Clinical trial NCT03329690
Conditions: Neoplasm, Gastrointestinal
Keywords: Adenocarcinoma Metastatic Adenocarcinoma of the Stomach Adenocarcinoma of the Gastroesophageal Junction HER2 Overexpression Adenocarcinoma, Locally Advanced DESTINY - Gastric 01
Sponsor: Daiichi Sankyo Co., Ltd.
Start date: 2017-11-02; Completion date: 2020-12-11
Enrollment: 233 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary purpose of this trial is to compare the efficacy and safety of DS-8201a and physician's choice treatment in HER2-overexpressing advanced gastric or gastroesophageal junction adenocarcinoma patients who have progressed on two prior treatment regimens including fluoropyrimidine agent, platinum agent, and trastuzumab.

Detailed description:

Arms: arm 1: Participants with HER2-overexpressing (IHC 3+ or IHC 2+/ISH+) advanced gastric or gastroesophageal junction adenocarcinoma, whose disease has progressed on two prior regimens, will receive DS-8201a once every 3 weeks. arm 2: Participants with HER2-overexpressing (IHC 3+ or IHC 2+/ISH+) advanced gastric or gastroesophageal junction adenocarcinoma, whose disease has progressed on two prior regimens, will receive monotherapy prescribed by the physician before enrollment. arm 3: A maximum of 20 non-randomized participants with HER2 IHC 2+/ISH- advanced gastric or gastroesophageal junction adenocarcinoma will receive DS-8201a once every three weeks. arm 4: A maximum of 20 non-randomized patients with HER2 IHC 1+ advanced gastric or gastroesophageal junction adenocarcinoma will receive DS-8201a once every 3 weeks.
Interventions: intervention 1: DS-8201a intervention 2: Physician's Choice
Intervention descriptions: intervention 1: DS-8201a is comprised of an antibody component conjoined to a drug component in a lyophilized powder, which is made into solution for intravenous administration. intervention 2: Either:

Irinotecan monotherapy (Starting dosage and usage is 150 mg/m2 biweekly, with dose reduction permitted)

Paclitaxel monotherapy (Starting dosage and usage is 80 mg/m2 weekly, with dose reduction permitted)

Protocol documents:
Prot_SAP_000.pdf: 
 
 
CLINICAL STUDY PROTOCOL 
 
A PHASE 2, MULTICENTER, OPEN-LABEL STUDY OF DS- 
8201A IN SUBJECTS WITH HER2-EXPRESSING 
ADVANCED GASTRIC OR GASTROESOPHAGEAL 
JUNCTION ADENOCARCINOMA 
[DESTINY-Gastric0l] 
DS8201-A-J202 
VERSION 6.0, 03 JUL 2020 
 
VERSION 1.0, 31 JUL 2017 
VERSION 1.1, 09 AUG 2017 
VERSION 2.0, 03 OCT 2017 
VERSION 3.0, 25 JAN 2018 
VERSION 4.0, 27 NOV 2018 
VERSION 5.0, 26 APR 2019 
 
 
DAIICHI SANKYO 
 
CONFIDENTIALITY STATEMENT 
Information contained in this document is proprietary to Daiichi Sankyo. The informatio n 
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 conta ined 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 Agreeme nt) without the prior written permission of an authorized 
represe ntative of Daiich i Sankyo. 
 
 
 
 
 
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INVESTIGATOR AGREEMENT 
A PHASE 2, MULTICENTER, OPEN-LABEL STUDY OF DS-8201A IN SUBJECTS 
WITH HER2-EXPRESSING ADVANCED GASTRIC OR GASTROESOPHAGEAL 
JUNCTION ADENOCARCINOMA 
 
Sponsor Approval: 
This clinical study protocol has been reviewed and approved by the Daiichi Sankyo 
representative listed below. 
PPD 
 
 
 
Print Name 
Signature 
 
Clinical Study Lead 
Title 
Date (DD MMM YYYY) 
Investigator's Signature: 
 
I have fully discussed the objectives of this study and the contents of this protocol with 
the Sponsor's representative. 
I understand that information contained in or pertaining to this protocol is confidential 
and should not be disclosed, other than to those directly involved in the execution or the 
ethical review of the study, without written authorization from the Sponsor. It is, 
however, permissible to provide information to a subject in order to obtain consent. 
I agree to conduct this study according to this protocol and to comply with its 
requirements, subject to ethical and safety considerations and guidelines, and to conduct 
the study in accordance with the Declaration of Helsinki, International Council for 
Harmonisation Guidelines on Good Clinical Practice (ICH E6), and applicable regional 
regulatory requirements. 
I agree to make available to Sponsor personnel, their representatives and relevant 
regulatory authorities, my subjects' study records in order to verify the data that I have 
entered into the case report forms (CRFs). 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 prema turely 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 executio n of the study, I will communicate 
my intention immediately in writing to the Sponsor. 
 
 
 
Print Name 
Signature 
 
 
Title 
Date (DD MMM YYYY) 


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PROTOCOL SYNOPSIS 
 
 
Protocol Number: 
DS8201-A-J202 
Investigational Product: 
DS-820 l a 
Active Ingredient(s)/INN: 
Trastuzuma b deruxtecan 
Study Title: 
 A Phase 2, multicenter, open-label study of DS-820la in 
subjects with HER2-expressing advanced gastric or 
gastroesophageal junction adenocarcinoma 
[DESTINY-Gastric01] 
Study Phase: 
Phase 2 
Indication Under 
Investigation: 
Human epidermal growth factor receptor 2 (HER2)­ 
overexpressing locally advanced or metastatic gastric or 
gastroesophageal junction adenocarcinoma 
 
 
Study Objective: 
Primary Cohort 
• 
To compare the efficacy and safety of DS-820 la and 
physician's choice treatment in HER2-overexpressing 
advanced gastric or gastroesophageal junctio n 
adenocarcinoma subjects who have progressed on 2 
prior regimens including fluorop yrimidine agent, 
platinum agent, and trastuzumab (brand, approved 
biosimilar). 
 
Exploratory Cohort 1 
• 
To determine the efficacy and safety of DS-820la in 
subjects with HER2 irnmunohistochemistry (IHC) 2+/in 
situ hybridization (ISH) negative advanced gastric or 
gastroesophageal junction adenocarcinoma. 
 
Exploratory Cohort 2 
• 
To determine the efficacy and safety of DS-820l a in 
subjects with HER2 IHC 1+ advanced gastric or 
gastroesophageal junction adenocarcinoma. 
Study Design: 
Phase 2, mult i-center, open-label, 3-coho rt study 
Primary Cohort 
Primary Cohort is a randomized study to compare the 
efficacy and safety of DS-820 la and the physician's choice 
treatment in subjects with HER2-overexpressing (IHC 3+ 
or IHC 2+/ISH +) advanced gastric or gastroesophageal 


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junction adenocarcinoma who have progressed on 2 prior 
regimens including fluoropyrimidine agent, platinum agent, 
and trastuzumab (brand, approved biosimilar). 
Randomization will be done in a 2:1 ratio into the 2 groups 
(DS-820l a: physician's choice treatment). 
Exploratory Cohort 1 
Exploratory Cohort 1 is a non-randomized cohort to assess 
the efficacy and safety of DS-820 l a to subjects with HER2 
IHC 2+/ISH negative advanced gastric or gastroesophageal 
junction adenocarcinoma who are treatment naive of anti­ 
HER2 therapy. 
Exploratory Cohort 2 
Exploratory Cohort 2 is a non-randomized cohort to assess 
the efficacy and safety of DS-820l a to subjec ts with HER2 
IHC 1+ advanced gastric or gastroesophageal junction 
adenocarcinoma who are treatment naive of anti-HER2 
therapy. 
Study Duration: 
Enrollment is planned to occur over approximately l 0 
months with treatment, and follow-up is projected to be 
continued for at least l0 months after last subject enrolled. 
Thus, the anticipated duration of the study is at least 20 
months. The study will be continued until either the 
completion of follow-up assessments for all the subjects 
who discontinue st udy treatment or at the time of DS-8201a 
approval for this target indication. 
Study Sites and Location: 
See Supplement 1 
 
Subject Eligibility Criteria: 
Common Inclusion Criteria (Primary Cohort, 
Exploratory Cohorts 1 and 2) 
1. Age 20 years. 
2. Has a pathologically documented locally advanced 
or metastatic adenocarcinoma of gastric or 
gastroesophageal junction. 
3. Progression on and after at least 2 prior regimens 
which had to include a fluoropyrimidine and a 
platinum. 
• 
Progression within 6 months of prior adjuvant 
or neoadjuvant chemotherapy will count as 
"rapid progressor" in neo-adjuvant/adjuvant 
setting, and thus equivalent to 
advanced/metastatic disease failing l regimen of 
therapy. 
• 
If prior combination therapy discontinued due to 
an adverse event (AE), and then one of the 


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agents continued, this is considered to be " 1 
prior regimen" and not "2 prior regimens" 
• 
The change in dosage form of 5-Fluorouracil 
medication (intravenous administration, oral 
administration) without progression is 
considered to be "1 prior regimen"   and not   " 
2 prior regimens" 
• 
If patient has received prior therapy with one of 
the drugs in physician's choice (i.e. irinotecan 
or paclitaxel) and has progressed on it then 
patient can be eligible if treating physician 
considers it appropriate to treat the patient with 
the other drng option from the physician's 
choice options. For example, if patient has 
received prior paclitaxel as a monotherapy or in 
combination with other drugs (e.g. 
ramucirumab) and has progressed on it then the 
patient will be eligible to receive irinotecan as 
long as they have not received and progressed 
on prior irinotecan therapy in this setting. Any 
patient who has received prior paclitaxel and 
irinotecan either as monotherapy or as 
combination therapy and have progressed on 
each one of these therapies (i.e. paclitaxel and 
irinotecan), would be ineligible for study 
participation. (Primary cohort only) 
4. Is willing and able to provide an adequate archived 
tumor sample available for tissue sc reening to 
confirm HER2 status by Central Laboratory (based 
on most recent archived tumor tissue sample). If 
archived sample is not available, fresh sample is 
required. 
5. Agree to submit fresh tumor samples for an 
assessment ofHER2 status before the registration if 
primary tumor is accessible by endoscopy. 
6. Has measurable disease assessed by the investigator 
based on Response Evaluation Criteria in Solid 
Tumours (RECIST) version l. l. 
7. Has an Eastern Cooperative Oncology Group 
Performance Status (ECOG PS) of O to 1. 
8. Has left ventricular ejection fraction (LVEF) 250% 
by either echocardiogram (ECHO) or multigated 
acquisition (MUGA) scan within 28 days before 
registration. 


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9. Has adequate organ function within 14 days before 
registration, defined as: 
 
Item 
Laboratory value 
Platelet count 
100000/mm3 (Platelet transfusion 
is not allowed within 1 week prior 
to screening assessment) 
Hemoglobin 
8.0 g/dL (Red blood ce ll 
transfusion is not allowed within 1 
week prior to screening 
assessment) 
Absolute 
neutrophil count 
l 500/mm3 (G-CSF administration 
is not allowed within 1 week prior 
to screening assessment) 
Creatinine 
Creatinine clearance 30 mL/min 
as calculated using the Cockcroft- 
Gault equation 
ALT/AST 
3 x ULN (if liver metastases are 
present, 5 x ULN) 
Total bilirubin 
1.5 x ULN or < 3 x ULN in the 
presence of documented Gilbe1t' s 
Syndrome or liver metastases at 
baseline 
Albumin 
2.5 g/dL 
International 
normalized ratio 
(INR)/Prothromb 
in time (PT) and 
activated partial 
thromboplastin 
time (aPTT) 
1.5 x ULN 
 
l0. Has adequate treatment washout period before study 
drug treatment, defined as: 
 
Treatment 
Washout period 
Major surgery 
4 weeks 
Radiation therapy 
4 weeks (if palliative 
stereotactic radiation therapy 
without abdominal radiation, 
2 weeks) 


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Chemotherapy 
23 weeks (22 weeks for 5- 
(including 
fluorouracil-based agents, 
antibody drug 
therapy and 
folinate agents and/or weekly 
Paclitaxel. 26 weeks for 
retinoid therapy) 
nitrosoureas or mitomycin C) 
Immunotherapy 
24 weeks 
Cytochrome P450 
23 x the elimination half-life of 
(CYP) 3A4 strong the inhibitor 
inhibitor and 
orgamc amon 
transporting 
polypeptide 
(OATP) inhibitor 
1B 
Other study drugs 
23 weeks 
 
11. Male and Female subjects of 
reproductive/childbearing potential must agree to 
use a highly effective form of contraception, avoid 
intercourse, or reliable contraceptive measures 
(double barrier met hods, which include a 
combination of any 2 of the following: diaphragm, 
condom, sponge,  spermicide,  bilateral  tubal 
ligation, or vasectomy) 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. For the purpose of this protocol, methods 
considered as highly effective methods of 
contraception including: 
• 
Combined (estrogen and progestogen 
containing) hormonal contraception associated 
with inhibition of ovulation: 
- 
Oral 
- 
Intravaginal 
- 
Transdermal 
• 
Progestogen-only hormonal contraception 
associated with inhibition of ovulation: 
- 
Oral 
- 
Injectable 
- 
Implantable 


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• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-rele asing system (IUS) 
• 
Bilateral tubal occlusion 
• 
Vasectomy or 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 contracept ion 
Non-child-bearing potential defined as pre­ 
menopausal fema les with a documented tubal 
ligation or hysterectomy;or postmenopausal 
defined as 12 months of spontaneous amenorrhea 
(in questionable cases, a blood sample with 
simultaneous follicle-stim ulating hormone [FSH] 
>40 mIU/mL and estradiol <40  pg/mL 
[<147 pmol/L] is confirmatory). Females on 
hormone replacement therapy (HRT) and whose 
menopausal status is in doubt will be required to use 
one of the contraception methods outlined for 
women of child-bearing potential if they wish to 
continue their HRT during the study. Otherwise, 
they must disco ntinue HRT to allow confirmation 
of post-menopausal status prior to study enrollment. 
For most forms of HRT, at least 2 to 4 weeks will 
elapse between the cessation of therapy and the 
blood draw; this interval depends on the type and 
dosage ofHRT. Following confirmation of their 
post-menopausal status, they can resume use of 
HRT during the study without use of a 
contraceptive method. 
Men who are fertile and sexua lly active should be 
willing to use highly effective methods of 
contraception if their partners are of reproductive 
potential. 
Male subjects must not freeze or donate sperm 
starting at Screening and throughout the study 
period, and at least 4 months after the final study 
drug administration. Preservation of sperm should 
be considered prior to enrolment in this study. 


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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. 
12. Is able to provide written informed  consent. 
Subjects must be fully informed about their illness 
and the investigationalnature of the study protocol 
(including foreseeable risks and possible toxicities) 
and must sign and date an Institutional Review 
Board (IRB)-approvedinformed consent form (ICF) 
before performance of  any study-specific 
procedures or examinations. 
 
Additional Inclusion Criteria for Primary Cohort 
13. Centrally confirmed HER2 overexpression (IHC 3+ 
or IHC 2+/ISH*+) 
* IS H: fluoresce nt in situ hybridization (FISH) or 
dual in situ hybridization (DISH) 
14. Progression on a trastuzumab containing regimen 
(can include an approved trastuzumab biosimilar). 
Progression on trastuzumab not required to be the 
most recent regimen. 
 
Additional Inclusion Criteria for Exploratory Cohort 1 
15. Centrally confirmed HER2 IHC 2+/ISH*negat ive 
* IS H: FISH or DISH 
16. Treatment nai"ve with anti-HER2 targeted therapy 
including approved trastuzumab biosimilar. 
 
Additional Inclusion Criteria for Exploratory Cohort 2 
17. Centrally confirmed HER2 IHC 1+** 
**: ISH does not matter. 
18. Treatment nai"ve with anti-HER2 targeted therapy 
including approved trastuzumab biosimilar. 
 
