Clinical trial NCT04014075
Conditions: Adenocarcinoma Gastric Stage IV With Metastases Adenocarcinoma - GEJ
Keywords: Human epidermal receptor 2 positive Unresectable or metastatic HER2 Prior treatment regimen included trastuzumab
Sponsor: Daiichi Sankyo
Start date: 2019-11-26; Completion date: 2024-02-13
Enrollment: 79 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will find out if trastuzumab deruxtecan is safe and works for participants with gastric or gastroesophageal junction cancer.

They must have human epidermal growth factor receptor 2 (HER2)-positive gastric or gastro-esophageal junction (GEJ) cancer:

* that cannot be removed surgically
* that has moved to other parts of the body
* that got worse during or after treatment that included trastuzumab

The study will enroll about 80 participants. Sites will be in North America and the European Union.

Detailed description:

Arms: arm 1: Participants who have centrally confirmed HER2-positive gastric or gastro-esophageal junction cancer will be treated with trastuzumab deruxtecan by intravenous (IV) infusion every 3 weeks, until progression of disease or withdrawal from treatment for other reasons.
Interventions: intervention 1: Trastuzumab deruxtecan
Intervention descriptions: intervention 1: Antibody component covalently conjugated to a drug component, prepared by dilution based on body weight for intravenous (IV) infusion

Protocol documents:
Prot_SAP_000.pdf: 
Proprietary and Confidential 
Page 1 
CLINICAL STUDY PROTOCOL 
 
A PHASE 2, OPEN-LABEL, SINGLE-ARM TRIAL OF 
TRASTUZUMAB DERUXTECAN IN HER2-POSITIVE, 
UNRESECTABLE OR METASTATIC GASTRIC OR 
GASTRO-ESOPHAGEAL JUNCTION (GEJ) 
ADENOCARCINOMA SUBJECTS WHO HAVE 
PROGRESSED ON OR AFTER A TRASTUZUMAB-
CONTAINING REGIMEN 
 
DS8201-A-U205 
 
IND NUMBER 136179 
EudraCT NUMBER 2019-001512-34 
 
VERSION 2.0, 28 JULY 2020 
 
DAIICHI SANKYO INC. 
 
 
 
CONFIDENTIALITY STATEMENT 
Information contained in this document is proprietary to Daiichi Sankyo Inc.  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 Inc. 


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INVESTIGATOR AGREEMENT 
A Phase 2, open-label, single-arm trial of trastuzumab deruxtecan  in HER2-positive, 
unresectable or metastatic gastric or gastro-esophageal junction (GEJ) adenocarcinoma 
subjects who have progressed on or after a trastuzumab-containing regimen
Sponsor Approval: 
This clinical study protocol has been reviewed and approved by the Daiichi Sankyo Inc. 
representative listed below. 
 
 
 
 
Print Name 
 
Signature 
 
Senior Director, Global Oncology R&D 
 
 
 
Title 
 
Date (DD MMM YYYY) 
 
I have fully discussed the objectives of this study and the contents of this protocol with the 
 
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 
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
PPD


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DOCUMENT HISTORY 
Version Number 
Version Date 
1.0 
23 April 2019 
 


Protocol DS8201-A-U205 
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SUMMARY OF CHANGES 
Please refer to the comparison document for protocol Version 2.0 (dated 28 July 2020) vs. 
protocol Version 1.0 (dated 23 April 2019) for actual changes in text.  The summary of changes 
below is a top-line summary of major changes in the current DS8201-A-U205 clinical study 
protocol (Version 2.0) by section. 
Amendment Rationale: 
This amendment is primarily driven by the updated safety information and to incorporate 
Coronavirus disease 2019 (COVID-19) associated directives/guidance.  Other minor changes are 
administrative and/or editorial. 
This amendment is considered to be non-substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union because it does not significantly impact the safety or physical/mental integrity of subjects 
nor the scientific value of the study. 
CONVENTIONS USED IN THIS SUMMARY OF CHANGES 
All locations (Section numbers and/or paragraph/bullet numbers) refer to the current protocol 
version, which incorporates the items specified in this Summary of Changes document. 
Minor edits, such as update to language that does not alter original meaning, update to version 
numbering, formatting, change in font color, corrections to typographical errors, use of 
abbreviations, moving verbiage within a section or table, change in style, or change in case, are 
not noted in the table below. 
Section # and Title 
Description of Change 
Brief Rationale 
Protocol Synopsis 
This section was updated 
To align with clinical and 
safety changes 
1.1.2.2. Clinical 
Experience in Gastric 
Cancer 
This section was updated with the latest 
available efficacy results 
To provide supporting 
evidence of increased clinical 
experience in gastric cancer 
1.1.2.3.3. 
 
Interstitial Lung 
Disease/Pneumonitis 
This section was updated 
To align with the latest safety 
information 
1.1.2.3.3.1. Left 
Ventricular Ejection 
Fraction Decrease 
This section was updated 
To align with the latest safety 
information 
1.1.2.6. Clinical 
Pharmacokinetics 
This section was updated 
To provide the latest available 
pharmacokinetic (PK) data 
2.3.3.  
Other Secondary 
Efficacy Endpoint(s) 
The definitions of progression-free survival 
(PFS) and OS (overall survival) were 
updated  
To align with the latest 
protocol template information 
2.3.4   
Cell-free RNA (cfRNA) was included for 
biomarker analysis 
To include testing for cfRNA 


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Section # and Title 
Description of Change 
Brief Rationale 
Exploratory 
Endpoints 
2.3.7   
Health Economic and 
Outcomes Research 
Endpoints 
“Health care resource utilization 
(hospitalization-related records)” was 
deleted from list of Health Economic and 
Outcomes Research (HEOR) endpoints 
based on patient-reported outcomes (PROs) 
To remove an unrequired 
endpoint 
Protocol Synopsis 
3.1.1.  
Overview 
3.2  
Discussion of Study 
Design 
The sample size was updated.  The number 
of sites was updated to approximately 45. 
The countries, Australia and Israel were 
removed from the list of geographical sites.  
To accommodate  dropouts or 
losses to follow-up 
Figure 3.1   
Study Design Schema 
The study design schema was updated. 
To provide clarification 
Protocol Synopsis 
 
3.1.2.  
Duration of the Study 
 
 
The duration of recruitment of subjects to 
the study was increased from 12-18 months 
to 18-24 months. 
The anticipated duration of the study was 
increased from 24-30 months to 30-36 
months as countermeasure to minimize 
COVID-19 impact on patient recruitment.  
 
To align with clinical changes 
3.1.3.  
Duration of Subject 
Participation 
This section was updated 
To provide clarification 
3.1.4. Definition of 
the End of the Study 
This section was updated 
To provide clarification 
4. Study Population 
 
This section was updated 
To provide clarification 
Protocol Synopsis 
4.1.  
Inclusion Criteria 
Criterion no. 5 was updated.   
Criteria nos. 10, 11, 12 and 13 were 
presented in a table as a single criterion no. 
8. 
For criterion no. 10, the contraception period 
was changed to “7 months for female and 4 
months for males” and the paragraph 
describing menopausal women on hormone 
replacement therapy was removed.  
 
Criterion no. 13 was added 
To align with the latest safety 
information 


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Section # and Title 
Description of Change 
Brief Rationale 
Protocol Synopsis 
4.2  
Exclusion Criteria 
Criteria nos. 2, 5, 12, 14, 17 and 18 were 
updated. 
Criteria nos. 4 and 20 were deleted. 
Criteria nos. 19 and 24 were added.  
 
To align with the latest safety 
information 
Table 5.1 
Management 
guidelines for 
Trastuzumab 
Deruxtecan 
Modification guidelines for changes in 
troponin levels were removed. 
To align with the latest safety 
information 
5.1.5 
Re-screening 
Procedures 
This section was updated 
To provide clarification 
5.2.1. Description 
5.2.3. Preparation 
The description of determining dose based 
on body weight was updated 
To provide clarification 
5.2.6.  
Drug Accountability 
This section was updated  
To provide clearer instructions 
to the site 
5.4.  
Dose Interruptions 
and Reductions 
This section was updated 
To provide clarification 
5.4.1. Guidelines for 
Dose Modifications 
This section was updated 
To align with the latest safety 
information 
Table 5.1  
Management 
Guidelines  
Guidelines for managing cardiac, pulmonary 
and hepatic toxicities were updated 
To align with the latest safety 
information 
5.6.  
Concomitant 
Medications, 
Treatments, and 
Procedures 
This section was updated 
To align with the latest safety 
information 
6.1.  
Tissue Screening 
This section was updated 
To provide clarification 
6.2.  
Screening (Day -28 to 
Day -1) 
This section was updated. 
 
To provide clarification and to 
align with the latest safety 
information 
6.3  
Treatment Period 
This section was updated 
To provide clarification and 
to align with the latest safety 
information 
6.4  
This section was updated 
To provide clarification and 


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Section # and Title 
Description of Change 
Brief Rationale 
End of treatment Visit 
to align with the latest safety 
information 
6.5.2. Long-
term/Survival Follow-
up (Every 3 Months 
±14 Days) 
This section was updated 
To align with the latest safety 
information 
6.6   
Additional 
PK Assessments due 
to COVID-19  
Infection  
 
Table 8.2 
Schedule of PK 
Sample Collections in 
Case of Chloroquine 
and 
Hydroxychloroquine 
Treatment 
This section and table were added  
To monitor potential 
drug-drug interactions 
between investigational/study 
drug treatment and COVID-19 
specific treatment 
7. Efficacy 
Assessments 
This section was updated 
To provide clarification 
7.2.1. Key 
Secondary Efficacy 
Endpoint 
The definition of PFS was updated 
To provide clarification 
8.3.3. 
Immunogenicity 
(Anti-drug 
Antibodies) 
The last paragraph in this section  was 
updated  
To clarify the anti-drug 
antibodies (ADA) testing 
9.  
Safety Evaluation and 
Reporting 
Several of the sub-sections in this section 
were updated 
To align with the latest safety 
information 
Protocol Synopsis 
11.1  
General Statistical 
Considerations 
11.3. 
Study 
Population Data 
11.4  
Efficacy Analysis 
Intent to treat (ITT) was changed to Full 
Analysis Set (FAS)  
To accommodate a change in 
convention  
11.6.1. 
Pharmacokinetic 
Analyses 
This section was updated 
To provide clarification. 


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Section # and Title 
Description of Change 
Brief Rationale 
11.6.3. Biomarker 
Analyses 
This section was updated 
To provide clarification. 
11.7.1 Adverse Event 
Analyses  
The definition of treatment-emergent 
adverse event (TEAE) has been updated 
To align with the latest safety 
information 
Protocol Synopsis 
 
11.8 Sample Size 
Determination 
 
This section was updated 
To provide clarification 
Table 17.1  
Schedule of Events 
The table was updated 
To provide clarification 
 
To align with the latest safety 
information 
17.7  
Instructions Related to 
COVID-19 
This section was added 
To provide management 
guidelines for COVID-19 
Throughout the 
protocol 
The words, “enrolled and enrollment” were 
replaced in most places by ‘first dose’ or 
‘recruit(ment)’ 
To provide clarification and 
avoid confusion when 
describing the timing of events 


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PROTOCOL SYNOPSIS 
EudraCT: 
2019-001512-34 
IND Number: 
136179 
Protocol Number: 
DS8201-A-U205 
Investigational Product: Trastuzumab deruxtecan (also known as fam-trastuzumab deruxtecan) 
Active 
Ingredient(s)/INN: 
Trastuzumab deruxtecan consists of an antibody component, 
MAAL-9001, covalently conjugated via a maleimide tetrapeptide 
linker, to a drug component MAAA-1181a/ trastuzumab deruxtecan 
Study Title: 
A Phase 2, open-label, single-arm trial of trastuzumab deruxtecan  in 
HER2-positive, unresectable or metastatic gastric or gastro-esophageal 
junction (GEJ) adenocarcinoma subjects who have progressed on or 
after a trastuzumab-containing regimen  
Study Phase: 
Phase 2 
Indication Under 
Investigation: 
Unresectable or metastatic gastric or GEJ adenocarcinoma that has 
progressed on or after a trastuzumab-containing regimen 
Study Objectives: 
Primary objective:   
 
To investigate the efficacy of trastuzumab deruxtecan based on the 
confirmed objective response rate (ORR) by independent central 
review by using Response Evaluation Criteria in Solid Tumors 
(RECIST) Version (v)1.1 
Secondary objectives: 
 
To evaluate the efficacy of trastuzumab deruxtecan on 
progression-free survival (PFS), based on independent central 
review using RECIST v1.1. 
Other secondary objectives are: 
 
To further evaluate the efficacy of trastuzumab deruxtecan by using 
the  endpoint of OS  
 
To further evaluate the efficacy of trastuzumab deruxtecan by using 
RECIST v1.1 for endpoints of PFS and ORR based on Investigator 
assessment, and duration of response (DoR) based on independent 
central review and Investigator assessment 


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 
To determine the pharmacokinetics (PK) of trastuzumab 
deruxtecan in serum 
 
To further evaluate the safety of trastuzumab deruxtecan based on 
treatment-emergent adverse events (TEAEs) and anti-drug 
antibodies (ADAs) 
 
To evaluate Health Economics and Outcomes Research (HEOR) 
endpoints based on patient-reported outcomes (PROs) 
Exploratory objectives:  
To evaluate the following: 
 
Disease control rate (DCR), based on independent central review 
and Investigator assessment 
 
Time to response, based on independent central review and 
Investigator assessment 
 
Best percentage change in the sum of diameters of measurable 
tumors 
 
Predictive, prognostic, and pharmacodynamics exploratory 
biomarkers in tissue samples and blood, and their association with 
disease status and/or response to treatment 
Study Design: 
This is an open-label, single-arm, multicenter Phase 2 study to evaluate 
the efficacy and safety of trastuzumab deruxtecan in unresectable or 
metastatic gastric cancer or GEJ previously treated with a trastuzumab-
containing regimen.  The sample size will be approximately 80subjects, 
recruited at approximately 45 study sites including but not limited to 
North America and the European Union (EU). 
Study Duration: 
Recruitment of subjects is planned to occur over approximately 18 to 
24 months.   
Subjects will be treated until progression of disease or until withdrawal 
of treatment due to other reason.  For each subject, there will be a 
40-day (+7 days) Follow-up Visit after the last study drug 
administration or before starting new anticancer treatment, whichever 
comes first. This will be followed by Long-term/Survival Follow-up 
Visits every 12 weeks (±14 days) from the date of the 40-day (+7 days) 
Follow-up Visit, until death, withdrawal of consent, or loss to follow-
up, whichever occurs first.  Tumor assessment will be performed every 
6 weeks (±7 days) from Cycle 1 Day 1 in the first year and every 12 
weeks (±7 days) thereafter until objective disease progression (based on 
radiologic assessment) or until start of new anticancer treatment, if 
patient discontinues study treatment for any reason other than disease 
progression.  


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The end of the study will occur when all subjects have either completed 
their last scheduled visit or died or withdrawn from study participation  
or move into another study or the Sponsor’s decides to discontinue the 
study. This is anticipated to occur approximately 12 months after the 
last subject’s first dose.   
The anticipated duration of the study is at least 30 to 36 months. 
Study Sites and 
Location: 
Approximately 45 sites possibly including but not limited to North 
America and the EU.  Other countries may also be considered. 
Subject Eligibility 
Criteria: 
Key Inclusion Criteria: 
 Men or women ≥18 years old (Please follow local 
regulatory requirements if the legal age of consent for study 
participation is >18 years old.) 
 Has pathologically documented gastric or GEJ cancer that 
is: 
 Unresectable or metastatic 
 Centrally confirmed HER2-positive disease 
(immunohistochemistry [IHC]3+, IHC2+/in-situ 
hybridization [ISH]+) as determined according to 
American Society of Clinical Oncology – College of 
American Pathologists (ASCO-CAP) guidelines new 
tumor biopsy obtained after progression on or after a 
first-line trastuzumab-containing regimen.  If a tumor 
biopsy was already collected after discontinuation of 
first-line treatment with a trastuzumab-containing 
regimen, it is acceptable to consider the biopsy to be a 
new biopsy for the purpose of this study, provided that 
there is sufficient tissue for exploratory biomarker 
studies.  
 Has experienced disease progression during or after first-
line therapy with a trastuzumab-containing regimen (brand 
or approved biosimilar).   
 Note: Prior adjuvant therapy with a trastuzumab-
containing regimen can be counted as a line of therapy if 
the subject progressed on or within 6 months of 
completing adjuvant therapy.  
 Has at least 1 measurable lesion per RECIST v1.1 as 
confirmed by the investigator review. 


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 Has left ventricular ejection fraction (LVEF) ≥50% within 
28 days before first dose per echocardiogram 
(ECHO)/multigated acquisition (MUGA) scan. 
 Has adequate organ function within 14 days before 
randomization, defined as: 
Parameter 
Laboratory value 
Adequate bone marrow function 
Platelet count  
 100 000/mm3  (Platelet transfusion is 
not allowed within 1 week prior to 
screening assessment) 
Hemoglobin  
≥ 9.0 g/dL  (Red blood cell transfusion is 
not allowed within 1 week prior to 
screening assessment) 
Absolute neutrophil 
count (ANC) 
 1500/mm3  
(granulocyte colony-stimulating factor 
[G-CSF] administration is not allowed 
within 1 week prior to screening 
assessment) 
Adequate renal function 
Creatinine 
Creatinine clearance ≥ 30 mL/min as 
calculated using the Cockcroft-Gault 
equation*  
Adequate hepatic function 
Alanine 
aminotransferase (ALT), 
Aspartate 
aminotransferase (AST) 
 ≤ 5  the upper limit of normal (ULN) 
Total bilirubin 
≤ 1.5 × ULN if no liver metastases or < 
3 × ULN in the presence of documented 
Gilbert’s Syndrome (unconjugated 
hyperbilirubinemia) or liver metastases 
at baseline. 
 
 
Serum Albumin 
≥ 2.5 g/dL  
Adequate blood clotting function 
International normalized 
ratio (INR) / 
Prothrombin time (PT) 
and activated partial 
≤ 1.5 × ULN 


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thromboplastin time 
(aPTT) 
*Cockcroft-Gault equation:  
        CLcr (mL/min) =  
[140 - age (years)] × weight (kg)
[72 × serum creatinine (mg/dL)]  {× 0.85 for females} 
 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. 
 
Key Exclusion Criteria: 
 Use of anticancer therapy after first-line treatment with a 
trastuzumab-containing regimen. 
 Uncontrolled or significant cardiovascular disease, including 
any of the following: 
 History of myocardial infarction (MI) within 6 months 
of first dose  
 History of symptomatic congestive heart failure (New 
York Heart Association Class II to IV) 
 Troponin levels consistent with MI as defined according 
to the manufacturer within 28 days prior to first dose 
 Corrected QT interval (QTc) prolongation to >470 ms 
(females) or >450 ms (male) based on Screening 
triplicate 12-lead electrocardiogram (ECG)  
 History of (non-infectious) interstitial lung disease (ILD)/ 
pneumonitis that required corticosteroid therapy or has 
current ILD /pneumonitis or is suspected to have such 
diseases by imaging during Screening. 
 Clinically  severe pulmonary compromise resulting from 
intercurrent pulmonary illnesses including, but not limited 
to, any underlying pulmonary disorder (ie, pulmonary 
emboli within 3 months of the first dose, severe asthma, 
severe chronic obstructive pulmonary disease (COPD), 
restrictive lung disease, pleural effusion etc.), and any 
autoimmune, connective tissue or inflammatory disorders 
with pulmonary involvement (ie, rheumatoid arthritis, 
Sjogren's, sarcoidosis, etc.), or prior pneumonectomy. 


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 Pleural effusion, ascites, or pericardial effusion that requires 
drainage, peritoneal shunt, or Cell-free and Concentrated 
Ascites Reinfusion Therapy (CART).  (Drainage and Cell-
free and CART are not allowed within 2 weeks prior to or 
during Screening.) 
 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 recruitment (1 week for stereotactic radiotherapy). 
Dosage Form,  
Dose and Route of 
Administration: 
Trastuzumab deruxtecan for injection 100 mg, Lyo-DP: a trastuzumab 
deruxtecan sterile lyophilized powder containing 100 mg of 
trastuzumab deruxtecan in a glass vial. 
The drug for intravenous (IV) infusion is prepared by dilution of the 
required volume of the drug product calculated based on the subject’s 
body weight (BW) in a volume of 100 mL, by the study site 
pharmacist.  The study drug will be administered as an IV infusion 
every 3 weeks (Q3W), initially for at least 90 minutes, and, if there is 
no infusion-related reaction (IRR), for at least 30 minutes thereafter.  In 
case an IRR occurred at the first infusion, all subsequent infusions will 
be over at least 90 minutes.   
The starting dose of trastuzumab deruxtecan will be 6.4 mg/kg  
Study Endpoints: 
Primary Endpoint (ie, primary outcome measure): 
 
Confirmed ORR, based on independent central review 
Key Secondary Endpoint:  
 
PFS, based on independent central review  
Other Secondary Endpoints 
 PFS, based on Investigator assessment 
 ORR, based on Investigator assessment 
 
OS 


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 
DoR, based on independent central review and Investigator 
assessment 
Exploratory Endpoints 
 
DCR, based on independent central review and Investigator 
assessment 
 
Time to response, based on independent central review and 
Investigator assessment 
 
Best percentage change in the sum of diameters of measurable 
tumors  
 
Serum extracellular domain of HER2 (HER2ECD) 
 
Biomarker analysis using cell-free deoxyribonucleic acid (cfDNA) 
and cell-free ribonucleic acid (cfRNA) 
Health Economic and Outcomes Research Endpoints:  
 
European Organization for Research and Treatment of Cancer 5-
dimension 5-level quality-of-life questionnaire (EORTC EQ-5D-
5L) 
 
Functional Assessment of Cancer Therapy-Gastric (FACT-Ga) 
questionnaire 
Pharmacokinetic Endpoints:  
 
Serum concentrations of trastuzumab deruxtecan, total anti-HER2 
antibody, and MAAA-1181a  
 
Cmax, Tmax, AUClast, AUC21d, and, if appropriate, AUCinf, 
t1/2, CL, and Vss for each of the components  
Safety Endpoints: 
 
Serious adverse events (SAEs)  
 
TEAEs  
 
Drug-related TEAEs 
 
Discontinuations due to adverse events (AEs) 
 
Adverse events of special interest (AESIs) 
 
Physical examination findings  
 
Eastern Cooperative Oncology Group performance status (ECOG 
PS)  
 
Vital sign measurements 
 
Standard clinical laboratory parameters  


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 
ECG parameters  
 
ECHO/MUGA scan findings  
 
ADAs  
Planned Sample  
Size: 
On the basis of historical data of current standard of care (SoC), 
western patients with second-line gastric or GEJ cancer have reported 
best ORR of ~27%.  Seventy-two subjects provide a 90% power to 
achieve a lower limit of 95% confidence interval (CI) for the ORR that 
exceeds 27% (threshold) under the expected ORR of 45%.  When 
potential dropouts are taken into consideration, approximately 80 
subjects (planned sample size) will be recruited.  The sample size 
computation was performed by using EAST v6.4. 
Statistical Analyses: 
Analysis Population: 
Full Analysis Set (FAS) will include all subjects who were recruited 
and have received at least 1 dose of the study drug.  (This is the same as 
the Safety Analysis Set.)  
Response Evaluable Set will include recruited subjects who took at 
least 1 dose of trastuzumab deruxtecan, had measurable disease at 
baseline per independent central review, and had at least 1 postbaseline 
tumor assessment. 
Safety Analysis Set will include all recruited subjects who received at 
least 1 dose of study drug. 
PK Analysis Set will include all recruited subjects who received at least 
1 dose of study drug and had measurable serum concentrations of 
trastuzumab deruxtecan, total anti-HER2 antibody, and/or 
MAAA-1181a. 
Primary Efficacy Analyses: 
The primary analyses will be on ORR (the sum of a best response of 
complete response (CR) rate and partial response (PR) rate) as assessed 
by independent central review based on RECIST v1.1.  The estimate of 
ORR and its 2-sided 95% exact CI will be provided by using Clopper-
Pearson method.  The primary efficacy analysis will be performed on 
the basis of the ITT population and repeated on the Response Evaluable 
Set as a supportive analysis. 
Secondary Efficacy Analyses: 
 
PFS, based on independent central review and Investigator 
assessments will be summarized separately with the median event 
time and its 95% CI using Brookmeyer and Crowley method. 


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 
OS will be summarized with the median event time and the 95% 
CI.   
 
ORR, based on Investigator assessment will be analyzed in the 
similar approach as used for the primary endpoint. 
 
An additional secondary efficacy endpoint is DoR, based on 
independent central review and on Investigator assessment.  This 
endpoint will be summarized with the median event time and its 
95% CI using Brookmeyer and Crowley method.   
Interim Analyses (optional): 
There is no plan for an interim analysis. 
Safety Analyses: 
SAEs, TEAEs, drug-related TEAEs, AESIs, discontinuations due to 
AEs, physical examination findings, ECOG PS, vital sign 
measurements, standard clinical laboratory parameters, ECG 
parameters, ECHO/MUGA scan findings, and ADAs.  TEAEs will be 
graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) v5.0.44  Safety 
analyses in general will be descriptive and will be presented in tabular 
format with the appropriate summary statistics. 
Health Economic and Outcomes Research Analyses (optional):  
The HEOR endpoints based on the following PRO questionnaires will 
be summarized: FACT-GA and EORTC EQ-5D-5L.  
Pharmacokinetic Analyses: 
Descriptive statistics will be provided for all serum concentration data 
(trastuzumab deruxtecan, total anti-HER2 antibody, and/or 
MAAA-1181a) at each time point and PK parameters. 
The population-PK analysis to evaluate the effect of intrinsic and 
extrinsic factors of trastuzumab deruxtecan, and if appropriate, total 
anti-HER2 antibody, and MAAA-1181a will be characterized including 
available PK data from the other trastuzumab deruxtecan clinical trials.  
After establishment of the population-PK model, a 
population-PK/pharmacodynamic model may be developed to evaluate 
the relationship between exposure and efficacy and toxicity.  The 
results of the nonlinear mixed effects population-PK and 
population-PK/pharmacodynamic models may be reported separately 
from the clinical study report. 
Biomarker Analyses:  
New tissue (taken after progression on or after first-line treatment with 
a trastuzumab-containing regimen) will be required for confirmation of 


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HER2-positive disease (IHC3+ or IHC2+ and evidence of HER2 
amplification by ISH), as well as exploratory biomarkers for eligibility 
assessment.  A biopsy on treatment at the end of Cycle 3 prior to Cycle 
4 Day 1 infusion (up to 7 days prior to start of Cycle 4) and at the end 
of treatment is required.  At least 2 cores are requested but, if the risk of 
biopsy complications from a second biopsy is unacceptable (at the 
discretion of the Investigator), then a single biopsy core will suffice.  
Biomarkers will be summarized using descriptive statistics.  
 


