days is required before resumption of DS-8201a. 
 
SARS-CoV-2 Assessment(s) 
All confirmed or suspected SARS-CoV-2 infection events must be recorded in the eCRF. If a 
subject presents to the clinic with symptoms suggestive of SARS-CoV-2, but the real-time 
RT-PCR test is not available at the site, a sample kit will be provided for sample collection to 
be tested at a central laboratory. 
Serum samples will be used for SARS-CoV-2 testing from each subject who provides 
consent. Samples will be collected prior to the study drug infusion, shipped to a central 
laboratory, and stored there until the tests become available. 
If subjects consent, the remaining serum samples will also be stored for future analysis. 
Sample collection, preparation, handling, storage, and shipping instructions are provided in 
the Study Laboratory Manual. 


Protocol DS8201-A-A104 
Version 6.0, 03 Jul 2020 
Proprietary and Confidential 
Page 121 
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.