 
Exclusion Criteria 
1. Medical history of myocardial infarction within 6 
  
months before registration, symptomaticcongestive 


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heart failure (CHF) (New York Heart Association 
Class II to IV, Section 17.4), troponin levels 
consistent with myocardial infarction as defined by 
manufacture, unstable angina, or serious cardiac 
arrh ythmia requiring treatment within 28 days 
before randomization/registration. 
2. Has corrected QT interval by Fridericia's formula 
(QTcF) prolongation to >470 msec (females) or 
>450 msec (males) based on average of the 
screening triplicatel 2-lead electrocardiogram 
(ECG). 
3. Has a history of (non-infectious) ILD/pneumonitis 
that required steroids, has current ILD/pneumonitis, 
or where suspected ILD/pneumonitis cannot be 
ruled out by imaging at screening. 
4. Has a pleural effusion, ascites or pericardia! 
effusion that requires drainage, pe ritoneal shunt, or 
Ce ll-free and Concentrated Ascites Reinfusion 
Therapy (CART). (Drainage and CART are not 
allowed within 2 weeks prior to screening 
assessment) 
5. Has unco ntrolled infection requiring intravenous 
(IV) inject ion of antibiotics, antivirals, or 
antifungals. 
6. Have been diagnosed with human 
immunodeficiency virus (HIV) infection 
7. Known active hepatitis B or C infection. 
8. Has clinically active brain metastases, defined as 
untreated and symptomatic, or requiring therapy 
with steroids or anticonvulsants to control 
associated symptoms. Subjects with treated brain 
metastases that are no longer symptomatic and who 
do not require treatment with steroids for at least 
three weeks may be included in the study if they 
have recovered from the acute toxic effect of 
radiotherapy. 
9. Has clinically significant corneal disease in the 
opinion of the investigator. 
10. Prior treatment with an antibody-drug conjugate 
(ADC) which consists of an exatecan derivative that 
is a topoisomerase I inhibitor. 
11. Has unresolved toxicities from previous anticancer 
therapy, defined as toxicities (other than chronic 
 


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Dosage Form, Dose and 
Route of Administration: 
toxicities per the discretion of the investigator,eg, 
alopecia, peripheral neuropathy, proteinuria, 
controllable hypertension,  and controllable 
diabetes) not yet resolved to National Cancer 
lnstitute' s Common Te1minology Criteria for 
Adverse Events (NCI-CTCAE) version 4.03, Grade 
:Sl o r ba seline. 
12. Has a diarrhea (watery stool), ileus, jaundi ce, or 
intestinal paralysis. 
13. Has a concomitant medical condition that would 
increase the risk of toxicity in the opinion of the 
investigator. 
14. Has known hypersensitivity to either the drug 
substances or inactive ingredients in the drug 
product. 
15. Has history of severe hypersensitivityreactions to 
other monoclonal antibodies. 
16. Has had non-gastric or gastroesop hagea l junction 
primary malignancies within 3 years, except 
adequately resected non-melanoma skin cancer, 
curatively treated in-situ disease, other curatively 
treated solid tumors. 
17. Is a lactating mother (women who are willing to 
temporarily interrupt breastfeeding will also be 
excluded), or pregnant as confirmed by pregnancy 
tests performed within 14 days before registration. 
Study Drug (DS-8201a) 
DS-820la for Injection 100 mg,. 
DP: 
The DS-820l a drug product is prov ided as a­ 
QOwder containing 100 mg of DS-8201a in a glass vial 
- 
DP). 
DS-820l a will be administered as an IV solution. S ubjects 
will receive the 6.4 mg/kg of DS-820la on Day 1 of each 
cycle, once every 3 weeks (Q3W). 
 
Physician's choice Treatment (lrinotecan or Paclitaxel) 
The physician's choice treatment is a limited choice of one 
of two standard regimens (irinotecan monotherapy or 
paclitaxel monotherapy). The investigator will pre-select 
the physician's choice treatment before the randomization 
of each subject. 
Irinotecan monotherapy 


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Starting dosage and usage is 150 mg/m2 biweekly. 
or 
Paclitaxel monotherapy 
Starting dosage and usage is 80 mg/m2 weekly. 
Study Endpoints: 
Primary Endpoint: 
• 
The objective response rate (ORR) assessed by the 
independent central imaging facility review based on 
RECIST version l. l (for Primary Cohort) 
 
Secondary Endpoints: 
 
• 
Efficacy endpoints (based on central review unless 
otherwise stated): 
- 
Overall survival (OS) , not based on central review 
- 
PFS 
- 
Duration of response (DoR) 
- 
Disease control rate (DCR) 
- 
Time to treatment failure (TTF) 
- 
ORR assessed by the investigator based on RECIST 
version 1.1 
- 
ORR (for each Exploratory Cohort l and 2) 
 
 
• 
Safety endpoints: 
- 
Serious adve rse events (SAEs) 
- 
Treatment-emergent adverse events (TEAEs) 
- 
AE of special interest (AESI) 
- 
Discontinuation due to AE 
- 
Discontinuation due to AESI 
- 
Physical examination findings (including ECOG PS) 
- 
Vital sign measurements 
- 
Standard clinical laboratory parameters 
- 
Elevated troponin levels 
- 
ECG parameters 
- 
ECHO/MUGA findings 


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- 
Ophthalmologic findings 
- 
Anti-drug antibodies (ADA) 
 
• 
Pharmacokinetic endpoints (DS-820la, total anti-HER2 
antibody and MAAA-l 18la): 
- 
Pharmacokinetics (PK) parameters: Cmax, Tmax, 
AUClast, and area under the serum concentration­ 
time curve up to 21 days (AUC0-21d) 
- 
Serum concentrations. 
 
• 
HEOR endpoints (in Primary Cohort only): 
- 
Functiona l Assessment of Cancer Therapy-Gastric 
(FACT-Ga) 
- 
EuroQoL 5 Dimensions 5 Levels (EQ-5D-5L) 
- 
Health care resourceutilization 
 
Exploratory Endpoints (based on central review unless 
otherwise stated): 
• 
Exploratory efficacy endpoints (based on central review 
unless otherwise stated): 
- 
Time to response 
- 
Best percent change in the sum of diameters of 
measurable tumors 
- 
PFS based on investigator assessment 
• 
Serum extracellular domain of HER2 (HER2ECD) 
• 
Biomarker analysis using cell free DNA (cfDNA) 
• 
Analysis of pre-treatment and post-progression biopsies 
for mechanisms of resistance to DS-820la 
Planned Sample Size: 
The total planned number of subjects is approx im ately 220. 
Primary Cohort: approximately 180 (DS-820l a group: 120, 
physician ' s choice group: 60) 
Exploratory Cohort 1: approximately 20 
Exploratory Cohort 2: approximately 20 
Statistical Analyses: 
The primary analysis for ORR and a formal interim 
analysis for OS will be performed when all subjec ts have 
completed tumor assessment approximately at 24 weeks (or 
discontinuedfrom the study) in Primary Cohort. The final 


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OS analysis will be performed when about 133 OS events 
are observed in Primary Cohort. 
Efficacy analyses: 
Primary efficacy analysis will be performed for all 
randomized subjects who received at least one dose of the 
study treatment and had measura ble tumors based on 
central review at baseline in Primary Cohort. The primary 
endpoint is ORR assessed by independent central imaging 
facility review based on RECIST version 1.1. A Cochran­ 
Mantel-Haenszel (CMH) test will be used to compare ORR 
between the treatment groups. The primary efficacy 
analysis for ORR will be assessed  for statistical 
significance at 2-sided alpha = 0.05. The estimate of ORR 
and its 2-sided 95% exact CI will be provided for each 
cohort/treatment group. In addition, ORR by fixed time 
points (eg, 3, 6, 9, 12 months) along with their 2-sided 95% 
exact Cis will be provided for each cohort/treatment group. 
The secondary efficacy endpoints include OS, PFS, DoR, 
DCR, TTF, and ORR assessed by the investigator based on 
RECIST version 1.1. OS and PFS will be compared 
between the treatment groups using stratified log-rank tests 
in Primary Cohort. To control the family-wise type I error 
rate (FWER) for primary and secondary efficacy endpoints, 
a serial hierarchically ordered gatekeeping strategy will be 
applied. The tests will be performed in the followi ng order: 
ORR, OS. The sequence oftests will continue until the test 
does not meet the significance level of 2-sided alpha= 
0.05. The HRs and their 95% Cis will be estimated, using 
stratified Cox proportional hazards models. Kaplan-Meier 
estimates and survival curves will also be presented for 
each cohort/treatment group. OS , PFS, DoR, and TTF will 
be summarized with median event times and their 2-sided 
95% CI for the median using Brookmeyer and Crowley 
methods for each cohort/treatment group. DCR and ORR 
assessed by the investigator based on RECIST version 1.1 
will be analyzed in the same manner as ORR analysis. 
Safety analyses: 
The safety endpoints will include SAEs, TEAEs, AESis, 
physical examination findings (including ECOG PS), vital 
sign measurements, standard clinical laboratory parameters, 
elevated troponin levels, ECG parameters, ECHO/MUGA 
findings, ADA, and ophthalmologic fmdings. TEAEs will 
be graded according to NCI-CTCAE version 4.03. Safety 
analyses in general will be descriptive and  will  be 
presented in tabular format with the appropriate summary 
statistics. 
Pharmacokinetic analyses: 


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PK parameter s for each subject will be estimated using 
non-compartmental methods. Descriptive statistics will be 
provided for all serum concentration data by 
cohort/treatment arm at each time and PK parameter by 
cohort/treatment arm. The population pharmacokinetics 
(pop-PK) analysis to evaluate the effect of intrinsic and 
extrinsic factors ofDS-820la, and if appropriate, total anti­ 
HER2 antibody, and MAAA-118l a will be characterized 
including available PK data from the Phase 1 (DS8201-A­ 
Jl Ol ). 
After establishment of the pop-PK model, a population 
pharmacokinetics/pharmacodynamics (pop-PK/PD) model 
will be developed to evaluate the relationship between 
exposure and efficacy and toxicity. 
The pop-PK and pop-PK/PD will be reported in a separate 
report from the clinical study report. 
HEOR analyses: 
HEOR endpoints (eg, EQ-5D-5L, FACT-Ga, health care 
resource utilization) will be summarized using standard 
methods of analysis for the corresponding questionnaires in 
Primary Cohort. 


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TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT ........................................................................... 2 
PROTOCOL SYNOPSIS ............................................................................................... 3 
TABLE OF CONTENTS ....................................................................................... 16 
LIST OF TABLES .................................................................................................. 24 
LIST OF FIGURES ................................................................................................ 25 
LIST OF ABBREVIATIONS ................................................................................ 26 
1. 
INTRODUCTION ................................................................................... 30 
1.1. 
Background ......................................................................................... 30 
l.2. 
. ....................................................................... Treatment of Gastric Cancer  
 30 
l.3. 
. ................................................................................ Investigational  Product  
 31 
1.3.1. 
Descr iption ............................................................................................... 31 
l.3.2. 
Nonclinical Studies ..................................................................................... 31 
1.3.2.1.  Pharmaco logy ......................................................................................... 31 
l.3.2.2. Safety Pharmacology ............................................................................... 32 
l.3.2.3. Pharmacokinetics and Drug Metabolism ...................................................... 32 
l.3.2.4. Toxicology ............................................................................................... 33 
l.3.3. 
Clinical Experience ............................................................................. 34 
l.3.4. 
Summary of Clinical Pharmacokinetics ........................................................ 35 
1.4. 
Study Rationale ................................................................................... 36 
l.5. 
Risks and Benefits for Study Subjects .................................................... 37 
2. 
STUDY OBJECTIVES AND HYPOTHESIS ........................................ 39 
2.l. 
Study Objectives ...................................................................................... 39 
2.2. 
Study Hypotheses ..................................................................................... 39 
2.3. 
Study Endpoints ....................................................................................... 39 
2.3.l . 
Primary Endpoint ...................................................................................... 39 
2.3.2. 
Secondary Endpoints ............................................................................... 39 
2.3.3. 
Exploratory Endpoints ............................................................................. 40 
3. 
STUDY DESIGN ............................................................................................ 42 
3.l. 
Overall Design ......................................................................................... 42 
3.1.l. 
Overview ............................................................................................. 42 
3.1.2. 
Duration of the Study ............................................................................... 43 
3.l. 3. 
Duration of Subject Participation ............................................................43 
3.2. 
Discussion of Study Design .................................................................. 43 


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3.2.l. 
Selection of Dose and Usage ................................................................... 43 
3.2.2. 
Treatment Cycle Period ........................................................................... 44 
4. 
STUDY POPULATION .......................................................................... 45 
4.1. 
Inclusion Criteria ..................................................................................... 45 
4.2. 
Exclusion Criteria .................................................................................... 48 
5. 
STUDY TREATMENT{S) ...................................................................... 51 
5.l. 
Assigning Subjects to Treatments and Blinding ...................................... 51 
5.l. l. 
Method of Cohort Allocation ................................................................... 51 
5.1.2. 
Treatment Group(s) ...................................................................................... 51 
5.1.3. 
Blinding .................................................................................................... 51 
5.l.4. 
Emergency Unblinding Procedure ........................................................... 51 
5.2. 
Study Drug (DS-820 la) ............................................................................ 52 
5.2.1. 
Description ............................................................................................... 52 
5.2.2. 
Labeling and Packaging ........................................................................... 52 
5.2.3. 
Preparation ............................................................................................... 52 
5.2.4. 
Administration ......................................................................................... 52 
5.2.5. 
Storage ..................................................................................................... 52 
5.2.6. 
Drug Accountability ............................................................................ 52 
5.2.7. 
Dose Interruptions and Reductions .......................................................... 53 
5.3. 
Physician' s Choice (Irinotecan or Paclitaxel) .......................................... 63 
5.3.l . 
Dosage and Usage .................................................................................... 63 
5.3.l. l.  Irinotecan monotherapy ........................................................................... 63 
5.3.l .2. Paclitaxel monotherapy ............................................................................ 63 
5.3.2. 
Administration Criteria ............................................................................ 64 
5.3.3. 
Dose Reductions....................................................................................... 64 
5.4. 
Method of Assessing Treatment Compliance ........................................... 65 
5.5. 
Prophylactic Treatment and Concomitant Medications ............................ 65 
5.5.l. 
Prophylactic Treatment ............................................................................ 65 
5.5.2. 
Concomitant Medications ......................................................................... 66 
5.5.3. 
Prohibited Concomitant Medications/Activities ..................................... 66 
5.6. 
Subject Withdrawal /Discontinuation ........................................................... 67 
5.6.l. 
Reasons for Discontinuation of Study Treatment. ................................... 67 
5.6.2. 
Reasons for Discontinuatio n of Study Follow-up ................................... 67 
5.6.3. 
Withdrawal Procedures ................................................................................ 68 


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5.6.4. 
Subject Rep lacement .................................................................................. 68 
5.6.5. 
Subject Re-screening Procedures ............................................................ 68 
6. 
STUDY PROCEDURES ......................................................................... 69 
6.1. 
Screening .................................................................................................. 69 
6.1.1. 
Tissue Screening ..................................................................................... 69 
6.1.2. 
Screening .................................................................................................. 70 
6.1.3. 
Registration .............................................................................................. 71 
6.1.4. 
Randomization ......................................................................................... 71 
6.1.5. 
Discontinuation during the Screening Period ........................................... 72 
6.2. 
Treatment Period ...................................................................................... 72 
6.2.l. 
Tumor Assessment. ................................................................................. 72 
6.2.2. 
Patient Reported Outcomes (EQ-5D-5L and FACT-Ga) ........................ 72 
6.2.3. 
Safety Monitoring for suspected ILD/pneumo nitis ................................ 73 
6.2.4. 
Schedule of Activity and Assessments for Subjects Receiving DS-820la 
73 
6.2.4. l.  Cycle 1, Day 1 ...................................................................................... 73 
6.2.4.2. Cycle 1, Day 8 .......................................................................................... 75 
6.2.4.3. Cycle 1, Day 15 ................................................................................... 75 
6.2.4.4. Cycle 1, Day22 ......................................................................................... 75 
6.2.4.5. Cycle 2, Day 1 ..................................................................................... 75 
6.2.4.6. Cycle 2, Day22 ......................................................................................... 77 
6.2.4.7. Cycle 3, Day 1 .......................................................................................... 77 
6.2.4.8. Cycle 3, Day 8 .......................................................................................... 78 
6.2.4.9. Cycle 3, Day 15 ................................................................................... 78 
6.2.4.10. Cycle 3, Day22 ......................................................................................... 79 
6.2.4.11. Cycle 4 and Subsequent Cycles, Day 1 .................................................... 79 
6.2.4.12. End of Treatment ...................................................................................... 80 
6.2.5. 
Schedule of Activity and Assessments for Subjects Receiving 
Physician' s Choice Treatment .................................................................. 81 
6.3. 
Follow-up ................................................................................................. 81 
6.4. 
Survival Status and New Treatment Follow-up ....................................... 82 
6.5. 
Follow-up of Anti-Drug Antibodies ......................................................... 82 
7. 
EFFICACY ASSESSMENTS ................................................................. 83 
7.1. 
Assessments of Efficacy Endpoint(s) ...................................................... 83 