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TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT...................................................................................................2 
DOCUMENT HISTORY.................................................................................................................3 
SUMMARY OF CHANGES ...........................................................................................................4 
PROTOCOL SYNOPSIS ................................................................................................................9 
LIST OF ABBREVIATIONS ........................................................................................................28 
1. 
INTRODUCTION ...........................................................................................................32 
1.1. 
Background ......................................................................................................................32 
1.1.1. 
Overview of the Disease ..................................................................................................32 
1.1.2. 
The Investigational Product: Trastuzumab Deruxtecan ..................................................34 
1.1.2.1. Description ......................................................................................................................34 
1.1.2.2. Clinical Experience in Gastric Cancer ............................................................................35 
1.1.2.3. Safety Information ...........................................................................................................38 
1.1.2.4. Intended Use Under Investigation ...................................................................................40 
1.1.2.5. Comparator Regimen .......................................................................................................41 
1.1.2.6. Clinical Pharmacokinetics ...............................................................................................41 
1.2. 
Study Rationale ...............................................................................................................41 
1.3. 
Risks and Benefits for Study Subjects .............................................................................43 
2. 
STUDY OBJECTIVES AND HYPOTHESIS ................................................................45 
2.1. 
Study Objectives ..............................................................................................................45 
2.1.1. 
Primary Objective ............................................................................................................45 
2.1.2. 
Secondary Objectives ......................................................................................................45 
2.1.3. 
Exploratory Objectives ....................................................................................................45 
2.2. 
Study Hypothesis .............................................................................................................46 
2.3. 
Study Endpoints ...............................................................................................................46 
2.3.1. 
Primary Endpoint .............................................................................................................46 
2.3.2. 
Key Secondary Efficacy Endpoint ..................................................................................46 
2.3.3. 
Other Secondary Efficacy Endpoint(s) ............................................................................46 
2.3.4. 
Exploratory Endpoints .....................................................................................................46 
2.3.5. 
Pharmacokinetic (PK) Endpoints (Trastuzumab Deruxtecan and MAAA-
1181a): .............................................................................................................................47 
2.3.6. 
Safety Endpoint(s) ...........................................................................................................47 


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2.3.7. 
Health Economic and Outcomes Research Endpoints ....................................................47 
3. 
STUDY DESIGN ............................................................................................................48 
3.1. 
Overall Design .................................................................................................................48 
3.1.1. 
Overview .........................................................................................................................48 
3.1.2. 
Duration of the Study ......................................................................................................48 
3.1.3. 
Duration of Subject Participation ....................................................................................48 
3.1.4. 
Definition of the End of the Study ..................................................................................49 
3.2. 
Discussion of Study Design .............................................................................................49 
4. 
STUDY POPULATION ..................................................................................................50 
4.1. 
Inclusion Criteria .............................................................................................................50 
4.2. 
Exclusion Criteria ............................................................................................................53 
5. 
STUDY TREATMENT(S) ..............................................................................................55 
5.1. 
Assigning Subjects to Treatments and Blinding .............................................................55 
5.1.1. 
Treatment Group(s) .........................................................................................................55 
5.1.2. 
Method of Treatment Allocation .....................................................................................55 
5.1.3. 
Blinding ...........................................................................................................................55 
5.1.4. 
Emergency Unblinding Procedure ..................................................................................55 
5.1.5. 
Re-screening Procedures .................................................................................................55 
5.2. 
Study Drug .......................................................................................................................55 
5.2.1. 
Description ......................................................................................................................55 
5.2.2. 
Labeling and Packaging ..................................................................................................56 
5.2.3. 
Preparation .......................................................................................................................56 
5.2.4. 
Administration .................................................................................................................56 
5.2.5. 
Storage .............................................................................................................................56 
5.2.6. 
Drug Accountability ........................................................................................................57 
5.3. 
Control Treatment ...........................................................................................................57 
5.4. 
Dose Interruptions and Reductions .................................................................................57 
5.4.1. 
Guidelines for Dose Modifications .................................................................................58 
5.5. 
Method of Assessing Treatment Compliance ..................................................................66 
5.6. 
Concomitant Medications, Treatments, and Procedures .................................................66 
5.7. 
Prohibited medications and treatments ............................................................................67 
5.7.1.1. Restricted products ..........................................................................................................68 


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5.8. 
Removal of Subjects from Treatment and/or Study ........................................................68 
5.8.1. 
Reasons for Discontinuation of Study Treatment ...........................................................68 
5.8.2. 
Reasons for Withdrawal from the Study .........................................................................68 
5.8.3. 
Withdrawal Procedures ...................................................................................................69 
6. 
STUDY PROCEDURES .................................................................................................70 
6.1. 
Tissue Screening ..............................................................................................................70 
6.2. 
Screening (Day -28 to Day -1) ........................................................................................71 
6.3. 
Treatment Period .............................................................................................................73 
6.3.1. 
Cycle 1 to Cycle 4 and Subsequent Cycles .....................................................................73 
6.3.1.1. Between 3 Days Before Through Immediately Before Infusion (All Cycles 
Unless Otherwise Noted) .................................................................................................73 
6.3.1.2. End of Infusion (All Cycles Unless Otherwise Noted) ...................................................75 
6.3.1.3. Cycle 1 Day 8 and Cycle 1 Day 15 (± 1 Day) .................................................................75 
6.4. 
End of treatment Visit .....................................................................................................75 
6.5. 
Follow-up ........................................................................................................................77 
6.5.1. 
40-day (+ 7 Days) Follow-up Visit .................................................................................77 
6.5.2. 
Long-term/Survival Follow-up (Every 3 Months ±14 Days) ..........................................77 
6.6. 
Additional PK assessments due to Coronavirus disease 2019 (COVID-19) ...................78 
7. 
EFFICACY ASSESSMENTS .........................................................................................79 
7.1. 
Primary Efficacy Endpoint ..............................................................................................79 
7.2. 
Secondary Efficacy Endpoint(s) ......................................................................................79 
7.2.1. 
Key Secondary Efficacy Endpoint ..................................................................................79 
7.2.2. 
Other Secondary Efficacy Endpoints ..............................................................................79 
7.2.3. 
Exploratory Efficacy Endpoints ......................................................................................79 
7.3. 
Appropriateness of Selected Efficacy Assessments ........................................................80 
8. 
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS ...........................81 
8.1. 
Pharmacokinetic (PK) Assessment(s) .............................................................................81 
8.2. 
Pharmacodynamic Assessment(s) ...................................................................................82 
8.3. 
Biomarker Assessment(s) ................................................................................................82 
8.3.1. 
Biomarker assessments ....................................................................................................82 
8.3.2. 
Additional Biomarker Assessments ................................................................................82 
8.3.3. 
Immunogenicity (Anti-drug Antibodies) .........................................................................83 
8.4. 
Pharmacogenomic Analysis ............................................................................................83 


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8.4.1. 
Genomic or Genetic Banking and Analysis ....................................................................83 
8.4.2. 
Disclosure of the Results of Genomic or Genetic Analysis ............................................83 
8.4.3. 
Storage and Disposal of Specimens for Genomic or Genetic Banking and 
Analysis ...........................................................................................................................83 
9. 
SAFETY EVALUATION AND REPORTING ..............................................................85 
9.1. 
Assessment of Safety Endpoints .....................................................................................85 
9.2. 
Adverse Event Collection and Reporting ........................................................................85 
9.3. 
Adverse Events of Special Interest ..................................................................................86 
9.3.1. 
Interstitial Lung Disease/Pneumonitis .............................................................................86 
9.3.1.1. Clinical Summary ............................................................................................................86 
9.3.1.2. Management Guidance ....................................................................................................86 
9.3.2. 
LVEF Decrease ...............................................................................................................87 
9.3.2.1. Clinical Summary ............................................................................................................87 
9.3.2.2. LVEF decrease Management Guidance ..........................................................................87 
9.4. 
Adverse Events ................................................................................................................88 
9.4.1. 
Definition of Adverse Event ............................................................................................88 
9.4.2. 
Serious Adverse Event ....................................................................................................88 
9.4.3. 
Severity Assessment ........................................................................................................89 
9.4.4. 
Causality Assessment ......................................................................................................89 
9.4.5. 
Action Taken Regarding Study Drug(s) ..........................................................................90 
9.4.6. 
Other Action Taken for Event .........................................................................................90 
9.4.7. 
Adverse Event Outcome ..................................................................................................90 
9.5. 
Reporting Serious Adverse Events and Adverse Event of Special Interest – 
Procedure for Investigators ..............................................................................................91 
9.6. 
Notifying Regulatory Authorities, Investigators, and Institutional Review 
Board/Ethics Committee .................................................................................................92 
9.7. 
Exposure in Utero During Clinical Studies .....................................................................92 
9.8. 
Clinical Laboratory Evaluations ......................................................................................93 
9.9. 
Vital Signs .......................................................................................................................94 
9.10. 
Electrocardiograms ..........................................................................................................94 
9.11. 
Physical Examinations and Functional Status .................................................................94 
9.12. 
Other Examinations .........................................................................................................94 
9.12.1. Cardiac Assessments .......................................................................................................94 


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9.12.2 
Pulmonary Assessments ..................................................................................................95 
9.12.3 
Ophthalmologic Assessment ...........................................................................................95 
9.12.4 
Brain Imaging ..................................................................................................................95 
10. 
OTHER ASSESSMENTS ...............................................................................................96 
10.1. 
Health Economics and Outcomes Research ....................................................................96 
10.1.1. EORTC Five-dimension Five-level Patient-reported Outcome Questionnaire ...............96 
10.1.2. Functional Assessment of Cancer Therapy-Gastric (FACT-Ga) Questionnaire .............96 
10.2. 
Pharmacoeconomic Assessment: Hospitalization-related Endpoint ...............................96 
11. 
STATISTICAL METHODS ...........................................................................................98 
11.1. 
General Statistical Considerations ...................................................................................98 
11.2. 
Analysis Sets ...................................................................................................................98 
11.2.1. Full Analysis Set ..............................................................................................................98 
11.2.2. Response Evaluable Set ...................................................................................................98 
11.2.3. Safety Analysis Set ..........................................................................................................98 
11.2.4. Pharmacokinetic Analysis Set .........................................................................................98 
11.3. 
Study Population Data .....................................................................................................98 
11.4. 
Efficacy Analysis .............................................................................................................99 
11.4.1. Primary Efficacy Analysis ...............................................................................................99 
11.4.2. Secondary Efficacy Analyses ..........................................................................................99 
11.4.3. Exploratory Efficacy Analyses ......................................................................................100 
11.5. 
Health Economics and Outcome Research Analyses ....................................................100 
11.5.1. EORTC Five-dimension Five-level Quality-of-life Questionnaire ...............................100 
11.5.2. FACT-Gastric Questionnaire .........................................................................................100 
11.6. 
Pharmacokinetic/Biomarker/Pharmacogenomic Analyses ...........................................100 
11.6.1. Pharmacokinetic Analyses .............................................................................................100 
11.6.2. Population-PK Analyses ................................................................................................100 
11.6.3. Biomarker Analyses ......................................................................................................101 
11.6.4. Pharmacogenomic Analyses (Optional) ........................................................................101 
11.7. 
Safety Analyses .............................................................................................................101 
11.7.1. Adverse Event Analyses ................................................................................................101 
11.7.2. Clinical Laboratory Evaluation Analyses ......................................................................102 
11.7.3. Vital Sign Analyses .......................................................................................................102 


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11.7.4. Electrocardiogram Analyses ..........................................................................................102 
11.7.5. Physical Examination Analyses ....................................................................................102 
11.7.6. Concomitant Medication Analyses ................................................................................102 
11.7.7. Immunogenicity (Anti-drug Antibody) Analyses .........................................................102 
11.7.8. Other Safety Analyses ...................................................................................................103 
11.8. 
Sample Size Determination ...........................................................................................103 
11.9. 
Statistical Analysis Process ...........................................................................................103 
12. 
DATA INTEGRITY AND QUALITY ASSURANCE ................................................104 
12.1. 
Monitoring and Inspections ...........................................................................................104 
12.2. 
Data Collection ..............................................................................................................104 
12.3. 
Data Management ..........................................................................................................105 
12.4. 
Study Documentation and Storage ................................................................................105 
12.5. 
Record Keeping .............................................................................................................106 
13. 
FINANCING AND INSURANCE ................................................................................107 
13.1. 
Finances .........................................................................................................................107 
13.2. 
Reimbursement, Indemnity, and Insurance ...................................................................107 
14. 
PUBLICATION POLICY .............................................................................................108 
15. 
ETHICS AND STUDY ADMINISTRATIVE INFORMATION .................................109 
15.1. 
Compliance Statement, Ethics, and Regulatory Compliance ........................................109 
15.2. 
Subject Confidentiality ..................................................................................................109 
15.3. 
Informed Consent ..........................................................................................................109 
15.4. 
Regulatory Compliance .................................................................................................110 
15.5. 
Protocol Deviations .......................................................................................................110 
15.6. 
Supply of New Information Affecting the Conduct of the Study .................................111 
15.7. 
Protocol Amendments ...................................................................................................111 
15.8. 
Study Termination .........................................................................................................112 
15.9. 
Data and Safety Monitoring Board ................................................................................112 
15.10. 
Address List ...................................................................................................................112 
16. 
REFERENCES ..............................................................................................................113 
17. 
APPENDICES ...............................................................................................................117 
17.1. 
Appendix1: Schedule of Events ....................................................................................117 
17.2. 
Appendix 2: Quality-of-life Questionnaires ..................................................................126 


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17.2.1. EORTC 5-dimension 5-level (EQ-5D-5L) Questionnaire ............................................126 
17.2.2. Functional Assessment of Cancer Therapy-Gastric (FACT-Ga) Questionnaire ...........129 
17.3. 
Appendix 3:Cockcroft-Gault Equation ..........................................................................132 
17.4. 
Appendix 4: Eastern Cooperative Oncology Group Performance Status (ECOG 
PS) .................................................................................................................................133 
17.5. 
Appendix 5: Response Evaluation Criteria in Solid Tumors Version 1.1 .....................134 
17.5.1. Measurability of Tumor at Baseline ..............................................................................134 
17.5.1.1. Definitions .....................................................................................................................134 
17.5.1.2. Specifications By Methods of Measurements ...............................................................135 
17.5.2. Tumor Response Evaluation ..........................................................................................137 
17.5.2.1. Assessment of Overall Tumor Burden and Measurable Disease ..................................137 
17.5.2.2. Baseline Documentation of Target and Non-target Lesions .........................................137 
17.5.2.3. Response Criteria ...........................................................................................................138 
17.5.2.4. Evaluation of Best Overall Response ............................................................................140 
17.6. 
Appendix 6: New York Heart Association Functional Classification ...........................143 
17.7. 
Appendix 7: Instructions Related to Coronavirus disease 2019 (COVID-19) ..............144 
Dose modification criteria for suspected or confirmed COVID-19 .............................................144 
Prior and Concomitant Medications ............................................................................................145 
PK Assessment(s) if Chloroquine or Hydroxychloroquine is Administered ...............................145 
Coronavirus disease 2019 (COVID-19) Assessments .................................................................145 
Statistical Analysis - Assessment of the Impact of Coronavirus Disease 2019 (COVID-
19) ..................................................................................................................................145 
 


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LIST OF TABLES 
Table 1.1: Efficacy Results in HER2-Positive Gastric/Gastro-esophageal Junction 
Cancer in Study DS8201-A-J101 (Enrolled Analysis Set) .........................................37 
Table 5.1: Management Guidelines for Trastuzumab Deruxtecan ..............................................58 
Table 8.1: Schedule of PK Sample Collection.............................................................................81 
Table 8.2: Schedule of PK Sample Collections in Case of Chloroquine and 
Hydroxychloroquine Treatment ..................................................................................81 
Table 17.1 Schedule of Events ...................................................................................................118 
Table 17.2 Time Point Response: Patients with Target (±Non-target) Disease .........................141 
Table 17.3: Time Point Response: Patients with Non-target Disease Only ................................141 
Table 17.4: Best Overall Response When Confirmation of CR and PR Required ......................142 
Table 17.5: COVID-19 Dose Modification Criteria ....................................................................144 
 


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LIST OF FIGURES 
Figure 1.1: Trastuzumab Deruxtecan Structure ............................................................................35 
Figure 3.1: Study Design Schema .................................................................................................48 
 


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LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
AC 
Adjudication Committee 
ADA 
anti-drug antibody 
ADC 
antibody-drug conjugate 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine transaminase 
ASCO-CAP 
American Society of Clinical Oncology – College of American Pathologists 
AST 
aspartate transaminase 
AUC  
areas under the plasma concentration-time curves 
AUC21d 
area under the plasma/serum concentration-time curve from time 0 to 21 days 
AUCinf 
area under the plasma/serum concentration-time curve from time 0 
extrapolated to infinity 
AUClast 
area under the plasma concentration-time curve, from time 0 to last point with 
quantifiable concentration 
BI 
before infusion 
BW 
body weight 
CART 
Cell-free and Concentrated Ascites Reinfusion Therapy 
cfDNA 
cell-free deoxyribonucleic acid 
cfRNA 
cell-free ribonucleic acid 
CI 
confidence interval 
CL 
clearance 
Cmax 
maximum plasma/serum concentration 
COVID-19 
coronavirus disease 2019 
CNS 
central nervous system 
CR 
complete response 
CrCl 
creatinine clearance 
CRF 
case report form 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP3A4 
cytochrome P450 3A4 
DCO 
data cutoff 


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ABBREVIATION 
DEFINITION 
DCR 
disease control rate 
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 
EORTC EQ-5D-5L 
European Organization for Research and Treatment of Cancer 5-dimension 5-
level patient-reported outcome questionnaire 
EOT 
end of treatment 
EQ-VAS 
EuroQual quality-of-life visual analogue scale  
EU 
European Union  
FACT-Ga 
Functional Assessment of Cancer Therapy-Gastric 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FDG-PET 
fluorodeoxyglucose-positron emission tomography 
FISH 
fluorescent in-situ hybridization 
GC 
gastric cancer 
GCP 
Good Clinical Practice 
GEJ 
gastro-esophageal junction 
HEOR 
Health Economics and Outcomes Research 
HER2 
human epidermal growth factor receptor 2  
HER2ECD 
extracellular domain of human epidermal growth factor receptor 2 
hERG 
human ether-a-go-go-related gene 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
HRT 
hormone replacement therapy 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 


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ABBREVIATION 
DEFINITION 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
ICU 
intensive care unit 
IHC 
immunohistochemistry 
ILD 
interstitial lung disease 
IQR 
interquartile range 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
ISH 
in-situ hybridization 
ITT 
intent to treat 
IV 
intravenous 
LD 
longest diameter 
LVEF 
left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
myocardial infarction 
MRI 
magnetic resonance imaging 
MUGA 
multigated acquisition 
NCCN 
National Comprehensive Cancer Network 
NE 
not evaluable 
NCI 
National Cancer Institute 
NL 
new lesion 
NSCLC 
non-small cell lung cancer 
NTL 
non-target lesion 
OATP 
organic anion-transporting polypeptide 
ORR 
objective response rate 
OS 
overall survival 
OTC 
over-the-counter 
PD 
progressive disease 
PD-L1 
programmed cell death ligand 1 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PR 
partial response 


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ABBREVIATION 
DEFINITION 
PRO 
patient-reported outcome 
PT 
preferred term 
PTX 
paclitaxel 
QoL 
quality-of-life 
QTc 
QT interval corrected for heart rate 
Ram 
ramucirumab 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RES 
Response Evaluable Set 
RT-PCR 
reverse transcription polymerase chain reaction 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SAVER 
Serious Adverse Event Report 
SD 
stable disease 
SID 
subject identification  
SoC 
standard of care 
SOC 
system organ class 
SOP 
standard operating procedure 
SpO2 
peripheral oxygen saturation 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
terminal elimination half-life 
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse event 
TL 
target lesion 
Tmax 
time of maximum plasma/serum concentration (Cmax) 
ToGA 
Trastuzumab for Gastric Cancer [study] 
ULN 
upper limit of normal 
US 
United States 
VAS 
visual analogue scale 
vs. 
versus 
VSS 
volume of distribution at steady-state 
WBRT 
whole brain radiotherapy 
WHO 
World Health Organization 


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1. 
INTRODUCTION 
1.1. 
Background  
1.1.1. 
Overview of the Disease 
Gastric cancer (GC) is the fifth most common cancer worldwide and the third leading cause of 
cancer-related deaths according to the most recent GLOBOCAN epidemiological estimates: in 
2018, 1,605,735 (1,033,701 stomach, 572,034 esophageal) new cases were reported globally, 
representing 8.8% of all cancers.1  Among all geographical regions in the world, the highest 
incidence of GC is observed in Eastern Asian countries, particularly in China (with nearly half of 
the world cases), Japan, and Korea.1  In 2018, based on GLOBOCAN data, there were an 
estimated 763,483 new cases of GC in China (673,615 deaths due to GC); 135,565 new GC 
cases in Japan (50,539 deaths); and 6567 new GC cases in South Korea (4856 deaths).  In 
comparison, 46,090 new cases (27,504 deaths) were reported in 2018 in the United States (US) 
and 186,097 new cases (47,228 deaths) in Europe.  The GLOBOCAN estimates for the US are 
similar to those from the American Cancer Society, which estimated 43,530 patients newly 
diagnosed with GC in the US in 2018, with an estimated 27,650 deaths.2,3  
Worldwide, GC is more frequent in men than in women.  In Japan, it remains the most common 
type of cancer among men.2  In Japan and South Korea, where screening is widely performed, 
early detection is often possible.  However, in approximately 50% of patients, GC is diagnosed at 
an advanced stage, with a poor outcome.2  
Human epidermal growth factor receptor 2 (HER2) gene amplification or protein expression has 
been associated with gastric and gastro-esophageal junction (GEJ) cancer, with authors reporting 
rates of HER2 amplification varying from 12% to 27% and HER2 overexpression of 9% to 
23%.2  The impact of HER2 status on survival outcomes in patients with GC remains unclear, 
with some analyses suggesting HER2 positivity is associated with a poor outcome,4,5,6,7 while 
others did not demonstrate any prognostic significance to HER2 overexpression.8,9,10  
Nevertheless, the HER2 status in patients with GC has important clinical implications in the 
management of patients with advanced or metastatic disease, and HER2 testing is recommended 
for all patients with metastatic GC at the time of diagnosis.2  
For patients with HER2 overexpressing locally advanced or metastatic gastric adenocarcinoma 
and a tumor score of 3+ by immunohistochemistry (IHC), or IHC 2+ and evidence of HER2 
amplification by fluorescent in-situ hybridization (FISH), the addition of trastuzumab to first-line 
chemotherapy is now part of standard of care (SoC) after its efficacy was demonstrated in the 
Trastuzumab for Gastric Cancer (ToGA) trial.11  In the ToGA trial, the addition of trastuzumab 
to chemotherapy resulted in significant improvement in median overall survival (OS) in the 
trastuzumab-plus-chemotherapy arm as compared to the chemotherapy-alone arm, with a 26% 
decrease in the death rate (hazard ratio [HR]: 0.74; 95% confidence interval [CI]: 0.60, 0.91; 
P-value = 0.0046).  The median OS was 13.8 months (95% CI: 12, 16) in the 
trastuzumab-plus-chemotherapy arm versus (vs.) 11.1 months (95% CI: 10, 13) in the 
chemotherapy-alone arm, without a clinically meaningful difference in toxicity between arms.  
However, unlike the results seen in patients with breast cancer, pertuzumab (PERJETA®) did not 
increase benefit when added to the SoC in first-line HER2-positive GC patients.12  


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There is no established molecular-based patient-enriched treatment option for advanced GC in 
the second-line setting globally.  After progression on first-line HER2-targeted systemic 
treatment, therapeutic options are limited and include cytotoxic systemic therapy, clinical trial or 
best supportive care (BSC).  Chemotherapy may improve symptoms, survival, and quality-of-life 
(QoL) compared with BSC alone.12  
Preferred regimens in second-line therapy for metastatic or locally advanced GC based on the 
National Comprehensive Cancer Network (NCCN) guidelines include ramucirumab (Ram)41 and 
paclitaxel (PTX)43 as single agents or in combination, as well as irinotecan and docetaxel as 
single agents.  Fluorouracil and irinotecan may also be considered as a second-line option 
provided they were not used in first line.2  
Overall, the prognosis of patients who failed first-line therapy is poor, with median survival 
ranging approximately from 5.0 to 9.0 months based on published studies.  In the Phase 3 
WJOG4007 study comparing treatment with weekly PTX (n = 108) and biweekly irinotecan 
(n = 111) in patients with advanced GC refractory to treatment with fluoropyrimidine plus 
platinum, there was no statistically significant difference between the 2 treatment arms with 
regard to median OS.13  The median OS was 9.5 months in the PTX arm and 8.4 months in the 
irinotecan arm (HR = 1.13 [95% CI: 0.86, 1.49]; P-value = 0.38).  The median progression-free 
survival (PFS) was 3.6 months in the PTX arm and 2.3 months in the irinotecan arm (HR = 1.14 
[95% CI: 0.88, 1.49]; P-value = 0.33); and the objective response rate (ORR) was 20.9% in the 
PTX arm and 13.6% in the irinotecan arm (P-value = 0.24). 
Ramucirumab, a vascular endothelial growth factor receptor 2 (VEGFR 2) antibody of the family 
of VEGFR receptor tyrosine kinases involved in angiogenesis, was approved by the Food and 
Drug Administration (FDA) for the treatment of patients with advanced gastric or GEJ cancer 
refractory to, or progressive following, first-line therapy with platinum- or 
fluoropyrimidine-based chemotherapy, based on the results of 2 randomized Phase 3 trials, 
REGARD (Ram vs. placebo) and RAINBOW (Ram + PTX vs. PTX-alone).14,15 41 
In the REGARD trial, 355 patients with advanced gastric or GEJ cancer that had progressed after 
first-line therapy were randomized to Ram or placebo.14  The median OS was 5.2 months in 
patients on Ram vs. 3.8 months in patients on placebo (P-value = 0.047).  A higher proportion of 
patients on Ram experienced hypertension compared to patients on placebo (16% vs. 8%).   
In the RAINBOW trial (665 patients), combination therapy with Ram + PTX resulted in a 
statistically significant longer median OS as compared with PTX-alone (9.6 months vs. 
7.4 months; P-value < 0.0001); a median PFS of 4.4 months (Ram + PTX) vs. 2.9 months 
(PTX-alone); and a statistically significant difference in ORR in favor of the Ram + PTX 
combination vs. PTX-alone (28% vs. 16%, respectively; P-value = 0.0001).15  Neutropenia and 
hypertension were more frequent in the Ram + PTX combination arm than in the PTX-alone 
arm.   
Subgroup analyses by region were conducted in Western (n = 398) and Japanese (n = 140) 
patients enrolled in the RAINBOW trial.16  In the Western population, the median OS was 
8.6 months (interquartile range [IQR]: 4.7, 13.6) in the Ram + PTX arm (n = 198) vs. 5.9 months 
(IQR: 3.1, 11.0) in the PTX-alone (n = 200) arm (HR: 0.73 [95% CI: 0.58, 0.91]; 
P-value = 0.0050 [stratified]).  The median PFS was 4.2 months in the Ram + PTX arm vs. 
2.8 months in the PTX-alone arm (HR: 0.631 [95% CI: 0.506, 0.786]; P-value < 0.0001 


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[stratified]); and the ORR was 26.8% (95% CI: 21.1, 33.3) in the Ram + PTX arm vs. 13.0% 
(95% CI: 9.0, 18.4) in the PTX-alone arm (P-value = 0.0004).  
In further studies in patients with advanced GC in second-line therapy conducted to date, 
potential chemotherapeutic regimens failed to improve the clinical outcomes over existing 
second-line options.17,18 
In the GATSBY study, a randomized, open-label, adaptive, Phase 2/3 study of trastuzumab 
emtansine vs. taxane (docetaxel or PTX) as second-line therapy in patients with unresectable, 
locally advanced or metastatic HER2-positive GC including GEJ cancer, trastuzumab emtansine 
was not superior to taxane.18  The median OS was 7.9 months (95% CI: 6.7, 9.5) with 
trastuzumab emtansine (2.4 mg/kg weekly) vs. 8.6 months (95% CI: 7.1, 11.2) with taxane (HR: 
1.15 [95% CI: 0.87, 1.51]; P-value = 0.86).  Treatment with trastuzumab emtansine resulted in 
fewer patients with ≥ Grade 3 adverse events (AEs) than with taxane, with a similar proportion 
of patients with serious AEs (SAEs), AEs resulting in death, and AEs leading to treatment 
discontinuation in both treatment arms.   
Similarly, in the Ty-TAN study, a randomized, Phase 3 study of lapatinib (an anti-HER2 agent) 
plus PTX vs. PTX-alone in Asian patients with advanced GC in second-line therapy, the addition 
of lapatinib to the standard PTX regimen did not result in a statistically significant difference in 
clinical outcomes.  The median OS was 11.0 months in the lapatinib-plus-PTX arm vs. 
8.9 months in the PTX-alone arm (P-value = 0.0144), with no significant difference between 
arms in median PFS (5.4 and 4.4 months, respectively).  The ORR was higher in the 
lapatinib-plus-PTX arm than in the PTX-alone arm (odds ratio: 3.85; P-value < 0.001).  
Therefore, unlike treatments for breast cancer, trastuzumab emtansine and lapatinib have not 
been approved in GC, and there is no established HER2-targeting drug for GC after treatment 
with a trastuzumab-containing regimen. 
In September 2017, the FDA granted accelerated approval to pembrolizumab for the treatment of 
patients with programmed cell death ligand 1 (PD-L1)-positive recurrent or advanced gastric or 
GEJ cancer who have received 2 or more lines of chemotherapy, including fluoropyrimidine- and 
platinum-containing chemotherapy, and if appropriate, HER2/neu-targeted therapy.  However, 
the Phase 3 study of pembrolizumab vs. PTX as second-line therapy in 592 patients with 
advanced PD-L1-positive gastric or GEJ adenocarcinoma who progressed on first-line therapy 
with platinum and fluoropyrimidine doublet therapy (KEYNOTE-061 trial) failed to show an 
improvement in OS and PFS vs. PTX alone.19  
In summary, patients with advanced GC who fail first-line chemotherapy (with or without 
trastuzumab) have a poor survival outcome and limited therapeutic options.  There is a 
significant unmet medical need in this patient population, and a molecular-based approach is 
required. 
1.1.2. 
The Investigational Product: Trastuzumab Deruxtecan 
1.1.2.1. 
Description  
Trastuzumab deruxtecan (, also known as fam-trastuzumab deruxtecan) is a novel HER2-
targeting antibody-drug conjugate (ADC) composed of an antibody component, MAAL-9001, 
covalently conjugated to a drug component, MAAA-1181a, through an enzyme-cleavable 


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maleimide tetrapeptide linker, MAAA-1162a.  The antibody component, MAAL-9001, is a 
recombinant humanized anti-human HER2 immunoglobulin G1 monoclonal antibody with the 
same amino acid sequence as trastuzumab.  The drug component, MAAA-1181a, an exatecan 
derivative, is a novel topoisomerase I inhibitor permeable to the cell membrane and more potent 
than SN-38, the active metabolite of irinotecan.20, 21  Trastuzumab deruxtecan has a high 
drug-to-antibody ratio (approximately 8) when compared with trastuzumab emtansine 
(Figure 1.1).   
Figure 1.1: 
Trastuzumab Deruxtecan Structure 
 
In studies of mechanism of action, trastuzumab deruxtecan was shown to induce HER2-mediated 
inhibition of Akt phosphorylation and to exhibit antibody-dependent cellular cytotoxic activities.  
After binding to the HER2 receptor, trastuzumab deruxtecan is internalized in tumor cells, 
cleaved by lysosomal enzymes, and releases MAAA-1181a in the cytoplasm.  The released drug 
MAAA-1181a inhibits topoisomerase I, causing deoxyribonucleic acid (DNA) damage and 
leading to apoptosis of the target cells.  Thus, trastuzumab deruxtecan exhibits HER2-specific 
cell growth inhibition and antitumor activity via a novel mechanism of action that combines the 
pharmacological activities of MAAL-9001, the antibody component, with those of 
MAAA-1181a, the drug component. 
In preclinical studies, trastuzumab deruxtecan has shown antitumor activity in a broad spectrum 
of tumor types across a range of high and low HER2-expressing tumors.20  
1.1.2.2. 
Clinical Experience in Gastric Cancer 
Encouraging findings from the dose-escalation part of an ongoing, first-in-human, 2-part, 
open-label, Phase 1 trial of trastuzumab deruxtecan (Study DS8201-A-J101) conducted in 
heavily-pretreated subjects with breast or gastric and GEJ carcinomas refractory to standard 
therapy, regardless of HER2 status, showed trastuzumab deruxtecan had antitumor activity even 
in low HER2-expressing tumors.  The maximum tolerated dose in the dose-escalation phase was 
not reached.22  Based on the Part 1 results of the study, doses of 5.4 mg/kg and 6.4 mg/kg were 


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selected for the dose-expansion phase of the study; a dose of 6.4 mg/kg was finally selected for 
Phase 2 and subsequent studies in HER2-positive GC patients. 
These promising findings from dose-escalation were replicated at the interim analysis of the 
dose-expansion part of the study, which included a cohort of subjects with advanced 
HER2-positive GC previously treated with trastuzumab (cohort 2b).23   
The efficacy results for all subjects with HER2-positive gastric/GEJ cancer as of the data cutoff 
date of 01 Feb 2019, are summarized in Table 1.1. 
Median duration of follow-up was 8.3 months (range: 1.4 months to 34.1 months). 
In the Enrolled Analysis Set, a confirmed ORR by ICR of 29.5% (95% CI: 16.8 to 45.2) was 
observed in subjects with gastric/GEJ cancer at doses of 5.4 mg/kg (26.3% [95% CI: 9.1 to 
51.2]) or 6.4 mg/kg (32.0% [95% CI: 14.9 to 53.5]).  In all subjects with gastric/GEJ cancer, 
13 subjects had BORs of complete response (CR) (1 [2.3%] subject) or PR (12 [27.3%] 
subjects). 
The median time to response was 1.7 months (95% CI: 1.4 to 2.8), which corresponded to the 
first postbaseline scan.  Among subjects who did not achieve a response, the majority still 
showed tumor regression with best response of stable disease.   
The median confirmed DoR based on ICR (calculated using the KM method) was 5.8 months in 
subjects with HER2-positive gastric/GEJ cancer who received 1 of the doses of 5.4 mg/kg or 
6.4 mg/kg.  Of the 13 subjects with confirmed response by ICR assessment who received 
5.4 mg/kg or 6.4 mg/kg, 8 (61.5%) subjects had progressed and none had died as of the data 
cutoff.  Based on the KM estimate of confirmed CR/PR by ICR assessment, the estimated 
proportion of subjects remaining in response was 44.0% at 6 months and 22.0% at 12 months 
and 18 months. 
At the time of the data cutoff, 30 of 44 (68.2%) subjects had PD based on ICR assessment and/or 
death.  The median PFS by ICR was 5.4 months (95% CI: 4.1 to 8.5) in all subjects with HER2 
positive gastric/GEJ cancer at doses of 5.4 mg/kg or 6.4 mg/kg.  
At the time of data cutoff, 18 of 44 (40.9%) subjects in the Enrolled Analysis Set had died.  The 
median OS was 20.2 months in all subjects with HER2-positive gastric/GEJ cancer at doses of 
5.4 mg/kg or 6.4 mg/kg.  Based on the KM analysis, the estimated proportion of subjects alive 
were 79.3% at 6 months, 58.0% at 12 months and 18 months, and 41.0% at 24 months.  
Overall, 41 of 44 (93.2%) subjects with HER2-positive gastric/GEJ cancer at doses of 5.4 mg/kg 
or 6.4 mg/kg had baseline and postbaseline tumor assessments by ICR.  The mean tumor 
shrinkage of target lesions was -27.22% (33.525).  Most subjects had tumor shrinkage by ICR 
(75.6% [31/41]), all of which occurred at the first postbaseline tumor assessment. 
Similarly, a dose of 6.4 mg/kg is the recommended dose for HER2-positive gastric cancer (GC) 
in the DS8201 A-J202 study and the planned dose for further clinical studies in HER2-positive 
GC.  
Further information on the efficacy and safety of trastuzumab deruxtecan in ongoing studies to 
date is available in the latest version of the Investigator’s Brochure (IB)21 . 