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8. 
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS .. 84 
8.1. 
Pharmacokinetic (PK) Assessment(s) ...................................................... 84 
8.2. 
Biomarkers .................................................................................................. 86 
8.2.1. 
Pharmacodynamic Assessments .............................................................. 86 
8.2.1.1. Pharmacodynamic Assessments in Blood Samples .................................. 86 
8.2.l.2. Pharmacodynamic Assessments in Newly Obtained Tumor Spec imens 86 
8.2.l .3.  Additional Biomarker Assessments ......................................................... 87 
8.2.1.4.  Disclosure of the Results of Additional Biomarker Assessments ............ 87 
8.3. 
SARS-CoV-2 Serum samples collection ................................................. 87 
8.4. 
Pharmacogenomic Analysis ..................................................................... 87 
8.4.1. 
Genomic or Genetic Banking Analysis .................................................... 87 
8.4.1.1. Disclosure of the Results of Genomic or Genetic Analysis ..................... 87 
8.5. 
Anonyrnization of Samples...................................................................... 88 
8.6. 
Sample Storage and Disposal......................................................................... 88 
8.7. 
Immunogenicity ....................................................................................... 88 
9. 
SAFETY EVALUATION AND REPORTING ...................................... 90 
9.1. 
Assessment of Safety Endpoint(s) ........................................................... 90 
9.2. 
Adverse Event Collection and Reporting ................................................ 90 
9.3. 
Adverse Events of Special Interest ............................................................. 91 
9.3.1. 
QT prolongation and LVEF decrease ...................................................... 91 
9.3.2. 
Interstitial Lung Disease/Pneumonitis ..................................................... 92 
9.3.2.1. 
Interstitial Lung  Disease Adjudication Committee .................................. 92 
9.3.3. 
Infusion-related Reactions ........................................................................ 93 
9.3.4. 
Independent Data Monitoring Committee (IDMC) ................................. 93 
9.4. 
Adverse Events ........................................................................................ 93 
9.4.l. 
Definition of Adverse Events ................................................................... 93 
9.4.2. 
Serious Adverse Events ........................................................................... 93 
9.4.3. 
Severity Assessment ................................................................................... 94 
9.4.4. 
Causality Assessment ........................................................................... 95 
9.4.5. 
Actions Taken Regarding Study Drug(s) ................................................. 95 
9.4.6. 
Other Actions Taken for Events ............................................................... 95 
9.4.7. 
Adverse Event Outcomes ...................................................................... 95 
9.5. 
Serious Adverse Events and Adverse Events of Special Interest 
Reporting-Procedure For Investigators ...................................................... 96 


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9.6. 
Notifying Regulatory Authoritie s, Investigators, and the Institutional 
Review Board/Ethics Committee ............................................................. 97 
9.7. 
Exposure In Utero Durin g C linical Studies ............................................. 98 
9.8. 
Clinical Laboratory Evaluations .............................................................. 99 
9.9. 
Vital Signs ........................................................................................... 99 
9.10. 
Electrocardiograms.................................................................................. 99 
9.11. 
Physical Examinations ........................................................................... 100 
9.12. 
Other Examinations ................................................................................ 100 
10. 
OTHER ASSESSMENTS ..................................................................... 101 
10.1. 
Patient Reported Outcome s ...................................................................... 101 
10.1.1 . EQ-5 D-5L .................................................................................................. 101 
10.1.2. FACT-Ga ............................................................................................... 101 
l0.1.3.  Health Care Resource Utilization .......................................................... 102 
11. 
STATISTICAL METHODS .................................................................. 103 
11.1. 
General Statistical Considerations ......................................................... 103 
11.2. 
Analysis Sets ...................................................................................... 103 
11.2.l. Full Analysis Set .................................................................................... 103 
11.2.2. 
Response Evaluable Set ...................................................................... 103 
11.2.3. 
Safety Analysis Set ............................................................................. 103 
11.2.4. 
Pharmacokinetic Set. ......................................................................... 104 
11.3. 
Study Population Data .............................................................................. 104 
11.4. 
Statistical Analyses ................................................................................ 104 
11.4.1. 
Efficacy Analyses .................................................................................. 104 
11.4.1.1. 
PrimaryEfficacy Analyses ................................................................. 104 
11.4.l.2.Secondary Efficacy Analyses ................................................................. 104 
11.4.1.3.Exploratory Efficacy Analyses ............................................................... 105 
11.4.2. 
Pharmacokinetic/Pharmacodynamic/Biomarker Analyses .................... 106 
11.4.2.1. 
Pharmacokinetic Analyses ..................................................................... 106 
11.4.2.2. 
Pharrnacodynamic Analyses .................................................................. 106 
11.4.2.3. 
Biomarker Analyses .......................................................................... 106 
11.4.2.4. 
PharmacogenomicAnalyses ..................................................................... 106 
11.4.3. Safety Analyses ................................................................................. 106 
11.4.3.1. Adverse Event Analyses ........................................................................ 107 
11.4.3.2. 
Clinical Laboratory Evaluation Analyses .............................................. 107 


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11.4.3.3. Vital Sign Analyses ................................................................................ 107 
11.4.3.4. 
ElectrocardiogramAnalyses .............................................................. 107 
11.4.3.5. Anti-Drug Antibodies Analyses............................................................. 108 
11.4.3.6. 
Other Safety Analyses ............................................................................ 108 
11.4.4. Other Analyses .................................................................................. 108 
11.4.4.1. Subgro up Analyses .................................................................................... 108 
11.4.4.2. Analyses of Exploratory HEOR Endpoints ............................................ 109 
11.5. 
Interim Analyses .................................................................................... 109 
11.6. 
Sample Size Determination .................................................................... 109 
11.7. 
Statistical Analysis Process .................................................................... 110 
12. 
DATA INTEGRITY AND QUALITY ASSURANCE ......................... 110 
12.1. 
Monitoring and Inspections ................................................................... 110 
12.2. 
Data Collection ...................................................................................... 111 
12.3. 
Data Management .............................................................................. 112 
12.4. 
Study Documentation and Storage ........................................................ 112 
12.5. 
Record Keeping ..................................................................................... 113 
13. 
FINANCINGANDINSURANCE ..................................................... 115 
13.1. 
Finances ................................................................................................. 115 
13.2. 
Reimbursement, Indemnity, and Insurance ............................................ 115 
14. 
PUBLICATION POLICY. .................................................................... 116 
15. 
ETHICS AND STUDY ADMINISTRATIVE INFORMATION ......... 117 
15.1. 
Compliance Statement, Ethics, and Regulatory Compliance ................ 117 
15.2. 
Subject Confidentiality .......................................................................... 117 
15.3. 
Informed Consent .................................................................................. 117 
15.4. 
Informed Consent for Pharmacogenomic Analysis .................................. 118 
15.5. 
Regulato ry Compliance .......................................................................... 118 
15.6. 
Protocol Deviations ................................................................................ 119 
15.7. 
Supply of New Information Affecting the Conduct of the Study .......... 119 
15.8. 
Protocol Amendments ............................................................................ 120 
15.9. 
Study Termination .................................................................................. 120 
15.10. 
Steering Committee ............................................................................... 120 
15.11. 
Data and Safety Monitoring Board ........................................................ 120 
15.12. 
Address List ........................................................................................... 121 
15.12.1. Sponsor .................................................................................................. 121 


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15.12.2. Medical Officer / External Medjcal Monitor/ Internal Medical Monitor 
121 
15.12.3. Coordinating Investigator ...................................................................... 121 
15.12.4. Sponsor' s Clinical Study Lead ............................................................... 121 
15.12.5. Sponsor's Clinical Operations Delivery Lead ....................................... 121 
15.12.6. Sponsor's Safety Contacts .................................................................. 121 
15.12.7. ARO ................................................................................................... 122 
15.12.8. 
CROs ................................................................................................. 122 
15.12.9. 
EDC Vendor ........................................................................................... 122 
15.12.10. 
. .......................................................................................................... EDC System 
Support .............................................................................................. 122 
15.12.11. 
IXRS Vendor ..................................................................................... 122 
15.12.12. 
Central Laboratory ............................................................................ 123 
15.12.13. 
Central Imaging ................................................................................. 123 
15.12.14. Bioanalytical Laboratory (Pharmacokinetics and Anti-Drug Antibodies)
 
123 
15.12.15. 
Sponsor's Biostatistician .................................................................. 123 
15.12.16. 
Data Safety Monitoring Board .......................................................... 123 
16. 
REFERENCES ...................................................................................... 124 
17. 
APPENDICES ....................................................................................... 128 
17.1. 
Cockcroft-Gault Equation ...................................................................... 128 
17.2. 
Eastern Cooperative Oncology Group Performance Status (ECOG PS) 
129 
17.3. 
Response Evaluation Criteria in Solid Tumors, Version 1.1 ................ 129 
17.3.1. 
Measurability of Tumor at Baseline ....................................................... 129 
17.3.1.1. Definitions.............................................................................................. 129 
17.3.1.2. Specifications by Methods of Measurements ......................................... 130 
17.3.2. Tumor Response Evaluation .................................................................. 131 
17.3.2.1. 
Assessmentof Overall Tumor Burden and Meas urable Disease ........... 131 
17.3.2.2. Baseline Documentation of "Target" and ''Non-target" Lesions .......... 131 
17.3.2.3. 
Response Criteria ...................................................................................... 132 
17.3.2.4. 
Evaluation of Best Overall Response ..................................................... 134 
17.3.2.5. 
Frequency  of Tumor Re-evaluation........................................................ 136 
17.4. 
New York Heart Association Functional Classification ........................ 137 
17.5. 
Quality of Life Questionnaires ............................................................... 138 


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17.5.1. 
FACT-G ................................................................................................. 138 
17.5.2.  EQ-5D-5L .......................................................................................... 141 
17.6. 
Instructions Related to SARS-CoV-2 .................................................... 144 
17.6.1. 
Dose Modification Criteria for Suspected or Confirmed SARS-CoV-2 
144 
17.6.2. 
Prior and Concomitant Medications- Prohibited The rapies/Products .... 145 
17.6.3. PK Assessme nt(s) if Chloroquine or Hydroxychloroquine is 
Administered .......................................................................................... 145 
17.6.4. 
SARS-CoV -2 Assessmen t(s) ................................................................. 145 
17.6.5. Statistical Analysis - Assessment of the Impact of SARS-CoV-2 ......... 145 
18. 
SCHEDULE OF EVENTS .................................................................... 146 
18.1. 
Schedule of Events for Subjects Receiving DS-820 la ..................... 146 
18.2. 
Schedule of Events for Subjects Receiving the physician's choice 
treatment. ............................................................................................... 150 


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LIST OF TABLES 
Table 1.1: Pharmacokinetic Parameters of DS-820la ........................................ 36 
Table 1.2:   Pharmacokinetic Parameters of Total Antibody .................................. 36 
Table 1.3:  Pharmacokinetic Parameters ofMAAA-l18la ................................. 36 
Table 5.1:    Dose Reduction Levels ofDS-820la ................................................... 54 
Table 5.2:    Dose or Schedule Modificationfo r DS-820la .................................... 54 
Table 5.3:    Dose Reduction Levels oflrinotecan................................................... 63 
Table 5.4:   Dose Reduction  Levels of Paclitaxel ................................................... 63 
Table 5.5:   Administration Criteria for Irinotecan and Paclitaxel ......................... 64 
Table 5.6:   Dose Reduction Criteria ...................................................................... 65 
Table 8.1:  Pharmacokinetic Parameters ............................................................... 84 
Table 8.2:   Pharmacokinetic Sampling Time Points ............................................... 84 
Table 8.3: Schedule of PK Sample Collection for Subjects Administered 
Chloroquine or Hydroxychloroquine .................................................. 85 
Table 8.4:   Extracellular Domain ofHER2 Sampling Time Points ....................... 86 
Table 8.5:   Cell Free DNA Sampling Time Points .................................................. 86 
Table 8.6:   Anti-Drug Antibodies (ADA) Sampling Time Points .......................... 89 
Table 12.1: EDC System ..................................................................................... 112 
Table 17.1: Eastern Cooperative Oncology Group Performance Status Scale ..... 129 
Table 17.2: Overall Response: Subjects with Target (±Non-target) Disease ....... 135 
Table 17.3: New York Heart Association Functional Classification ................... 137 
Table 17.4: SARS-CoV-2 Dose Modification Criteria ........................................ 144 


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LIST OF FIGURES 
Figure 3. l: Study Design Schema of DS8201-A-J202 .......................................... 43 


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LIST OF ABBREVIATIONS 
 
 
 
 
- 
- 
ABBREVIATION 
DEFINITION 
AC 
Adjudication Committee 
ACC 
American College of Cardiology 
ADA 
anti-drug antibodies 
ADC 
antibody-drug conjugate 
adverse event 
AE 
ALP 
alkaline phosphatase 
ALT 
L-alanine aminotransferase 
AST 
L-aspartate aminotransferase 
AUC 
area under the plasma/serum concentration-time curve 
AUC21d 
area under the plasma/serum concentration-timecurve up to 21 
days 
AUCinf 
area under the plasma/serum concen tration-time curve up to 
infinity 
AUClast 
area under the plasma/serum concentration-time curve up to the 
last quantifiable time 
BCRP 
breast cancer resistance protein 
Bl 
before infusion 
BSEP 
bile salt export pump 
CART 
Cell-free and Concentrated Ascites Reinfusion Therapy 
CDlSC 
Clinical Data InterchangeStandards Consortium 
cfDNA 
cell free DNA 
CHF 
congestive heart failure 
CL 
total body clearance 
Cmax 
maximum plasma/serum concentration 
COVID-19 
coronavirus disease 2019 
CR 
Complete Response 
CrCI 
creat inin e clearance 
CRF 
case report form 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 


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ABBREVIATION 
DEFINITION 
DAR 
drug-to-antibody ratio 
DCR 
disease control rate 
DISH 
dual in situ hybridizat ion 
DLT 
dose limiting toxicity 
DNA 
deoxyribonucle ic acid 
DoR 
duration of response 
EC 
Ethics Committee 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOGPS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
electroniccase report form 
EDC 
electronic data capture 
El U 
Exposure 1n Utero 
EOl 
end of infusion 
EOT 
end of treatment 
EQ-5D-5L 
EuroQoL 5 Dimensions 5 Levels 
FACT-G 
Functional Assessment of Cancer Therapy-General 
FACT-Ga 
Functional Assessment of Cancer Therapy-Gastric 
FAS 
full analysis set 
Fili 
first-in-human 
FISH 
fluoresce nt in situ hybridization 
FWER 
family-wise type l error rate 
GCP 
Good Clinical Practice 
GEJ 
gastro-esophageal junction 
HER2 
human epidermal growth factor receptor 2 
HER2ECD 
extracellular domain of HER2 
hERG 
human ether-a-go-go-related gene 
HIV 
human immunodeficiency virus 
HNSTD 
highest non-severely toxic dose 
1B 
Investigator 's Brochure 
lCF 
informed consent form 
lCH 
International Conference on Harmonization 
lgGl 
immunoglobulin G1 


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ABBREVIATION 
DEFINITION 
IHC 
immunohistoc hemistry 
ILD 
inte rstitial lung disease 
INN 
international nonproprietary name 
lRB 
Institutional Review Board 
ISH 
in situ hybridization 
IV 
intravenous(ly) 
IXRS 
interactive web/voice response system 
LVEF 
left ventricular eject ion fraction 
MAAA-118la 
the drug component of DS-8201a - a derivative of exatecan, a 
topoisomerase I inhibitor 
MAAL-9001 
the antibody component of DS-8201a - a humanized IgGl 
monoclonal antibody produced in-house with reference to the same 
amino acid sequence of trastuzumab 
MATE 
multidrug and toxin extrusion 
MedDRA 
Medical Dictionary for Regu latory Activities 
MRI 
magnetic resonance imaging 
mRNA 
messenger RNA 
MTD 
maximum tolerated dose 
MUGA 
multigated acquis ition (scan) 
NAB 
neutralizing anti-drug antibody 
NCI 
Nationa l Cancer Institute 
NE 
Not Evaluable 
NRU 
neu tral red uptake 
OAT 
organic anion transporter 
OATP 
organic anion transport ing polypep tide 
OCT 
organic cation transporter 
ORR 
objective response rate 
OS 
overall survival 
PD 
Progressive Disease 
PFS 
progression-free survival 
P-gp 
P-glycoprote in 
PK 
pha rmacoki netics 
pop-PK 
population pharmacokinetics 
pop-PK/PD 
population pharmacok inetics/pharmacodyn amics 


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ABBREVIATION 
DEFINITION 
PR 
Partial Response 
PRO 
patient reported outcomes 
PT 
Preferred Term 
Q3W 
once every 3 weeks 
QoL 
quality of life 
QTc 
corrected QT interval 
QTcF 
correcte d QT interval by Fridericia's formula 
REClST 
Response Evaluation Criteria in Solid Tumours 
RNA 
ribonucleic acid 
RT-PCR 
reverse transcription polymerase chain reaction 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SAYER 
Serious Adverse Event Report 
SD 
Stable Disease 
SMQ 
Standardised MedDRA Query 
soc 
System Organ Class 
SOP 
standard operating procedure 
SpO2 
per iph era l oxygen saturation 
STD10 
se verely toxic dose in 10% of the animals 
SUS AR 
Suspected Unexpected Serious Adverse Reaction 
t112 
te rminal elimination half-life 
T-DMl 
trastuzumab emtansine 
TEAE 
treatment-emergent adverse event 
Tmax 
time to reach maximum plasma/serum concentration 
TTF 
time to treatme nt failure 
ULN 
upper limit of normal 
Vss 
volume of dis tribution at the steady state 


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• • • 
• • • • • 
•
•
•
Anti-PD-l antibody, nivolumab was compared with placebo for the 
1. 
INTRODUCTION 
1.1. 
Background 
Gastric cancer is the fifth most common cancer worldwide; there are approximately  
950,000 new cases diagnosed and 720,000 deaths worldwide annually. Among various 
geog raphical regions in the world, the highest incidence and mortality of gastric cancer 
were registered from North-Eastern Asian countries, including Japan and Korea, 
accounting for more than half of the world.1 In Korea and Japan, gastric cancer is more 
likely to be diagnosed at an early stage, resulting in more favorable 5-year survival rates of 
55.6% to 66.0%,2 and 50.0%, respectively.3 In patients with gastric cancer who are 
refractory to standard therapies, the median life expectancy is a maximum of 
approximately 6 months, and there remain high unmet medical needs.4 
DS-820la is an antibody-drug conjugate (ADC) targeting human epidermal growth factor 
receptor 2 (HER2). In the ongoing Phase 1 clinical study, DS8201-A-Jl01, in subjects 
with advanced solid tumors, DS-820l a was well tolerated at repeated doses of up to 
8.0 mg/kg intravenously (IV) once every 3 weeks (Q3W). 
 
1.2. 
Treatment of Gastric Cancer 
Across Asian populations, HER2 overexpression (immunohistochernistry [IHC] 3+ and 
IHC 2+/in situ hybridization [ISH] +) in gastric cancer is reported in approximately 9.8% 
to 23.0% of cases,5 6 7 8 9 10 HER2 IHC 2+/ISH negative is 2.5% to 20.1%, HER2 IHC 1+ 
is 14.0% to 42.9% of cases,5 8 9 10 and it is considered to be an important target molecule 
for gastric cancer therapy due to initiation of a strong pro-tumorigenic signalingcascade.11 
Trastuzumab is the only approved anti-HER2 therapy worldwide for gastric cancer 
patients with HER2-overexpressing tumors that are defined as either IHC 3+ or IHC 
2+/fluorescent in situ hybridization (FISH) positive. The addition of trastuzumab to 
chemotherapy with capecitabine (or 5-FU) and cisplatin is recommended as first-line 
chemotherapy for patients with HER2-overexpressingadvanced gastric cancer in Japan 
and Korea. However, after treatment failure of trastuzumab, there is no anti-HER2- 
specific treatment for the patients. As a second line, combination therapy of ramucirumab 
plus paclitaxel is recommended. In patients with good performance status, agents that had 
not been used in the previo us chemotherapy are selected as the third-line therapy 
(Irinotecan or Taxane), with response rates of about 3.0% to 23.2%, median progression­ 
free survival (PFS) of 2.3 to 3.5 months, and median overall survival(OS) of 4.0 to 6.7 
months.12 13 14 15 
treatment of subjects who had progressed after treatment with standard therapies. 
Nivolumab improved median OS from 4.14 to 5.26 mo.16 
It is known that trastuzumab has an impact on changes in HER2 expression. It is reported 
that loss of HER2 positivity after progression of trastuzumab treatment was observed in 
14/48 (29.2%).17 The majority of patients with HER2-overexpressing advanced gastric 
cancer eventually acquire resistance or show intolerance to these drugs. In addition, after 
failure of tras tuzumab as first line treatment, there is no HER2 specific treatment option as 
second line or latter. Therefore, HER2-overexpressing advanced gastric cancer is 
considered a serious and life-threateningdisease and this patient population has a high 
unmet medical need. 


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1.3. 
Investigational Product 
1.3.1. 
Description 
DS-820l a consists of an antibody component, MAAL-9001, covalently conjugated via a 
maleimide tetrapeptide linker, to a drug component, MAAA-l 18 la. MAAL-9001 is an in­ 
house humanized immunoglobulin G1 (IgG1) monoclonal antibody with the same amino 
acid sequence as trastuzumab. MAAA-118la, an exatecan derivative,18•19•20 is a 
topoisomerase I inhibitor that is cell-membrane permeable, and more potent than SN-38 
(active metabolite of irinotecan). This ADC achieves a high drug-to-antibody ratio (DAR) 
(7 to 8) with homogeneous conjugation with MAAA-l 18la.21 DS-820la is cleaved by 
lysosomal enzymes and releases MAAA-l 18la in the cytoplasm after it binds  to the 
HER2 receptor, and gets internalized in tumor cells. 
The DS-820la Phase I clinical study, DS8201-A-J101, was injtiated with the antibod y 
component. MAAL-9001, 
. To suppo rt1202 studv, 
MAAL-900- 
products have shown 
 
 
However, in a xenograft study, 
no difference was seen in antitumor activity between the two products. Following single 
IV administration ofDS-820la to cynomolgus monkeys, mean Cmax ofDS-820la was 
similar,  whlle AUClast was approximately 22% lower, for 
material as 
compared to 
material. DS-820 Ia drug product manufactured from 
material will be supplied to thls study. 
1.3.2. 
Nonclinical Studies 
 
1.3.2.1. 
Pharmacology 
DS-820la inhlbits tumor growth mainly by topoisomerase I inhibition-derived DNA 
damage, and induces apoptosis by the payload that is released from DS-8201a after 
internalization in cancer cells via HER2. DS-8201a is expected to inhibit tumor growth 
 
 
cell growth inhlbition studies conducted using several cancer cell lines have shown that 
DS-820la has more potent growth inhlbition against HER2-positive cells than the 
monoclonal antibody alone, suggesting that the conjugation of the warhead enhances the 
growth-inhibitory action of DS-8201a. Moreover, no growth inhibition was observed in 
HER2-negative cells, thus confinning the HER2 specificity of DS-8201a. Similarly, when 
the in vivo antitumor activity of DS-8201a in a tumor-bearing mouse model of a HER2- 
positive gastric cancer cell line (NCI-N87) was studied, it was confirmed that DS-820 l a 
exhibited potent, dose-dependentantitumor activity with tumor regression, and that thls 
activity was even stronger than that of the antibody portion alone. In addition, in vivo 
studies in tumor-bearing mouse models have confirmed that DS-820l a has antitumor 
activity even against HER2 low-expressing tumors that are insensitive to other anti-HER2 
therapies. DS-8201a is therefore expected to be effective against HER2 low-expressing 
tumors, and is also expected to be effective against trastuzumab insensitive tumors.21 
Moreover, DS-8201a demonstrated potent efficacy in mice inoculated with a mixture of 


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•
HER2-positive and -negative cells while trastuzumab emtansine (T-DM l) did not, due to 
more potent bystander killing and higher cell membrane permeability of the conjugated 
toxin.21 22 The effect therefore supports the efficacy ofDS-820la against tumors with 
HER2 heterogeneity. 
 
1.3.2.2. 
Safety Pharmacology 
In a safety pharmacology study in monkeys treated with single intravenous doses of 
DS-820l a, no effects on the cardiovasc ular syste m, the respiratory system, or the central 
nervous system 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-l 18la, MAAA-l 18ladid not 
inhibit the hERG channel current at concentrations of up to 10 µmol/L (approximately 
5000 ng/mL). 
1.3.2.3. 
Pharmacokinetics and Drug Metabolism 
The plasma DS-820l a concentrations decreased exponentially following a single 
intravenous administration ofDS-820la  at 0.1 mg/kg to 3.0  mg/kg to cynomolgus 
monkeys. The volume of distributionat the steady state (Vss) was close to the plasma 
volume. CL decreased as the dose increased, and the pharmacokinetics (PK) were found 
to be non-linear. Both DS-820 l a and the total antibody, bound and unbound antibody 
combined, exhibited similar plasma concentration-t ime profiles at all dose levels, as well 
as similar AUC. All individual plasma concentrations ofMAAA-l18la, the released drug 
from DS-820la, were below the lower limit of quanti fication(0.100 ng/mL) at 0.1 and 
0.3 mg/kg. A low-plasma level of MAAA-l 18la was detected at limited time points with 
1.0 and 3.0 mg/kg. No anti-DS-820l a antibodies were detected in any of the animals. 
The mean plasma protein binding ratios of MAAA-1181a at l O ng/mL to 100 ng/mL were 
from 90.3% to 92.5% in mice, 94.2% to 96.7% in rats, 86.5% to 89.1% in monkeys, and 
96.8% to 98.0% in humans. 
The release rates ofMAAA-l l8la from DS-820la gradually increased throughout the 
incubation period in mouse, rat, and monkey plasma with release rates from 1.2% to 3.9% 
on Day 21. On the other hand, the release rate reached a plateau on Day 14 in human 
plasma with release  rates from 2.2% to 2.4%.  These results indicate that most DS-820l a 
is stable in plasma. 
No major differences were found between the metabolite profiles of DS-8201a in rat, 
monkey, and human hepatocytes. MAAA- l 18la was metabolized by cytochrome P450 
(CYP) enzymes; CYP3A4 was the primary CYP enzyme in the metabolism ofMAAA- 
118l a, while CYP3A5 and CYP2D6 were also involved in the metabolism. 
In monkeys, excretion of radioactivityfrom administered 14C-DS-820 l a into feces was 
predominant. In rats, excretion of radioactivity from administered 14C-labeled 
MAAA- l 18la (14C-MAAA-l 18la) into feces via bile was predominant. 
MAAA-118 la did not show any inhibition potential to CYP1A2, CYP2B6, CYP2C8, 
CYP2C9, CYP2Cl9, CYP2D6, and CYP3A (50% inhibitory concentration [ICso] 
>50 µmol/L ). MAAA-l 18la did not show any induction potential to CYP3A4, CYP1A2, 
and CYP2B6 up to 30 µmol/L. MAAA-1181a did not inhibit organic anion transporter 
(OAT) 3, organic cation transporter (OCT) 1, OCT2, organic anion transporting 
polypeptide (OATP) 1B3, multidrug and toxin extrusion (MATE) 1, MATE2-K, P- 


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glycoprotein (P-gp), breast cancer resistance protein (BCRP), and bile salt export pump 
(BSEP) (ICso >30 µmol/L). MAAA-l 18la inhibited OATl and OATPlBl with the ICso 
values of 12.7 and 14.4 µmol/L, respectively, however the values were much higher than 
the Cmax ofMAAA-l 18la in humans (9.25 ng/rnL [0.019 µmol/L] at 8.0 mg/kg ofDS- 
820la). In addition, MAAA-l 18la was found to be a substrate of OATPlBl and 1B3. 
1.3.2.4. 
Toxicology 
In a study of intermittent intravenous dosing of DS-820 la in rats (Q3W dosing for 
6 weeks), no deaths or moribund animals were found at dose levels up to 197 mg/kg, the 
maximum dose. The major observed findings included testicular and intestinal toxicity at 
dose levels of 20 mg/kg and greater, and lymphatic/hematopoietic, skin, incisor tooth, and 
renal toxicity at dose levels of 60 mg/kg and greater. Except for the testicular and incisor 
tooth changes, these changes all recovered. 
In an intermittent intravenous dosing study ofDS-820la in cynomolgus monkeys (Q3W, 
6 weeks), one female was sacrificed moribund at 78.8 mg/kg, the highest dose level. The 
major toxicity findings in this moribund animal were observed in the intestine, 
hematopoietic system, skin, and kidneys. The cause of the moribundity appeared to be 
deteriorated condition of the animal, which included decreased body weight and food 
consumption, as well as bone marrow toxicity and intestinal toxicity. The major findings 
of toxicity in the survivinganimals were observed in the intestine at dose levels of 
10 mg/kg and greater, and in the lung, testes, and skin at dose levels of 30 mg/kg and 
greater. In addition, hematopoietic system toxicity, renal toxic ity, and electrocardiogram 
(ECG) abnormalities (shortened PR interval and corrected QT interval [QTc] 
prolongation) were found at 78.8 mg/kg. Except for pulmonary and skin toxicity 
(pigmentation), these findings tended to recover. 
Thus, as described above, the severely toxic dose in 10% of the animals (STD10) in a rat 
intermittent intravenous dosing study ofDS-820la was found to be greater than 
197 mg/kg. In the monkey study, due to observed moribundity at 78.8 mg/kg and 
evidence of critical pulmonary toxicity (eg, interstitial inflammation and/or alveolar 
edema) in the surviving animals, it was concluded that the highest non-severely toxic dose 
(HNSTD) is 30 mg/kg. 
In an intermittent intravenous dose toxicity study of MAAA-1181a (monohydrate) (once 
weekly dosing for 4 weeks), findings in the lymphatic/hematopoieticsystem, intestinal 
tract, and the cornea of the eye were observed at 3 mg/kg and greater in rats but there were 
no deaths or moribundity up to 30 mg/kg. Findings similar to those in rats were observed 
in cynomolgus monkeys at dose levels of l mg/kg and greater. In addition, 1 female 
monkey died and 1 male monkey was sacrificed moribund at 12 mg/kg. Although effects 
on the heart (focal myocardial cell degeneration/necrosis) were found in the  moribund 
male along with the above-mentioned toxicities, there were no abnormal heart findings in 
the female that died, even though both animals exhibited worsening clinical conditions 
associated with sustained decreases in food consumption, bone marrow toxicity, and 
intestinal toxicity. These changes were considered to be the cause of death and 
moribundity. The common adverse findings in both DS-820la and MAAA-l 18la studies 
were intestinal and lymphatic/hematopoieticsystem toxicities. For DS-820la treatment, 
pulmonary, testicular, skin and renal toxicities were observed while heart, liver, and 
corneal toxicities were found only in the MAAA-118la study. 