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Table 1.1: 
Efficacy Results in HER2-Positive Gastric/Gastro-esophageal Junction 
Cancer in Study DS8201-A-J101 (Enrolled Analysis Set) 
Efficacy Variable 
HER2-Positive Gastric/GEJ Cancer 
5.4 mg/kg 
(N = 19) 
6.4 mg/kg 
(N = 25) 
Total 
(N = 44) 
Confirmed ORR, n (%) (95% CIa) 
ORR by ICR 
5 (26.3) 
(9.1, 51.2) 
8 (32.0) 
(14.9, 53.5) 
13 (29.5) 
(16.8, 45.2) 
ORR by investigator 
6 (31.6) 
(12.6, 56.6) 
13 (52.0) 
(31.3, 72.2) 
19 (43.2) 
(28.3, 59.0) 
ORR by ICR in response evaluable set, n/N 
5/18 (27.8) 
(9.7, 53.5) 
8/23 (34.8) 
(16.4, 57.3) 
13/41 (31.7) 
(18.1, 48.1) 
Confirmed best overall response by ICR, n (%) 
CR 
0 
1 (4.0) 
1 (2.3) 
PR 
5 (26.3) 
7 (28.0) 
12 (27.3) 
Stable disease 
10 (52.6) 
14 (56.0) 
24 (54.5) 
PD 
4 (21.1) 
3 (12.0) 
7 (15.9) 
NE 
0 
0 
0 
Confirmed best overall response by investigator, n (%) 
CR 
0 
0 
0 
PR 
6 (31.6) 
13 (52.0) 
19 (43.2) 
Stable disease 
10 (52.6) 
7 (28.0) 
17 (38.6) 
PD 
3 (15.8) 
5 (20.0) 
8 (18.2) 
NE 
0 
0 
0 
Confirmed DoR, medianb (95% CI) (months) 
DoR by ICR 
5.6 
(2.9, -) 
6.9 
(3.5, -) 
5.8 
(3.5, -) 
DoR by investigator 
7.1 
(3.0, -) 
7.0 
(3.9, 12.2) 
7.1 
(4.7, 12.2) 
Confirmed DCR,c n (%) (95% CIa) 
DCR by ICR 
15 (78.9) 
(54.4, 93.9) 
22 (88.0) 
(68.8, 97.5) 
37 (84.1) 
(69.9, 93.4) 
DCR by investigator 
16 (84.2) 
(60.4, 96.6) 
20 (80.0) 
(59.3, 93.2) 
36 (81.8) 
(67.3, 91.8) 
Time to response by ICR, medianb (95% CI) (months) 
1.6 (1.2, 3.1) 
2.2 (1.4, 2.9) 
1.7 (1.4, 2.8) 
Duration of confirmed stable disease by ICR, medianb 
(95% CI) (months) 
4.3 (2.5, 11.4) 
6.6 (2.6, 11.2) 
4.4 (4.1, 11.0) 
PFS 
 
 
 
PFS by ICR 
 
 
 
Events, n (%) 
15 (78.9) 
15 (60.0) 
30 (68.2) 
Medianb (95% CI) (months) 
4.3 (2.6, 8.6) 
8.2 (4.2, 11.0) 
5.4 (4.1, 8.5) 
PFS by investigator 
 
 
 
Events, n (%) 
15 (78.9) 
21 (84.0) 
36 (81.8) 
Medianb (95% CI) (months) 
4.4 (2.5, 5.9) 
6.6 (2.8, 8.4) 
5.6 (3.0, 8.4) 


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Efficacy Variable 
HER2-Positive Gastric/GEJ Cancer 
5.4 mg/kg 
(N = 19) 
6.4 mg/kg 
(N = 25) 
Total 
(N = 44) 
Overall survival 
 
 
 
Events, n (%) 
9 (47.4) 
9 (36.0) 
18 (40.9) 
Medianb (95% CI) (months) 
18.9 (5.7, -) 
26.2 (10.0, -) 
20.2 (10.0, -) 
Survival at 6 months, % (95% CId) 
77.0 
(49.7, 90.7) 
81.3 
(57.6, 92.6) 
79.3 
(62.8, 89.1) 
Survival at 12 months, % (95% CId) 
54.0 
(25.8, 75.6) 
61.3 
(34.2, 80.1) 
58.0 
(38.7, 73.2) 
Survival at 18 months, % (95% CId) 
54.0 
(25.8, 75.6) 
61.3 
(34.2, 80.1) 
58.0 
(38.7, 73.2) 
Survival at 24 months, % (95% CId) 
33.8 
(9.8, 60.2) 
51.1 
(23.0, 73.6) 
41.0 
(20.8, 60.3) 
CI = confidence interval; CR = complete response; DCR = disease control rate; DoR = duration of response; 
GEJ = gastro-esophageal junction; HER2 = human epidermal growth factor receptor 2; ICR = independent central 
review; NE = non-evaluable; ORR = objective response rate; PD = progressive disease; PFS = progression-free 
survival; PR = partial response  
a 95% exact binomial CI. 
b Median is from Kaplan-Meier estimate.  CI for median was computed using the Brookmeyer-Crowley method. 
c DCR was calculated as the proportion of subjects demonstrating CR, PR, or stable disease for a minimum of 
6 weeks (±1 week) from the first dosing date. 
d CI for the rate at a fixed time point was computed by applying asymptotic normality to the log-log transformation 
of the rate. 
Dashes (-) represent data that are not estimable 
The range includes the censored observations where using “+” after the value indicates censoring.  Months were 
days × 12 / 365.25. 
Part 1 (5.4 mg/kg and 6.4 mg/kg) and Part 2 subjects are included. 
Data cutoff date: 01 Feb 2019.   
Source: Preliminary data as of 01 Feb 2019. 
1.1.2.3. 
Safety Information 
1.1.2.3.1. Nonclinical Safety Information 
In telemetered male cynomolgus monkeys treated with single IV doses of trastuzumab 
deruxtecan, no effects on the cardiovascular, respiratory, or central nervous systems (CNS) were 
observed at dose levels up to 78.8 mg/kg.  In addition, in human ether-a-go-go-related gene 
(hERG) studies of MAAA-1181d, monohydrate of MAAA-1181a, MAAA 1181d did not inhibit 
the hERG channel current at concentrations of up to 10 µmol/L (approximately 5000 ng/mL). 
1.1.2.3.2. Clinical Safety Information 
As of 08 Jun 2019, 3 clinical studies (Studies DS8201-A-J102, DS8201-A-A103, and 
DS8201-A-A104) were completed, and 9 clinical studies (Studies DS8201-A-J101, 
DS8201-A-U201, DS8201-A-J202, DS8201-A-J203, DS8201-A-U204, DS8201-A-U105, 
DS8201-A-U301, DS8201-A-U302, and DS8201-A-U303) were ongoing, with an estimated 
1036 subjects exposed.   


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Further information on the safety of trastuzumab deruxtecan in ongoing studies to date is 
available in the latest version of the IB21.  
DS8201-A-J101 study 
As of the data cutoff date of 01 Feb 2019, there were 289 subjects in total who received at least 
1 dose of trastuzumab deruxtecan (27 subjects during the Dose Escalation Phase [Part 1] and 
262 subjects during the Dose Expansion Phase [Part 2]) across all tumor types and doses.  
Median duration of treatment across all tumor types and doses is 7.4 months, and 25.3% of 
subjects had ≥12 months of treatment.  Across tumor types by dose, the median duration of 
treatment was similar between 5.4 mg/kg (7.1 months) and 6.4 mg/kg (7.8 months).  Median 
duration of treatment was longest in HER2-positive breast cancer (8.5 months in subjects dosed 
with 5.4 mg/kg and 9.0 months in subjects dosed with 6.4 mg/kg). 
No dose limiting toxicity (DLT) was reported, and the maximum tolerated dose (MTD) was not 
reached in the Dose Escalation Phase. 
A total of 288 (99.7%) subjects experienced at least 1 TEAE, with most of the common TEAEs 
being gastrointestinal or hematological in nature.   
 Gastrointestinal: Nausea was most frequently reported, was predominantly Grade 1 or 
Grade 2, occurred early in the treatment (the majority occurring in the first 1 to 
3 cycles), and was manageable under routine clinical practice.  The median time to 
event onset was 3.0 days for nausea, 11.0 days for vomiting, and 26.5 days for 
diarrhea. 
 Hematological: Events were predominantly Grade 1 or Grade 2, occurred early in 
treatment (the majority occurring in the first 1 to 3 cycles), and were manageable 
under routine clinical practice.  Platelet count decrease (grouped term for preferred 
terms [PTs] platelet count decreased and thrombocytopenia) was commonly seen, 
with 11.8% of subjects having events of Grade 3 or above.  The median time to onset 
was 9.0 days for platelet count decrease, 41.0 days for neutrophil count decrease 
(grouped term including PTs of neutropenia and neutrophil count decreased), and 
30.5 days for anemia (grouped term including PTs of anaemia, hemoglobin 
decreased, and red blood cell count decreased).  The time to onset for febrile 
neutropenia ranged from 11 days to 326 days. 
DS8201-A-U201 study 
As of the data cutoff date of 21 Mar 2019, there were 253 subjects in the 5.4-mg/kg, 6.4-mg/kg, 
and 7.4-mg/kg dose cohorts who received at least 1 dose of trastuzumab deruxtecan.  The safety 
evaluation for this study mainly focuses on the 184 subjects in Parts 1, 2a, and 2b who received 
the recommended dose of trastuzumab deruxtecan at 5.4 mg/kg (overall 5.4-mg/kg dose cohort 
hereafter). 
The overall median treatment duration (interval between last dose and first dose) was 
7.0 months.  In the overall 5.4-mg/kg dose cohort, the median treatment duration was 
6.9 months. 


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Overall, most subjects (252 of 253 [99.6%] subjects) experienced at least 1 TEAE, with 
250 (98.8%) subjects having at least 1 drug-related TEAE based on the investigator’s 
assessment. 
Further information on the safety of trastuzumab deruxtecan in ongoing studies to date is 
available in the latest version of the IB21. 
1.1.2.3.3. Interstitial Lung Disease/Pneumonitis 
Based on the cumulative review of the safety data including available nonclinical, clinical, 
epidemiologic information, and scientific literature (published and unpublished), and taking into 
consideration biological plausibility, ILD/pneumonitis, which was previously classified as an 
important potential risk was reclassified as an important identified risk.   
For latest clinical data, refer to IB. 
An independent ILD Adjudication Committee for the trastuzumab deruxtecan 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. This additional data collection will cover a more 
in-depth relevant medical history (eg, smoking, radiation, COPD and other chronic 
lung conditions), diagnostic evaluation, treatment and outcome of the event. This data collection 
will be triggered for adverse events (AEs) reported by using selected 42 Preferred Terms [all 
from the  ILD Standard MedDRA Query (SMQ)] plus 2 PTs of acute respiratory failure and 
respiratory failure.  
1.1.2.3.3.1. Left Ventricular Ejection Fraction Decrease  
Based on the cumulative review of the safety data including available nonclinical, clinical, 
epidemiologic information,  scientific literature (published and unpublished) including literature 
from products in the same class, left ventricular ejection fraction (LVEF) decrease is considered 
to be important potential risk associated with trastuzumab deruxtecan.   
For latest clinical data, refer to the IB21. 
1.1.2.3.4. Anemia, Neutrophil Count Decrease (including febrile neutropenia), and Platelet 
Count Decrease 
Anemia, neutrophil count decrease (including febrile neutropenia), and platelet count decrease 
are considered to be important identified risks, based on available preclinical, clinical, and 
literature review of products of similar class. 
For latest clinical data, refer to the IB21. 
1.1.2.4. 
Intended Use Under Investigation 
This study will investigate the efficacy of trastuzumab deruxtecan in subjects with 
HER2-positive unresectable or metastatic gastric or GEJ adenocarcinoma that has progressed on 
or after a prior trastuzumab-containing regimen when treated in an advanced setting. 


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1.1.2.5. 
Comparator Regimen 
Not applicable 
1.1.2.6. 
Clinical Pharmacokinetics 
As of 08 Jun 2019, PK data were available for 3 completed clinical studies for trastuzumab 
deruxtecan (Studies DS8201 A J102, DS8201-A-A103, and DS8201 A A104), and preliminary 
PK data were also available for 2 ongoing clinical studies (Studies DS8201-A-J101 and 
DS820-A-U201).  PK data for the ongoing studies are provided as follows. (Please refer to the 
IB21 for PK data from the completed studies). 
DS8201-A-J101 (Ongoing) 
Preliminary PK data from the Dose Escalation part of the study as of 01 Feb 2019 show that the 
trastuzumab deruxtecan Cmax was dose proportional across the dose range of 0.8 mg/kg to 
8.0 mg/kg.  The area under the serum concentration-time curve up to the last quantifiable time 
(AUClast) increased greater than dose proportionally from 0.8 mg/kg to 3.2 mg/kg and then 
increased dose proportionally from 3.2 mg/kg and above.  The total anti-HER2 antibody 
exposure was similar to trastuzumab deruxtecan.  On a molar basis, the trastuzumab deruxtecan 
exposures at the 5.4-mg/kg dose were approximately 39-fold to 44-fold higher than those for 
MAAA 1181a. 
Preliminary PK data from the Dose Expansion part of the study as of 01 Feb 2019 showed that 
the trastuzumab deruxtecan, total anti-HER2 antibody, and MAAA-1181a exposures were 
similar between HER2-positive and HER2-low breast cancer.  The trastuzumab deruxtecan and 
total anti-HER2 antibody exposures appeared to be numerically lower in HER2-positive GEJ 
cancer than in breast cancer.  MAAA-1181a exposures were consistent across all tumor types 
evaluated. 
DS8201-A-U201 (Ongoing) 
Preliminary PK data as of 21 Mar 2019 showed that the ratio of trastuzumab deruxtecan and total 
anti-HER2 antibody was approximately 1 for Cmax and approximately 0.8 for areas under the 
plasma concentration-time curves (AUC) and trough concentrations.  The serum concentrations 
of MAAA-1181a gradually increased and reached peak concentrations, with longer median 
Tmax (approximately 7 hours) than those for trastuzumab deruxtecan (approximately 4 hours).  
On a molar basis, the trastuzumab deruxtecan Cmax and trough concentrations were 
approximately 54-fold and 74-fold higher, respectively, than those for MAAA-1181a.  These 
results demonstrate the in vivo stability of the ADC. 
For further details related to the clinical PK of trastuzumab deruxtecan, please see the latest 
version of the IB.21   
1.2. 
Study Rationale 
Gastric cancer is diagnosed at an advanced stage in approximately 50% of patients, when it has a 
poor outcome (details in Section 1.1.1).2  Overexpression or amplification of HER2 has been 
reported in approximately 15% of gastric or GEJ tumors.  The tumor’s HER2 status has 
important clinical implications in the management of patients with metastatic disease, and HER2 


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testing is recommended at the time of diagnosis for all patients with metastatic GC.  In first-line 
therapy for advanced GC, preferred regimens based on NCCN guidelines include combination of 
a fluoropyrimidine and cisplatin or oxaliplatin.  For patients with HER2-overexpressing 
metastatic adenocarcinoma and tumor score of 3+ by IHC, or IHC 2+ and evidence of HER2 
amplification by the in-site hybridization (ISH) method, the addition of trastuzumab to first-line 
chemotherapy is now part of SoC after its efficacy was demonstrated in the ToGA trial.2, 11  
There is no established targeted therapy for HER2-positive advanced GC in the second-line 
setting after progression on first-line treatment with a trastuzumab-containing regimen.  
Preferred second-line regimens for metastatic or locally advanced GC include Ram + PTX (as 
single agents or in combination) or other chemotherapeutic agents as detailed in Section 1.1.1.  
Further studies of potential chemotherapeutic regimens in patients with HER2-positive advanced 
GC in second-line therapy conducted to date failed to improve the clinical outcomes over 
existing second-line treatment options.1, 18  Thus, patients with HER2-positive advanced GC who 
fail first-line chemotherapy have no molecular-based patient-enriched treatment options.  As the 
survival outcome for these patients is generally poor, there is a high unmet medical need for this 
patient population. 
Preliminary clinical data from Phase 1 study DS8201-A-J101 of trastuzumab deruxtecan in 
45 heavily-pretreated subjects with HER2-positive gastric or GEJ adenocarcinoma who had 
received trastuzumab show encouraging efficacy, with an acceptable safety profile (details in 
Section 1.1.2.2).  Similar preliminary results were seen in subjects who had also received prior 
CPT-11 treatment.23 
Given the results from the interim analysis of study DS8201-A-J101, trastuzumab deruxtecan, 
administered earlier during treatment (in the second-line setting), may further improve the 
survival outcome of patients with HER2-positive GC and compare favorably with the SoC 
treatment, Ram + PTX.   
For targeted therapy to be efficacious, it is important that tumor cells express the target receptor.  
In the GC patient population, HER2 protein down-regulation is reported in 30% to 60% of 
patients after trastuzumab-containing therapy.25, 26, 27  This loss of HER2 expression after 
treatment with trastuzumab may be the potential mechanism for resistance to future 
HER2-targeted therapy in GC patients.  Enrollment in the Phase 1 DS8201-A-J101 trial was 
based on the tumor locally confirmed HER2 status from archival tissue and most subjects had 
received additional chemotherapy after progression on or after a trastuzumab-containing regimen 
and prior to study enrollment.  In contrast, the DS8201-A-U205 trial is enrolling subjects who 
have progressed on or after a trastuzumab-containing regimen and have not received any 
additional systemic therapy.  Thus, it is important to ensure the tumor is still HER2 positive 
based on tissue biopsy after a trastuzumab-containing regimen in order for the study subjects to 
expect to receive benefit from trastuzumab deruxtecan treatment.   
The sample size was 80 subjects in the original protocol to accommodate dropouts or loss to 
follow-ups.  Seventy-two is the number of targeted subjects without considering any potential 
dropouts. 
This is a Phase 2 trial to determine the efficacy and safety of trastuzumab deruxtecan in subjects 
with advanced or metastatic HER2-positive gastric or GEJ cancer who have previously 
progressed on or after a trastuzumab-containing regimen. 


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1.3. 
Risks and Benefits for Study Subjects 
Trastuzumab deruxtecan is being developed for the treatment of HER2-expressing malignant 
tumors.  Nonclinical studies have demonstrated a potent antitumor activity of trastuzumab 
deruxtecan in tumor-bearing mouse models.  Based on the preliminary clinical observations in 
the Phase 1 study (DS8201-A-J101), trastuzumab deruxtecan demonstrates antitumor activity in 
HER2 expressing cancers including GC.  As of 08 Jun 2018, the HER2-positive GC cohort had 
an ORR of 43.2% and a DCR of 79.5%.21, 24 
As of 01 Feb 2019 from Study DS8201-A-J101, the overall efficacy results in subjects with 
HER2-positive breast cancer at 5.4 mg/kg or 6.4 mg/kg demonstrated a confirmed ORR by ICR 
of 52.5%.  Among the subjects with HER2-low breast cancer, confirmed ORR by ICR was 
37.0%.  The overall efficacy results in subjects with HER2-positive gastric/GEJ cancer at 
5.4 mg/kg or 6.4 mg/kg demonstrated a confirmed ORR by ICR of 29.5%.  The overall efficacy 
results in subjects with other cancers demonstrated a confirmed ORR by ICR of 29.5%. 
The most frequently reported TEAEs (at least 20% of subjects) in Study DS8201-A-J101 were 
gastrointestinal or hematological in nature. See Section 1.1.2.3.2.  The majority of the TEAEs 
were Grade 1 or Grade 2 in severity based on the Common Terminology Criteria for Adverse 
Event (CTCAE) v5.0.  Overall, the study-reported AEs are manageable and consistent with the 
expected safety profile of trastuzumab deruxtecan based on data available from nonclinical 
toxicology studies as well as from drugs of similar class.   
Based on the cumulative review of the safety data, including available nonclinical, clinical, and 
epidemiologic information and scientific literature (published and unpublished) and taking into 
consideration biological plausibility, ILD, anemia, neutrophil count decrease including febrile 
neutropenia, and platelet count decrease are classified as important identified risks. LVEF 
decrease is classified as an important potential risk. Infusion-related reactions, which were 
previously classified as an important potential risk, are reclassified as an identified risk. QT 
prolongation is no longer considered an important potential risk and has been removed from the 
list of safety concerns for trastuzumab deruxtecan.  
In the trastuzumab deruxtecan clinical program, the inclusion/exclusion criteria and 
monitoring/management guidelines are currently in place in all protocols to mitigate the 
important identified risks of ILD, anemia, neutrophil count decrease including febrile 
neutropenia, and platelet count decrease, and important potential risk of LVEF decrease.  
ILD is a known serious risk of trastuzumab deruxtecan, and cases with fatal outcomes have been 
reported. Most events were Grade 1 or Grade 2 and were manageable by dose modification and 
following clinical treatment guidelines for drug-induced ILD, with specific recommendations 
including close monitoring of signs/symptoms of ILD (eg, cough, fever, and dyspnea) to identify 
potential ILD and proactively managing ILD with dose modification and treatment (eg, steroids). 
ILD requires proper monitoring, dose modification, and supportive care instituted in a timely 
fashion.  
Other identified risks of trastuzumab deruxtecan in order of descending frequencies are nausea, 
decreased appetite, alopecia, vomiting, fatigue, constipation, diarrhoea, WBC count decrease, 
stomatitis, aspartate aminotransferase increased, cough, headache, abdominal pain, alanine 


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aminotransferase increased, hypokalaemia, epistaxis, dyspnoea, dyspepsia, dizziness, dry eye, 
upper respiratory tract infection, asthenia, and infusion-related reactions.  
These identified risks were generally manageable through dose modification and routine clinical 
practice.  
Trastuzumab deruxtecan has demonstrated a generally acceptable safety profile in the treated 
populations.  
In conclusion, given the data available on the efficacy and safety of trastuzumab deruxtecan, the 
overall benefit/risk remains positive for clinical development. 


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2. 
STUDY OBJECTIVES AND HYPOTHESIS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objective 
The primary objective of this study is to investigate the efficacy of trastuzumab deruxtecan based 
on confirmed ORR, as assessed by an independent central imaging facility review using 
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, in subjects with HER2-positive 
unresectable or metastatic gastric or GEJ adenocarcinoma that has progressed on or after a 
trastuzumab-containing regimen.  
2.1.2. 
Secondary Objectives 
The key secondary objective is to evaluate the efficacy of trastuzumab deruxtecan on PFS, based 
on independent central review using RECIST v1.1. 
Other secondary objectives are as follows: 
 To further evaluate the efficacy of trastuzumab deruxtecan using the following 
endpoints: 
 OS 
 PFS, based on Investigator assessment using RECIST v1.1 
 ORR, based on Investigator assessment using RECIST v1.1 
 DoR, based on independent central review and Investigator assessment using 
RECIST v1.1 
 To determine the PK of trastuzumab deruxtecan in serum 
 To further evaluate the safety of trastuzumab deruxtecan based on TEAEs and 
anti-drug antibodies (ADAs) 
 To evaluate Health Economics and Outcomes Research (HEOR) endpoints based on 
patient-reported outcomes (PROs) 
2.1.3. 
Exploratory Objectives 
The exploratory objectives are to evaluate the following:  
 DCR, based on independent central review and Investigator assessment 
 Time to response, based on both independent central review and Investigator 
assessment 
 Best percentage change in the sum of diameters of measurable tumors 
 Predictive, prognostic, and pharmacodynamics exploratory biomarkers in tissue 
samples and blood, and their association with disease status and/or response to 
treatment. 


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2.2. 
Study Hypothesis 
Trastuzumab deruxtecan confers an ORR benefit in subjects with unresectable or metastatic 
HER2-positive gastric or GEJ cancer who have previously progressed on or after a 
trastuzumab-containing regimen in the first-line setting. 
2.3. 
Study Endpoints 
The efficacy endpoints will be based on central assessments unless otherwise stated. 
2.3.1. 
Primary Endpoint 
The primary endpoint (ie, primary outcome measure) is confirmed ORR, defined as the 
proportion of subjects who achieved a best overall response of confirmed CR or partial response 
(PR), as determined by independent central review using RECIST v1.1.   
2.3.2. 
Key Secondary Efficacy Endpoint 
The key secondary efficacy endpoint is PFS, based on independent central review using RECIST 
v1.1. 
2.3.3. 
Other Secondary Efficacy Endpoint(s) 
The other secondary efficacy endpoints are as follows: 
 PFS, defined as the time interval from the date of first dose of study drug to the date 
of disease progression or death due to any cause. 
 ORR, based on Investigator assessment using RECIST v1.1 
 OS, defined as OS is defined as the time interval from the date of first dose of study 
drug to the date of death due to any cause.   
 DoR, defined as the time from the date of first documentation of objective response  
to the date of the first documentation of disease progression, based on independent 
central review and Investigator assessment, or to death due to any cause, using 
RECIST v1.1. 
2.3.4. 
Exploratory Endpoints  
 DCR, defined as CR rate plus PR rate plus stable disease (SD) rate, based on 
independent central review and Investigator assessment 
 Time to response, based on both independent central review and Investigator 
assessment 
 Best percentage change in the sum of diameters of measurable tumors 
 Serum extracellular domain of HER2 (HER2ECD) 
 Biomarker analysis using cell-free DNA (cfDNA) and cell-free RNA (cfRNA) 


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2.3.5. 
Pharmacokinetic (PK) Endpoints (Trastuzumab Deruxtecan and MAAA-1181a): 
The PK endpoints are as follows: 
 Serum concentration for trastuzumab deruxtecan, total anti-HER2 antibody, and 
MAAA-1181a 
 Cmax, Tmax, area under the plasma concentration-time curve, from time 0 to last point with 
quantifiable concentration (AUClast), AUC21d, and, if appropriate, AUCinf, t1/2, CL, 
and Vss for each of the components.  
2.3.6. 
Safety Endpoint(s) 
The safety endpoints are as follows: 
 SAEs 
 TEAEs 
 Drug-related TEAEs 
 Discontinuations due to AEs  
 Adverse events of special interest (AESIs) 
 Physical examination findings  
 Eastern Cooperative Oncology Group performance status (ECOG PS) 
 Vital sign measurements 
 Standard clinical laboratory parameters  
 Electrocardiogram (ECG) parameters  
 Echocardiogram (ECHO)/multigated acquisition (MUGA) scan findings  
 ADAs 
2.3.7. 
Health Economic and Outcomes Research Endpoints 
The HEOR endpoints based on PROs are as follows: 
 European Organization for Research and Treatment of Cancer (EORTC) 5-dimension 
5-levels quality-of-life questionnaire (EQ-5D-5L; see sample in Section 17.2.1)28, 29, 
30, 31 
 Functional Assessment of Cancer Therapy-Gastric (FACT-Ga) questionnaire (see 
sample in Section 17.2.2)32  




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Most subjects are expected to receive between 10 and 20 cycles of treatment.  If the study 
treatment is delayed more than 28 days from the planned date of administration, the subject will 
be withdrawn from the study drug (see Section 5.8.2).   
Long-term/Survival Follow-up Visits will occur every 3 months (± 14 days) from the date of the 
40-day (+7 days) Follow-up Visit, until death, withdrawal of consent, or loss of follow-up, 
whichever comes first, and can be conducted via phone or in person at a site visit.  In the event 
subjects withdraw consent to participate in the study, survival status will be obtained from public 
records (death certificate, obituary, etc.) unless prohibited by local laws. 
3.1.4. 
Definition of the End of the Study 
The end of the study will occur when all recruited subjects have either completed their last 
scheduled visit or died or withdrawn from study participation or moved into another study or 
when the Sponsor decides to discontinue the study.  This is anticipated to occur approximately 
12 months after the last subject is enrolled.   
3.2. 
Discussion of Study Design 
The sample size will be approximately 80 subjects, recruited at approximately 45 study sites 
including, but not limited to, North America and the EU. 
Modeling results on efficacy and safety endpoints supported the selection of 5.4, 6.4, and 
7.4 mg/kg, given the benefit:risk considerations.  The selected dose of 6.4 mg/kg was based on 
clinical data from DS8201-A-J101 and subsequent exposure-response analysis of doses up to 
8.0 mg/kg.  Early efficacy results at the most recent DCO date (18 Apr 2018) from 
45 heavily-pretreated subjects with gastric or GEJ adenocarcinoma enrolled in the ongoing 
Phase 1 study DS8201-A-J101 are encouraging.22 
On the basis of the Part 1 results of the study, IV doses of 5.4 mg/kg and 6.4 mg/kg were 
selected for the dose-expansion phase of the study.  The promising findings from dose-escalation 
were replicated at the interim analysis of the dose-expansion part of the study, which included a 
cohort of subjects with advanced HER2-positive GC previously treated with a 
trastuzumab-containing regimen.  Patients with GC had received a median of 3.0 (range: 1 to 7) 
prior treatment regimens before entering the study.  With a median duration of follow-up of 
204.0 days (95% CI: 136.0, 267.0), the confirmed ORR was 43.2%, the median DoR was 
7.0 months (95% CI not available), and the median PFS was 5.6 months (95% CI: 3.0, 8.3; 
range: 1.2 to 19.6+).  Given the comparable efficacy and no additional safety risks for the 
6.4 mg/kg dose, this dose was selected for Phase 2 and subsequent studies in HER2-positive GC 
subjects. 