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In a human cross-reactivity study ofDS-820la with a panel of human tissues, DS-820l a­ 
related cell membrane staining was found only in the placenta. In a cross-reactivity study 
of DS-820l a with selected cynomolgus monkey tissues (eg, brain, liver, kidney, lung, 
heart, intestines, lymphoid organs, testes, and skin), neither membranous nor cytoplasmic 
staining was noted in any tissues. 
In an in vitro 3T3 neutral red uptake (NRU) phototoxicity study, MAAA-l 18la was found 
to be phototoxic to Balb/c 3T3 mouse fibrobla sts . However, in an in vivo single dose 
phototoxicity study of MAAA-l 181a in pigmented rats, no phototoxic reaction was noted at 
3 mg/kg, the highest dose tested. 
 
1.3.3. 
Clinical Experience 
The DS-820la first-in-human(FIH) study (Protocol DS8201-A-Jl01) is an open-label, dose-
finding study to assess the safety and tolerability of DS-820la in subjects with advanced 
solid tumors. The study is being conducted in 2 parts; dose escalation (Part 1) and dose 
expansion (Part 2): Part l was a dose escalation phase in patients with either advanced 
breast cancer or gastric/gastro-esophageal junction (GEJ) adenocarcinoma.  Part 2 is the 
expansion phase and focuses on HER2 -positive breast cancer, HER2-positive 
gastric/GEJ junction adenocarcinoma, and HER2 low breast cancer, as well as other 
HER2-expressing solid cancers. 
Preliminary results from Part 1 indicate that DS-820 la has an acceptable safety and PK 
profile and antitumor activity in gastric cancer patient s, with tumors that were previously 
treated with trastuzumab. 
As of the 8 June 2017, 148 subjects received DS-820la in this study. 
In the Part 1, a total of 24 subjects, 3 in 0.8 mg/kg cohort, 3 in 1.6 mg/kg cohort, 3 in 3.2 
mg/kg cohort, 6 in 5.4 mg/kg cohort, 6 in 6.4 mg/kg cohort and 3 in 8.0 mg/kg cohort, 
received DS-820 l a. 17 Breast cancer patients, 6 gastric cancer patients and 1 
gastroesophageal junction cancer patient have been enrolled. No DLTs (defined as 
occurring during cycle 1) were reported in any subject. Two doses, 5.4 mg/kg and 6.4 
mg/kg were chosen for expansion in Part 2. 
In Part 2, a total of 124 subjects, 48 in Part 2a, 41 in Part 2b, 10 in Part 2c and 25 in Part 
2d, received DS-820la. Of those, 47 subjects, 30 subjects in Part 2a and 17 subjects in 
Part 2b, received 5.4 mg/kg, and the other 77 subjects received 6.4 mg/kg of DS-820 l a. In 
Part 2d, 11 colorectal cancer patients, 6 non-small cell lung cancer patients, 4 
parotid/submandibular gland cancer patients, 2 Paget' s disease patients, 1 
cholangiocarcinoma patient and 1 esophageal cancer patient have been enrolled. 
In Part 1 and 2, For 148 subjects who have received DS-820la in the study, the most 
common AEs{>20%) of any grades were nausea (65%), decreased appetite (53%), 
vomiting (34%), platelet count decreased (31%), anemia (28%), alopecia (26%), diarrhea 
(24%), constipation (24%), neutrophil count decreased (24%), white blood cell count 
decreased (24%), and malaise (22%). The majority of the AEs were of Grade 1 or 2 
severity; 52 of 148 subjects (35 .1%) experience d Grade 3 AEs and 10 subjects (6.8%) 
experienced Grade 4 AEs as the worst grade experienced. 
Adverse events of special interest (AESI) detailed in the Phase 1 protocol included 
infusion reactions, cardiac events, and interstitial lung disease. Periodic cardiac 


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assessments are performed including echocardiogram (ECHO) or multigated acquisition 
(MUGA) scan performed at every 2 cycles (42 days) and 12 lead triplicate ECGs 
performed at least every cycle (21 days). As of 8 June 2017, a total of 13 (8.7%) subjects 
exper ienced TEAEs relating to cardiotoxicity in the on-going study. Of these 13 subjects, 
9 experienced QT prolongation(7 Grade 1 and 2 Grade 2, all non-serious), all considered 
related to the study therapy. Two subjects experienced ejection fraction decreased (Grade 
2, non-serious, related), 1 subject experienced Grade 2 tachycardia and 1 subject 
experienced heart rate decreased (related). No action was taken regarding the study drug 
therapy and no subjects discontinued study therapy.  Pulmonary assessments are 
performed at the time of imaging for tumor assessments as well as evaluation of peripheral 
oxygen saturation (SpO2) on Day l of every cycle and at end of treatment (EOT). In the 
event of suspicion of drug induced lung disease, recommendat ions include consultation 
with a pulmonologist and interruption of DS-820 l a treatment pending final diagnosis. 
Study treatment is permanently discontinued upon confirmation of drug induced 
interstitial lung disease (ILD) or pneumonitis of any grade. As of 8 June 2017, there were 
3 subjects (where one received 8.0 mg/kg and the other 2 received 6.4 mg/kg) who had 
expe rienced one serious and 2 non-serious pneumonitis (one was Grade l and the other as 
Grade 2). There were also 2 subjects who experienced interstitial lung disease ( l serious 
and Grade 3 in severity, and the other non-se rious; with Grade 1 severity). 
Overall efficacy res ults from all cohorts in Part 1 demonstrated an objective response rate 
(ORR) of 34.8% and disease control rate (DCR) of 91.3%. Subjects in the higher dose 
levels (2::5. 4 m g/kg, 15 subjects) showed ORR of 53.3%. 
Overall efficacy results from all cohorts in Part 2 demonstrated an ORR of 48.8% and 
DCR of 85.7%. Breast cancer cohorts with HER2 positive and low expression,Part 2a and 
2c, showed ORR of 61.5% and 50.0%, and DCR of 96.2% and 90.0% respective ly. The 
HER2 positive gastric cancer cohort showed ORR of 48.4% and DCR of 80.6%. 
Please refer to the current 1Bof updated clinical study information for DS-8201a. 
 
1.3.4. 
Summary of Clinical Pharmacokinetics 
PK was evaluated in 24 Japanese subjects who received DS-820 l a. Following a single 
intravenous administration, PK parameters  at 5.4, 6.4, and 8.0 mg/kg are shown in 
Table l. l , Table 1.2, and Table 1.3. The maximum serum co ncentration (Cmax) of 
DS-820la at 6.4 mg/kg was achieved with median time to reach Cmax (Tmax) of 0.09 d 
(2.16 h). Cmax and AUClast at 6.4 mg/kg were 181 µg/mL and 90 l µg d/mL, 
respectively. The systemic exposure at 6.4 mg/kg in subjects in Cycle l exceeded the 
systemic efficacious expos ure observed during non-clinical pharmacology evaluation. 
Mean t112 of DS -820 l a was 7.33 d at 6.4 mg/kg. The Vss for DS-820la is 58.6 mL/kg, 
which is similar to the serum volume. 
PK parameter s of total antibody were close to that of DS-8201a. 
Cmax and AUClast were 6.80 ng/mL and 31.0 ng d/mL at 6.4 mg/kg, respectively,which 
were quite low. The t112 ofMAAA-l l8la was similar to that of DS-820 l a. 


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,
,
Table 1.1: 
Phar macokinetic Parameters of DS-8201a 
 
Dose 
(mg/kg) 
C max 
(Jtg/mL ) 
T max 
(h) 
AUClast 
(J•g•d/ mL) 
AUCinf 
(J•g•d/ mL) 
h 12 
(d) 
CL 
(mL/d/ kg) 
Vss 
( mL/ kg) 
5.4 (N = 6) 
127 (17.2) 
1.92 
(1.92, 2.16) 
544 (165) 
590 (186) 
6.03 
(0.603) 
10.1 (3.90) 
75.2 
(24.2) 
6.4 (N = 6) 
181 (33.1) 
2.16 
(1.44, 4.08) 
901 (155) 
1030 (209) 
7.33 (1.64) 
6.41 (1.12) 
58.6 
(11.0) 
8.0 (N = 3) 
216 (52.0) 
1.92 
(1.92, 2.16) 
914 (235) 
1020 (279) 
6.97 (0.36) 
8.17 (1.93) 
69.7 
(13.1) 
AUC = area under the serum concentration-time curve; AUClast = area under the serum concentration-time 
curve up to the last quantifiable time; AUCinf = area under the serum concentration-time curve up to 
infinity; CL= total body clearance; Cmax = maximum serum concentration; N = number; tl/2 = terminal 
elimination half-life; Tmax = time to Cmax; Vss = volume of distribution at the steady state. 
 
 
Table 1.2: 
Pharmacokinetic Parameters of Total Antibody 
 
Dose 
( mg/kg) 
Cmax 
(Jtg/mL ) 
T max 
(h) 
AUClast 
(11g•d / mL) 
AUCinf 
(11g•d/mL) 
t 112 
(d) 
5.4 (N = 6) 
116 (13.9) 
1.92 (1.92, 6.96) 
609 (151) 
682 (172) 
6.78 (2.39) 
6.4 (N = 6) 
146 (18.9) 
3.84 (2.16, 6.96) 
878 (97.1) 
1050 (149) 
8.25 (2.16) 
8.0 (N = 3) 
178 (18.5) 
2.16(1.92, 6.72) 
1090 (213) 
1270 (296) 
7.35 (0.417) 
AUC = area under the serum concentration-time curve; AUClast = area under the serum concentration-time 
curve up to the last quantifiable time; AUCinf = area under the serum concentration-time curve up to 
infinity; Cmax = maximumserum concentration; N = number; 1112 = terminal elimination half-life; 
Tmax = time to Cmax. 
 
 
Table 1.3: 
Pharmacokinetic Parameters of MAAA-1181a 
 
Dose 
(mg/kg) 
C max 
(ng/mL) 
Tmax 
(h) 
AUClast 
(ng•d/mL) 
AUCinf 
(ng•d/mL) 
tin 
(d) 
5.4 (N = 6) 
10.8 (7.56) 
5.28 
(3.84, 23.76) 
40.6 (19.8) 
43.6 (21.2) 
6.11 (0.811) 
6.4 (N=6) 
6.80 (1.72) 
6.72 (4.08, 7.20) 
31.0 (5.11) 
34.2 (5.63) 
6.28 (1.17) 
8.0 (N= 3) 
9.25 (3.18) 
6.72 (6.72, 6.96) 
39.4 (6.43) 
43.4 (9.16) 
6.36 (1.53) 
AUC = area under the serum concentration-time curve; AUClast = area under the serum concentration-time 
curve up to the last quantifiable time; AUCinf = area under the serum concentration-time curve up to 
infinity; Cmax = maximumserum concentration; N = number; 1112 = terminal elimination half-life; 
Tmax = time to Cmax. 
 
1.4. 
Study Rationale 
HER2 is a member of the HER superfamily that initiates signal transduction via the 
PI3K/AKT and RAS/MAPK pathways.23 24 In human advanced solid tumors, expression 
of HER2 protein has been reported in various tum or tissues and in a variety of cultured 
tumor cell lines including breast cancer,25 gastric cancer,26 27 pancreatic cancer,28 lung 
cancer,29 colorectal cancer,30 and ovarian cancer.31 


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DS-820la is expected to inhibit tumor growth based on the follow ing reasons 
the MAAA-l 18la that is released from DS-820 la after the 
DS-820l a is an ADC that targets HER2. A humanized IgGl monoclonal antibody with 
reference to the amino acid sequence of trastuzumab is used as the antibody component 
and a derivative of exatecan, a topoisomerase I inhibitor, is used as the drug component. 
 
 
 
internalization induces apoptos is by inhibiting topoisomerase I. 
In nonclinical studies, the fact that DS-8201a binds specifically to the extrace llular domain 
ofHER2 (HER2ECD) and does not bind to other HER family proteins has been  
confinned. In vitro studies indicate that DS-820l a exhibits HER2 expression-dependent 
cell growth inhibition activity. Moreover, no growth inhibition was confirmed in HER2 - 
negative cells, thus confirming the HER2 specificity of DS-820Ia . h1 vivo studies using a 
tumor-bearing mouse model suggest that administration ofDS-8201a results in the 
regression of not only HER2-overexpressing tumors but also HER2 low expressing 
tumors. DS-820 l a exhibit s an anti-tumor effect with tumor regression in tumors that 
express low levels of HER2 and is therefore also expected to be effective against tumors 
that express low levels of HER2, for which HER2 therapy including trastuzumab has not 
been approved.  One reason for this may be that the DAR for DS-8201a is approxin1aet ly 8, 
compared  to an average DAR of 3.5  for cunently approved ADC's for other indications. 
In the Phase 1 study, DS8201-A-Jl O1, the preliminary results as of 8 June 2017, indicate 
that DS-820 l a has tolerable safety and PK profiles, and antitumor activity. There have 
been no reported DLTs, and MTD was not reached in the 0.8 mg/kg to 8.0 mg/kg Q3W 
cohorts. HER2-positive gastric cancer subjects from Phase! Part 2b cohort, ORR was 
48.4% (N = 15/31) and DCR was 80.6% (N = 25/31). DoR was 4.7 months. 
Based on preclinical and clinical observations in the Phase 1 study (DS8201-A-Jl 01), DS- 
820la was well tolerated and antitumor activity in HER2-overexpressing gastric cancer 
subjects was observed. For the past few decades, the  main approach to treatment of 
patients who failed trastuzumab treatment as first line depended on the use of conventional 
cytotoxic chemotherapies and  non-HER2 specific antibody. Therefore  the Phase  2 study 
is conducted to detennine the efficacy and safety profile of DS-8201a for HER2- 
overexpressing gastric cancer as a Primary Cohort. In addition, the efficacy and safety of 
HER2 low-expressing patients (IHC 2+/ISH negative or IHC 1+) will be exploratively 
assessed in Exploraty Cohort 1 and 2, res pectively. 
1.5. 
Risks and Benefits for Study Subjects 
Based on the clinical observations in the Phase 1 study (DS8201-A-Jl O1), DS -82 01 a 
d e monstrated antitumor activity in HER2-overexpressing gastric cancer subjects (see 
Section 1.3.3). 
Overall, the reported AEs (see Section 1.3.3) were consistent with the safety profile of 
DS-820l a, expected based on the nonclinical toxicology data. The following TEAEs were 
considered as identified risk: nausea, decreased appetite, vomiting,  platelet count 
decreased, anaemia, alopecia, diarrhoea, neutrophil count decreased, and white blood cell 
count decreased. The majority of the TEAEs were of Grade 1 and Grade 2 severity. 
Subjects receiving DS-8201a should be monitored for signs and symptoms of any of the 


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toxicities observed in nonclinical studies and to other products of the same class, which 
are discussed below. 
In nonclinical toxicology studies, intestinal, hematopoietic, pulmonary (interstitial 
inflammation and/or alveolar edema), testicular, skin, and renal toxicities were found in 
association with the administration of DS-8201a. 
Ophthalmologic safety monitoring, 
which includes visual ac uity, slit lamp exam, and fundoscopy will also be part of the 
overall evaluation. These assessments will be performed at baseline and at specific 
intervals described in the protocol and at the EOT, when an additional exam will also be 
performed. Moreover, at the discretion of the investigator, op hthalmologic testing can be 
performed at any time during the study. 
In addition to these toxicities, as with other products of the same class, the possibility of 
cardiotoxicity, related to the potentia l for QT prolongation were found in association with 
the administration of DS-820l a and cannot be excluded. Left ventricular eject ion fraction 
(LVEF) will be measured by either ECHO or MUGA scan. All ECHOs/MUGAs, will be 
evaluated by the investigator or delegated physician to monitor cardiac function and 
troponin will be evaluated to assess cardiac function. 
Pulmonary toxicity was observed in association with the administration of DS-820l a in 
both pre-clinical and clinical studies. Interstitial lung disease/pneumonitis is considered an 
important identified risk based on a comprehens ive cumulative review of the available 
safety data from the DS8201-A-Jl 01 clinical study as well as the results of potential 
interstitial lung disease (ILD)/pneumonitis cases reviewed by the independent ILD 
Adjudication Committee (AC), available data from recent epidemio logy/literature, 
biological plausibility , and safety information from drugs of s imilar class . Refer to the 
current 1B for a summary of preliminary clinical study data. 
Additional sa fety assessments should be conducted as needed, at the investigator's 
discretion. It can also not be denied that hepatotoxicity, embryo-fetal toxicity, or visual 
disturbances/corneal toxicity may occur in subjects receiving DS-820l a. As with any 
therapeutic antibodie s, there is a possibility of infusion related reactions, and immune 
responses causing allergic or anaphylactic reactions ofDS-820la. 
Based on the efficacy and safety data observed in the nonclinical studies, the current 
clinical experience of the Phase 1 study, and the information from other products of the 
same class, the benefit-risk balance suppo rts clinical development of DS-820 l a in this 
patient population. For up to date assessments of risks and benefits to subjects, plea se refer 
to the current 1B for DS-820la. 


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2. 
STUDY OBJECTIVES AND HYPOTHESIS 
2.1. 
Study Objectives 
Primary Cohort 
• 
To compare the efficacy and safety of DS-820l a and physician's choice treatment in 
HER2-overexpressingadvanced gastric or gastroesophageal junction adenocarcinoma 
subjects who have progressed on 2 prior regimens including fluoropyrimidine agent, 
platinum agent and trastuzumab (brand, approved biosimilar). 
 
 
Exploratory Cohort 1 
• 
To determine the efficacy and safety of DS-820la in subjects with HER2 IHC 2+/ISH 
negative advanced gastric or gastroesophageal junction adenocarcinoma. 
 
 
Exploratory Cohort 2 
• 
To determine the efficacy and safety of DS-820l a in subjects with HER2 IHC 1+ 
advanced gastric or gastroesophageal junction adenocarcinoma. 
 
 
2.2. 
Study Hypotheses 
DS-820la confers a significant ORR benefit comparing physician's choice treatment in 
HER2-overexpressing advanced gastric cancer patients who have been treated and 
progressed with at least 2 prior regimens 
 
2.3. 
Study Endpoints 
2.3.1. 
Primary Endpoint 
• 
ORR assessed by the independentcentral imaging fac ilit y review based on 
Respo nse Evaluation Criter ia in So lid Tumours (RECIST) version 1.1 (for 
Primary Cohort) 
 
2.3.2. 
Secondary Endpoints 
• 
Efficacy endpoints (based on central review unless otherwise stated): 
- 
OS (not central review) 
- 
PFS 
- 
DoR 
- 
DCR 
- 
Time to treatment failure (TTF) 
- 
ORR assessed by the investigator based on RECIST version 1.1 
- 
ORR (for each Exploratory Cohort 1 and 2) 


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• 
Safety endpoints: 
- 
Serious adverse events (SAEs) 
- 
TEAEs 
- 
AESI 
- 
Discontinuation due to AE 
- 
Discontinuation due to AESI (AE of special interest) 
- 
Physica l examination findings (including Eastern Cooperative Onco logy 
Group Performance Status [ECOG PS]) 
- 
Vital sign measurements 
- 
Standard clinical laboratory parameters 
- 
Elevated troponin levels 
- 
ECG parameters 
- 
ECHO/MUGA findings 
- 
Ophthalmologic findings 
- 
Anti-drug antibodies (ADA) 
• 
Pharmacokinetic endpoints (DS-820 la, total anti-HER2 antibody and MAAA­ 
l 18 la): 
- 
PK parameters: Cmax, Tmax, and AUClast, AUC0-21d 
- 
Serum concentrations 
• 
HEOR endpoints (in Primary Cohort) 
- 
EuroQoL 5 Dimensions 5 Levels (EQ-5D-5L) 
- 
Functional Assessment of Cancer Therapy-Gastric (FACT-Ga) 
- 
Health care resource utilization 
 
2.3.3. 
Ex ploratory Endpoints 
• 
Exploratoryefficacy endpoints (based on central review unless otherwise 
stated): 
- 
Time to response 
- 
Best percent change in the sum of diameters of measurable tumors 
- 
PFS based on investigator assess ment 
• 
Serum extracellular domain ofHER2 (HER2ECD) 
• 
Biomarker analysis using cell free DNA (cfDNA) 


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• 
Analysis of pre-treatment and post-progression biopsies for mechanisms of 
resistance to DS-820la 


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3. 
STUDY DESIGN 
 
3.1. 
Overall Design 
3.1.1. 
Overview 
This is a Phase 2, multi-center, open-label, 3-cohort study to investigatethe efficacy and 
safety of DS-820la in subjects with HER2-overexpressing advanced gastric or 
gastroesophageal junction adenocarcinoma who have progressed on 2 prior regimens 
including fluoropyrimidine agent, platinum agent and trastuzumab (brand, approved 
biosimilar) when compared to treatment of physician' s choice. Additional exploratory 
cohorts in treatment naive subjects with HER2 expressing advanced gastric or 
gastroesophageal junction adenocarcinoma. The  study  design schema is  shown in 
Figure 3.1 
Primary Cohort 
Primary Cohort is a randomized cohort to compare the efficacy and safety of DS-820la 
and the physician's choice treatment in subjects with HER2-overexpressing (IHC 3+ or 
IHC 2+ / ISH +) advanced gastric or gastroesophagea l junction adenocarcinoma who have 
progressed on 2 prior regimens including fluoropyrimidine agent, platinum agent and 
trastuzumab (brand, approved biosimilar). Randomization will be done in a 2:1 ratio into 
the 2 groups (DS-820l a: physician's choice treatment). Randomization will be stratified 
by region (Japan or Korea), ECOG PS (0 or 1), and HER2 status (IHC 3+ or IHC 2+/ISH 
+). 
Exploratory Cohort 1 
Exploratory Cohort l is a non-randomized cohort to assess the efficacy and safety ofDS- 
820la to subjectswithHER2 IHC 2+/ISH negative advanced gastric or gastroesophageal 
junction adenocarcinoma who are in treatment nai"ve of anti-HER2 therapy. 
Exploratory Cohort 2 
Exploratory Cohort 2 is a non-randomized cohort to assess the efficacy and safety ofDS- 
820la to subjects with HER2 IHC 1+ advanced gastric or gastroesophageal junction 
adenocarcinoma who are in treatment na:ive of anti-HER2 therapy. 
The total number of subjects planned is approximately 220 (Primary Cohort: 
approximately 180, Exploratory Cohort 1: approximately 20, and Exploratory Cohort 2: 
approximate ly 20). 


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Figure 3.1: 
Study Design Schema of DS8201-A-J202 
 
l'rima1 ' Cohort 
• HER2-overexpressing 
(lHC 3+ or IHC 2+/ISH +) 
· Progress ion on a trastuzumab containing 
 
Centrally  Confirm   1--  - e'.,.·g.m.,.e_n_  --------------------------------------- f 
  
HER2 status 
 
(All cohort) 
 
 
DS-8201a group: 
N = appm ximate ly 120 
 
2: I 
 P
ysician 's  choice group: 
Progression on and 
after at least 2 prior 
Ex plo r Rto ry C ohort I 
• HER2 IHC 2+/ISH negative 
N - approximately 60 
regimens which 
had to include a 
fluoropyrirnidine 
and a platinum. 
• Treatment naive with anti-HER2 targeted therapy , ------- --.. 
DS-820l a : 
  
N -  approximately 20 
 
Exploratory Coho rt 2 
• HER2 JHC I+ 
,     Treatment naive  with anli-HER2  targeted  therapy   ,-- - 
- D"S"- ',.8...2,.,0..,.l--a  -: 
- 
-... 
N= a roximately 20 
 
 
 
 
3.1.2. 
Duration of the Study 
Enrollment is planned to occur over approximately l O months with treatment, and follow­ 
up is projected to be contin ued for at least l O months after last subject enro lled. Th us, the 
anticipated duration of the study is at least 20 months. The study will be contin ued until 
either the completion of follow-up assessments for all the subjects who discontinue study 
treatment or at the time of DS-820l a approval for this target indication. 
 
3.1.3. 
Duration of Subject Participation 
Subjects will receive study medication until a discontinuation criterion is met. 
After discontinuation from study treatment, all subjects, regardless of whether they 
discontinuedprio r to or subsequent to disease progression, may be contacted every 3 
months until death or until follow-up data collection is no longer needed (at the Daiichi 
Sankyo's discretion), to obtain info1mation about subseq uent treatment(s) and survival 
status. 
 
3.2. 
3.2.1. 
DS-820la 
Discussion of Study Design 
Selection of Dose and Usage 
DS-820la was administered at 0.8 mg/kg to 8.0 mg/kg Q3W in the prior Phase 1 study 
(DS8201-A-Jl 01), and DLT did not occurred and the MTD was not reached up to 
8.0 mg/kg. Although 8.0 mg/kg was shown to be tolerable, dose reductions were observed 
two out of three patients, and subsequent exposure-response analysissupported 5.4 mg/kg 
and 6.4 mg/kg are appropriate assessment dose in expansion cohort of Phase! study.  On 
the basis of efficacy, tolerability and PK profile established in the Phase 1 study and pre­ 
clinical studies, the dose of 6.4 mg/kg will be used in this trial. 
Irinotecan monotherapy 
Starting dosage and usage is 150 mg/m2 biweekly. 
Paclitaxel monotherapy 


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Starting dosage and usage is 80 mg/m2 weekly. 
3.2.2. 
Treatment Cycle Period 
Each treatment cycle of DS-820la will be 21 days.  Dosing for the every 3 weeks 
treatment will occur on Day1 of each cycle. Cycle allowance is ± 3 days. Treatment after 
25 days (Day 26) from previous treatment is regarded as treatment delay. 


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4. 
STUDY POPULATION 
Subjects, who must satisfy all of the following inclusion criteria, not meet any of the 
following exclusion criteria, and have given their written informed consent freely, are 
included in the study. 
 
4.1. 
Inclusion Criteria 
Subjects must satisfy all of the following criteria to be included in the study: 
Common Inclusion Criteria (Primary Cohort, Exploratory Cohorts 1 and 2) 
1. Age 20 years. 
2. Has a pathologically documented locally advanced or metastatic adenocarcinoma 
of gastric or gastroesophageal junction. 
3. Progression on and after at least 2 prior regimens which had to include a 
fluorop yrimidine and a platinum. 
• 
Progression within 6 months of prior adjuvant or neoadjuvant chemotherapy 
will count as "rapid progressor" in neo-adjuvant/adjuvant setting, and thus 
equivalent to advanced/metastatic disease failing 1 regimen of therapy. 
• 
If prior combination therapy discontinueddue to an AE, and the n one of the 
agents continued, this is considered to be " 1 prior regimen" and not "2 prior 
regimens" 
• 
The change in dosage form of 5-Fluorouracil medication (intravenous 
admin istration, oral administration) without progression is considered to be "1 
prior regimen" and not "2 prior regimens" 
• 
If patient has received prior therapy with one of the dmg in physician' s choice 
(i.e. irinotecanor paclitxel) and has progressed on it than patient can be eligible 
if treating physician considers it appropriate to treat the patient with the other 
dmg option from the physician's choice options. For example, if patient has 
received prior paclitaxel as a monotherapy or in combination with other drugs 
(e.g. ramuciruma b) and has progressed on it then the patient will be eligible to 
receive irinotecan as long as they have not received and progressed on prior 
irinotecan therapy in this setting. Any patient who has received prior paclitaxel 
and irinotecan either as monotherapy or as combination therapy and have 
progressed on each one of these therapies (i.e. paclitaxel and irinotecan), would 
be ineligible for study participation. (Primary cohort only) 
4. Is willing and able to provide an adequate archived tumor sample available for 
tissue screening to confirm HER2 status by Central Laboratory (based on most 
recent archived tumor tissue samp le). If arc hived sample is not available, fresh 
sample is required. 
5. Agree to submit fresh tumor samples for an assessment of HER2 status before the 
registration if primary tumor is accessible by endoscopy 
6. Has measurable disease assessed by the investigator based on RECIST version 1.1. 
7. Has an ECOG PS of0 to 1. 


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8. Has LVEF 50% by either ECHO or MUGA scan within 28 days before 
registration. 
9. Has adequate organ function within 14 days before registration, defined as: 
 
Item 
Laboratory value 
Platelet count 
2 I00000/mm3 (Platelet transfusion is not 
allowed within I week prior to screening 
assessment) 
Hemoglobin 
28.0 g/dL(Red blood cell transfusion is 
not allowed within I week prior to 
screening assessment) 
Absolute neutrophil count 
21500/mm3 (G-CSF administration is not 
allowed within I week prior to screening 
assessment) 
Creatinine 
Creatinine clearance 230 mL/min as 
calculated using the Cockcroft-Gault 
equation 
ALT/AST 
:S3 x ULN (ifl iver metastases are 
present, :S5 x ULN) 
Total bilirubin 
:Sl. 5 x ULN or < 3 x ULN in the 
presence of documented Gilbe11' s 
Syndrome or liver metastases at baseline 
Albumin 
.5 g/dL 
International normalized ratio 
(INR)/Prothrombin time (PT) 
and activated partial 
thromboplastin time (aPTT) 
::; 1.5 x ULN 
 
 
l 0. Has adequate treatment washout period before study drug treatment, defined as: 
 
Treatment 
Washout period 
Major surgery 
24 weeks 
Radiation therapy 
24 weeks (if palliative stereotactic 
radiation therapy without abdominal 
radiation, 22 weeks) 
Chemotherapy (including 
antibody drug therapy and 
retinoid therapy) 
23 weeks (22 weeks for 5-fluorouracil- 
based agents, folinate agents and/or 
weekly Paclitaxel. 26 weeks for 
nitrosoureas or mitomycin C) 
Immunotherapy 
4 weeks 
CYP3A4 strong inhibitor 
and organic anion 
transporting polypeptide 
(OATP) inhibitor 1B 
23 x the elimination half-life of the 
inhibitor 
Other study drugs 
23 weeks 


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11. Male and Female subjects of reproductive/childbearing potential must agree to use 
a highly effective form of contraception, avoid intercour se, or reliable 
contraceptive measures (double barrier methods, which include a combination of 
any 2 of the following: diaphragm, condom, sponge, spermicide, bilateral tubal 
ligation, or vasectomy) 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. For 
the purpose of this protocol, methods considered as highly effective methods of 
contraception including: 
• 
Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation: 
-Oral 
- Intravaginal 
- Transdermal 
• 
Progestogen-only hormonal contraception associated with inhibition of 
ovulation: 
-Oral 
- Injectable 
- Implantable 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasingsystem (IUS) 
• 
Bilateral tubal occlusion 
• 
Vasectomy or Vasectornized partner 
• 
Complete sexual abstinence defined as refraining from heterosexual interco urse 
during and upon completion of the stud y 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 
Non-child-bearing potential defined as pre-menopausal females with a 
documented tubal ligation or hysterectomy;or postmenopausal defined as 12 
months of spontaneousamenorrhea (in questionable cases, a blood sample with 
simultaneous follicle-stimulating hormone [FSH] >40 mIU/mL and estradiol 
<40 pg/mL [<147 pmol/L] is confirmatory). Females on hormone replace ment 
therapy (HRT) and whose menopausal status is in doubt will be required to use 
one of the contraceptio n methods outlined for women of child-bearing potential 
if they wish to continue their HRT during the study. Otherwise, they must 
disco ntinue HRT to allow confirmation of post-menopausal status prior to study 
enrollment. For most forms of HRT, at  least 2 to 4 weeks will elapse between 
the cessatio n of therapy and the blood draw; this interval depends on the type 
and dosage ofHRT. Following confirmation  of their post-menopausal status, 
they can resume use of HRT during the study without use of a contracept ive 
method. 