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4. 
STUDY POPULATION 
Each subject will sign a Tissue Screening Informed Consent Form (ICF) and a Main ICF 
provided by the site.  A subject is considered a participant in the study upon the Investigator or 
designee obtaining the main informed consent from the subject (Section 15.3). 
Investigators will maintain a confidential Screening Log of all potential study candidates that 
includes limited subject information (initials, age, gender) and outcome of the Screening process 
(ie, first dose of the study, reason for ineligibility, refused to participate, and/or others). 
Investigators will be expected to maintain a log of all subjects receiving doses in the study 
indicating their assigned study number. 
Investigators will maintain a confidential subject identification (SID) code list.  This confidential 
list of the names of all subjects, allocated study numbers on recruitment to the study, allows the 
Investigator to reveal the identity of any subject when and/or if necessary. 
4.1. 
Inclusion Criteria 
Each subject must satisfy all of the following criteria to be included in the study: 
1. Must be able to comprehend, sign, and date a main ICF approved by the Institutional 
Review Board (IRB) or Ethics Committee (EC) before any study-specific procedures or 
tests are performed. 
2. Men or women ≥18 years of age (please follow local regulatory requirements if the legal 
age of consent for study participation is >18 years of age) 
3. Has pathologically documented gastric or GEJ cancer that is: 
 Unresectable or metastatic, and 
 Centrally confirmed HER2-positive disease (IHC3+ or IHC2+ and evidence of HER2 
amplification by ISH) as determined according to American Society of Clinical 
Oncology – College of American Pathologists (ASCO-CAP) guidelines based on a 
new tumor biopsy obtained after progression on or after a first-line 
trastuzumab-containing regimen.  If a tumor biopsy was already collected after 
discontinuation of first-line treatment with a trastuzumab-containing regimen, it is 
acceptable to consider that biopsy to be a new biopsy for the purpose of this study, 
provided that there is sufficient tissue for exploratory biomarker studies. 
4. Experienced disease progression (based on RECIST version 1.1 criteria) during or after 
first-line therapy with a trastuzumab-containing regimen.  Note: Prior first-line treatment 
with trastuzumab brand name (Herceptin) or approved biosimilar is acceptable.  
 Note: Prior adjuvant therapy with a trastuzumab-containing regimen can be 
counted as a line of therapy if the subject progressed on or within 6 months of 
completing adjuvant therapy. 
5. Has at least 1 measurable lesion per RECIST v1.1 (details in Section 17.5) as confirmed 
by the investigator review  
6. ECOG PS of 0 or 1 


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7. LVEF ≥50% within 28 days before first dose per ECHO/MUGA scan 
8. Has adequate organ function within 14 days before randomization, defined as: 
Parameter 
Laboratory Value 
Adequate Bone Marrow Function 
Platelet count  
 100 000/mm3  (Platelet transfusion is not allowed 
within 1 week prior to screening assessment) 
Hemoglobin  
≥ 9.0 g/dL  (Red blood cell transfusion is not allowed 
within 1 week prior to screening assessment) 
Absolute neutrophil count 
(ANC) 
 1500/mm3  
(granulocyte colony-stimulating factor [G-CSF] 
administration is not allowed within 1 week prior to 
screening assessment) 
Adequate renal function 
Creatinine 
Creatinine clearance ≥ 30 mL/min as calculated using 
the Cockcroft-Gault equation*  
Adequate hepatic function 
Alanine aminotransferase 
(ALT), Aspartate 
aminotransferase (AST) 
 ≤ 5  the upper limit of normal (ULN) 
Total bilirubin 
≤ 1.5 × ULN if no liver metastases or < 3 x ULN in the 
presence of documented Gilbert’s Syndrome 
(unconjugated hyperbilirubinemia) or liver metastases at 
baseline. 
 
 
Serum Albumin 
≥ 2.5 g/dL  
Adequate Blood Clotting Function 
International normalized ratio 
(INR) / Prothrombin time (PT) 
and activated partial 
thromboplastin time (aPTT) 
≤ 1.5 × ULN 
*Cockcroft-Gault equation:  
        CLcr (mL/min) =  
[140 - age (years)] × weight (kg)
[72 × serum creatinine (mg/dL)]  {× 0.85 for females} 
9. Has adequate treatment washout period before randomization, defined as: 
Treatment 
Washout Period 
Major surgery 
≥ 4 weeks 
Radiation therapy including palliative 
stereotactic radiation to chest 
≥ 4 weeks (palliative stereotactic radiation 
therapy to other areas ≥ 2 weeks) 


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Treatment 
Washout Period 
Chemotherapy (Immunotherapy [non-
antibody-based therapy]), retinoid 
therapy 
≥ 3 weeks (≥ 2 weeks or 5 half-lives , 
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 NSCLC - baseline CT scan 
must be completed after discontinuation of 
TKI) 
 Antibody-based anticancer therapy 
≥ 4 weeks 
Chloroquine /Hydroxychloroquine 
>14 days 
10. Male and female subjects of reproductive/childbearing potential must agree to use a 
highly effective form of contraception or avoid intercourse during and upon completion 
of the study and for at least 7 months for females and 4 months for males after the last 
dose of study drug.34  Methods considered as highly effective methods of contraception 
include:  
 Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation (oral, intravaginal, transdermal) 
 Progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable, implantable) 
 Intrauterine device 
 Intrauterine hormone-releasing system 
 Bilateral tubal occlusion 
 Vasectomized partner 
 Complete 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 drug.  Periodic abstinence (calendar, 
symptothermal, post-ovulation methods) is not an acceptable method of 
contraception. 
11. If the subject is a female of childbearing potential, she must have a negative serum 
pregnancy test at Screening and/or 72 hours before the first dose of study drug, during the 
Treatment Period, and for 7 months, following the last dose of study drug.  A female is 
considered of childbearing potential following menarche and until becoming 
postmenopausal (no menstrual period for a minimum of 12 months) unless permanently 
sterile (undergone a hysterectomy, bilateral salpingectomy or bilateral oophorectomy) 
with surgery at least 1 month before the first dose or confirmed by follicle stimulating 
hormone (FSH) test. 


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12. Male subjects must not freeze or donate sperm starting at Screening and throughout the 
study period, and at least 4 months after the final study drug administration. 
13. Female subjects must not donate, or retrieve for their own use, ova from the time of 
Screening and throughout the study treatment period, and for at least 7  months after the 
final study drug administration. 
4.2. 
Exclusion Criteria 
Subjects who meet any of the following criteria will be disqualified from entering the study: 
1. Use of anticancer therapy after first-line treatment with a trastuzumab-containing 
regimen. 
2. Uncontrolled or significant cardiovascular disease, including any of the following: 
 History of myocardial infarction (MI) within 6 months of first dose  
 History of symptomatic congestive heart failure (New York Heart Association Class 
II to IV) (details in Section 17.6)35  
 Troponin levels consistent with MI as defined according to the manufacturer within 
28 days prior to first dose 
 QTc prolongation to >470 ms (females) or >450 ms (male) based on Screening 
triplicate 12-lead ECG  
3. History of non-infectious ILD/pneumonitis that required corticosteroid therapy or has 
current ILD/pneumonitis or is suspected to have such diseases by imaging at Screening. 
4. Clinically  severe pulmonary compromise resulting from intercurrent pulmonary illnesses 
including, but not limited to, any underlying pulmonary disorder (i.e. pulmonary emboli 
within three months of the first dose, severe asthma, severe COPD, restrictive lung 
disease, pleural effusion etc.), and any autoimmune, connective tissue or inflammatory 
disorders with pulmonary involvement (i.e. Rheumatoid arthritis, Sjogren's, sarcoidosis 
etc.), or prior pneumonectomy. 
5. 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.) 
6. Spinal cord compression or clinically active CNS metastases, defined as untreated and 
symptomatic or requiring therapy with corticosteroids or anticonvulsants to control 
associated symptoms.  Baseline brain CT/MRI scan is mandatory.  
 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 signing of main ICF (1 week for stereotactic radiotherapy). 


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7. History of other malignancy(ies), except adequately treated non-melanoma skin cancer, 
curatively treated in-situ disease, or other solid tumors curatively treated, with no 
evidence of disease for ≥3 years 
8. History of severe hypersensitivity reactions to either the drug substance or inactive 
ingredients in the drug product 
9. History of severe hypersensitivity reactions to other monoclonal antibodies 
10. Current uncontrolled infection requiring IV antibiotics, antivirals, or antifungals  
11. Substance abuse or any other medical conditions such as clinically significant cardiac or 
pulmonary diseases or psychological conditions, that may, in the opinion of the 
Investigator, interfere with the subject’s participation in the clinical study or evaluation of 
the clinical study results 
12. Social, familial, or geographical factors that would interfere with study participation or 
follow-up 
13. Known human immunodeficiency virus (HIV) infection, or active hepatitis B or C 
infection.  Subjects should be tested for HIV prior to enrollment if required by local 
regulations or IRB/EC.  Subjects positive for hepatitis C (HCV) antibody are eligible 
only if polymerase chain reaction is negative for HCV RNA.  
14. Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than 
alopecia) not yet resolved to Grade ≤1 or baseline.  Subjects with chronic Grade 2 
toxicities may be eligible per the discretion of the Investigator after consultation with the 
Sponsor Global Clinical Lead or designee (eg, Grade 2 chemotherapy-induced 
neuropathy) 
15. Prior treatment with an ADC consisting of an exatecan derivative that is a topoisomerase 
I inhibitor.   
16. Therapeutic radiation therapy (including palliative stereotactic radiation to chest) or 
major surgery within 4 weeks before study drug treatment or palliative stereotactic 
radiation therapy within 2 weeks before study drug treatment (please refer to exclusion 
criterion 6 for whole brain radiotherapy and stereotactic radiotherapy for CNS 
metastases). 
17. Systemic treatment with anticancer chemotherapy therapy [Immunotherapy 
(non-antibody-based therapy)], retinoid therapy) within 3 weeks (≥ 2 weeks or 
5 half-lives , 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). 
18. Antibody-based anticancer therapy within 4 weeks of Cycle1, Day1 
19. Participation in a therapeutic clinical study within 3 weeks before study treatment (for 
small-molecule targeted agents, this non-participation period is 2 weeks or 5 half-lives, 
whichever is longer); or current participation in other investigational procedures. 
20. Pregnant or breastfeeding subjects or subjects planning to become pregnant. 
21. Subject is an immediate family member of study site personnel or of Sponsor personnel. 


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5. 
STUDY TREATMENT(S) 
5.1. 
Assigning Subjects to Treatments and Blinding 
5.1.1. 
Treatment Group(s) 
This is an open-label study with a single trastuzumab deruxtecan treatment arm. 
5.1.2. 
Method of Treatment Allocation 
Prior to the subject’s first dose, all eligibility criteria must be met.  
5.1.3. 
Blinding 
Not applicable 
5.1.4. 
Emergency Unblinding Procedure 
Not applicable 
5.1.5. 
Re-screening Procedures 
Re-screening (tissue and main screening) is permitted for any subject who failed to meet 
eligibility criteria upon initial screening.  The limit of re-screening is once each for tissue 
screening and main screening after HER2 confirmation.  If the subject fails eligibility using HER 
2 prescreened tissue sample testing, then a different sample can be submitted for HER2 
eligibility analysis.  
The Re-screening Subject ID number must remain the same as the main Screening Subject ID 
number.  The initial Screening information and the reason for initial Screening ineligibility will 
be recorded on the Screening Log.  No data from the initial evaluation will be entered into the 
clinical database for a subject who was re-screened.  
5.2. 
Study Drug 
5.2.1. 
Description 
Trastuzumab deruxtecan drug product (trastuzumab deruxtecan for injection 100 mg) will be 
supplied as Lyo-DP.  Lyo-DP is a sterile lyophilized powder provided in an amber glass vial for 
IV infusion.  Each glass vial contains 100 mg of trastuzumab deruxtecan.  Each vial is designed 
for single use and is not to be used to treat more than 1 subject. 
Lyo-DP is reconstituted with 5 mL of water for injection to provide a solution with a 
concentration of 20 mg/mL of trastuzumab deruxtecan in a buffer containing L histidine, L 4 
histidine hydrochloride monohydrate, sucrose, and polysorbate 80.   
The starting dose of 6.4 mg/kg is based on body weight (BW) taken at the screening visit 
(baseline) and thereafter, within 3 days before infusion of Day 1 of all cycles.   


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5.2.2. 
Labeling and Packaging 
Trastuzumab deruxtecan for injection will be supplied as Lyo-DP by the Sponsor.  Trastuzumab 
deruxtecan for injection 100 mg, will be packaged and labeled in compliance with regulatory 
requirements.  The packaging will clearly display the name of the study treatment, the lot 
number, storage condition, and other required information in accordance with local regulations. 
5.2.3. 
Preparation 
Prior to use, trastuzumab deruxtecan 100 mg for IV infusion will be prepared by the study site 
pharmacist by dilution of the required volume of study treatment calculated based on the 
subject’s BW in a volume of 100 mL, according to the pharmacy instructions provided by the 
Sponsor.  The starting dose of trastuzumab deruxtecan will be 6.4 mg/kg.   
The subject’s weight at screening (baseline) could be used to calculate the initial dose.  If during 
the course of treatment, subject weight changes by ±10% from the baseline BW, the trastuzumab 
deruxtecan dose to be administered will be recalculated based on the updated BW.  See 
Section 5.2.4. 
Prepared study drug solutions should be used as directed in the pharmacy instructions.  Refer to 
the Pharmacy Instructions for detailed information about preparation of trastuzumab deruxtecan. 
Procedures for proper handling and disposal of anticancer drugs should be followed in 
compliance with the standard operating procedures (SOPs) of the study site. 
5.2.4. 
Administration 
Treatment cycles will be 21 days (±2 days) in length.  Trastuzumab deruxtecan at a BW-based 
dose of 6.4 mg/kg will be administered as an IV infusion on Day 1 (±2 days) of every 21-day 
cycle (Q3W).   
The first infusion of trastuzumab deruxtecan will occur over at least 90 minutes.  If there is no 
infusion-related reaction (IRR), the subsequent infusions of trastuzumab deruxtecan will be over 
at least 30 minutes.  In case of IRR of any severity grade at any time during the first 
administration of trastuzumab deruxtecan, all subsequent infusions will occur over 
approximately 90 minutes.   
Refer to the Pharmacy Instructions for detailed information about administration of trastuzumab 
deruxtecan. 
5.2.5. 
Storage 
Trastuzumab deruxtecan Lyo-DP must be stored in a secure, limited-access storage area 
protected from light at temperatures between 2°C and 8°C.   
If storage conditions are not maintained per specific requirements, the site should contact the 
Sponsor or contract research organization (CRO).   
Instructions and precautions for storage and handling of infusion solutions are available in the 
Pharmacy Instructions. 


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5.2.6. 
Drug Accountability 
When a drug shipment is received, the Investigator or designee will check the amount and 
condition of the drug, check for appropriate local language in the label, check the drug expiration 
date, and acknowledge receipt in the Interactive Voice/Web Response System (IXRS).  The 
original form will be retained at the site.   
The Investigator or designee shall contact Sponsor as soon as possible if there is a problem with 
the drug shipment.   
A Drug Accountability Record will be provided for the study drug or the site can use their own 
after getting approval from the Sponsor.  The record must be kept current and should contain the 
following: 
 Dates and quantities of drug received  
 SID number and/or subject initials or supply number (as applicable)  
 The date and quantity of investigational product dispensed and remaining  
 The initials of the dispenser.   
At the end of the study, or as directed, the Investigator will appropriately dispose of empty 
carton(s), empty vial(s), and vial(s) with remaining study drug, preparation materials, 
administration materials, etc. using clinical site disposal procedure to prevent infection or other 
illness/injury.  The site may destroy the empty containers/vials and any unused drug after drug 
accountability has been verified by the site personnel as per their SOP.  Alternatively, the 
investigational product may be returned only after the study monitor has completed a final 
inventory to verify the quantity to be returned. The return of study drug must be documented and 
the documentation must be included in the shipment.  At the end of the study, a final study drug 
reconciliation statement must be completed by the Investigator or designee and provided to the 
Sponsor.  Unused drug supplies may be destroyed by the Investigator when approved in writing 
by the Sponsor and the Sponsor has received copies of the study site’s drug handling and 
disposition SOPs and it is assured that the Sponsor will receive copies of the certificate of 
destruction that is traceable to the study treatment. 
All trastuzumab deruxtecan inventory forms must be made available for inspection by a Sponsor 
authorized representative or designee and regulatory agency inspectors.   
5.3. 
Control Treatment 
Not applicable 
5.4. 
Dose Interruptions and Reductions 
  All dose modifications should be based on the worst preceding toxicity (CTCAE v5.0).  
Specific criteria for interruption, re-initiation, dose reduction and/or discontinuation of 
trastuzumab deruxtecan are listed in Table 5.1 which is applicable only to TEAEs that are 
assessed as related to use of trastuzumab deruxtecan by the investigator(s).  For non-drug related 
TEAEs, follow standard clinical practice.  All interruptions or modifications must be recorded on 


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the AE and drug administration electronic case report form (eCRF).  Appropriate clinical experts 
should be consulted as deemed necessary.   
Prophylactic or supportive treatment for expected toxicities, including management of study drug 
induced AEs will be as per treating physician discretion and institutional guidelines.   
5.4.1. 
Guidelines for Dose Modifications 
Two dose reductions of trastuzumab deruxtecan will be permitted, from the original dose of 
6.4 mg/kg to 5.4 mg/kg and subsequently to 4.4 mg/kg.  Trastuzumab deruxtecan dose increases 
are not allowed in the study.  There will be no dose modifications for Grade 1 or Grade 2 AEs 
unless specified in Table 5.1. 
Once the dose of trastuzumab deruxtecan 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 subjects will be withdrawn from the 
study treatment if further toxicity meeting the requirement for dose reduction occurs. 
A dose may be delayed for up to 28 days (49 days from the last infusion date) from the planned 
date of administration.  If a subject is assessed as requiring a dose delay longer than 28 days, the 
subject will be withdrawn from the study. 
Treatment cycles for a subject for whom trastuzumab deruxtecan dosing is temporarily withheld 
for any reason may have future cycles scheduled based on the date the last trastuzumab 
deruxtecan dose is administered. 
All confirmed or suspected COVID-19 events must be recorded in the eCRF.  Please refer to 
Section 17.7  for additional information on dose modification.  
Table 5.1: 
Management Guidelines for Trastuzumab Deruxtecan 
Worst CTCAE v5.0 Toxicity 
Grade (unless otherwise 
specified) 
Management Guidelines for Trastuzumab Deruxtecan 
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.   


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Worst CTCAE v5.0 Toxicity 
Grade (unless otherwise 
specified) 
Management Guidelines for Trastuzumab Deruxtecan 
Grade 2  
(therapy or infusion interruption 
indicated but responds promptly 
to symptomatic treatment [eg, 
antihistamines, nonsteroidal anti-
inflammatory drugs (NSAIDs), 
narcotics, IV fluids]; 
prophylactic medications 
indicated for ≤24 hours) 
Administration of trastuzumab deruxtecan 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 trastuzumab deruxtecan 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, then maintain dose. 
Grade 4  
Delay dose until resolved to ≤ Grade 2, then reduce dose by 1 level. 
Febrile Neutropenia  
(absolute neutrophil count <1 × 
109/L, fever >38.3°C or a 
sustained temperature of ≥38°C 
for more than 1 hour) 
Delay dose until resolved, then reduce dose by 1 level. 
Lymphocyte Count Decreased 
Grade 1 to Grade 3 lymphopenia  No dose modification 
Grade 4  
(<0.2 × 109/L) 
Delay dose until resolved to ≤ Grade 2: 
 
If resolved in ≤14 days from day of onset, maintain dose 
 
If resolved in >14 days from day of onset, reduce dose by 1 
level. 
Anaemia 
Grade 3  
(hemoglobin <8.0 g/dL); 
transfusion indicated 
Delay dose until resolved to ≤ Grade 2, then maintain dose. 
Grade 4  
(life-threatening consequences, 
urgent intervention indicated) 
Delay dose until resolved to ≤ Grade 2, then reduce dose by 1 level. 


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Worst CTCAE v5.0 Toxicity 
Grade (unless otherwise 
specified) 
Management Guidelines for Trastuzumab Deruxtecan 
Platelet Count Decreased 
Grade 3  
(platelets <50 to 25 × 109/L) 
Delay dose until resolved to ≤ Grade 1: 
 
If resolved in ≤7 days from day of onset, maintain dose 
 
If resolved in >7 days from day of onset, reduce dose by 1 
level. 
Grade 4  
(platelets <25 × 109/L) 
Delay dose until resolved to ≤ Grade 1, then reduce dose by 1 level. 
Cardiac Toxicity 
Symptomatic congestive heart 
failure 
Discontinue subject from study treatment. 
Decrease in LVEF 10-20% 
(absolute value), but LVEF 
>45% 
Continue treatment with trastuzumab deruxtecan. 
LVEF 40% to ≤45% and 
decrease is <10% (absolute 
value) from baseline level 
Continue treatment with trastuzumab deruxtecan. 
Repeat LVEF assessment within 3 weeks. 
LVEF 40% to ≤45% and 
decrease is ≥10% (absolute 
value) from baseline level 
Interrupt trastuzumab deruxtecan dosing. 
Repeat LVEF assessment within 3 weeks. 
If LVEF has not recovered to within 10% (absolute value) from 
baseline, discontinue subject from study treatment. 
LVEF <40% or >20% (absolute 
value) drop from baseline level 
Interrupt trastuzumab deruxtecan dosing. 
Repeat LVEF assessment within 3 weeks. 
If LVEF <40% or >20% drop from baseline level is confirmed, 
discontinue subject from study treatment. 
Electrocardiogram prolonged 
Grade 3 (Average QTc >500 ms 
or >60 ms change from baseline) 
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 is any changes in serum electrolytes that 
can be corrected if attributed to trastuzumab deruxtecan, reduce 
dose by 1 level. 
Grade 4  
(Torsade de pointes or 
polymorphic ventricular 
tachycardia or signs/symptoms 
of serious arrhythmia) 
Discontinue subject from study treatment. 
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 


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Worst CTCAE v5.0 Toxicity 
Grade (unless otherwise 
specified) 
Management Guidelines for Trastuzumab Deruxtecan 
“Other Non-Laboratory Adverse Events” dose modification section 
as follows. 
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 (complete blood count).  Other 
blood tests could be considered as needed. 
 
Consider bronchoscopy and bronchoalveolar lavage if 
clinically indicated and feasible should be considered 
 
Pulmonary function tests and pulse oximetry (peripheral 
oxygen saturation [SpO2]) 
 
Arterial blood gases if clinically indicated 
 
1 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 as outlined for Grades 1 through 4. 
All events of ILD/pneumonitis regardless of severity or seriousness 
will be followed until resolution including after drug 
discontinuation. 
Grade 1 
The administration of trastuzumab deruxtecan 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 to 2 weeks (or as 
clinically indicated). 
 
 
Consider starting systemic steroids (e.g. at least 0.5 
mg/kg/day prednisone or equivalent) until improvement, 
followed by gradual taper over at least 4 weeks. 
 
 
If worsening of diagnostic observations despite initiation of 
corticosteroids, then follow Grade 2 guidelines.* 
For Grade 1 events, trastuzumab deruxtecan can be restarted only if 
the event is fully resolved to Grade 0, then: 
 
If resolved in ≤28 days from day of onset, maintain dose 
 
If resolved in >28 days from day of onset, reduce dose 1 
level. 


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Worst CTCAE v5.0 Toxicity 
Grade (unless otherwise 
specified) 
Management Guidelines for Trastuzumab Deruxtecan 
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 patient is asymptomatic, then patient should still be considered 
as Grade 1 even if steroid treatment is given 
Grade 2 
Permanently discontinue subject from study treatment. 
• 
Promptly start and treat with systemic steroids (e.g., at least 
1mg/kg/day prednisone or equivalent) for at least 14 days 
or until complete resolution of clinical and chest CT 
findings, then followed by a gradual taper over at least 4 
weeks.  
• 
Monitor symptoms closely. 
• 
Re-image as clinically indicated. 
• 
If worsening or no improvement in clinical or diagnostic 
observations in 5 days,  
 
Consider increasing dose of steroids (eg, 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 previously. 
 
Escalate care as clinically indicated. 
Grade 3 and 4 
Permanently discontinue subject from study treatment. 
 
• 
Hospitalization is required. 
• 
Promptly initiate empiric high-dose methylprednisolone IV 
treatment (eg, 500 to1000 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.  


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Worst CTCAE v5.0 Toxicity 
Grade (unless otherwise 
specified) 
Management Guidelines for Trastuzumab Deruxtecan 
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 by 1 
level. 
Grade 4 
Discontinue subject from study treatment. 
Blood Creatinine Increased 
Grade 3  
(>3 to 6 × ULN) 
Delay dose until resolved to ≤Grade 2 or baseline, then reduce dose 
by 1 level. 
Grade 4  
>6 × ULN) 
Discontinue subject from study treatment. 
Hepatic Toxicity 
Aspartate amino transaminase (AST) or Alanine amino transaminase (ALT) with Simultaneous 
Blood Bilirubin Increased 
AST/ALT ≥3.0 × ULN with 
simultaneous blood bilirubin 
>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 
work-up, permanently discontinue study treatment. 
Monitor AST/ALT and blood bilirubin twice weekly until 
resolution or return to baseline. 
AST or ALT Increased 
Grade 2  
(>3.0 - 5.0 × ULN if baseline 
was normal; >3.0 - 5.0 × 
baseline if baseline was 
abnormal) 
No action for Grade 2 AST/ALT but if hepatic event meets 
combination abnormalities (ALT or AST ≥3 × ULN with 
concurrent [± 21 days] blood bilirubin  ≥2 × ULN),  
 
Repeat testing within 7 days (see Section 9.4.2 for SAE 
reporting), and  
 
Delay dose until resolved to ≤ baseline.   
If confirmed Hy’s Law case, discontinue subject from study drug. 


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Worst CTCAE v5.0 Toxicity 
Grade (unless otherwise 
specified) 
Management Guidelines for Trastuzumab Deruxtecan 
Grade 3  
(>5.0 - 20.0 × ULN if baseline 
was normal; >5.0 - 20.0 × 
baseline if baseline level was 
abnormal) 
In subjects without liver 
metastases and subjects with 
liver metastases and baseline 
level ≤3 × ULN 
Repeat testing within 3 days.  Delay dose until resolved to ≤ Grade 
1, if baseline level ≤3 × ULN, otherwise ≤ 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 by 1 
level. 
Grade 3  
(>8.0 - 20.0 × ULN if baseline 
level was normal; >8.0 – 20.0 × 
baseline level if baseline level 
was abnormal) 
In subjects with liver metastases, 
if the baseline level was >3 × 
ULN 
Repeat testing within 3 days.  Delay dose until resolved to ≤ 
baseline level, then: 
 
If resolved in ≤7 days from day of onset, maintain dose 
 
If resolved in >7 days from day of onset, reduce dose by 1 
level. 
Grade 4  
(>20 × ULN if baseline level 
was normal; >20.0 × baseline 
level if baseline level was 
abnormal) 
Discontinue subject from study treatment. 
Total Bilirubin Increased 
Grade 2  
(>1.5 - 3.0 × ULN if baseline 
level was normal; >1.5 - 3.0 × 
baseline if baseline level was 
abnormal) 
If no documented Gilbert’s syndrome or liver metastases at 
baseline, delay dose until resolved to ≤ Grade 1: 
 
If resolved in ≤7 days from day of onset, maintain dose 
 
If resolved in >7 days from day of onset, reduce dose by 1 
level. 
If documented Gilbert’s syndrome or liver metastases at baseline, 
continue study treatment. 


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Worst CTCAE v5.0 Toxicity 
Grade (unless otherwise 
specified) 
Management Guidelines for Trastuzumab Deruxtecan 
Grade 3  
(>3.0 - 10.0 × ULN if baseline 
level was normal; >3.0 - 10.0 × 
baseline if baseline level was 
abnormal) 
In subjects with liver metastases, 
if the baseline level was >3 × 
ULN 
If no documented Gilbert’s syndrome or liver metastases at 
baseline, repeat testing within 3 days.  Delay dose until resolved to 
≤ Grade 1: 
 
If resolved in ≤7 days from day of onset, reduce dose by 1 
level 
 
If resolved in >7 days from day of onset, discontinue 
trastuzumab deruxtecan. 
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 by 1 
level 
 
If resolved in >7 days from day of onset, discontinue 
trastuzumab deruxtecan. 
Grade 4  
(>10.0 × ULN if baseline level 
was normal; >10.0 × baseline 
level if baseline level was 
abnormal) 
Discontinue subject from study treatment. 
Blood Alkaline Phosphatase Increased 
Grade 3  
(>5.0 - 20.0 × ULN if baseline 
level was normal; >5.0 - 20.0 × 
baseline if baseline level was 
abnormal)  
or  
Grade 4  
(>20.0 × ULN if baseline level 
was normal; >20.0 × baseline 
level if baseline level was 
abnormal) 
No modification unless determined by the Investigator to be 
clinically significant or life-threatening. 
Gastrointestinal 
Nausea 
Grade 3  
Delay dose until resolved to ≤Grade 1  
 
If resolved in ≤7 days from day of onset, maintain dose 
 
If resolved in >7 days from day of onset, reduce dose by 1 
level. 
Diarrhea/Colitis 


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Worst CTCAE v5.0 Toxicity 
Grade (unless otherwise 
specified) 
Management Guidelines for Trastuzumab Deruxtecan 
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 by 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 by 1 
level. 
Grade 4 
Discontinue subject from study treatment. 
Other Non-laboratory Adverse Events 
Grade 3 
Delay dose until resolved to ≤Grade 1 or baseline:  
 
If resolved in ≤7 days from day of onset, maintain dose 
 
If resolved in >7 days from day of onset, reduce dose by 1 
level. 
Grade 4 
Discontinue subject from study treatment. 
CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; ECG = 
electrocardiogram; ILD = interstitial lung disease; IV = intravenous; LVEF = left ventricular ejection fraction; 
ms = milliseconds; NSAID = nonsteroidal anti-inflammatory drug; PK = pharmacokinetic; QTc = QT interval 
corrected for heart rate; ULN = upper limit of normal 
All dose modifications should be based on the worst preceding toxicity.   
In addition, Investigators may consider dose reduction or discontinuation of the study drug 
according to the subject’s condition and after discussion with the Sponsor Global Clinical Lead 
or designee. 
5.5. 
Method of Assessing Treatment Compliance 
Intravenous trastuzumab deruxtecan will be administered only to subjects participating in the 
study and under the supervision of clinical study personnel at the site.  Start and stop times of IV 
infusion and amount of drug administered are to be recorded by clinical study personnel. 
5.6. 
Concomitant Medications, Treatments, and Procedures 
Medications used from the time the subject signs the ICF to 40 days (+7 days) after the last 
administration of trastuzumab deruxtecan will be recorded.  All concomitant medications and 
therapies, including all prescription, over-the-counter (OTC), and herbal remedies will be 
recorded on the eCRF.   
Permitted Therapies/Products: 
 Hematopoietic growth factors may be used for prophylaxis or treatment based on the 
clinical judgment of the Investigator after the subject starts receiving study drug (see 


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Section 4.1).Prophylactic or supportive treatment of study drug-induced AEs will be 
otherwise as per Investigator’s discretion and institutional guidelines.   
 Concomitant use of dietary supplements, medications not prescribed by the 
Investigator, and alternative/complementary treatments is discouraged but not 
prohibited. 
 On the basis of the currently available clinical safety data, it is recommended that 
subjects who receive prophylactic anti-emetic agents prior to infusion of trastuzumab 
deruxtecan and on subsequent days. Antiemetics such as 5-hydroxytryptamine 
receptor (5-HT3) antagonists or Neurokinin-1 (NK1) receptor antagonists and/or 
steroids (e.g. dexamethasone) should be considered and administered in accordance 
with the prescribing information or institutional guidelines 
5.7. 
Prohibited medications and treatments 
With the exception of medications that are under investigation in the study the following 
medications, treatments, and procedures will be prohibited during the treatment period (refer to 
Exclusion Criteria no. 17, 18 and 19 in Section 4.2 for required washout periods). The Sponsor 
must be notified if a patient receives any of these during the study: 
 Other anticancer therapy, including cytotoxic, targeted agents, immunotherapy, 
antibody, retinoid, or anticancer hormonal treatment [concurrent use of hormones for 
noncancer-related conditions (e.g. insulin for diabetes and hormone replacement 
therapy) is acceptable]. 
 Chloroquine or hydroxychloroquine;  
 if treatment with chloroquine or hydroxychloroquine is required for COVID-19, 
trastuzumab deruxtecan must be interrupted and a washout period of  >14 days is 
required before restarting trastuzumab deruxtecan. 
 Other investigational therapeutic agents. 
 Radiotherapy (except for palliative radiation to known metastatic sites as long as it 
does not affect assessment of response or interrupt treatment for more than the 
maximum time specified in dose modification section). 
 Radiotherapy to the thorax and to other tumor sites (except for palliative radiation to 
known metastatic sites, as long as it does not affect the assessment of response or 
interrupt treatment for more than the maximum time specified in the dose 
modification section [Section 5.4]). 
 Concomitant use of chronic systemic (IV or oral) corticosteroids or other 
immunosuppressive medications.  (Inhaled or topical 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.   


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5.7.1.1. 
Restricted products 
 Use of e-cigarettes and vaping is strongly discouraged but not prohibited. 
5.8. 
Removal of Subjects from Treatment and/or Study 
5.8.1. 
Reasons for Discontinuation of Study Treatment 
Any subject who is withdrawn from the study treatment for any reason will have the reason for 
withdrawal recorded.  Subjects may be withdrawn from study treatment after signing the ICF for 
the following reasons:  
 Progressive disease per criteria set forth in RECIST v1.1 (refer to Section 17.5 for 
details)  
 Clinical progression (definitive clinical signs of PD) but a recent radiographic 
assessment did not meet the criteria for PD according to RECIST v1.1 (refer to 
Section 17.5 for details) 
 AE 
 Withdrawal by subject 
 Physician decision 
 Death 
 Pregnancy 
 Protocol deviation 
 Study termination by the Sponsor 
 Loss to follow-up 
 Sponsor decision. 
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 and approval from the Sponsor’s Medical Monitor.   
All subjects who are withdrawn from study treatment should complete protocol-specified 
withdrawal procedures (details in Section 5.8.3) and follow-up procedures (details in 
Section 6.5). 
Discontinued subjects will be followed for survival, either through direct contacts or by 
collecting public records (eg, death certificates) as allowed by local laws. 
5.8.2. 
Reasons for Withdrawal from the Study 
Subject participation in the study will continue until 1 of the following occurs: 
 Subject withdraws. 
 Subject dies. 


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 Study is terminated. 
 Subject is lost to follow-up. 
 Sponsor decides to terminate the study. 
All subjects will be followed for survival status even after consent for study procedures is 
withdrawn.  Subjects discontinued from the study because of withdrawal of consent will be 
followed for survival by collecting public records (eg, death certificates) unless prohibited by 
local laws.  Recruited subjects will not be replaced. 
5.8.3. 
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 from the study as a result of 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 obtained after the last 
administration of study drug during the EOT Visit (±7 days) (see Section 6.4) and the 40-day 
(+7 days) Follow-up Visit (see Section 6.5.1). 


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6. 
STUDY PROCEDURES 
A study visit schedule in tabular format is provided in Table 17.1. 
6.1. 
Tissue Screening 
To determine eligibility, subjects must have gastric or GEJ cancer that has confirmed 
HER2-positive disease (tumor score of IHC 3+ or IHC 2+ and evidence of HER2 amplification 
by FISH), as determined according to ASCO-CAP HER2 test guideline recommendations 
evaluated at a central laboratory based on a new tissue biopsy obtained after progression on or 
after a trastuzumab-containing treatment regimen.36   
Please refer to the study Laboratory Manual for required tumor sample specifications and 
shipping instructions.  
The following procedures will be conducted at the time of Tissue Screening: 
 Obtain a signed and dated written Tissue Screening ICF from the subject prior to 
collecting tissue.   
 Obtain an adequate recent tumor tissue sample for HER2 testing.   
 A tissue sample is considered a recent sample if it is collected from a biopsy 
performed after a subject’s discontinuation of the last treatment regimen and most 
recent disease progression and prior to the patient’s consent for tissue screening.  
The sample must be a formalin-fixed paraffin embedded (FFPE) block and not 
stored slides cut previously from such an FFPE block.  This recent sample must 
have sufficient tissue remaining after HER2 pre-screening for exploratory 
biomarker analyses.  At least 2 cores are requested but if the risk of biopsy 
complications from a second biopsy is unacceptable (at the discretion of the 
Investigator), then a single mandatory biopsy core will suffice.  Refer to the study 
Laboratory Manual for preparation, number of slides required, storage, and 
shipment procedures.  
 Bone biopsies are not acceptable (Section 4.1)  
 Fine needle aspirate is not an acceptable technique; 
 When perform new biopsy and send wet tissue to the central laboratory, an additional 
biopsy for exploratory biomarker analyses is not needed. 
 If a recent tissue sample is not available or is inadequate, a new tumor biopsy is 
mandatory for HER2 screening.  
 Prepare and send the tissue samples to the central laboratory as per instructions 
provided in the central Laboratory Manual.  
 The central laboratory will assess the HER2 status and provide results to investigators 
and Daiichi Sankyo Inc. (DSI) 
 If a new tumor biopsy is performed after the subject signs the tissue screening ICF 
but before the main ICF, report any SAEs directly related to tissue pre-screening 
procedure (ie, tumor biopsy) via paper SAVER forms.  Unless documentation of 


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other AEs is required by local law, only SAEs directly related to tumor biopsy will be 
recorded during tissue screening. 
 Assign Subject ID (SID) number. 
6.2. 
Screening (Day -28 to Day -1) 
The duration of the Screening Period is up to 28 days Informed consent will be obtained from the 
subject before any study-specific procedures are initiated.  After the subject has a positive HER2 
pre-screening result the subject is eligible to enter the screening period.   
The following activities and/or assessments will be performed within 14 days before the first 
dose, during the Screening Period, except as specified otherwise: 
 Obtain a signed and dated Main ICF before any study-related procedures or 
assessments are conducted. 
 Obtain: 
 Demographics (eg, birth date, sex, race, ethnicity) 
 Medical and surgical history, including all previous, now resolved, significant 
medical conditions, date of diagnosis, extent of disease, disease staging, and 
previous cancer therapies (including prior radiation therapy). 
 From the time the subject signs the Main ICF:  
 Record concomitant medications (details in Section 5.6).   
 Record AEs.  For details on AE collection and reporting, refer to Section 9.2. 
 Perform a complete physical examination, including weight and height (details in 
Section 9.11). 
 Obtain vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, 
and body temperature; details in Section 9.9). 
 Obtain SpO2; details in Section 9.12. 
 Assess functional status using the ECOG PS scale (details in Section 17.3). 
 Confirm subject eligibility (inclusion and exclusion criteria in Section 4). 
 Obtain a new tumor biopsy and submit the tissue sample to the central laboratory for 
exploratory biomarker testing.  Tumor biopsy is not required at Screening,  
- 
If a new tumor biopsy was already performed and wet tissue sample (not slide) 
was submitted for HER2 testing during pre-screening as per Section 6.1 above.   
- 
If there is sufficient remaining pre-screening tissue sample after HER2 
confirmation, this specimen can be used and there is no need for an additional 
biopsy.  Refer to Laboratory Manual for further guidance. 
 Details regarding shipping instructions to the central laboratory will be provided in 
the Laboratory Manual. 


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 Collect and send blood samples to the laboratory for the following tests (details in 
Section 9.8)  
 Hematology 
 Blood chemistry 
 Coagulation (should also be performed as clinically indicated throughout the 
study) 
 Troponin (preferably high-sensitivity troponin-T); the test used to test troponin 
should remain the same throughout the course of a subject’s time on study.   
 Perform an HIV antibody test as required by local regulations or IRB/ECs (may be 
done within 28 days of enrollment).   
 Perform hepatitis B surface antigen and hepatitis C antibody test (may be done within 
28 days of first dose).  Patients positive for hepatitis C virus (HCV) antibody are 
eligible only if polymerase chain reaction is negative for HCV RNA. 
 Obtain urine sample for urinalysis (protein, glucose, blood, microscopy assessment 
[if indicated], and specific gravity; details in Section 9.8).   
 Perform an ECHO or MUGA scan for measurement of the LVEF.  (Note: The same 
test [ECHO or MUGA scan] must be used for the subject throughout the study; 
details in Section 9.12.1.) 
 Perform a 12-lead ECG in triplicate within 3 days before first dose (details in 
Section 9.10).  Electrocardiograms should be performed before blood draws. 
 Perform a tumor assessment by computed tomography (CT) or magnetic resonance 
imaging (MRI) scans of the chest, abdomen, pelvis, and any other sites of disease 
within 28 days before first dose.  CT/MRI scan obtained within 2 weeks of signing 
the main ICF could be used as baseline assessment. Note: To assess the objective 
response or future progression, it is necessary to estimate the overall tumor burden at 
baseline and use it as comparator for subsequent measurements.  Therefore, all 
lesions (target and non-target) have to be assessed at Screening according to RECIST 
v1.1 (details in Section 17.5).  Copies of CT or MRI images should be provided to 
central review within 2 weeks after confirmation of eligibility. 
 A CT or MRI of the brain must be performed for all subjects (details in 
Section 9.12.4) within 28 days before recruitment.  CT/MRI scan obtained within 
2 weeks of signing the main ICF could be used as baseline assessment.  Copies of CT 
or MRI images should be provided to central review vendor within 2 weeks after 
Cycle1 Day.   
 Perform ophthalmologic assessment, including visual acuity testing, slit lamp 
examination, and fundoscopy (details in Section 9.12.3). 
 For women of childbearing potential (as defined in Section 4.1), perform a serum or 
urine pregnancy test within 72 hours prior to the beginning of dosing and document 
the results.  A positive urine pregnancy test result must be confirmed immediately 


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using a serum test, with a confirmed negative test result within 72 hours prior to drug 
administration.  For subjects of non-childbearing potential (as defined in Section 4.1), 
no pregnancy test will be required. 
6.3. 
Treatment Period 
6.3.1. 
Cycle 1 to Cycle 4 and Subsequent Cycles 
6.3.1.1. 
Between 3 Days Before Through Immediately Before Infusion (All Cycles Unless 
Otherwise Noted)   
The following activities and/or assessments will be performed between 3 days before through 
immediately before the infusion for all cycles unless otherwise noted.  (Note: All assessments 
performed at Cycle 1 are not to be used for screening purposes).   
 Assess the HEOR outcomes: The subject must complete the HEOR outcomes 
questionnaires (FACT-Ga and EQ-5D-5L) before any other assessments or 
procedures are done.  The EQ-5D-5L should be completed before the FACT-Ga 
questionnaire (details in Section 10.1; sample questionnaires in Section 17.2).  Both 
questionnaires will be self-administered before infusion (BI) and before the 
completion of any other study-related procedures at Cycle 1 Day 1, at every other 
cycle (Cycles 3, 5, 7, etc.), and at the EOT Visit. 
 Obtain vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, 
and body temperature) (details in Section 9.9) and SpO2 (details in Section 9.12).  
More frequent examinations may be performed at the discretion of the Investigator 
and if medically indicated. 
 Perform a physical examination, including weight (details in Section 9.11). More 
frequent examinations may be performed at the discretion of the Investigator and if 
medically indicated. 
 Assess functional status using the ECOG PS scale (details in Section 17.4).   
 Perform 12-lead ECG  at every infusion before blood draws. Triplicate ECG to be 
performed if an abnormality is noted.  Electrocardiograms should be performed 
before blood draws (details in Section 9.10).   
 Collect and send blood samples to the laboratory for the following clinical laboratory 
tests (details in Section 9.8).  These need not be repeated if performed within 3 days 
before the first dose of study drug. 
 Hematology  
 Blood chemistry 
 Coagulation, if clinically indicated. 
 For women of childbearing potential (as defined in Section 4.1), perform a serum or 
urine pregnancy test within 72 hours prior to the beginning of dosing and document 
the results.  A positive urine pregnancy test result must be confirmed immediately 
using a serum test, with a confirmed negative test result within 72 hours prior to drug 


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administration.  For subjects of non-childbearing potential (as defined in Section 4.1), 
no pregnancy test will be required. 
 Obtain blood samples for:  
 Pharmacogenomics assessment (optional) on Cycle 1 Day 1 only, if the subject 
provides consent by signing the consent form allowing pharmacogenomics 
sample banking.  This sample is not required for study participation (details in 
Section 8.4).  
 Collect blood samples for HER2ECD and for cfDNA and cfRNA biomarkers 
(details in Section 8.3) within 3 days BI on Cycle 1 Day 1 and on Day 1 of every 
3 cycles (Cycles 4, 7, etc.).   
 Pharmacokinetic assessment within 8 hours BI at Cycles 1, 2, 3, 4, 6, and 8 
(details in Section 8.1). 
 Collect a blood sample for ADA measurement within 8 hours BI on Day 1 of 
Cycles 1, 2, and 4, and then every 4 cycles (Cycles 8, 12, 16, etc.).  If the ADA 
test is positive at any follow-up visit, collect samples for ADA measurements 
every 3 months ±14 days up to 1 year after the last dose of study treatment, or 
until the ADA level returns to baseline or is undetectable, or the subject starts a 
new anticancer treatment or withdraws consent to participate in the study (details 
in Section 8.3.2). 
 If subject provides consent, samples should be collected prior to study drug infusion 
on Day 1 of Cycle 1 then starting at Cycle 5, Day 1 and every 4 cycles thereafter.  For 
subjects with suspected or confirmed COVID-19, follow the dose modifications in 
Section 17.1. 
 Record concomitant medications and AEs. 
 Perform a tumor assessment every 6 weeks (±7 days) starting at Cycle 1 Day 1 in the 
first year and every 12 weeks (±7 days) thereafter until objective disease progression 
or until start of new anticancer treatment, if patient discontinues study treatment for 
any reason other than disease progression.  Refer to RECIST v1.1 guidelines in 
Section 17.5.   
 Perform a CT or MRI of the brain every 6 weeks (±7days) from Cycle 1 Day 1.  The 
brain CT/MRI scan is mandatory for all subjects with stable brain metastases at 
baseline.  For all other subjects, the brain CT/MRI is to be performed as clinically 
indicated (details in Section 9.12.4).  
 Perform an ECHO or MUGA scan for measurement of the LVEF (Note: The same 
test [ECHO or MUGA scan] must be used for the subject throughout the study; 
details in Section 9.12.1) on Cycle 5 (±7days) Day 1 BI and every 4 cycles ±7 days 
thereafter (at Day 1 of Cycles 9, 13, etc.). 
 Collect a tumor sample at the end of Cycle 3/prior to Cycle 4 Day 1 (up to 7 days 
prior to start of Cycle 4) infusion for biomarker analysis, including HER2 status.  At 
least 2 core biopsies are requested at Cycle 3 but if the risk of biopsy complications 


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from a second core biopsy is unacceptable (at the discretion of the Investigator), then 
a single core biopsy will suffice.   
 Administer trastuzumab deruxtecan as an IV infusion over at least 90 minutes for the 
first dose (details in Section 5.2.4).  If no IRR of any severity is recorded during the 
first administration, administer subsequent infusions over a minimum of 30 minutes.  
If IRR is recorded during the first administration, all subsequent infusions will occur 
over approximately 90 minutes.  Record the start and stop times of infusion and 
amount of drug administered.   
6.3.1.2. 
End of Infusion (All Cycles Unless Otherwise Noted) 
 Obtain vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, 
and body temperature; details in Section 9.9) and SpO2 (details in Section 9.12) for 
Cycles 1, 2, and 3.  More frequent examinations may be performed at the discretion 
of the Investigator and if medically indicated. 
 Collect PK blood (serum) samples at the following time points (details in 
Section 8.1):  
 Within 15 minutes after the end of infusion at Cycles 1, 2, 3, 4, 6, and 8 
 At 5 hours ± 2 hours from the infusion start time at Cycle 1 Day 1 only. 
 Continue recording of concomitant medications and AEs. 
6.3.1.3. 
Cycle 1 Day 8 and Cycle 1 Day 15 (± 1 Day) 
 Obtain vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, 
and body temperature; details in Section 9.9) and SpO2 (details in Section 9.12).  
More frequent examinations may be performed at the discretion of the Investigator 
and if medically indicated. 
 Collect and send blood samples to the laboratory for the following clinical laboratory 
tests (details in Section 9.8).   
 Hematology  
 Blood chemistry 
 Coagulation, if clinically indicated.  
 Collect PK blood (serum) sample (details in Section 8.1). 
 Continue recording of concomitant medications, and AEs. 
6.4. 
End of treatment Visit 
The EOT is defined as the date the Investigator decides to discontinue study treatment (+7 days).  
An EOT Visit should be scheduled 30 days (±7 days) after a subject’s last dose of study drug.  
After treatment discontinuation, all subjects will be followed for survival.  The following 
procedures should be performed (details in Table 17.1): 


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 Assess HEOR outcomes: The subject must complete the HEOR outcomes 
questionnaires (FACT-Ga and EQ-5D-5L) before any other assessments or 
procedures are done.  The EQ-5D-5L should be completed before the FACT-Ga 
questionnaire (details in Section 10.1; sample questionnaires in Section 17.2).   
 For women of childbearing potential (as defined in Section 4.1), perform a serum or 
urine pregnancy test and document the results.  For subjects of non-childbearing 
potential (as defined in Section 4.1), no pregnancy test will be required.   
 Obtain vital signs: systolic and diastolic blood pressure, pulse rate, respiratory rate, 
and body temperature (Section 9.9). 
 Obtain SpO2 (details in Section 9.12).   
 Perform a physical examination, including weight (details in Section 9.11). 
 Assess functional status using the ECOG PS scale (details in Section 17.4). 
 Collect and send blood samples to the laboratory for the following clinical laboratory 
tests (details in Section 9.8).   
 Hematology  
 Blood chemistry 
 Coagulation (if clinically indicated). 
 Collect a blood sample for troponin (preferably high-sensitivity troponin-T)  
 Collect blood samples for biomarker analysis (HER2ECD, cfDNA and cfRNA) 
(details in Section 8.3). 
 Collect a blood sample for ADA measurement (details in Section 8.3.2). 
 Perform ophthalmologic assessment, including visual acuity testing, slit lamp 
examination, and fundoscopy. 
 Perform an ECHO or MUGA scan for measurement of the LVEF (Note: The same 
test [ECHO or MUGA scan] must be used for the subject throughout the study 
[details in Section 9.12.1]). 
 Perform 12-lead ECG.  (details in Section 9.10).  
 Mandatory tumor sample for HER2 status and biomarker analysis. 
 Continue recording of concomitant medications, AEs, and hospitalization-related 
records. 
 Tumor assessments to evaluate efficacy will be performed until progression of 
disease or the start of a new anticancer treatment in cases of study treatment 
discontinuation due to reasons other than disease progression.  Tumor assessments 
should include all sites of disease identified at Screening and any other locations if 
PD is suspected (eg, MRI of the brain if brain metastases are suspected) should also 
be imaged, per RECIST v1.1 (Section 17.5).  If the previous scan was within the last 
6 weeks, this assessment does not need to be performed at the EOT Visit.  Copies of 


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CT or MRI images should be provided to the central review vendor within 2 weeks 
from images being taken. 
6.5. 
Follow-up 
6.5.1. 
40-day (+ 7 Days) Follow-up Visit 
Forty days (+7 days) after last study drug administration or before starting new anticancer 
treatment, whichever comes first, the following procedures will be performed as specified in the 
Schedule of Events (Table 17.1).  If EOT is >47 days after last treatment, the EOT assessments 
can also function as the Follow-up Visit.   
 Obtain vital signs: systolic and diastolic blood pressure, pulse rate, respiratory rate, 
and body temperature (Section 9.9). 
 Obtain SpO2 (details in Section 9.12).   
 Perform a physical examination, including weight (details in Section 9.11). 
 Assess functional status using the ECOG PS scale (details in Section 17.4). 
 Collect and send blood samples to the laboratory for the following clinical laboratory 
tests (details in Section 9.8).   
 Hematology  
 Blood chemistry 
 Coagulation if clinically indicated. 
 Collect a blood sample for ADA measurement.  If the ADA test is positive, collect a 
sample for ADA measurement every 3 months ±14 days, up to 1 year after the last 
dose of study treatment, or until the ADA level returns to baseline or is undetectable, 
or until the subject starts a new anticancer treatment or withdraws consent to 
participate in the study (details in Section 8.3.2). 
 Continue recording of concomitant medications, AEs, and hospitalization-related 
records. 
 Record of any additional anticancer therapy for gastric/GEJ cancer, including names 
of drugs, dosage, dates of administration, response to therapy, if available, and reason 
for discontinuation, if applicable. 
 Perform tumor assessment if not performed at EOT Visit if study treatment was 
discontinued for any reason other than disease progression.  If study treatment was 
discontinued for reason other than PD, perform at the 40-day Follow-up Visit if not 
performed at the EOT Visit, and perform every 3 months after the first year, until PD 
or the start of a new anticancer treatment. 
6.5.2. 
Long-term/Survival Follow-up (Every 3 Months ±14 Days) 
After completion of the 40-day (+7 days) Follow-up Visit, the Long-term/Survival Follow-up 
Visits will be performed every 3 months (±14 days) from the date of 40-day (+7 days) Follow-up 


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Visit until death, withdrawal of consent, loss to follow-up, or study closure, whichever occurs 
first.   
The following activities will take place during Long-term/Survival Follow-up Visits at the study 
site or by telephone contact: 
 Collect a blood sample for ADA measurement.  If the ADA test is positive collect a 
sample for ADA measurement every 3 months ±14 days, up to 1 year after the last 
dose of study treatment, or until the ADA level returns to baseline or is undetectable, 
or until the subject starts a new anticancer treatment or withdraws consent to 
participate in the study (details in Section 8.3). 
 Perform tumor assessment every 6 weeks (±7 days) from Cycle 1 Day 1 in the first 
year and every 12 weeks (±7 days) thereafter until objective disease progression 
(based on radiologic assessment) or until start of new anticancer treatment, if patient 
discontinues study treatment for any reason other than disease progression.  If study 
treatment was discontinued for reason other than PD, perform at the 40-day 
Follow-up Visit if not performed at the EOT Visit, and perform every 3 months after 
the first year, until PD or the start of a new anticancer treatment. 
 Record of any new subsequent line of therapy for gastric/GEJ cancer, including 
names of drugs, dosage, dates of administration, response to therapy, if available, and 
reason for discontinuation of each, if applicable. 
 Once subjects progress or start other anticancer treatment, they will be followed for 
survival until death, withdrawal of consent, loss to follow-up, or study closure.  If 
direct contacts are not possible due to withdrawal of consent or the subject becomes 
lost to follow-up, the site must make every effort to collect survival status from public 
records (eg, death certificates) in accordance with local laws.  Further details on how 
subjects will be followed for survival status if they withdraw consent are available in 
Section 5.8.3. 
6.6. 
Additional PK assessments due to Coronavirus disease 2019 
(COVID-19) 
In case of chloroquine or hydroxychloroquine administration for COVID-19, additional PK 
serum samples should be collected at the following time points (See Table 8.2)  


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7. 
EFFICACY ASSESSMENTS 
Baseline tumor assessments will be performed prior to first dose (Cycle 1 Day 1) recruitment, 
and every 6 weeks (±7 days) from Cycle 1 Day 1 during the treatment period during the first 
year, and every 12 weeks (±7 days) thereafter until progression of disease or the start of a new 
anticancer treatment in cases of study treatment discontinuation due to reasons other than disease 
progression (see Schedule of Events in Table 17.1).  All tumor scans during the study period 
should be submitted for independent central review in a timely manner.  Copies of CT or MRI 
images should be provided to central review within 2 weeks after the images are taken (baseline 
image is within 2 weeks after Cycle1 Day1). 
7.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint (ie, primary outcome measure) is confirmed ORR, defined as the 
proportion of subjects who achieved a best overall response of confirmed CR or confirmed PR, 
as determined by independent central review using RECIST v1.1 (details in Section 17.5). 
7.2. 
Secondary Efficacy Endpoint(s) 
7.2.1. 
Key Secondary Efficacy Endpoint 
The key secondary efficacy endpoints is PFS, based on independent central review, defined as 
the time from the date of start of study treatment to the earliest date of the objective disease 
progression per RECIST v1.1 or death due to any cause.  (details in Section 17.5) or death due to 
any cause.  Subjects who are alive with no objective documentation of (radiographic) disease 
progression by the DCO date for PFS analysis will be censored at the date of their last evaluable 
tumor assessment. 
7.2.2. 
Other Secondary Efficacy Endpoints 
Other secondary efficacy endpoints include the following: 
 PFS, based on Investigator assessment 
 OS 
 ORR, based Investigator assessment 
 DoR, based on both independent central review and Investigator assessment   
7.2.3. 
Exploratory Efficacy Endpoints 
Exploratory efficacy endpoints include the following: 
 DCR, based on both independent central review and Investigator assessment, defined 
as the sum of CR, PR, and SD rates, assessed according to RECIST v1.1 (details in 
Section 17.5) 
 Time to response, based on both independent central review and Investigator 
assessment 
 Best percentage change in the sum of diameters of measurable tumors 


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7.3. 
Appropriateness of Selected Efficacy Assessments 
All selected efficacy endpoints provide evidence of drug activity.  ORR is defined as the 
proportion of subjects with CR and PR as defined by RECIST v 1.1 in this trial. ORR is a direct 
measure of drug antitumor activity, which can be evaluated in a single-arm study.  Because ORR 
is directly attributable to study drug effect, it is an appropriate measure of efficacy in single-arm 
trials.  
Patients with GC face an illness associated with significant symptoms.  Moreover, they are also 
aware that despite the availability of various treatments, it is ultimately incurable.  The success 
of modern therapies in achieving better disease control and prolonged survival means that more 
GC patients can receive several lines of treatment and, in the process, the key goals are to 
prolong survival and to improve health-related QoL.  That is why it is particularly valuable to 
involve subjects in clinical studies by asking them to provide assessment of their health and QoL.  
The HEOR assessments considered most appropriate for this population are the FACT-Ga and 
the EQ-5D-5L. 
The index scores will be used in further analyses and economic models to generate evidence for 
access and reimbursement purposes. 


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8. 
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS 
8.1. 
Pharmacokinetic (PK) Assessment(s) 
Blood samples for trastuzumab deruxtecan PK analyses will be obtained at the time points 
specified in Table 8.1 and in the Schedule of Events (Table 17.1).   
Table 8.1: 
Schedule of PK Sample Collection 
Cycle 
Sampling Time Point (Acceptable Ranges) 
1 
Day 1: 
Before infusion: Within 8 hours before the beginning of infusion 
End of infusion: Within 15 minutes after the end of infusion 
5  ± 2 hours from the infusion start time 
Day 8 ± 1 days 
Day 15 ± 1 days 
2, 3, 4, 6,  
and 8 
Day 1: 
Before infusion: Within 8 hours before the beginning of infusion 
End of infusion: Within 15 minutes after the end of infusion 
In case of chloroquine or hydroxychloroquine administration for COVID-19, additional PK 
serum samples should be collected at the following time points (Table 8.2):  
Table 8.2: 
Schedule of PK Sample Collections in Case of Chloroquine and 
Hydroxychloroquine Treatment 
Day of chloroquine or hydroxychloroquine 
administration 
Sampling Time point 
Day 1 
Prior to chloroquine or hydroxychloroquine dose  
Day 3 or 4 
Prior to chloroquine or hydroxychloroquine dose 
(within 4 hours)  
EOT with chloroquine or hydroxychloroquine  
Prior to chloroquine or hydroxychloroquine dose 
(within 4 hours) 
Prior to re-initiation of trastuzumab deruxtecan 
BI (within 8 hours) 
BI = before infusion; EOT = End of Treatment 
At each time point, blood will be collected for trastuzumab deruxtecan, total anti-HER2 antibody 
and MAAA-1181a PK analysis.  The actual time of study drug administration and the exact time 
of blood sampling for trastuzumab deruxtecan PK analysis must be recorded on the electronic 
CRF (eCRF), including those samples collected in case of chloroquine or hydroxychloroquine 
administration for COVID-19.   
Instructions for the handling of blood samples and shipping of serum samples are included in a 
separate document (ie, the study Laboratory Manual).  The PK samples will be shipped to a 
central laboratory for forwarding to a Sponsor-designated bioanalytical laboratory. 