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Men who are fertile and sexually active should be willing to use highly effective 
methods of contraception if their partners are ofr eproductive potential. 
Male subj ects must not freeze or donate sperm starting at Screening and 
througho ut the study period, and at least 4 months after the final study drug 
administration. Preservation of sperm should be considered prior to enrolment in 
this study. 
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. 
12. Is able to provide written informed consent. Subjects must be fully informed about 
their illness and the investigational nature of the study protocol (including 
foreseea ble risks and possible toxicities) and must sign and date an Institutional 
Review Board (IRB)-approved informed consent form (ICF) before performance 
of any study-specific procedures or examinations. 
 
Additional Inclusion Criteria for Primary Cohort 
13. Centrally confirmed HER2 overexpression (IHC 3+ or IHC 2+/ISH*+) . 
* IS H: FISH or dual in situ hybridization (DISH) 
14. Progression on a trastuzumab containing regimen (can include an approved 
trastuzumab biosimilar). Progression on trastuzuma b not required to be the most 
recent regimen. 
 
Additional Inclusion Criteria for Exploratory Cohort 1 
15. Centrally confirmed HER2 IHC 2+/ISH*negative. 
* ISH: FISH or DISH 
16. Treatment nai've with anti-HER2 targeted therapy including approved trastuzumab 
biosirnilar. 
 
Additional Inclusion Criteria for Exploratory Cohort 2 
17. Centrally confirmed HER2 IHC 1+**. 
* *: ISH does not matter. 
18. Treatment nai've with anti-HER2 targeted therapy includin g approved trastuzumab 
biosimilar. 
 
 
4.2. 
Exclusion Criteria 
Subjects who meet any of the following criteria will be disqualified from entering the 
study: 


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l.  Medical history of myocardial infarction within 6 months before registration, 
symptomaticcongestive heart failure (CHF) (New York Heart Association Class II 
to IV, Section 17.4), troponin levels consistent with myocardial infarction as 
defined by manufacture , unstable angina, or se rious cardiac arrhythmia requiring 
treatment within 28 days before randomization/registration. 
2. Has a corrected QT interval by Fridericia's formula (QTcF) prolongation to 
>470 msec (females) or >450 msec (males) based on average of the screening 
triplicatel 2-lead ECG. 
3. Has a history of (non-infectious) ILD/pneumonitis that required steroids, has 
current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out 
by imaging at screening. 
4. Has a pleural effusion, ascites or pericardia! effusion that requires drainage, 
peritoneal shunt, or Cell-free and Concentrated Ascites Reinfusion Therapy 
(CART). (Drainage and CART are not allowed within 2 weeks prior to screening 
assessment) 
5. Has uncontrolled infection requiring IV injection of antibiotics, antivirals, or 
antifungals. 
6. Have been diagno sed with human immunodeficiency virus (HIV) infection 
7. Known active hepatitis B or C infection. 
8. Has clinically active brain metastases, defined as untreated and symptomatic, or 
requiring therapy with steroids or anticonvulsants to control associated symptoms. 
Subjects with treated brain metastases that are no longer symptomatic and who do 
not require treatment with steroids for at least three weeks may be included in the 
study if they have recovered from the acute toxic effect ofr adiotherapy. 
9. Has clinically significantcorneal disease in the opinion of the investigator. 
10. Prior treatment with an ADC which consists of a n exatecan derivative that is a 
topoisomerase I inhibitor. 
11. Has unreso lved toxicitie s from previous ant icancer therapy, defined as toxicities 
(other than chronic toxicities per the discretion of the investigator, eg, alopecia, 
peripheral neuropathy, proteinuria, controllable hypertension, and controllable 
diabetes) not yet resolved to National Cancer Institute's Common Tenninology 
Criteria for Adverse Events (NCI-CTCAE) version 4.03, Grade :Sl or baseline. 
12. Has a diarrhea (watery stool), ileus, jaundice , or intestina l para lysis. 
13. Has a concomitant medical condition that would increa se the risk of toxicity in the 
opinion of the investigato r. 
14. Has known hypersensitivity to either the drug substances or inactive ingredients in 
the drug product. 
15. Has history of severe hypersensitivity reactions to other monoclonal antibodies. 
16. Has had non-gastric or gastroesophageal junction primary malignancieswithin 3 
years, except adequate ly resected non-melanoma skin cancer, curatively treated in­ 
situ disease, other curatively treated solid tumors. 


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17. Is a lactating mother (women who are willing to temporarily interrupt 
breastfeeding will also be excluded), or pregnant as confirmed by pregnancy tests 
performed within 14 days before registration. 


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5. 
STUDY TREATMENT(S) 
5.1. 
Assigning Subjects to Treatments and Blinding 
5.1.1. 
Method of Cohort Allocation 
Subjects are allocated to each cohort acco rding to the centrally confirmed HER2 status. 
Primary Cohort 
HER2-overexpressing (IHC 3+ or IHC 2+/ISH +) 
Exploratory Cohort 1 
HER2 IHC 2+/ISH negative 
Exploratory Cohort 2 
HER2 IHC 1+• 
* : IS H d oes not matter. 
 
5.1.2. 
Treatment Group(s) 
Primary Cohort 
Subjects will be randomized to either the DS-820 la group or the physician's choice group. 
For subjects randomized to DS-820 la the starting dose will be 6.4 mg/kg. 
The physician's choice treatment is a limited choice of one of two standard regimens 
(irinotecan monotherapy or paclitaxel monotherapy). The investigator will pre-select the 
physician' s choice treatment before the randomization of each subject. Physician' s choice 
treatment will be administered in accordance with Section 5.3. 
Exploratory Cohort 1 and 2 
All subjects in Exploratory Cohort 1 and 2 will be assigned to the DS-820l a treatment of 
the 6.4 mg/kg. 
 
5.1.3. 
Blin ding 
This study is an open-label study and no blinding will be performed. It is not feasible to 
blind treatment allocations for individual subjects because of different treatment schedules 
and different AE profiles between DS-820l a and physician's choice treatment. To reduce 
any potential bias, the primary endpoint of ORR is assessed with blinded condition by the 
independent central imaging facility review based on RECIST version 1.1. The treatment 
arm will not be provided to the reviewer. Additionally, Daiichi Sankyo will not have 
access to aggregate efficacy data except when data from both the DS-820 la and the 
physician' s choice groups are combined in the Primary Cohort. No interim analysis will 
be performed except the inte rim analysis specified in Section 11.5. 
 
5.1.4. 
Emergency Unblinding Procedure 
Not applicable. 


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5.2. 
Study Drug (DS-8201a) 
5.2.1. 
Description 
DS-8201a for Injection100 mg,. 
DP: 
The DS -820 1a drug product 
 
Each vial is designed for single use only and is not to be used 
to treat more than one subjec t. 
5.2.2. 
Labeling and Packaging 
DS-820I a drug product will be supplied by Daiichi Sankyo. This will be clinical labeled 
in compliance with the regulatory requirements and packaged. The packaging will clearly 
display the name of the investigational product, the investiga tional product manufacturing 
code, the drug number, storage conditions, and other required information in accordance 
with local regulations. 
5.2.3. 
Preparation 
The drug so lution for IV infusion is prepared by dilution of the required volume of the 
drug product calculated based on the subject' s body weight. Pi-epared medicinal solutions 
should be used immediately. The preparation will be conducted in accordance with the 
pharmacy instructions provided by Daiichi Sankyo. Procedures for proper handling and 
disposal of anticancer drugs should be followed in compliance with the standard operating 
procedures (SOPs) of the study si te. Refer to the pharmacy instruction for detailed 
info rmation about preparation and administration of DS-820 1a. 
 
5.2.4. 
Administration 
The study drug will be administered every 3 weeks at 6.4 mg/kg. The initial dose of DS- 
8201a will be infused  in trave nously  into each subject for approximately 90  minutes  on 
Day I of Cycle I . If there is no infusion-related reaction after the initial dose , the secon d 
and thereafter dose ofDS-8201a will be infused intraveno us ly into each subject for 
approximately 30 minutes. The subject' s weight at screening (baseline) will be used to 
calculate the initial dose. If the subject' s weight changes by ±10% of the  baseline  weight, 
the dose will be recalculated. 
5.2.5. 
Storage 
Drug supplies must be stored in a secure, limited access storage area under the storage 
conditions listed below: 
• 
Stored 
 
If storage con d itio ns are not maintained per spec ified requirements, Daiichi Sankyo or 
contract research organization (CRO) should be contacted. 
5.2.6. 
Drug Accountability 
When a study drug shipment is received, the investigato r or designee will check the 
amount and condition of the drug, check the appropriateness of the label, drug expiration 


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date and sign the Receipt of Shipment Form provided by Daiichi Sankyo. The Receipt of 
Shipment Form should be signed and the original Form will be retained at the site. In 
addition, the investigator or designee shall contact Daiichi Sankyo as soon as possible if 
there is a problem with the shipment. 
A Drug Accounta bility Record will be provided for the study drug. The record must be 
kept current and should contain the dates and quantities of study drng received, subject's 
information (the site subject ident ifier and the subject ID) for whom the study drug was 
dispensed, the drug number, the date and quantity of study drug dispensed and remaining, 
as well as the initials or seal of the dispenser. 
At the endof the study, or as directed, all unused DS-820la will be returned to a designee 
as instructed by Daiichi Sankyo. The study drug will be returned only after the study 
monitor has completed a final inventoryto verify the quantity that should be returned. 
Return of the study drug must be documented and the docume ntation 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 designeeand provided by Daiichi Sankyo. Other 
procedures related to study drug management and collection will be performed in 
accordance with the pharmacy instructions provided by Daiichi Sankyo. 
All investigational product invento ry forms must be made available for inspection by a 
sponsor-authorized represe ntativeor designee and regulatory agency inspectors. The 
supervisor of investigational products is responsible for the accountability of all used and 
unused study supplies at the site. 
5.2.7. 
Dose Interruptions and Reductions 
The investigator will evaluate which toxicities are attributa ble to DS-8201a and adjust the 
dose of DS-820l a as recommended below. All dose modifications should be based on the 
worst preceding toxicity (NCI-CTCAE version 4.03). Specific criteria for interruption, 
reinitiation, dose reduction, and/or discontinuation of DS-820la are listed in Table 5.2. 
All interruptions or modifications must be recorded on the case report form (CRF). 
Appropriate clinical experts should be consulted as deemed necessary. 
For Grade 3 or Grade 4 events, monitoring (including local laboratory tests when 
appropriate) should be performed at intervals no greater than 7 days until AE is 
determined to be resolving or subject is discontinued at EOT. 
Prophylactic or supportive treatment for expected toxicities, including management of 
study-drug induced AEs will be as per the treating physician's discretion and institutional 
guidelines. 
Dose Reduction Guidelines: 
NOTE: There will be no dose modifications for Grade 1 or Grade 2 AEs unless specified 
in Ta ble 5.2. 
Two dose reductions will be permitted. The adjustment for a reduced dosing of DS-820 la 
is as shown in Table 5.1. 


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Table 5.1: 
Dose Reduction Levels of DS-8201a 
 
Starting Dose 
Dose Level - 1 
Dose Level - 2 
6.4 mg/kg 
5.4 mg/kg 
4.4 mg/kg 
Once the dose of DS-820 la has been reduced because of toxicity, all subsequent cycles 
should be administered at that lower dose level unless further dose reduction is required. 
More than 2 dose reductions are not allowed and the subject will be withdrawn from 
the study treatment if further toxicity meeting the requirement for dose reduction 
occurs. However, further dose reduction may be conducted based on consultation 
between the Investigator and Daiichi Sankyo. DS-820l a dose increases are not allowed in 
the study. 
 
 
Dose Interru ption and Modification Guidelines: 
A dose can be delayed for up to 28 days (Day 50) from the planned date of administration. 
If a subject is assessed as requiring a dose delay of longer than 28 days, the subject will be 
withdrawn from the study. 
Treatment cycles for a subjec t for whom DS-820l a dosing is temporarily withheld for any 
reason may have future cycles scheduled based on the date of the last DS-820l a dose. 
All confirmed or suspected severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 
2) infection events must be recorded in the eCRF. Please refer to Appendix 17.6 for 
additional information on dose modification. 
 
Table 5.2: Dose or Schedule Modification for DS-8201a 
 
Worst toxicity NCI-CTCAE 
v4.03 Grade (unless 
otherwise specified) 
Dose or schedule modification for DS-8201a 
No toxicity 
Maintain dose and schedule 
Infusion Related Reaction 
Grade I (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 
sho uld 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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Table 5.2: 
Dose or schedule modificationfor DS-8201a (Continued) 
 
Worst toxicity CTCAE 
v4.03 Grade (unless 
otherwise specified) 
Dose or schedule modification for DS-8201a 
Grade 2 (Therapy or infusion 
interruptionindicated but 
responds promptly to 
symptomatic treatment (e.g., 
antihistamines, nonsteroidal 
anti-inflammatory drugs 
(NSAIDs), narcotics, IV 
fluids); prophylactic 
medications indicated for :::;24 
hr s) 
• Administrationof DS-8201a should be interrupted and symptomatic 
treatment started (e.g. antihistamines, NSAIDs, narcotics, IV fluids). 
• If the event resolves or improves to grade I, infusion can be 
re-started at a 50% reduced infusionrate. 
• Subsequent administrations should be conducted at the reduced rate. 
Gr ade 3 or 4 (P ro longed or 
life-threatening 
consequences, urgent 
intervention indicated) 
• 
A dministration of DS-8201a should be discontinued immediately 
and permanently. 
• Urgent intervention indicated. Antihistamines, steroids, 
epinephrine, bronchodilators, vasopressors, intravenous fluid 
therapy, oxygen inhalation etc., should be administered. 
Hematologic Toxicity 
Neutrophil Count Decreased and/or White Blood Cell Count Decreased 
Grade 3 
Delay dose until resolved to :::;Grade 2, then mai n tain dose 
Grade 4 
• 
Delay dose until resolved to :::;Grade 2 
• Red uce dose I level 
Febrile Neutropenia 
(absolute neutrophil count 
<I x I09/L, fever >38.3°C or 
a sustained temperature of 
2:'.38°C for more than one 
hour) 
• Delay dose until resolved 
• Reduce dose I level 
Lymphocyte Count Decreased 1 
Grade I to Grade 3 
Iymphopenia 
No dose modification 
Grade 4 (<0.2 x J09JL) 
Delay dose until resolved to :::;G ra de 2: 
If resolved in :::;14 days from day of onset, maintain dose 
If resolved in >14 days from day of onset, reduce dose I level 


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Table 5.2: 
Dose or schedule modificationfor DS-8201a (Continued) 
 