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Serum concentrations of trastuzumab deruxtecan, total anti-HER2 antibody, and MAAA-1181a 
will be measured using validated assays at the bioanalytical laboratory. 
The PK parameters listed in Section 2.3.5 for each subject will be estimated using standard 
non-compartmental methods. 
8.2. 
Pharmacodynamic Assessment(s) 
Not applicable 
8.3. 
Biomarker Assessment(s) 
8.3.1. 
Biomarker assessments 
Biomarker analyses will be used to investigate the effect of trastuzumab deruxtecan at the 
molecular and cellular levels, as well as to determine how changes in the biomarkers may relate 
to exposure and clinical outcomes.   
Plasma samples for assessment of biomarkers such as cfDNA, cfRNA or serum samples for 
assessment of biomarkers such as HER2ECD will be collected for all subjects within 3 d before 
the beginning of the infusion on Cycle 1 Day 1; on Day 1 of every 3 cycles thereafter (Cycles 4, 
7, etc.); and at the EOT Visit.  The sample collection information as required should be recorded 
on the eCRF page(s) and central laboratory requisition form(s).  
Tumor specimens will be used to assess HER2 expression using IHC and/or ISH, and possibly, 
but not limited to, mRNA expression and mutation profiling, using next-generation sequencing 
technology or other methods.  
For HER2 testing by central laboratory during pre-screening, a new tumor biopsy is required if 
recent tumor tissue is inadequate or not available for HER2 testing by the central laboratory.  A 
tissue sample is considered a “recent sample” if it is collected from a biopsy performed after the 
subject’s discontinuation of the last treatment regimen and most recent disease progression and 
prior to patient’s consent for tissue screening.   
A new tumor biopsy is mandatory at the end of Cycle 3 / prior to Cycle 4 Day 1 infusion (up to 
7 days prior to start of Cycle 4), and at the EOT Visit (see Table 17.1).  Detailed instructions for 
the collection, handling, and shipping of biomarker samples are outlined in the study Laboratory 
Manual. 
8.3.2. 
Additional Biomarker Assessments 
During the study, in addition to the biomarkers specified above, exploratory biomarker research 
may be conducted on any collected samples.  These studies would extend the search for other 
potential biomarkers relevant to the effects of trastuzumab deruxtecan, cancer and/or the 
resistance to the treatment.  This may include the development of ways to detect, monitor or treat 
cancer.  These additional investigations would be dependent upon clinical outcome, reagent and 
sample availability.   
The remaining samples (tumor tissues, blood and plasma) may be stored for up to 15 years at the 
longest, according to the regulation in each country or region respectively, and further analyzed 
to address scientific questions related to trastuzumab deruxtecan and/or cancer.   


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8.3.3. 
Immunogenicity (Anti-drug Antibodies)  
Blood samples for ADA analyses will be collected at the time points specified in the Schedule of 
Events (Table 17.1).  If the ADA test is positive at any follow-up visit, collect samples for ADA 
measurements every 3 months ±14 days up to 1 year after the last dose of study treatment, or 
until the ADA level returns to baseline or is undetectable, or the subject starts a new anticancer 
treatment or subject withdraws consent to participate in the study. 
Serum concentrations of trastuzumab deruxtecan and/or total anti-HER2 antibody may be 
measured using the same ADA samples for purpose of ADA assessment.   
Details for ADA serum sampling, processing, storage, and shipment for ADA samples will be 
provided in the study Laboratory Manual. 
The ADA testing will be performed by using a validated ADA assay following tiered-assay steps 
including screening, confirmatory, and titer determination testing.  The neutralizing ADA assay 
will be performed by using the sample confirmed positive.  Sample storage time will not exceed 
15 years. 
8.4. 
Pharmacogenomic Analysis 
8.4.1. 
Genomic or Genetic Banking and Analysis 
A single blood sample for pharmacogenomics analysis will be collected before drug 
administration on Cycle 1 Day 1 from each subject who consents to this test.  Participation in this 
part of the study is optional for all subjects. 
The DNA samples will be extracted from the blood sample for pharmacogenomics analysis.  The 
pharmacogenomic samples may be analyzed for genes involved in absorption, distribution, 
metabolism, elimination, safety, and efficacy of trastuzumab deruxtecan.  Additionally, samples 
may be analyzed for genes involved in trastuzumab deruxtecan related signaling pathways, or to 
examine diseases or physiologic processes related to trastuzumab deruxtecan.  This information 
may be useful in increasing the knowledge of differences among individuals in the way they 
respond to the study treatment, as well as helping in the development of new drugs or 
improvement of existing drugs. 
Specimen shipping and handling details will be included in the study Laboratory Manual. 
8.4.2. 
Disclosure of the Results of Genomic or Genetic Analysis 
Please refer to the ICF for details on disclosure of results. 
8.4.3. 
Storage and Disposal of Specimens for Genomic or Genetic Banking and 
Analysis 
Samples will be retained for up to 15 years at the longest, according to the regulations in each 
country or region respectively, or until the sample has been exhausted or until the Sponsor 
instructs the laboratory for sample storage and/or analysis to destroy the sample (in accordance 
with laboratory procedures).   
During the period of storage, the samples will not be immortalized or sold to anyone.   


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Subjects will have the right to withdraw consent and have their sample destroyed at any time.  
However, the data will not be discarded if the genetic analysis has been completed before the 
subject withdraws consent. 


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9. 
SAFETY EVALUATION AND REPORTING 
9.1. 
Assessment of Safety Endpoints 
Safety parameters will include SAEs, TEAEs, drug-related TEAEs, AESIs, discontinuations due 
to AEs, ECHO/MUGA scan findings; ophthalmologic findings, physical examination findings, 
ECOG PS, vital sign measurements, standard clinical laboratory parameters (central laboratory) 
(blood chemistry, coagulation, and hematology), ADA, and ECG parameters.  AEs will be 
categorized using the Medical Dictionary for Regulatory Activities (MedDRA).  AEs and 
abnormal laboratory test results, if applicable, will be graded using National Cancer Institute 
(NCI) CTCAE v5.0.  Safety analyses in general will be descriptive and will be presented in 
tabular format with the appropriate summary statistics. 
9.2. 
Adverse Event Collection and Reporting 
A Treatment-emergent adverse event (TEAE) is defined as an AE that occurs, having been 
absent before the first dose of study drug, or has worsened in severity or seriousness after the 
initiating the study drug until 47 days after last dose of the study drug. SAEs with an onset or 
worsening 48 days or more after the last dose of study drug, if considered related to the study 
treatment, are also TEAEs. 
All clinical AEs and SAEs (see Section 9.4.1 and Section 9.4.2 for definitions), whether 
observed by the Investigator or reported by the subject, that occur after the subject signs the ICF 
(including those reported at each follow-up visit) will be recorded on the AE eCRF page.  
Medical conditions (including laboratory values/vital signs that are out of range) that were 
diagnosed or known to exist prior to signing the ICF after the subject signs the pre-screening ICF 
until the first study drug administration, should be recorded as part of medical history.   
All AEs, SAEs, and AESIs are to be reported according to the procedures in Section 9.5.   
If a tumor biopsy is needed after the subject signs the pre-screening ICF and before the main 
ICF, report any SAEs directly related to tissue screening procedures (ie, tumor biopsy) along 
with any associated treatment.  Unless documentation of other AEs is required by local law, only 
SAEs directly related to tumor biopsy before the subject signs the main ICF, will be recorded 
during tissue screening. 
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 9.4.  
The Investigator’s assessment must be clearly documented in the site’s source documentation 
with the Investigator’s signature.   


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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 (refer to Section 9.4.2 for definitions).   
For deaths, the underlying or immediate cause of death should always be reported as an SAE.  
Disease progression/worsening of GC will not be recorded as an AE on the Adverse Event 
eCRF.  However, events associated with disease progression, such as nausea, vomiting, and 
diarrhea, may be recorded as AEs. 
Death due to disease progression should be recorded on the Death eCRF.  
Any serious, untoward event that may occur subsequent to the reporting period that the 
Investigator assesses as related to study drug should also be reported and managed as an SAE. 
9.3. 
Adverse Events of Special Interest 
Based on available preclinical data, review of the cumulative literature, reported toxicities for the 
same class of agents, and biological plausibility, the following events are considered to be 
AESIs: ILD/pneumonitis, and LVEF decrease.  
9.3.1. 
Interstitial Lung Disease/Pneumonitis 
9.3.1.1. 
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 ILD/pneumonitis cases reviewed by the independent 
ILD AC, available data from recent epidemiology/literature, biological plausibility, and safety 
information from drugs of similar class.  Refer to the current IB for a summary of preliminary 
clinical study data.21   
9.3.1.2. 
Management Guidance 
Interstitial lung disease/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 “Other Non-Laboratory Adverse Events” dose modification section of 
the protocol (Section 5.4).   
If the AE is suspected to be ILD/pneumonitis, treatment with study drug should be interrupted 
pending further evaluations. 


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Evaluations should include: 
 High resolution CT 
 Pulmonologist consultation  (infectious disease consultation as clinically indicated) 
 Pulmonary function tests and pulse oximetry (SpO2) 
 Blood culture and CBC (other blood tests could be considered as needed) 
 Bronchoscopy and bronchoalveolar lavage if clinically indicated and feasible should 
be considered 
 Arterial blood gases if clinically indicated 
 1 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; Section 5.4). 
All events of ILD regardless of severity or seriousness will be followed until resolution including 
after drug discontinuation. 
Interstitial Lung Disease Adjudication Committee 
An independent ILD AC for the trastuzumab deruxtecan 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.  This additional data collection will cover a more in-depth relevant medical history 
(eg, smoking, radiation, chronic obstructive pulmonary disease and other chronic lung 
conditions), diagnostic evaluation, treatment and outcome of the event.  This data collection will 
be triggered for AEs reported by using selected 42 PTs [all from the ILD Standard MedDRA 
Query (SMQ)] plus 2 PTs of acute respiratory failure and respiratory failure.  
9.3.2. 
 LVEF Decrease 
9.3.2.1. 
Clinical Summary  
LVEF decrease is considered to be an important potential risk based on the available preclinical 
data, clinical data, literature and available safety information for drugs of similar class.  Refer to 
the current IB for a summary of preliminary clinical study data.21   
9.3.2.2. 
LVEF decrease Management Guidance 
Left ventricular ejection 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 at EOT locally.  Patients may also have local 
troponin testing as clinically indicated during the treatment phase based on subject-reported 
cardiac signs or symptoms suggesting congestive heart failure, MI, or other causes of cardiac 


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myocyte necrosis.  An additional sample will be submitted for central laboratory troponin-T 
testing, and ECG will be performed in triplicate.  If the ECG is abnormal, follow institutional 
guidelines.  
ECG will be taken in triplicate at screening. Subsequent ECGs will be performed in triplicate if 
an abnormality is noted. 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 the ECG was performed, the date performed, the results, and 
the findings for each parameter will be recorded in the eCRF. 
9.4. 
Adverse Events 
9.4.1. 
Definition of Adverse Event 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product 
and that does not necessarily have to have a causal relationship with this treatment.  An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product (International Conference on 
Harmonisation [ICH] E2A Guideline).37 
It is the responsibility of Investigators, based on their knowledge and experience, to determine 
those circumstances or abnormal laboratory findings that should be considered AEs. 
9.4.2. 
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 
 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).37  
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. 


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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. 
9.4.3. 
Severity Assessment 
The severity of AEs will be graded using the NCI CTCAE v5.0.  For each episode, the highest 
severity grade attained should be reported. 
The NCI CTCAE guidelines do not allow certain grades for certain AEs.  For example, pain can 
be Grade 1 to 3 only (ie, cannot be life-threatening or fatal), whereas sepsis can be only Grade 4 
or 5 (ie, can only be life-threatening or fatal).  In addition, alopecia can be only Grade 1 or 2.  
The NCI CTCAE guidelines should be followed closely. 
 Grade 1: Mild = asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
 Grade 2: Moderate = minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living 
 Grade 3: Severe = Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care activities of daily living 
 Grade 4: Life-threatening consequences; urgent intervention indicated 
 Grade 5: Death related to AE. 
Severity versus Seriousness:  
Severity is used to describe the intensity of a specific event while the event itself, however, may 
be of relatively minor medical significance (such as severe headache).  Seriousness of an event is 
based upon a universal and global Regulatory definition for reporting SAEs to regulatory 
agencies.  For example, 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 grade may or may not be assessed as serious 
based on the seriousness criteria.  Overall, the severity of an event may be graded by the 
Investigator as Grade 1 or 2, but if the subject presents to the emergency facility for evaluation 
and is hospitalized overnight for observation that immediately makes the event serious based 
upon hospitalization without regard to the Investigator assessment of severity. 
9.4.4. 
Causality Assessment 
The Investigator should assess causal relationship between an AE and the study drug on the basis 
of his/her clinical judgment and the following definitions.  The causality assessment must be 


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made on the basis of the available information and can be updated as new information becomes 
available. 
 Related: 
 The AE follows a reasonable temporal sequence from study drug administration, 
and cannot be reasonably explained by the subject’s clinical state or other factors 
(eg, disease under study, concurrent diseases, and concomitant medications). 
or 
 The AE follows a reasonable temporal sequence from study drug administration, 
and is a known reaction to the drug under study or its chemical group, or is 
predicted by known pharmacology. 
 Not Related: 
 The AE does not follow a reasonable sequence from study drug administration, or 
can be reasonably explained by the subject’s clinical state or other factors 
(eg, disease under study, concurrent diseases, concomitant medications).   
9.4.5. 
Action Taken Regarding Study Drug(s) 
The final action taken in response to an AE will be recorded as follows: 
 Dose Not Changed: No change in study drug dosage was made. 
 Drug Withdrawn: The study drug was permanently stopped. 
 Dose Reduced: The dosage of study drug was reduced. 
 Drug Interrupted: The study drug was temporarily stopped. 
 Not Applicable: Subject died, study treatment had been completed prior to 
reaction/event, or reaction/event occurred prior to start of treatment. 
9.4.6. 
Other Action Taken for Event 
Other actions taken for an AE will be recorded as follows: 
 None: No treatment was required 
 Medication required: Prescription and/or OTC medication was required to treat the 
AE. 
 Hospitalization or prolongation of hospitalization required: Hospitalization was 
required or prolonged due to the AE, regardless of whether medication was required. 
 Other. 
9.4.7. 
Adverse Event Outcome 
Outcome of an AE will be recorded as follows: 
 Recovered/Resolved: The subject fully recovered from the AE with no residual effect 
observed. 


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 Recovered/Resolved with Sequelae: The residual effects of the AE are still present 
and observable (include sequelae/residual effects). 
 Recovering/Resolving: The AE improved but has not fully resolved. 
 Not Recovered/Not Resolved: The AE itself is still present and observable. 
 Fatal: Death is a direct outcome of the AE. 
 Unknown: Should be used if subject is lost to follow-up before an outcome can be 
determined. 
9.5. 
Reporting Serious Adverse Events and Adverse Event of Special 
Interest – Procedure for Investigators 
All AEs, AESIs, SAEs, and medication errors, including overdose, will be reported in the eCRF. 
Additional relevant information regarding the AESIs ILD/pneumonitis, QT prolongation and 
LVEF decrease for the trastuzumab deruxtecan clinical program regardless of seriousness is to 
be collected through the targeted questionnaires within the clinical study database.  Additional 
relevant information regarding the AESI IRR is to be collected through the narrative form within 
the clinical study database. 
Serious events that are also efficacy endpoints (eg, PD) and/or safety endpoints will be exempted 
from SAE processing and expedited reporting.  Disease progression should not be reported as an 
AE/SAE.  However, when a subject dies from PD with no other immediate causes, “disease 
progression” should be reported as an SAE and captured on the designated eCRF page.  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 eCRF electronic data 
capture (EDC) AE page(s) in the clinical database within 24 hours of becoming aware of the 
event: 
 SAEs (see Section 9.4.2 for definition). 
 All potential ILD cases should be reported within 24 hours; including both serious 
and non-serious potential ILD cases (potential ILD is defined by the Event 
Adjudication Site Manual List of PTs). 
 Hepatic events (both serious and non-serious) that meet the potential Hy’s Law 
criteria defined as an elevated (ALT or AST) ≥3 × ULN and an elevated blood 
bilirubin >2 × ULN that may occur either at different time points or simultaneously 
during the study conduct.  A targeted questionnaire is 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 an SAE, a 
non-serious AE, or no AE occurs and is considered by the Investigator as clinically 
relevant, ie, poses an actual or potential risk to the subject.   


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 Overdose is always serious. By definition an overdose is medically important, 
which meets the seriousness criterion of important medical event. An overdose 
can occur with or without an AE. AEs can either be serious or non-serious. 
Details of the overdose including trastuzumab deruxtecan dosage, clinical course, 
associated AEs, and outcome must be captured in the Narrative form of the CRF 
within eDC. 
All events (serious and non-serious) must be reported with Investigator’s assessment of the 
event’s seriousness, severity, and causal relationship with 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.  Follow-up information and 
response to non-urgent safety queries should be combined for reporting to provide the most 
complete data possible within each follow-up.  In the event that eCRF is unavailable, report 
SAEs by faxing the paper Serious Adverse Event Report (SAVER) Form to the CRO using the 
provided fax cover sheet and the appropriate fax number provided for your country.  Once eCRF 
becomes available, please enter SAEs reported on the SAVER Form into eCRF as soon as 
possible.  Please refer to eCRF Completion Guide for additional instructions. 
Please call the local SAE Hotline (see Study Manual) or your study monitor for any questions on 
SAE reporting. 
9.6. 
Notifying Regulatory Authorities, Investigators, and Institutional 
Review Board/Ethics Committee 
Daiichi Sankyo and/or CRO will inform Investigators IRBs/ECs, and regulatory authorities of 
any suspected unexpected serious adverse reactions (SUSARs) occurring in other study centers 
or other studies of the investigational drug, as appropriate per local reporting requirements.  
Daiichi Sankyo and/or CRO will comply with any additional local safety reporting requirements. 
In the US, upon receipt of the Sponsor’s notification of SUSARs that occurred with the study 
drug, unless delegated to the Sponsor, it is the Investigator’s responsibility to inform the IRB/EC 
per Sponsor’s instruction. 
In the European Economic Area states, it is the Sponsor’s responsibility to report SUSARs to all 
ECs. 
9.7. 
Exposure in Utero During Clinical Studies 
Daiichi Sankyo must be notified of any subject or the female partner of any subject who becomes 
pregnant while receiving or within 7 months for females and 4 months for males of discontinuing 
the study drug.   


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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 an SAE (ie, postpartum complications, spontaneous or 
induced abortion, stillbirth, neonatal death, or congenital anomaly, including that in an aborted 
fetus), the Investigator should follow the procedures for reporting SAEs outlined in Section 9.5.   
9.8. 
Clinical Laboratory Evaluations 
The following clinical laboratory tests will be performed as described in the Schedule of Events 
(Table 17.1): 
1. Hematology tests 
 Red blood cell count, hemoglobin, hematocrit, platelet count, white blood cell count, 
and differential white blood cell count (neutrophils, lymphocytes, monocytes, 
eosinophils, and basophils) 
2. Blood chemistry tests 
 Total protein, albumin, alkaline phosphatase, ALT, AST, blood bilirubin, blood urea 
nitrogen, blood urea, calcium, chloride, serum creatinine, lactate dehydrogenase, 
potassium, sodium, and magnesium 
 A coagulation test (international normalized ratio) will be performed at Screening and 
thereafter as clinically indicated  
 Creatinine clearance (CrCl; mL/min) will be calculated using the Cockcroft-Gault 
equation (Section 17.3)  
3. Blood samples for troponin (preferably high-sensitivity troponin-T) should be obtained at 
Screening, at the EOT Visit locally, and as clinically indicated.   
4. Urinalysis 
 Protein, glucose, blood, microscopy assessment (if indicated), and specific gravity. 
5. Pregnancy test (serum or urine) for all female subjects of childbearing potential.  A 
positive urine pregnancy test result must be confirmed immediately using a serum test. 
Information will be entered in the CRF on whether the parameter was measured and the date of 
measurement.  For clinical laboratory parameters, the reference range of the institution that 
performs the measurements will be used.  Local laboratory test results will be transferred to a 
central laboratory for data entry.   
All laboratory values must be appraised by the Investigator as to clinical significance and used to 
take appropriate clinical management measures.  All abnormal laboratory values considered 


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clinically significant by the Investigator should be recorded on the AE page of the eCRF.  If the 
abnormal laboratory value constitutes an SAE, relevant procedures must be followed 
(Section 9.5).  Abnormal laboratory values (NCI CTCAE Grade 3 or 4) occurring during the 
clinical study will be followed until repeat test results return to normal (or baseline), stabilize, or 
are no longer clinically significant. 
9.9. 
Vital Signs 
Information will be entered in the eCRF on whether the parameter is measured, the date of the 
measurement, and measurement results for the following items: systolic and diastolic blood 
pressure, pulse rate, respiratory rate, and body temperature.  Blood pressure and pulse rate will 
be measured after the subject has rested in a recumbent position for 5 minutes or more.   
Vital signs will be collected as described in the Schedule of Events (Table 17.1).   
9.10. 
Electrocardiograms 
Standard supine/semi-recumbent 12-lead ECGs ) will be performed as described in the Schedule 
of Events (Table 17.1).  The ECG will be measured after the subject has rested in a recumbent 
position for 5 minutes or more.  Electrocardiograms should be performed before blood draws.   
Standard ECG parameters will be measured, including heart rate, PR interval, RR interval, QT 
intervals, and QRS duration.  All ECGs must be evaluated by Investigator or delegated physician 
for the presence of abnormalities. 
QTc intervals will be calculated at each time point according to Fridericia’s formula. 
9.11. 
Physical Examinations and Functional Status 
Physical examination will be performed as described in the Schedule of Events (Table 17.1). 
The following body systems/organs will be evaluated: general appearance; dermatological; head; 
ears, nose, mouth, and throat; pulmonary; cardiovascular; abdominal; genitourinary (optional); 
lymphatic; musculoskeletal/ extremities; and neurological.   
Weight (kg) and height (cm; collected at Screening only) will be recorded. 
Functional status will be assessed using the ECOG PS scale (refer to Section 17.4). 
9.12. 
Other Examinations 
9.12.1. 
Cardiac Assessments 
Either an ECHO or MUGA scan will be performed as shown in the Schedule of Events 
(Table 17.1).   
The same method (ECHO or MUGA scan) should be used for the same subject during the entire 
study.  


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9.12.2 Pulmonary Assessments 
Pulmonary assessments, including CT and additional assessments as outlined in the SOE and 
ILD management algorithm and SpO2, will be performed as described in the Schedule of Events 
(Table 17.1).   
An ILD AC will review all cases of (potential) ILD on an ongoing basis (details in 
Section 9.3.1.2). 
9.12.3 Ophthalmologic Assessment 
An ophthalmologic assessment (including visual acuity testing, slit lamp examination, and 
fundoscopy) will be performed according to the Schedule of Events (Table 17.1).   
9.12.4 Brain Imaging 
Baseline brain CT/MRI scan is mandatory.  A CT or MRI scan of the brain will be performed as 
shown in the Schedule of Events (Table 17.1).   
For all subjects with asymptomatic brain metastases at Screening, subsequent CT/MRI brain 
imaging should be performed every 6 weeks (±7 days) from Cycle 1 Day 1.  For subjects without 
brain metastases at Screening, CT/MRI brain imaging will be performed as per Investigator’s 
discretion based on symptoms suspicious of new brain metastases.  Baseline CT/MRI scan 
obtained within 2 weeks of signing main ICF could be used as baseline assessment.  Copies of 
CT or MRI images should be provided to central review within 2 weeks the images taken the 
image taken (baseline image should be provided after confirmation of subject eligibility).  
The same technique (CT or MRI) should be used for the same subject throughout the study.  


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10. 
OTHER ASSESSMENTS 
10.1. 
Health Economics and Outcomes Research 
Health Economics and Outcomes Research based on PRO will be used to evaluate study 
treatment.  The impact of GC on symptoms and QoL will be assessed based upon the EORTC 
EQ-5D-5L (Section 17.2.1) and FACT-Ga (Section 17.2.2) questionnaires.  The EQ-5D-5L 
should be completed before the FACT-Ga questionnaire.   
Both questionnaires will be self-administered at BI, and before the completion of any other 
study-related procedures (including blood collection) on Cycle 1 Day 1, on Day 1 of every other 
cycle beginning with Cycle 3 Day 1 (ie, Cycle 3, 5, 7, etc.), and at the EOT Visit (Table 17.1).   
10.1.1. 
EORTC Five-dimension Five-level Patient-reported Outcome Questionnaire 
The EORTC EQ-5D-5L is a self-administered generic measure of standardized health status that 
consists of 2 parts: the EQ-5D-5L descriptive system and the EuroQual quality-of-life visual 
analogue scale (EQ-VAS) (see sample in Section 17.2.1).   
 The descriptive system consists of 5 dimensions (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression).  Each dimension has 5 levels: No problems, 
Slight problems, Moderate problems, Severe problems, and Extreme problems.  The 
respondent is asked to indicate his/her health state by ticking (or placing a cross) in 
the box against the most appropriate statement in each of the 5 dimensions.  This 
decision results in a 1-digit number expressing the level selected for that dimension.  
The digits for 5 dimensions can be combined in a 5-digit number describing the 
respondent’s health state.  The numerals 1 to 5 have no arithmetic properties and 
should not be used as a cardinal score.   
 The EQ-VAS records the respondent’s self-rated health on a 20 cm vertical, VAS 
with endpoints labeled “the best health you can imagine” and “the worst health you 
can imagine.”  This information can be used as a quantitative measure of health as 
judged by the individual respondents.   
10.1.2. 
Functional Assessment of Cancer Therapy-Gastric (FACT-Ga) Questionnaire 
The FACT-Ga questionnaire is a self-administered questionnaire that measures QoL in GC.28,29  
The questionnaire is divided into 5 domains (Physical Well-Being, Social/Family Well-Being, 
Emotional Well-Being, Functional Well-Being, and Additional Concerns) (see sample in 
Section 17.2.2).  For each statement reflecting his/her QoL with GC, the respondent is asked to 
choose 1 of 5 responses (Not at all [0], A little bit [1], Somewhat [2], Quite a bit [3], or Very 
much [4]) applying to the past 7 days.   
10.2. 
Pharmacoeconomic Assessment: Hospitalization-related Endpoint 
Time to hospitalization will be assessed.  Each hospitalization event will prompt the completion 
by the site of a detailed hospitalization eCRF containing the following components: 
 Date of admission to hospital 


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 Date of discharge from hospital 
 Primary reason for hospitalization 
 Discharge status from hospital (died, discharged home, discharged to home health 
care, discharged to nursing home care, discharged to long-term care, other). 
 Use of intensive care unit (ICU) services in hospital (Yes/No) 
 If yes, date of admission to ICU 
 If yes, date of discharge from ICU. 


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11. 
STATISTICAL METHODS  
Full details will be specified in the Statistical Analysis Plan (SAP). 
11.1. 
General Statistical Considerations 
Continuous variables will be summarized by the number of observations, mean, standard 
deviation, median, minimum, and maximum values.  Categorical variables will be summarized 
using frequency counts and percentages.   
Assessments of change from baseline to post-treatment or the ratio of post-treatment to baseline 
will include only those subjects with both baseline and post-treatment measurements.  The last 
non-missing value of a variable taken before the first dose of study treatment will be used as the 
baseline value, unless otherwise specified.  In general, missing or dropout data will not be 
imputed for the purpose of data analysis, unless otherwise specified.   
The primary efficacy analysis will be performed on the basis of the Full Analysis Set (FAS) 
population and repeated on the Response Evaluable Set (RES) as a supportive analysis.  The 
other efficacy analyses will be performed on the FAS.  Safety analyses will be performed using 
the Safety Analysis Set.  Analysis of PK parameters will be based on the PK Analysis Set.  All 
other exploratory analyses will be performed on the basis of the FAS and availability of 
assessment. 
11.2. 
Analysis Sets 
11.2.1. 
Full Analysis Set 
The FAS will include all subjects who were recruited and have received at least 1 dose of the 
study drug.  (This is the same as the Safety Analysis Set.) 
11.2.2. 
Response Evaluable Set 
The RES will include recruited subjects who took at least 1 dose of trastuzumab deruxtecan, had 
measurable disease at baseline, and had at least 1 postbaseline tumor assessment. 
11.2.3. 
Safety Analysis Set 
The Safety Analysis Set will include all recruited subjects who received at least 1 dose of study 
drug.  (This is the same as the FAS.) 
11.2.4. 
Pharmacokinetic Analysis Set 
The PK Analysis Set will include all recruited subjects who received at least 1 dose of study drug 
and had measurable serum concentrations of trastuzumab deruxtecan, total anti-HER2 antibody, 
and/or MAAA-1181a. 
11.3. 
Study Population Data 
Subject disposition will be summarized for the FAS population.  The total number of subjects for 
each defined analysis set will also be tabulated.  The demographic and baseline characteristics 
will be summarized descriptively for the FAS population, Safety Analysis Set, RES, and PK 


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Analysis Set.  Study drug exposure, treatment duration, and compliance with study therapy as 
well as prior and concomitant medications will be summarized using descriptive statistics for the 
FAS population. 
11.4. 
Efficacy Analysis 
Definitions of the efficacy endpoints are provided in Section 7. 
The convention to be followed when assessing response or progression will be to assign a single 
date to evaluations performed within that time point.  The date of response (CR, PR, SD, or not 
evaluable [NE]) will be recorded as the date of the last radiographic evaluation included in the 
series for that assessment.  The date of PD will be recorded as the date of the earliest 
radiographic evaluation included in the series for that assessment.   
11.4.1. 
Primary Efficacy Analysis 
The primary efficacy endpoint is ORR by independent central review.  Only confirmed ORR will 
be considered in the primary analysis.  Analysis of ORR will be performed for all enrolled 
subjects at the 18-week tumor assessment.  The estimate of ORR and its 2-sided 95% exact CI 
will be provided using Clopper-Pearson method.  The primary efficacy analysis will be 
performed on the basis of the ITT population and repeated on the RES as a supportive analysis. 
11.4.2. 
Secondary Efficacy Analyses 
The key secondary endpoint PFS as assessed based on independent central review.  Subjects who 
are alive with no objective documentation of (radiographic) disease progression as assessed by 
independent central review by the DCO date for PFS analysis will be censored at the date of their 
last evaluable tumor assessment.  Kaplan-Meier estimate and survival curve will be presented.  
The median event time and the corresponding 95% CI will be provided using the Brookmeyer 
and Crowley method. 
Additional secondary efficacy endpoints are as follows: 
 PFS by Investigator assessment will be analyzed in the same way as that used for 
PFS, based on independent central review. 
 OS: If a subject is alive at the time of data analysis, OS will be censored at the last 
contact date at which the subject is known to be alive.  Kaplan-Meier estimate and 
survival curve will be presented.  The median event time and the corresponding 95% 
CIs will be provided using Brookmeyer and Crowley method. 
 ORR based on Investigator assessment, measured for responding subjects (PR or CR) 
only, will be analyzed in the similar approach as used for the primary endpoint.  
 DoR will be measured for responding subjects (PR or CR) only.  Subjects who are 
alive and progression-free at the time of the analyses will be censored at the date of 
the last evaluable tumor assessment.  DoR based on independent central review and 
Investigator assessment will be summarized separately with median event times and 
its 95% CIs using the Brookmeyer and Crowley method.  DoR will be analyzed based 
on tumor assessment by independent central review and by Investigator. 


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11.4.3. 
Exploratory Efficacy Analyses 
 DCR will be measured for subjects with CR, PR, or SD.  DCR will be analyzed on 
the basis of tumor assessment by independent central review and by Investigator. 
 Time to response is defined as the time from the date of first dose to the date of the 
first documentation of confirmed objective response. Time to response will be 
measured for responding subjects (PR or CR) only.  Time to response based on 
independent central review and Investigator assessment will be summarized 
separately with median event times and their 95% CIs for the median by using 
Brookmeyer and Crowley methods by part/dose group and overall.  
 Best percentage change in tumor size will be graphed by using waterfall plot. 
11.5. 
Health Economics and Outcome Research Analyses  
Health Economic and Outcomes Research endpoints based on the hospitalization-related data 
collection form and the 2 PRO questionnaires (EQ-5D-5L and FACT-Ga) will be summarized.  
A detailed analysis plan of QoL endpoints will be provided in the SAP.  Some descriptive 
analysis will be performed. 
11.5.1. 
EORTC Five-dimension Five-level Quality-of-life Questionnaire 
Based on results of the EQ-5D-5L assessment, the EQ-5D-5L summary index score across 
disease states will be assessed.  Descriptive statistics for the actual value and change from 
baseline will be computed for the EQ-5D-5L health profile utilities and EQ-5D VAS by 
scheduled time of evaluation (including EOT Visit) for all subjects.  Results of the EQ-VAS will 
be presented as a measure of overall self-rated health status. 
11.5.2. 
FACT-Gastric Questionnaire 
Descriptive statistics for the actual value and change from baseline will be computed for by 
scheduled time of evaluation (including the EOT Visit) and treatment group. 
11.6. 
Pharmacokinetic/Biomarker/Pharmacogenomic Analyses 
Pharmacokinetic analyses will be performed on the PK Analysis Set (definition in 
Section 11.2.4). 
11.6.1. 
Pharmacokinetic Analyses 
Serum concentrations for trastuzumab deruxtecan, total anti-HER2 antibody, and MAAA-1181a 
will be listed, plotted, and summarized by using descriptive statistics at each time point.  PK 
parameters for trastuzumab deruxtecan, total anti-HER2 antibody, and MAAA-1181a will be 
listed and summarized using descriptive statistics. 
11.6.2. 
Population-PK Analyses 
The population-PK analysis to evaluate the effect of intrinsic and extrinsic factors of trastuzumab 
deruxtecan, and if appropriate, total anti-HER2 antibody and MAAA-1181a will be characterized 
including available PK data from the other trastuzumab deruxtecan clinical trials.   


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After establishment of the population-PK model, a population-PK/pharmacodynamic model may 
be developed to evaluate the relationship between exposure and efficacy and toxicity.  The 
results of the nonlinear mixed effects population-PK and population-PK/pharmacodynamic 
models may be reported separately from the clinical study report. 
11.6.3. 
Biomarker Analyses 
A new tissue sample after progression on first-line treatment with a trastuzumab-containing 
regimen will be requested for analysis of HER2 status by IHC and/or ISH for eligibility 
assessment.  Remaining tissue samples, if available, will be used to perform exploratory 
biomarker analysis.  If there is no sample left over then a new biopsy would be needed at the 
screening visit prior to C1D1.  Mandatory biopsies on treatment will be collected between the 
end of Cycle 3 and the beginning of Cycle 4 (Day 1) and at EOT to assess exploratory 
biomarkers.  In addition, biomarkers in plasma and serum may be analyzed.  Biomarkers will be 
summarized by using descriptive statistics. 
11.6.4. 
Pharmacogenomic Analyses (Optional) 
See details on the optional pharmacogenomics in Section 8.4.  Pharmacogenomic analyses will 
be described in a separate SAP, as applicable. 
11.7. 
Safety Analyses 
Safety analysis will be performed using the Safety Analysis Set. 
Safety analyses in general will be descriptive and presented in tabular format with the 
appropriate summary statistics.  A summary and display of TEAEs will be presented. 
Terminology of the latest version of MedDRA will be used to assign system organ class (SOC) 
and PT classification to AEs and diseases, based on the original terms entered on the eCRF. 
The incidence of TEAEs will be summarized by SOC, PT, relationship to the study treatment, 
and severity.  A by-subject listing will be provided for those subjects who experience an SAE, 
including death, or experience an AE associated with early withdrawal from the study or study 
treatment. 
11.7.1. 
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 48 days or more after the last dose 
of study drug, if considered related to the study treatment, are also TEAEs.  
Non-SAEs or non-related SAEs that occur 48 days or more after the last dose will not be 
included in the analysis of TEAE but will be summarized separately and briefly stated in the text.  
TEAEs will be coded by using the latest version of MedDRA and assigned grades based on NCI 
CTCAE v5.0.  The number and percentage of subjects reporting TEAEs will be tabulated by 
SOC, PT, relationship to the study treatment, and the worst CTCAE grade.   
Similarly, the number and percentage of subjects reporting serious TEAEs will be tabulated, as 
well as TEAEs leading to discontinuation of study treatments. 


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A by-subject data listing of AEs (including TEAEs) will be provided that will include, but is not 
limited to, the verbatim term, SOC, PT, CTCAE grade, and relationship to study treatment.  
Deaths, other SAEs, AESIs, and other significant AEs, including those leading to discontinuation 
of study treatments, will be listed.   
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.  
11.7.2. 
Clinical Laboratory Evaluation Analyses 
Descriptive statistics will be provided for the clinical laboratory test results and changes from 
baseline at each scheduled time of evaluation, including the EOT Visit.  The change from 
baseline will be summarized for the maximum and minimum post-treatment values. 
Abnormal clinical laboratory results will be graded according to NCI CTCAE v5.0, if applicable, 
and the grade will be presented in a by-subject data listing.  A shift table will present a 2-way 
frequency tabulation for baseline and the worst post-treatment value according to NCI CTCAE 
grade. 
All clinical laboratory test results and abnormal clinical laboratory test results deemed of clinical 
significance or of Grade 3 or 4 will be listed.   
11.7.3. 
Vital Sign Analyses 
Descriptive statistics will be provided for the vital signs measurements by scheduled time of 
evaluation, as well as for the change from baseline.  In addition, the change from baseline will be 
presented for the maximum and minimum post-treatment values.  All vital sign data will be also 
listed. 
11.7.4. 
Electrocardiogram Analyses 
Descriptive statistics will be provided for ECG parameters and changes from baseline by 
scheduled time of evaluation, including the EOT Visit and maximum post-treatment values.  In 
addition, the number and percentage of subjects with categorical ECG interval values meeting 
the CTCAE v5.0 criteria will be tabulated.  The QT intervals will be corrected for heart rate by 
Fridericia’s formula (QTcF = QT/[RR]1/3).  The ECG data will also be listed. 
11.7.5. 
Physical Examination Analyses 
Physical examination findings will be listed. 
11.7.6. 
Concomitant Medication Analyses 
Concomitant medications will be coded using the most recent version of the World Health 
Organization (WHO) Drug Dictionary.  Number and percentage of subjects taking concomitant 
medications will be summarized.  Concomitant medications will also be listed. 
11.7.7. 
Immunogenicity (Anti-drug Antibody) Analyses 
Immunogenicity will be assessed through characterization of incidence and titer of ADA.  The 
number and percentage of subjects will be calculated for the presence or absence of development 


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of ADA after the start of administration, defining subjects who are negative for ADA at all time 
points as negative and subjects who are positive for ADA at ≥1 time point after drug treatment as 
positive.  The raw values and change from baseline for ADA titers will be summarized by time 
point using descriptive statistics. 
All other safety variables per Section 9.12 will be listed. 
11.7.8. 
Other Safety Analyses 
All other safety endpoints (eg, ECOG PS and LVEF) will be listed and an analysis of change 
from baseline will be performed. 
11.8. 
Sample Size Determination 
On the basis of historical data of current SoC, western patients with second-line gastric or GEJ 
cancer have reported best ORR of ~27%.  Seventy-two subjects provides a 90% power to 
achieve a lower limit of 95% CI for the ORR that exceeds 27% (threshold) under the expected 
ORR of 45%.  Taking into consideration potential dropouts, a sample size of approximately 
80 subjects will be recruited.  The sample size computation was performed by using EAST v6.4. 
11.9. 
Statistical Analysis Process 
The clinical study data will be analyzed by the Sponsor or its designated agent/CRO. 
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 by using SAS® v9.3 or higher (SAS Institute Inc., Cary, 
NC 27513). 


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12. 
DATA INTEGRITY AND QUALITY ASSURANCE 
The Investigator/investigational site will permit study-related monitoring, audits, IRB/EC review 
and regulatory inspections by providing direct access to source data/documents.  Direct access 
includes permission to examine, analyze, verify, and reproduce any records and reports that are 
important to the evaluation of a clinical study. 
12.1. 
Monitoring and Inspections 
The Sponsor/CRO monitor and regulatory authority inspectors are responsible for contacting and 
visiting the Investigator for the purpose of inspecting the facilities and, upon request, inspecting 
the various records of the study (eg, eCRFs, source data, and other pertinent documents). 
The 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 Study 
Monitor and review of study data remotely.  The frequency of the monitoring visits will vary 
based on the activity at each study site.  The Study Monitor is responsible for inspecting the 
eCRFs and ensuring completeness of the study essential documents.  The Study Monitor should 
have access to subject medical records and other study-related records needed to verify the 
entries on the eCRFs.  Detailed information is provided in the monitoring plan. 
The Study Monitor will communicate deviations from the protocol, SOPs, GCP, and applicable 
regulations to the Investigator and will ensure that appropriate action designed to prevent 
recurrence of the detected deviations is taken and documented. 
The Investigator agrees to cooperate with the Study 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 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 
All relevant observations and data related to the study, as per the study protocol, will be recorded 
on eCRF pages.  A representative of Daiichi Sankyo or their designee will provide instruction for 
completing the eCRF.  Adequate and accurate case records should be maintained, including the 
evaluation of inclusion and exclusion criteria, medical history, physical examinations, clinical 
assessments, a record of clinical safety laboratory sample collection, drug administration, AEs, 
and final evaluation.  
The eCRF should be kept current to enable the monitor to review the subject’s status throughout 
the course of the study.   


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An eCRF must be completed for each subject who signs a main ICF and undergoes any 
Screening procedures.  For subjects who are screened but not recruited, minimal data will be 
recorded on the eCRF, including demography, subject status, and AEs (or SAEs, as appropriate).  
All study-related data for these subjects will be maintained in the medical records at the site. 
The Investigator will sign and date the indicated places on the eCRF via the EDC system’s 
electronic signature.  These signatures will indicate that the Investigator inspected or reviewed 
the data on the eCRF, the data queries, and the site notifications, and agrees with the content. 
All written information and other material to be used by subjects and investigative staff must use 
vocabulary and language that are clearly understood. 
12.3. 
Data Management 
Each subject will be identified in the database by a unique SID number as defined by the 
Sponsor. 
To ensure the quality of clinical data across all subjects and study centers, a Clinical Data 
Management review will be performed on subject data according to specifications given to 
Sponsor or Designee.  Data will be vetted both electronically and manually for eCRFs and the 
data will be electronically vetted by programmed data rules within the application.  Queries 
generated by rules and raised by reviewers will be generated within the EDC application.  During 
this review, subject data will be checked for consistency, completeness and any apparent 
discrepancies.   
Data received from external sources such as central laboratories will be reconciled to the clinical 
database. 
Serious AEs in the clinical database will be reconciled with the safety database. 
All AEs will be coded using MedDRA.   
All concomitant medications and prior cancer therapies will be coded using the WHO Drug 
Dictionary. 
12.4. 
Study Documentation and Storage 
The Investigator will maintain a Signature List of appropriately qualified persons to whom 
he/she has delegated study duties.  All persons authorized to make entries and/or corrections on 
eCRFs will be included on the Signature List. 
Source documents are original documents, data, and records from which the subject’s CRF data 
are obtained.  These include, but are not limited to, hospital records, clinical and office charts, 
laboratory and pharmacy records, PRO QoL questionnaire, 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 


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records will be retained in a secure file for the period required by the institution or study site 
policy.  Prior to transfer or destruction of these records, the Sponsor must be notified in writing 
and be given the opportunity to further store such records. 
12.5. 
Record Keeping 
The Investigator and study staff are responsible for maintaining a comprehensive and centralized 
filing system (Trial Master File) of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from the Sponsor and/or applicable regulatory 
authorities.  Essential documents include: 
 Subject files containing completed eCRFs, 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 
center, accountability records and final reconciliation and applicable correspondence. 
In addition, all original source documents supporting entries in the eCRFs must be maintained 
and be readily available. 
All study-related essential documentation will be retained by the Investigator until at least 
2 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 2 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 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 the Sponsor in writing of the new responsible 
person and/or the new location. 


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


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14. 
PUBLICATION POLICY 
The Sponsor is committed to meeting the highest standards of publication and public disclosure 
of information arising from clinical studies sponsored by the company.  The Sponsor will 
comply with US, EU, and Japanese policies for public disclosure of the clinical study protocol 
and clinical study results, and for sharing of clinical study data.  The Sponsor will follow the 
principles set forward in “Good Publication Practice for Communicating Company-Sponsored 
Medical Research (GPP3),”38 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).39 
In order to ensure 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. 


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15. 
ETHICS AND STUDY ADMINISTRATIVE INFORMATION 
15.1. 
Compliance Statement, Ethics, and Regulatory Compliance 
This study will be conducted in compliance with the protocol, the ethical principles that have 
their origin in the Declaration of Helsinki, the ICH consolidated Guideline E6 for GCP 
(CPMP/ICH/135/95), and applicable regulatory requirement(s) including the following: 
 US FDA GCP Regulations: Code of Federal Regulations Title 21, parts 11, 50, 54, 56 
and 312 as appropriate;  
and/or 
 Directive 2001/20/EC of the European Parliament and of the Council on the 
approximation of the laws, regulations and administrative provisions of the Member 
States relating to the implementation of GCP in the conduct of clinical trials on 
medicinal product for human use;  
and/or 
 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 eCRFs or other 
documents submitted to the Sponsor or the CRO, subjects should be identified by a unique 
subject identifier as designated by the Sponsor.  Documents that are not for submission to the 
Sponsor or the CRO (eg, signed ICF) should be kept in strict confidence by the Investigator. 
In compliance with ICH GCP Guidelines, it is required that the Investigator and institution 
permit authorized representatives of the company, of the regulatory agency(ies), and the IRB/EC 
direct access to review the subject’s original medical records for verification of study-related 
procedures and data.  The Investigator is obligated to inform the subject that his/her study-related 
records will be reviewed by the above named representatives without violating the 
confidentiality of the subject. 
15.3. 
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 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 


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have their origin in the Declaration of Helsinki.  The consent form and any revision(s) should be 
approved by the IRB/EC 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 ICF should 
be provided to the subject.  The date and time (if applicable) that informed consent was given 
should be recorded on the eCRF. 
15.4. 
Regulatory Compliance 
The study protocol, subject information and consent form, the IB, written instructions to be given 
to the subject, available safety information, subject recruitment procedures (eg, advertisements), 
information about payments and compensation available to the subjects, and documentation 
evidencing the Investigator’s qualifications should be submitted to the IRB/EC for ethical review 
and approval according to local regulations, prior to the study start.  The written approval should 
identify all documents reviewed by name and version. 
Changes in the conduct of the study or planned analysis will be documented in a protocol 
amendment and/or the SAP. 
The Investigator and/or Sponsor must submit and, where necessary, obtain approval from the EC 
or IRB for all subsequent protocol amendments and changes to the ICF.  The Investigator should 
notify the EC or IRB of deviations from the protocol or SAEs occurring at the study center and 
other AE reports received from the Sponsor/CRO, in accordance with local procedures. 
As required by local regulations, the Sponsor’s local Regulatory Affairs group or representative 
to whom this responsibility has been delegated will ensure all legal aspects are covered, and 
approval from the appropriate regulatory bodies obtained, prior to study initiation.  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 are made only after approval by the relevant 
regulatory bodies, as needed. 
In the event of any prohibition or restriction imposed (eg, clinical hold) by an applicable 
regulatory authority(ies) in any area of the world, or if the Investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the investigational 
drug, the Sponsor should be informed immediately.   
In addition, the Investigator will inform the Sponsor immediately of any urgent safety measures 
taken by the Investigator to protect the study subjects against any immediate hazard, and of any 
suspected/actual serious GCP non-compliance that the Investigator becomes aware of. 
15.5. 
Protocol Deviations 
The Investigator should conduct the study in compliance with the protocol agreed to by Sponsor 
and, if required, by the regulatory authority(ies), and which was given approval/favorable 
opinion by the IRBs/ECs. 


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


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15.8. 
Study Termination 
The Sponsor has the right to terminate the study at any time and study termination may also be 
requested by (a) competent authority(ies). 
15.9. 
Data and Safety Monitoring Board 
A Data Monitoring Committee is not applicable for this trial given that it is an open-label trial.  
However, measures are put in place for monitoring the safety of the subjects participating in the 
study.  Individual subject data will be reviewed on an ongoing basis and aggregate safety data 
will be monitored monthly by the study team across the duration of the trial following the 
Sponsor’s established safety monitoring SOPs.  The data review and analysis will be based on 
the available Investigator reported data in the clinical database. 
15.10. 
Address List 
A list of key study personnel (including personnel at the sponsor, CRO, laboratories, and other 
vendors) and their contact information (address, telephone, fax, email) will be kept on file and 
regularly updated as necessary.  See the site Study Instruction for all appropriate addresses. 


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16. 
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2. NCCN Guidelines Version 2.2018, Gastric Cancer. Available at: 
https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf. Accessed 25 Sep 2018. 
3. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7-
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4. Chua TC, Merrett ND. Clinicopathologic factors associated with HER2-positive gastric 
cancer and its impact on survival outcomes—a systematic review. Int J Cancer. 
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5. Gómez-Martin C, Garralda E, Echarri MJ, et al. HER2/neu testing for anti-HER2-based 
therapies in patients with unresectable and/or metastatic gastric cancer. J Clin Pathol. 
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6. Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a novel 
therapeutic target. Ann Oncol. 2008;19(9):1523-9. 
7. Jørgensen JT, Hersom M. HER2 as a prognostic marker in gastric cancer – a systematic 
analysis of data from the literature. J Cancer. 2012;3:137-44. 
8. Kunz PL, Mojtahed A, Fisher GA, et al. HER2 expression in gastric and 
gastroesophageal junction adenocarcinoma in a US population: clinicopathologic analysis 
with proposed approach to HER2 assessment. Appl Immunohistochem Mol Morphol. 
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9. Janjigian YY, Werner D, Pauligk C, et al. Prognosis of metastatic gastric and 
gastroesophageal junction cancer by HER2 status: a European and USA international 
collaborative analysis. Ann Oncol. 2012;23(10):2656-62. 
10. Grabsch H, Sivakumar S, Gray S, et al. HER2 expression in gastric cancer: rare, 
heterogeneous and of no prognostic value – conclusions from 924 cases of two 
independent studies. Cell Oncol. 2010;32(1-2):57-65. 
11. Bang YJ, Van Cutsem E, Feyereislova A, et al; ToGA Trial Investigators. Trastuzumab 
in combination with chemotherapy versus chemotherapy alone for treatment of HER2-
positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, 
open-label, randomised controlled trial. Lancet. 2010;376(9742):687-97. 
12. Glimelius B, Ekström K, Hoffman K, et al. Randomized comparison between 
chemotherapy plus best supportive care with best supportive care in advanced gastric 
cancer. Ann Oncol. 1997;8(2):163-8. 
13. Hironaka S, Ueda S, Yasui H, et al. Randomized, open-label, phase III study comparing 
irinotecan with paclitaxel in patients with advanced gastric cancer with severe peritoneal 
metastasis after failure of prior combination chemotherapy using fluoropyrimidine plus 
platinum: WJOG 4007 trial. J Clin Oncol. 2013;31(35):4438-44. 


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14. Fuchs CS, Tomasek J, Yong CJ, et al. Ramucirumab monotherapy for previously treated 
advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an 
international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 
2014;383(9911):31-9. 
15. Wilke H. Muro K, Van Cutsem E, et al; RAINBOW Study Group. Ramucirumab plus 
paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced 
gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, 
randomised phase 3 trial. Lancet Oncol. 2014;15(11):1224-35. 
16. Shitara K, Muro K, Shimada Y, et al. Subgroup analyses of the safety and efficacy of 
ramucirumab in Japanese and Western patients in RAINBOW: a randomized clinical trial 
in second-line treatment of gastric cancer. Gastric Cancer. 2016;19(3):927-38. 
17. Tabernero J, Hoff PM, Shen L, et al. Pertuzumab plus trastuzumab and chemotherapy for 
HER2-positive metastatic gastric or gastro-oesophageal junction cancer (JACOB): final 
analysis of a double-blind, randomised, placebo-controlled phase 3 study. Lancet Oncol. 
2018;19(10):1372-84.  
18. Thuss-Patience PC, Shah MA, Ohtsu A, et al. Trastuzumab emtansine versus taxane use 
for previously treated HER2-positive locally advanced or metastatic gastric or gastro-
oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-
label, adaptive, phase 2/3 study. Lancet Oncol. 2017;18(5):640-53. 
19. Helwick C. Metastatic gastric cancer: dual HER2-targeting study does not meet primary 
endpoint. 25 Nov 2017. Available at: http://www.ascopost.com/issues/november-25-
2017/metastatic-gastric-cancer-dual-her2-targeting-study-does-not-meet-primary-
endpoint/. Accessed 09 Oct 2018. 
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):5097-108. 
21. Trastuzumab Deruxtecan Global Investigator’s Brochure Version 6.0, September 09 2019 
22. Doi T, Shitara K, Naito Y, et al. Safety, pharmacokinetics, and antitumour activity of 
trastuzumab deruxtecan (DS-8201), a HER2-targeting antibody-drug conjugate, in 
patients with advanced breast and gastric or gastro-oesophageal tumours: a phase 1 dose-
escalation study. Lancet Oncol. 2017;18(11):1512-22. 
23. Iwasa S, Shitara K, Takahashi S, et al. Updated results of phase 1 study of trastuzumab 
deruxtecan (DS-8201a) in subjects with HER2-expressing gastric cancer. J Clin Oncol. 
2018;36(Suppl 4);abstract 118. 
24. Iwata H, Tamura K, Doi T, et al. Trastuzumab deruxtecan (DS-8201a) in subjects with 
HER2-expressing advanced solid tumors: long-term results from a large phase 1 study 
with multiple expansion cohorts. J Clin Oncol. 2018;36(Suppl 15);abstract 2501. 
25. Janjigian YY, Riches JC, Ku GY, et al. Loss of human epidermal growth factor receptor 
2 (HER2) expression in HER2-overexpressing esophagogastric (EG) tumors treated with 
trastuzumab. J Clin Oncol. 2015;33(Suppl 3):abstract 63. 


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26. Kashiwada T, Saeki H, Uenosono Y, et al. Multicenter observational study on re-
evaluation of HER2 status in patients with HER2-positive advanced or recurrent gastric 
cancer refractory to trastuzumab. J Clin Oncol. 2018;36(Suppl 15);abstract 4038.  
27. Pietrantonio F, Caporale M, Morano F, et al. HER2 loss in HER2-positive gastric or 
gastroesophageal cancer after trastuzumab therapy: implication for further clinical 
research. Int J Cancer. 2016;139(12):2859-64. 
28. Eremenco SL, Cashy J, Webster K, et al. FACT-Gastric: a new international measure of 
QOL in gastric cancer. J Clin Oncol. 2004;22(Suppl 14):abstract 8123.  
29. Garland SN, Pelletier G, Lawe A, et al. Prospective evaluation of the reliability, validity, 
and minimally important difference of the functional assessment of cancer therapy-gastric 
(FACT-Ga) quality-of-life instrument. Cancer. 2011;117(6):1302-12. 
30. Maeda H, Sato M, Kobayashi M, et al. Validity of the Japanese version of functional 
assessment of cancer therapy-gastric (FACT-Ga) and its sensitivity to ascites volume 
change: a retrospective analysis of Japanese clinical trial participants. Support Care 
Cancer. 2016;24(11):4515-21. 
31. Zhou HJ, So JB, Yong WP, et al. Validation of the functional assessment of cancer 
therapy-gastric module for the Chinese population. Health Qual Life Outcomes. 
2012;10:145. 
32. van Reenen M, Janssen B. EQ-5D-5L user guide: basic information on how to use the 
EQ-5D-5L instrument. Version 2.1. Apr 2015. Available at: https://euroqol.org/wp-
content/uploads/2016/09/EQ-5D-5L_UserGuide_2015.pdf. Accessed 15 Jul 2018. 
33. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron. 1976;16(1):31-41. 
34. Clinical Trial Facilitation Group (CTFG). Recommendations related to contraception and 
pregnancy testing in clinical trials. 15 Sep 2014. Available at: 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf. 
Accessed 15 Jul 2018. 
35. American Heart Association. Classification of Functional Capacity and Objective 
Assessment. 1994. Available from: 
https://professional.heart.org/professional/General/UCM_423811_Classification-of-
Functional-Capacity-and-Objective-Assessment.jsp. Accessed 09 Oct 2018. 
36. Bartley AN, Washington MK, Ventura CB, et al. HER2 testing and clinical decision 
making in gastroesophageal adenocarcinoma: guideline from the College of American 
Pathologists, American Society for Clinical Pathology, and American Society of Clinical 
Oncology. Arch Pathol Lab Med. 2016;140(12):1345-63. 
37. International Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline. Clinical 
Safety Data Management: Definitions and Standards for Expedited Reporting E2A. 27 
Oct 1994. Available at: 


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https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E2A
/Step4/E2A_Guideline.pdf. Accessed 15 Jul 2018.  
38. Battisti WP, Wager E, Baltzer L, et al. Good publication practice for communicating 
company-sponsored medical research: GPP3. Ann Intern Med. 2015;163(6):461-4. 
39. International Committee of Medical Journal Editors. Recommendations for the conduct, 
reporting, editing, and publication of scholarly work in medical journals. Dec 2017. 
Available at: http://www.icmje.org/recommendations/. Accessed 15 Jul 2018. 
40. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-47.  
41. CYRAMZA (ramucirumab) prescribing information. Nov 2014. Available at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125477s002lbl.pdf. 
Accessed 15 Jul 2018. 
42. 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. 
43. TAXOL® (paclitaxel) Injection prescribing information. Apr 2011. Available at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020262s049lbl.pdf. 
Accessed 15 Jul 2018. 
44. US Department of Health and Human Services. National Institutes of Health. National 
Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) Version 
5.0. Published: 27 Nov 2017. Available at: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Q
uick_Reference_8.5x11.pdf. Accessed 15 Jul 2018. 
 


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17. 
APPENDICES 
17.1. 
Appendix1: Schedule of Events 
 


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Table 17.1 
Schedule of Events 
 
Tissue 
screenin
g 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycles  
4-x 
End of 
treatment
b 
40-day 
follow-
upc 
Follow
-up 
every  
3 
month
s  
±14 dd 
Comments 
Day -28 
to Day -1 
Day 1a 
Day 
8 
±1 d 
Day 
15 
±1 d 
Day 1 
(±2 days) 
Day 1 
(±2 days) 
Day 1 
(±2 days) 
BI 
EOI 
BI 
EOI 
BI 
EOI 
BI 
EOI 
Informed 
consent 
● 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assign subject 
ID 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor sample 
for HER2 status 
and biomarkers 
● 
 
 
 
 
 
 
 
 
 
● 
 
● 
 
 
New tissue post-trastuzumab 
therapy is required for 
eligibility. Collect a mandatory 
tumor sample at the end of 
Cycle 3/prior to Cycle 4 Day 1 
infusion for biomarker analysis, 
including HER2 status. At least 
2 core biopsies are requested at 
Cycle 3 but if the risk of biopsy 
complications from a second 
core biopsy is unacceptable (at 
the discretion of the 
Investigator), then a single 
mandatory core biopsy will 
suffice.  
Medical/surgical 
history 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect within 14 days before 
recruitment 
Demographics 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect within 14 days before 
recruitment 


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Tissue 
screenin
g 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycles  
4-x 
End of 
treatment
b 
40-day 
follow-
upc 
Follow
-up 
every  
3 
month
s  
±14 dd 
Comments 
Day -28 
to Day -1 
Day 1a 
Day 
8 
±1 d 
Day 
15 
±1 d 
Day 1 
(±2 days) 
Day 1 
(±2 days) 
Day 1 
(±2 days) 
BI 
EOI 
BI 
EOI 
BI 
EOI 
BI 
EOI 
HEOR outcomes  
 
 
● 
 
 
 
 
 
● 
 
● 
 
● 
 
 
The subject must complete the 
HEOR outcomes questionnaires 
(FACT-Ga and EQ-5D-5L) 
before any other assessments or 
procedures are done. The EQ-
5D-5L should be completed 
before the FACT-Ga 
questionnaire (details in 
Section 10.1 ; sample 
questionnaires in 
Section 17.2 ). Both 
questionnaires will be self-
administered BI and before the 
completion of any other study-
related procedures at Cycle 1 
Day 1, at every other cycle 
(Cycle 3, 5, 7, etc.), and at the 
EOT Visit. 
Pregnancy test 
 
● 
● 
 
 
 
● 
 
● 
 
● 
 
● 
 
 
For women of childbearing 
potential (as defined in 
Section 4.1), perform a serum 
or urine pregnancy test within 
72 hours prior to the beginning 
of dosing and document the 
results. A positive urine 
pregnancy test result must be 
confirmed immediately using a 
serum test, with a confirmed 
negative test result within 72 
hours prior to drug 
administration. For subjects of 
non-childbearing potential (as 
defined in Section 4.1), no 
pregnancy test will be required.  
Vital signs 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
● 
● 
 
Within 14 days before first dose 
and within 3 days BI, measured 
in a supine/semi-recumbent 
position. 


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Tissue 
screenin
g 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycles  
4-x 
End of 
treatment
b 
40-day 
follow-
upc 
Follow
-up 
every  
3 
month
s  
±14 dd 
Comments 
Day -28 
to Day -1 
Day 1a 
Day 
8 
±1 d 
Day 
15 
±1 d 
Day 1 
(±2 days) 
Day 1 
(±2 days) 
Day 1 
(±2 days) 
BI 
EOI 
BI 
EOI 
BI 
EOI 
BI 
EOI 
SpO2 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
● 
● 
 
Within 14 days before first dose 
and within 3 days BI 
Physical 
examination 
 
● 
● 
 
 
 
● 
 
● 
 
● 
 
● 
● 
 
Within 14 days before first dose 
and within 3 days BI 
Height 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
● 
● 
 
 
 
● 
 
● 
 
● 
 
● 
● 
 
Within 3 days BI 
Inclusion/ 
exclusion  
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
Within 14 days before first dose 
ECOG PS 
 
● 
● 
 
 
 
● 
 
● 
 
● 
 
● 
● 
 
Within 14 days before first dose 
and within 3 days BI 
12-lead ECG  
 
● 
● 
 
 
 
 
 
 
 
● 
 
● 
 
 
ECG will be taken in triplicate 
at screening. Subsequent ECGs 
will be performed in triplicate if 
an abnormality is noted. ECGs 
will be taken in close 
succession, while in a 
supine/semi-recumbent 
position. ECGs will be taken at 
every 4th cycle.   
Hematology,  
blood chemistry,  
coagulation tests 
 
● 
● 
 
● 
● 
● 
 
● 
 
● 
 
● 
● 
 
Within 14 days before first dose 
and within 3 days BI  
Coagulation test (international 
normalized ratio) will be 
performed at Screening and 
thereafter as clinically 
indicated.  


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Tissue 
screenin
g 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycles  
4-x 
End of 
treatment
b 
40-day 
follow-
upc 
Follow
-up 
every  
3 
month
s  
±14 dd 
Comments 
Day -28 
to Day -1 
Day 1a 
Day 
8 
±1 d 
Day 
15 
±1 d 
Day 1 
(±2 days) 
Day 1 
(±2 days) 
Day 1 
(±2 days) 
BI 
EOI 
BI 
EOI 
BI 
EOI 
BI 
EOI 
Troponin 
 
● 
 
 
 
 
 
 
 
 
 
 
● 
  
 
Collect blood samples for 
troponin (preferably high-
sensitivity troponin-T) at 
Screening (for eligibility), EOT, 
and if at any time a subject 
reports signs or symptoms 
suggesting congestive heart 
failure, MI, or other causes of 
myocyte necrosis.  
 See Section 6.2 Section 6.4  
HIV antibody 
test 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Section 4.2  
Hepatitis B/C 
Serology 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Section 4.2  
COVID-19 
Sample 
 
 
 
● 
 
 
 
 
 
 
 
● 
 
 
 
 
If subject provides consent, 
samples should be collected 
prior to study drug infusion 
then starting at C5 D1 and 
every 4 cycles thereafter.  
Section 6.3.1  
For subjects with suspected or 
confirmed COVID-19 
infections, follow the dose 
modifications in Section 17.7  
Urinalysis 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
Within 14 days before first 
dose. 
Ophthalmologic 
assessment  
 
● 
  
 
 
 
 
 
 
 
  
 
● 
 
 
Within 14 days before first dose 
and EOT. Includes visual acuity 
testing, slit lamp examination, 
and fundoscopy 


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Tissue 
screenin
g 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycles  
4-x 
End of 
treatment
b 
40-day 
follow-
upc 
Follow
-up 
every  
3 
month
s  
±14 dd 
Comments 
Day -28 
to Day -1 
Day 1a 
Day 
8 
±1 d 
Day 
15 
±1 d 
Day 1 
(±2 days) 
Day 1 
(±2 days) 
Day 1 
(±2 days) 
BI 
EOI 
BI 
EOI 
BI 
EOI 
BI 
EOI 
Echocardiogram  
or MUGA scan 
(LVEF)  
 
● 
 
 
 
 
 
 
 
 
● 
 
● 
 
 
At Screening (within14 days 
before recruitment) and BI on 
Cycle 5 Day 1, and then every 4 
cycles ± 7 days (Cycles 9, 13, 
etc.) and at the EOT Visit.  Use 
same test throughout the study. 
Tumor 
assessment 
 
● 
 
 
 
 
 
 
 
 
 
● 
● 
  
● 
Within 28 days before 
recruitment and every 6 weeks 
(± 7days) from Cycle 1 Day 1 
in the first year and every 12 
weeks (± 7days)  thereafter until 
objective disease progression or 
until start of new anticancer 
treatment, if patient 
discontinues study treatment for 
any reason other than disease 
progression. To be done at EOT 
if not done within the previous 
6 weeks. If study treatment was 
discontinued for reason other 
than PD, perform at 40-day 
Follow-up Visit if not 
performed at EOT, and perform 
Q3M after the first year, until 
PD or the start of a new 
anticancer treatment. 
CT/MRI of the  
brain 
 
(Baseline 
brain CT/MRI 
scan is mandatory) 
 
● 
 
 
 
 
 
 
 
 
 
● 
● 
 
 
A CT or MRI of the brain must 
be performed for all subjects 
(details in Section 9.12.4 ) 
within 28 days before 
recruitment.  CT/MRI scan 
obtained within 2 weeks of 
signing main ICF could be used 
as baseline assessment.  Copies 
of CT or MRI images should be 
provided to central review 
vendor within 2 weeks after 
Cycle1 Day1.   


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Tissue 
screenin
g 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycles  
4-x 
End of 
treatment
b 
40-day 
follow-
upc 
Follow
-up 
every  
3 
month
s  
±14 dd 
Comments 
Day -28 
to Day -1 
Day 1a 
Day 
8 
±1 d 
Day 
15 
±1 d 
Day 1 
(±2 days) 
Day 1 
(±2 days) 
Day 1 
(±2 days) 
BI 
EOI 
BI 
EOI 
BI 
EOI 
BI 
EOI 
Administer 
trastuzumab 
deruxtecan 
 
 
● 
 
 
● 
 
● 
 
● 
 
 
 
 
 
Administer Q3W ± 2 days 
unless discontinuation criteria 
are met.  The first infusion of 
trastuzumab deruxtecan will 
occur over at least 90 minutes.  
If there is no IRR, the 
subsequent infusions of 
trastuzumab deruxtecan will be 
over at least 30 minutes.  In 
case of IRR of any severity 
grade at any time during the 
first administration of 
trastuzumab deruxtecan, all 
subsequent infusions will occur 
over 90 minutes. 
Blood samples  
for biomarker 
analysis 
 
 
● 
 
 
 
 
 
 
 
● 
 
● 
 
 
Cycle 1 Day 1 sample can be 
collected within 3 days before 
beginning infusion; thereafter, 
samples will be collected every 
3 cycles (Cycles 4, 7, etc.) until 
EOT. See Section 8.3  
Blood sample  
for pharmaco- 
genomics 
 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
Participation in this part of the 
study is optional for all 
subjects. 
Blood (serum) 
sample for PK 
 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
 
 
Cycle 1 Day 1: Within -8 hours 
BI, within 15 minutes of EOI, at 
5 ± 2 hours from infusion start 
time; Cycle 1 Day 8 ±1 day; 
Cycle 1 Day 15 ±1 day; Cycles 
2, 3, 4, 6, and 8: Day 1 within -
8 hours BI and within 15 
minutes of EOI. 


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Tissue 
screenin
g 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycles  
4-x 
End of 
treatment
b 
40-day 
follow-
upc 
Follow
-up 
every  
3 
month
s  
±14 dd 
Comments 
Day -28 
to Day -1 
Day 1a 
Day 
8 
±1 d 
Day 
15 
±1 d 
Day 1 
(±2 days) 
Day 1 
(±2 days) 
Day 1 
(±2 days) 
BI 
EOI 
BI 
EOI 
BI 
EOI 
BI 
EOI 
PK Sampling for 
CQ/HCQ 
Administratione 
 
 
 
If CQ or HCQ is administered for COVID-19, additional PK 
blood samples should be collected at the following visits: 
 
Prior to the first CQ or HCQ dose (Day 1) 
 
Day 3 or Day 4 of CQ or HCQ treatment, prior to CQ or 
HCQ dose (within 4h) 
 
Last day of the CQ/HCQ treatment, prior to CQ/HCQ 
dose (within 4h)  
 
The day of trastuzumab deruxtecan  resumption, after the 
CQ/HCQ washout periodg, (within 8h BI of trastuzumab 
deruxtecan) 
 
 
 
gA washout period of  > 14 d is 
required before restarting 
trastuzumab deruxtecan. 
 
See Table 8.2  
Blood sample  
for ADA 
 
 
● 
 
 
 
● 
 
 
 
● 
 
● 
● 
● 
Within 8 hours BI on Day 1 in 
Cycles 1, 2, and 4, and then 
every 4 cycles (Cycles 8, 12, 
16, etc.). If positive ADA at any 
Follow-up Visit, collect 
samples every 3 months ± 14 
days up to 1 year after the last 
dose, or until the ADA returns 
to baseline or is undetectable, or 
start of new anticancer therapy, 
or subject withdraws consent 
from the study. 
Record of 
anticancer 
therapy for 
gastric/GEJ 
cancer 
 
 
 
 
 
 
 
 
 
 
 
 
 
● 
● 
Include names of drugs, dosage, 
dates of administration, 
response to therapy, if 
available, and reason for 
discontinuation, if applicable. 
Concomitant 
medications 
 
● 
● 
Collect from the time the 
subject signs the main ICF 
 
 
● 
● 
Collect from the time the 
subject signs the main ICF 


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Tissue 
screenin
g 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycles  
4-x 
End of 
treatment
b 
40-day 
follow-
upc 
Follow
-up 
every  
3 
month
s  
±14 dd 
Comments 
Day -28 
to Day -1 
Day 1a 
Day 
8 
±1 d 
Day 
15 
±1 d 
Day 1 
(±2 days) 
Day 1 
(±2 days) 
Day 1 
(±2 days) 
BI 
EOI 
BI 
EOI 
BI 
EOI 
BI 
EOI 
AEs 
● 
● 
● 
Collect from the time the 
subject signs the main ICF At 
Tissue Screening, SAEs are 
recorded only if directly related 
to tissue screening procedure, 
unless documentation of other 
AEs is required by local law. 
Survival  
follow-up 
 
 
● 
 
ADA= anti-drug antibody; AEs = adverse events; BI = before infusion; CQ = Chloroquine; COVID-19 = coronavirus disease 2019; CT = computed tomography; d = day; ECG = 
electrocardiogram; ECOG PS= Eastern Cooperative Oncology Group PS = performance status; EOI = end of infusion; EOT = end of treatment; EQ-5D-5L = European 
Organization for Research and Treatment of Cancer 5-dimension 5-level patient-reported outcome questionnaire; FACT-Ga = Functional Assessment of Cancer Therapy-Gastric; 
HCQ = hydroxychloroquine; HEOR = Health Economics and Outcome Research; HER2 = human epidermal growth factor receptor 2; HIV = human immunodeficiency virus; 
ID = identification number; ILD = interstitial lung disease; IRR = infusion-related reaction;  LVEF = left ventricular ejection fraction; MI = myocardial infarction; MRI = magnetic 
resonance imaging; MUGA = multigated acquisition; PD = progressive disease; PK = pharmacokinetics; Q3M = every 3 months; SpO2 = peripheral oxygen saturation 
a Cycle 1 Day 1 (first dose) for the subject should occur within 28 days from signing the Main ICF. 
b The date the Investigator decides to discontinue study treatment (+7 days).  Refer to Section 6.4 to determine whether new tests need to be conducted. 
c 40 days (+7 days) after the last study drug administration or before starting new anticancer treatment, whichever comes first.  If EOT is >47 days after last treatment, then the 
EOT assessments can also function as the 40-day Follow-up Visit.  Refer to Section 6.5.1 to determine whether new tests need to be conducted. 
d Long-term/Survival follow-up will occur every 3 months (± 14 days) from the date of the 40-day (+7 days) Follow-up Visit, until death, withdrawal of consent, or loss of follow-
up, whichever comes first, and can be conducted via phone or in person at a site visit. 
e If subject provides consent, samples should be collected 
For suspected ILD/pneumonitis, treatment with study drug should be interrupted pending evaluation.   
Evaluations should include:   
 
High resolution CT;  
 
Pulmonologist consultation (Infectious Disease consultation as clinically indicated); 
 
Pulmonary function tests and pulse oximetry (SpO2);  
 
Blood culture and CBC. Other blood tests could be considered as needed; 
 
Consider bronchoscopy and bronchoalveolar lavage if clinically indicated and feasible; 
 
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. 


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17.2. 
Appendix 2: Quality-of-life Questionnaires 
17.2.1. 
EORTC 5-dimension 5-level (EQ-5D-5L) Questionnaire 
Note: The EQ-5D-5L questionnaire should be completed before the FACT-Ga questionnaire.   
Source:  
Available at: https://euroqol.org/wp-content/uploads/2016/09/EQ-5D-
5L_UserGuide_2015.pdf.  
 


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17.4. 
Appendix 4: Eastern Cooperative Oncology Group Performance 
Status (ECOG PS) 
0 
Normal activity.  Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous activity, but ambulatory 
and able to carry out work of a light or sedentary nature (eg, light housework, office 
work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but unable to carry out 
any work activities.  Up and about more than 50% of waking hours. 
3 
In bed >50% of the time.  Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally confined 
to bed or chair. 
5 
Dead 
Source: Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol. 1982;5(6):649-55.42 


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17.5. 
Appendix 5: Response Evaluation Criteria in Solid Tumors 
Version 1.1 
This appendix is provided for convenience.  The complete RECIST v1.1 guidelines are found as 
follows: 
Source:  
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in 
solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 
2009;4(2)5:228-47.  
17.5.1. 
Measurability of Tumor at Baseline 
17.5.1.1. Definitions 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
follows:  
17.5.1.1.1. 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. 
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 follow-up, 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. 
17.5.1.1.2. Non-measurable 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes 
with ≥10 to <15 mm short axis) as well as truly non-measurable lesions.  Lesions considered 
truly non-measurable include: leptomeningeal disease, ascites, pleural or pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques. 
17.5.1.1.3. Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 


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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. 
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 non-cystic lesions are present in the same patient, these are preferred for 
selection as target lesions. 
Lesions with prior local treatment: 
 Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion.   
17.5.1.2. Specifications By Methods of Measurements 
17.5.1.2.1. Measurement of Lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed.  All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 
17.5.1.2.2. Method of Assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.   
Clinical lesions:  
Clinical lesions will only be considered measurable when they are superficial and ≥10mm 
diameter as assessed using calipers (eg, skin nodules).  For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
suggested.  As noted above, when lesions can be evaluated by both clinical exam and imaging, 


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imaging evaluation should be undertaken since it is more objective and may also be reviewed at 
the end of the study. 
Chest X-ray:  
Chest CT is preferred over chest X-ray, particularly when progression is an important endpoint, 
since CT is more sensitive than X-ray, particularly in identifying new lesions.  However, lesions 
on chest X-ray may be considered measurable if they are clearly defined and surrounded by 
aerated lung. 
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). 
Ultrasound:  
Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement.  Ultrasound examinations cannot be reproduced in their entirety for independent 
review at a later date and, because they are operator-dependent, it cannot be guaranteed that the 
same technique and measurements will be taken from one assessment to the next.  If new lesions 
are identified by ultrasound in the course of the study, confirmation by CT or MRI is advised.  If 
there is concern about radiation exposure at CT, MRI may be used instead of CT in selected 
instances. 
Endoscopy, laparoscopy:  
The utilization of these techniques for objective tumor evaluation is not advised.  However, they 
can be useful to confirm complete pathological response when biopsies are obtained or to 
determine relapse in trials where recurrence following CR or surgical resection is an endpoint. 
Tumor markers:  
Tumor markers alone cannot be used to assess objective tumor response.  If markers are initially 
above the ULN, however, they must normalize for a patient to be considered in CR.  Because 
tumor markers are disease-specific, instructions for their measurement should be incorporated 
into protocols on a disease-specific basis. 
Cytology, histology: 
These techniques can be used to differentiate between PR and CR in rare cases if required by 
protocol (for example, residual lesions in tumor types such as germ-cell tumors, where known 
residual benign tumors can remain).  When effusions are known to be a potential adverse effect 
of treatment (eg, with certain taxane compounds or angiogenesis inhibitors), the cytological 
confirmation of the neoplastic origin of any effusion that appears or worsens during treatment 
can be considered if the measurable tumor has met criteria for response or SD in order to 
differentiate between response (or SD) and PD. 


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17.5.2. 
Tumor Response Evaluation 
17.5.2.1. 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.  Only patients 
with measurable disease at baseline should be included in protocols where objective tumor 
response is the primary endpoint.  Measurable disease is defined by the presence of at least 
1 measurable lesion (as detailed above in Section 17.5.1).  In studies where the primary endpoint 
is tumor progression (either time to progression or proportion with progression at a fixed date), 
the protocol must specify if entry is restricted to those with measurable disease or whether 
patients having non-measurable disease only are also eligible. 
17.5.2.2. 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 (and a maximum of 2 lesions per organ) representative of all involved organs 
should be identified as target lesions (TL) and will be recorded and measured at baseline (this 
means in instances where patients 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 
[LD]), 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 in Section 17.5.1.1.1, pathological 
nodes which are defined as measurable and may be identified as TL 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 x 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 (NTL).  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 TLs 
will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be included 
in the sum, then, as noted above, only the short axis is added into the sum.  The baseline sum 
diameters will be used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
NTLs and should also be recorded at baseline.  Measurements are not required and these lesions 


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should be followed as “present,” “absent,” or in rare cases “unequivocal progression.”  In 
addition, it is possible to record multiple NTLs involving the same organ as a single item on the 
CRF (eg, “multiple enlarged pelvic lymph nodes” or “multiple liver metastases”). 
17.5.2.3. Response Criteria 
This section provides the definitions of the criteria used to determine objective tumor response 
for TLs. 
17.5.2.3.1. Evaluation of Target Lesions 
 CR: Disappearance of all TLs.  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 TLs, taking as reference the 
baseline sum diameters. 
 PD: At least a 20% increase in the sum of diameters of TLs, 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 [NLs] 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. 
17.5.2.3.2. Special Notes on the Assessment of Target Lesions 
Lymph nodes:  
Lymph nodes identified as TLs 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 TLs, 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.  Case report forms or other data collection methods may 
therefore be designed to have target nodal lesions recorded in a separate section where, in order 
to qualify for CR, each node must achieve a short axis <10 mm.  For PR, SD and PD, the actual 
short axis measurement of the nodes is to be included in the sum of TLs. 
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 TLs at baseline become so 
faint on CT scan that the radiologist may not feel comfortable assigning an exact measure and 
may report them as being “too small to measure.”  When this occurs, it is important that a value 
be recorded on the CRF.  If it is the opinion of the radiologist that the lesion has likely 
disappeared, the measurement should be recorded as 0 mm.  If the lesion is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm should be assigned 
(Note: It is less 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; 


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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 LDs of the fragmented portions should be added 
together to calculate the TL sum.  Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each individual 
lesion.  If the lesions have truly coalesced such that they are no longer separable, the vector of 
the LD in this instance should be the maximal LD for the “coalesced lesion.” 
17.5.2.3.3. Evaluation of Non-target Lesions 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of NTLs.  While some NTLs 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 NTLs 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 NTL(s) and/or maintenance of tumor 
marker level above the normal limits. 
 PD: Unequivocal progression of existing NTLs.  (Note: the appearance of 1 or more 
NLs is also considered progression). 
17.5.2.3.4. Special Notes on Assessment of Progression of Non-target Disease 
The concept of progression of NTLs requires additional explanation as follows: 
When the patient 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 NTLs 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 patient has only non-measurable disease:  
This circumstance arises in some Phase 3 trials when it is not a criterion of study entry to have 
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 


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when assessing patients 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).  Examples include an increase in a pleural effusion 
from “trace” to “large,” an increase in lymphangitic disease from localized to widespread, or 
may be described in protocols as “sufficient to require a change in therapy.”  If “unequivocal 
progression” is seen, the patient 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. 
17.5.2.3.5. New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of NLs are important.  There are no specific criteria for the identification 
of new radiographic lesions; however, the finding of a NL should be unequivocal: ie, not 
attributable to differences in scanning technique, change in imaging modality or findings thought 
to represent something other than tumor (for example, some ‘new’ bone lesions may be simply 
healing or flare of pre-existing lesions).  This is particularly important when the patient’s 
baseline lesions show partial or complete response.  For example, necrosis of a liver lesion may 
be reported on a CT scan report as a “new” cystic lesion, which it is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a NL and will indicate disease progression.  An example of this is the 
patient who has visceral disease at baseline and while on study has a CT or MRI brain ordered 
which reveals metastases.  The patient’s brain metastases are considered to be evidence of PD 
even if he/she did not have brain imaging at baseline. 
If a NL is equivocal, for example because of its small size, continued therapy and follow-up 
evaluation will clarify if it represents truly new disease.  If repeat scans confirm there is 
definitely a NL, then progression should be declared using the date of the initial scan. 
While fluorodeoxyglucose-positron emission tomography (FDG-PET) response assessments 
need additional study, it is sometimes reasonable to incorporate the use of FDG-PET scanning to 
complement CT scanning in assessment of progression (particularly possible “new” disease).  
Please refer to the complete guidelines for further details.40 
17.5.2.4. Evaluation of Best Overall Response 
The best overall response (BOR) is the best response recorded from the start of the study 
treatment until the end of treatment, taking into account any requirement for confirmation.  On 
occasion, a response may not be documented until after the end of therapy so protocols should be 
clear if post-treatment assessments are to be considered in determination of BOR.  Protocols 
must specify how any new therapy introduced before progression will affect best response 
designation.  The patient’s BOR assignment will depend on the findings of both target and 
non-target disease, and will also take into consideration the appearance of NLs.  Furthermore, 
depending on the nature of the study and the protocol requirements, it may also require 
confirmatory measurement. 


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17.5.2.4.1. 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 
patients who have measurable disease at baseline.   
When patients have non-measurable (therefore non-target) disease only, Table 17.3 is to be used. 
Table 17.2 
Time Point Response: Patients with Target (±Non-target) Disease 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No  
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No  
PR 
SD 
Non-PD or not all evaluated 
No  
SD 
Not All Evaluated 
Non-PD  
No 
NE 
PD   
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; NE = not evaluable 
 
Table 17.3: 
Time Point Response: Patients with Non-target Disease Only 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PD 
Not All Evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR = complete response; PD = progressive disease; NE = not evaluable 
17.5.2.4.2. Missing Assessments and Non-Evaluable Designation 
When no imaging/measurement is done at all at a particular time point, the patient is NE at that 
time point.  If only a subset of lesion measurements are made at an assessment, usually the case 
is also considered NE at that time point, unless a convincing argument can be made that the 
contribution of the individual missing lesion(s) would not change the assigned time point 
response.  This would be most likely to happen in the case of PD.  For example, if a patient had a 
baseline sum of 50 mm with 3 measured lesions and at follow-up only 2 lesions were assessed, 
but those gave a sum of 80 mm, the patient will have achieved PD status, regardless of the 
contribution of the missing lesion. 


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17.5.2.4.3. Best Overall Response: All Time Points 
The BOR is determined once all the data for the patient are known. 
Best response determination in trials where confirmation of CR or PR is NOT required:  
Best response in these trials is defined as the best response across all time points (for example, a 
patient 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.  If the minimum time is not met when SD is 
otherwise the best time point response, the patient’s best response depends on the subsequent 
assessments.  For example, a patient who has SD at first assessment, PD at second, and does not 
meet minimum duration for SD, will have a best response of PD.  The same patient lost to 
follow-up after the first SD assessment would be considered non-evaluable. 
Best response determination in trials where confirmation of complete or partial response IS 
required:  
Complete or partial responses may be claimed only if the criteria for each are met at a 
subsequent time point as specified in the protocol (generally 4 weeks later).  In this 
circumstance, the BOR can be interpreted as in Table 17.4. 
Table 17.4: 
Best Overall Response When Confirmation of CR and PR Required 
Overall Response  
First Time Point 
Overall Response 
Subsequent Time Point 
BEST Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa 
CR 
SD 
SD provided minimum criteria for SD duration 
met, otherwise PD 
CR 
PD 
SD provided minimum criteria for SD duration 
met, otherwise PD 
CR 
NE 
SD provided minimum criteria for SD duration 
met, otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration 
met, otherwise PD 
PR 
NE 
SD provided minimum criteria for SD duration 
met, otherwise NE 
NE 
NE 
NE 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; SD = stable disease. 
a  If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR).  
Best response would depend on whether minimum duration for SD was met.  However, sometimes “CR” may be 
claimed when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not 
CR at the first time point.  Under these circumstances, the original CR should be changed to PR and the best 
response is PR. 


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17.5.2.4.4. Special Notes on Response Assessment 
When nodal disease is included in the sum of TLs 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 patients with CR may 
not have a total sum of “zero” on the CRF. 
In trials where confirmation of response is required, repeated “NE” time point assessments may 
complicate best response determination.  The analysis plan for the trial must address how 
missing data/assessments will be addressed in determination of response and progression.  For 
example, in most trials it is reasonable to consider a patient with time point responses of 
PR-NE-PR as a confirmed response. 
Patients 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 patients is to be determined by evaluation of target and non-target disease as shown in 
Table 17.2 to Table 17.4. 
In some circumstances it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of complete response depends upon this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) before assigning a status of 
CR.   
For equivocal findings of progression (eg, very small and uncertain NLs; 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 
17.6. 
Appendix 6: 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: New York Heart Association Criteria Committee. Functional capacity and objective assessment. In: Dolgin, 
M, editor. Nomenclature and criteria for diagnosis of diseases of the heart and great vessels. Boston: Little, Brown 
& Co; 1994 p. 253-256. 


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17.7. 
Appendix 7: Instructions Related to Coronavirus disease 2019 
(COVID-19) 
Due to the potential impact of COVID-19, on subject safety, the Sponsor recommends the 
following dose modification and management plan for subjects with confirmed or suspected 
COVID-19 while being treated with trastuzumab deruxtecan.  Dose modifications will be based 
on the worst CTCAE grade.  Use CTCAE version 5.0 general grading criteria to evaluate 
COVID-19.  All dose modifications (discontinuation, interruptions or reductions) must be 
recorded on the AE and drug administration eCRFs 
Dose modification criteria for suspected or confirmed COVID-19 
If COVID-19 is suspected, interrupt trastuzumab deruxtecan and rule out COVID-19 per local 
guidance. 
 If COVID-19 is ruled out, follow dose modification and management guidance as 
outlined in Section 5.4.1  
 If COVID-19 is confirmed or is still suspected after evaluation follow dose 
modification as outlined in Table 17.5 below and manage COVID-19 per local 
guidance until recovery.  COVID-19 recovery is defined as no signs/symptoms of 
COVID-19, 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: 
COVID-19 Dose Modification Criteria 
COVID-19 Worst Toxicity NCI CTCAE Version 5.0 
Grade (unless otherwise specified) 
Schedule Modification for trastuzumab deruxtecan  
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 drug if chest CT findings are not 
completely resolved 
Grade 4 
Discontinue study drug 
COVID-19 = Coronavirus disease 2019; CT = computed tomography 
a Closely monitor signs/symptoms after resuming trastuzumab deruxtecan, 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 5.1). 


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Prior and Concomitant Medications 
 Chloroquine or hydroxychloroquine; 
 Concomitant treatment is not allowed during the study treatment (Section 4.2). 
 If treatment is absolutely required for COVID-19, trastuzumab deruxtecan must 
be interrupted. 
 If administered, then a washout period of  more than 14 days is required before 
restarting trastuzumab deruxtecan. 
PK Assessment(s) if Chloroquine or Hydroxychloroquine is Administered 
Additional PK serum samples should be collected from each subject who provides consent, if 
chloroquine or hydroxychloroquine is administered for COVID-19, at the time points specified 
in the Schedule of Events Section 17.1. 
The chloroquine or hydroxychloroquine administration and the exact time of blood sample 
collection for PK analysis must be recorded on the eCRF. 
Coronavirus disease 2019 (COVID-19) Assessments 
All confirmed or suspected COVID-19 events must be recorded in the eCRF.  If a subject 
presents to the clinic with symptoms suggestive of COVID-19, but the real-time RT-PCR test is 
not available at the site, the participant must not have any signs or symptoms of COVID 19 
infection for at least 2 weeks and nearly or completely resolved chest CT findings/a sample kit 
will be provided for sample collection to be tested at a central laboratory.  The results will be 
provided to the site from the central laboratory. 
Serum samples will be used for COVID-19 testing from each subject who provides 
consent.  Samples will be collected prior to the study drug infusion, will be shipped to a central 
laboratory and stored there until the tests become available. 
If subjects consent, the remaining serum samples will also be stored for future analysis. 
Sample collection, preparation, handling, storage, and shipping instructions are provided in the 
Study Laboratory Manual. 
Statistical Analysis - Assessment of the Impact of Coronavirus Disease 2019 (COVID-19) 
If deemed appropriate, analyses will be performed to explore the impact of COVID-19 on the 
safety, efficacy, and any other endpoints, as appropriate, reported for the study. 
As a result of the impact of COVID-19 on study conduct, adjustments to the statistical analysis 
and interpretation will be made, if required.  These will be described in the SAP.