Worst toxicity CTCAE 
v4.03 Grade (unless 
otherwise specified) 
Dose or schedule modification for DS-8201a 
Anaemia 
Grade 3 (Hemoglobin (Hb) 
<8.0 g/dL); transfusion 
indicated 
Delay dose until resolved to ::;Grade 2, then main tain dose 
Grade 4 Life threatening 
consequences; urgent 
intervention indicated 
Delay dose until resolved to ::;Grade 2, then reduce dose 1 level 
Platelet Count Decreased 
Grade 3 
(plate lets <50 - 25 x 109/L) 
Delay dose until resolved to ::;Grade 1: 
• If resolved in9 days from day of onset, maintain dose 
• If resolved in >7 days from day of onset, reduce dose 1 leve l 
Grade 4 
(platelets <25 x 109/L) 
Delay dose until resolved to ::;Grade 1, then reduce dose 1 level 
Cardiac Toxicity 
Symptomatic CHF 
Discontinue subject from study treatment 
Decrease in LVEF I0% to 
20% (absolute value), but 
LVEF >45% 
Contin ue treatme nt wit h DS-82 0 l a 
LVEF 40% to ::;45% and 
decrease is <10% (absolute 
value) from baseline 
Contin ue treatment with DS-8201a 
Repeat LVEF assessment within 3 weeks 
LVEF 40% to 45% and 
decrease is 10-20% (absolute 
value) from baseline 
Interrupt DS-820l a dosing 
Repeat LVEF assessment within 3 weeks 
If LVEF has not recovere d to within 10% (absol ute value) from baseline, 
discontinuesubject from study treatment 
If LVEF recovers to within 10% from baseline, resume study drug 
treatment 
LVEF <40% or >20% 
(absolute value) drop from 
baseline 
Interrupt DS-8201a dosing 
Repeat LVEF assessment within 3 weeks 
If LVEF <40% or >20% drop from baseline is confirmed, discontinue 
subject from study treatment 
Electrocardiogram QT prolonged 
Grade 3 
(QTc>500 ms on 2 separate 
ECGs) 
Delay dose until resolved to ::;Grade 1 (corrected QT ::; 480 ms) , 
determine if another medication the subject was taking may be 
responsible and can be adjusted or if there are any changes in serum 
electrolytes that can be corrected, then if attributed to DS-8201a, reduce 
dose I level 


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Table 5.2: 
Dose or schedule modificationfor DS-8201a (Continued) 
 
Worst toxicity CTCAE 
v4.03 Grade (unless 
otherwise specified) 
Dose or schedule modification for DS-8201a 
Grade 4 
(QTc >500 or >60 ms change 
from baseline and Torsade de 
pointes or polymorphic 
ventricular tachycardia or 
signs/symptoms of serious 
arrhythmia) 
Discontinue subject from study treatment 
Troponin 
Grade 1 
(Levels above the upper limit 
of normal and below the level 
of myocardial infarction as 
defined by the manufacturer) 
If troponin levels are above the upper limit of normal and below the 
level of myocardial infarction as defined by the man ufacture r (CTCAE 
Grade 1) at baseline, no repeat testing is required if the troponin level is 
not Grade 3. 
For new diagnosed Grade 1, repeat troponin testing at 3 ± 1 hours after 
initial troponin test. 
• 
If repeat troponin level at 3 ± 1 hours rises significantly per 
institutional guidelines, 
- 
perform ECG in triplicate; 
- 
repeat troponin testing at 6 ± 1 hours after initial troponin test; 
- 
follow institutional guidelines for management of detectable 
troponin testing. 
• 
Ifr epeat troponin level at 3 ± 1 hours does not rise 
significantly per institutional guidelines, 
- 
 repeat troponin testing at 6 ± 1 hours or at 24 ± 2 hours after 
initial troponin test. 
Continue treatment with DS-8201a. 
Grade 3 
(Levels consistent with 
myocardial infarction as 
defined by the manufacturer) 
Perform ECG in triplicate 
Repeat troponin testing at 6 hours (±1 hr) and 12 hours (±1 hr) after 
initial troponin test. 
Follow institutional guidelines for management of detectable troponin 
testing.If AMI confirmed, discontinue subject from study therapy. 
Otherwise: 
Delay dose until resolved to S Grade 1: 
• 
If resolved in :S 7 days from day of onset, maintain dose 
• 
If resolved in > 7 days from day of onset, reduce dose 1 
level 


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Table 5.2: 
Dose or schedule modificationfor DS-8201a (Continued) 
 
Worst toxicity CTCAE 
v4.03 Grade (unless 
otherwise specified) 
Dose or schedule modification for DS-8201a 
Pulmonary Toxicity 
If a subject develops radiographic changes potentially consistent with 
ILD/pneumonitis or develops an acute onset of new or worsening 
pulmonary or other related signs/symptoms such as dysp nea, co ugh or 
fever, rule out ILD/pneumonitis. 
If the AE is confirmed to have an etiology other than ILD/pneumonitis, 
follow the management guidance outlined in the "Other Non-Laboratory 
Adverse Events" dose modification section below. 
If the AE is suspected to be ILD/pneumonitis, treatment with study drug 
sho uld be inte rrupted pending further evaluations. 
Evaluations should include: 
· high resolution CT 
· pulmonologist consultation(Infectious Disease consultation as 
clinically indicated) 
· blood culture and CBC. Other blood tests could be considered as 
needed 
· consider bronchoscopy and bronchoalveolar lavage if clinica lly 
indicated and feasible 
· pulmonary function tests and pulse oximetry (Sp0 2) 
· arte rial blood gases if clinically indicated 
· one blood sample collection for PK analysis as soon as 
ILD/pneumonitis is suspected, iff easible. 
Other tests could be considered, as needed. 
If the AE is confirmed to be ILD/pneumonitis, follow the ILD 
management guidance as outlined below. 
All events ofI LD/pneumonitis regardless of severity or seriousness will 
be followed until resolution including after drugdiscontinuation. 


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Table 5.2: 
Dose or schedule modification for DS-8201a (Continued) 
 
Worst toxicity NCI-CTCAE 
v4.03Grade (unless 
otherw ise specified) 
Dose or schedule modification for DS-8201a 
Grade I 
The administration of DS-820 Ia must be interrupted for any 
ILD/pneumonitis events regardless of grade. 
· Monitor and closely follow-up in 2 to 7 days for onset of clinical 
symptoms and pulse oximetry 
· Consider follow-up imaging in 1-2 weeks (or as clinically indicated). 
· Consider starting systemic steroids (e.g. at least 0.5 mg/kg/day 
prednisone or equivalent) until improvement,followed by gradual 
taper over at least 4 weeks. 
· If worsening of diagnostic observations despite initiation of 
corticosteroids, then follow Grade 2 guidelines.* 
For Grade I events, DS-820 la can be restarted only if the event is fully 
resolved to Grade 0: 
• 
If resolved in 98 days from day of onset, maintain dose 
• 
If resolved in >28 days from day of onset, reduce dose I 
leve l 
However, if the event grade I ILD/pneumonitis occurs beyond cycle day 
22 and has not resolved within 49 days from the last infusion, the drug 
should be discontinued. 
* If subject is asymptomatic, then subject should still be considered as 
Grade l 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 
I mg/kg/day prednisone or equivalent) for at least 14 days or until 
complete resolution of clinical and chest CT findings, then followed 
by a gradual taper over at least 4 weeks. 
· Monitor symptoms closely. 
· Re-image as clinically indicated. 
· If worsening or no improvement in clinical or diagnostic 
observations in 5 days, 
· Consider increasing dose of steroids (e.g., 2 mg/kg/day 
prednisone or equivalent) and administration may be 
switc hed to IV (e.g. methylpredniso lone). 
· Re-consider additional work- up for alternative etiologies as 
described above. 
· Escalate care as clinically indicated. 


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Table 5.2: 
Dose or schedule modification for DS-8201a (Continued) 
 
Worst toxicity NCI-CTCAE 
v4.03 Grade (unless 
otherwise specified) 
Dose or schedule modification for DS-8 201a 
Grade 3 and 4 
Permanently discontinue subject from study treatment. 
· Hospitalization required. 
· Promptly initiate empiric high-dose methylprednisolone IV 
treatment (e.g., 500-1000 mg/day for 3 days), followed by at least 
1.0 mg/kg/day of prednisone (or equivalent) for at least 14 days or 
until complete resolution of clinical and chest CT findings, then 
followed by a gradual taper over at least 4 weeks. 
· Re-image as clinically indicated. 
· If still no improvement within 3 to 5 days, 
Re-consider additional work-up for alternati ve etiologies as 
described above. 
Consider other immuno-suppressantsand/or treat per local 
practice. 
Ocular 
Grade 3 
Delay dose until resolved to :S::Grade 
1 : 
If  resolved in9 
days from day of onset, maintain dose 
If resolved in >7 days from day of onset, reduce dose 1 level 
Grade 4 
Discontinue subject from study treatment 
Blood creatinine increased 
Grade 3 (>3.0 to 6.0 x upper 
limit of normal [ULN]) 
Delay dose until resolved to :S::Grade 
2 or base l ine , then reduce dose 1 
level 
Grade 4 (>6.0 x ULN) 
Discontinue subject from study treatment 
Hepatic Toxicity 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) with simultaneous Total 
bilirubin (TBL) 
AST/ALT 2:3.0 x ULN with 
simultaneous TBL >2.0 x 
ULN 
Delay study medication until drug-induced liver injury can be ruled out. 
If drug-induced liver injury is ruled out, the subject should be treated 
accordingly, and resumption of stu dy drug may occur after discussion 
between the Investigator and Sponsor. 
If drug-induced liver injury cannot be ruled out from diagnostic workup, 
permanently discontinue study treatment. 
Monitor AST/ALT and TBL twice weekly until resolution or return to 
baseline. 


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Table 5.2: 
Dose or schedule modificationfor DS-8201a (Continued) 
 
Worst toxicity NCI-CTCAE 
v4.03 Grade (unless 
otherwise specified) 
Dose or schedule modification for DS-8201a 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
Grade 2 (>3.0 to 5.0 x ULN) 
No action for Grade 2 ALT/AST 
Grade 3: >5.0 to 20.0 x ULN 
In subjects witho ut liver 
metastases and subjects with 
liver metastases and baseline 
level ::;3 x ULN: 
Repeat testing within 3 days. Delay dose until resolved to ::;Grade 1 if 
baseline ::; 3 x ULN, othe1w ise delay dose until resolved to ::; baseline, 
then: 
• If resolved in9 
days from day of onset, maintain dose 
If resolved in >7 days from day ofonset, reduce dose l level 
Grade 3: >8.0 to 20.0 x ULN) 
In subjects with liver 
metastases, if the baseline 
level was >3 x ULN 
Repeat testing within 3 days. Delay dose until resolved to ::;baseline 
level, then: 
• If resolved in ::;7 days from day of onset, maintain dose 
If resolved in >7 days from day of onset, reduce dose 1 level 
Grade 4 (>20 x ULN) 
Discontinue subject from study treatment 
Total Bilirubin increased 
Grade 2 (>1.5 to 3.0 x ULN) 
If no documented Gilbe1i 's syndrome or liver metastases at baseline, 
delay dose until resolved to ::;Grade 1: 
• If reso lved in ::;7 days from day of onset, maintain dose 
• If resolved in >7 days from day of onset, reduce dose 1 level 
If documented Gilbe1i ' s syndrome or liver metastases at baseline, 
continue study treatment 
Grade 3 (>3.0 to 10.0 x ULN) If no documented Gilbe1i 's syndrome or liver metastases at baseline, 
repeat testing within 3 days. Delay dose until resolved to ::;Grade 1: 
• If resolved in ::;7 days from day of onset, reduce dose 1 level 
• If resolved in >7 days from day ofonset, discontinue  DS-82 01a 
If docum ented Gilbe1i ' s syndrome or liver metastases at baseline, repeat 
testing within 3 days. Delay dose until resolved to< Grade 2: 
• If resolved in ::; 7 days from day of onset, reduce dose 1 level 
• If resolved in> 7 days from day of onset, discontinue DS- 
8201a 
Grade 4 (>10.0 x ULN) 
Discontinue subject from study treatment 
Blood Alkaline Phosphatase Increased 
Grade 3 or 4 (>5.0 x ULN) 
No modification unless determined by the investigator to be clinically 
significant or life-threatening. 


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Table 5.2: Dose or schedule modificationfor DS-8201a (Continued) 
 
Worst toxicity NCI-CTCAE 
v4.03 Grade (unless 
otherwise specified) 
Dose or schedule modification for DS-8201a 
Gastrointestinal 
Nausea 
Grade 3 
Delay dose until resolved to :SGrade 1 
• If reso lved in :S7 days from day of onset, maintain dose 
• If resolved in >7 days from day of onset, reduce dose I level 
Diarrhea/Colitis 
Grade 3 
Delay dose until resolved to :SGrade 1 
• If reso lved in :S3 days from day of onset, maintain dose 
• 
If resolved in >3 days from day of onset, reduce dose I level 
Grade 4 
Discontinue subject from study treatment 
Other Laboratory AEs 
Grade 3 
Delay dose until resolved to :SGrade 1 or baseline level: 
• If resolved in :S7 days from day of onset, maintain dose 
• If resolved in >7 days from day of onset, reduce dose I level 
Grade 4 
Discontinue subject from study treatment 
Other Non-laboratory AEs 
Grade 3 
Delay dose1mtil resolved to :SGrade 1 or baseline: 
• If resolved in :S7 days from day of onset, maintain dose 
• If resolved in >7 days from day of onset, reduce dose 1 
level 
Grade 4 
Discontinue subject from study treatment 
1 There will be no dose modifications for Grade I to Grade 3 lymphopenia 
All dose modifications should be based on the worst preceding toxicity. 
NCI: National Cancer Institute, CTCAE: Common Terminology Criteria for Adverse Events. 
In addition, investigators may consider dose reductions or discontinuatio ns of the study 
drug according to the subject' s conditionand after discussion with the Daiichi Sankyo's 
Clinical Study Lead or designee. 


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5.3. 
Physician's Choice (Irinotecan or Paclitaxel) 
The physician's choice treatment is a limited choice of one of two standard regimens 
(irinotecanmonotherapy or paclitaxel monotherapy). The investigator will pre-select the 
physician's choice treatment before the randomization of each subject and record the 
decision in medical record. 
Dose reductions of the physician's choice treatment are allowed for toxicity and must be 
documented in the source record. Once a dose reduction is made, there is no dose re­ 
escalation allowed. Switching between irinotecan and paclitaxel during this study is not 
allowed. Tumor assessments are done every 6 weeks from the day of first dosing, 
irrespective of dose delays or interruptions, until investigator-assessedPD, death, or post 
treatment after discontinuation. 
 
5.3.1. 
Dosage and Usage 
Treatment is continued with the following regimen until the criteria defined in Section 
5.6.l. 
 
5.3.1.1. 
Irinotecan monotherapy 
Starting dosage and usage is 150 mg/m2 biweekly,and two dose reductions will be 
permitted. 
The adjustment for a reduced dosing of irinotecan is referred as shown in Table 5.3. 
 
 
Table 5.3: 
Dose Reduction Levels of Irinotecan 
 
Starting Dose 
Dose Level -1 
Dose Level - 2 
150 mg/m2 
120 mg/m2 
100 mg/m2 
Once the dose of irinotecan has been reduced because of toxicity, all subsequent 
treatments should be administered at that lower dose level unless further dose reduction is 
required. More than 2 dose reductions are not allowed and the subject will be 
withdrawn from the study treatment if further toxicity meeting the requirement for 
dose reduction occurs. However, further dose reduction may be conducted  based on 
consu ltation between the Investigator and Daiichi Sankyo. Irinotecan dose increases are 
not allowed in the study. 
5.3.1.2. 
Paclitaxel monotherapy 
Starting dosage and usage is 80 mg/m2 weekly, and one dose reduction will be permitted. 
The adjustment for a reduced dosing of paclitaxel is referred as shown in Table 5.4. 
 
Table 5.4: 
Dose Reduction Leve ls of Paclit axel 
 
Starting Dose 
Dose Level -1 
80 mg/m2 
60 mg/m2 


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Once the dose of pac litaxel has been reduced because of toxicity, all subseq uent treatment 
should be administered at that lower dose level unless further dose reduction is required. 
More than one dose reductions are not allowed and the subject will be withdrawn 
from the study treatment if further toxicity meeting the requirement for dose 
reduction occurs. However, further dose reduction may be conducted based on 
consulta tio n be tween the Investigator and Daiichi Sankyo. Paclitaxel dose increases are 
not allowed in the study. 
5.3.2. 
Administration Criteria 
Administration of the physician's choice treatment can be delayed for up to 49 days (Day 
50) from the date of last administration. If toxicities are not resolve within the authorised 
dose delay period, subjects discontinue study treatment. 
If a subject develops an acute onset of new or worsening pulm onary or other related 
signs/symptoms such as dyspnea, cough or feve r, follow the indication of Pulmonary 
Toxicity described in Table 5.2. 
Prior to commencing treatment, the following criteria are referred as shown in Table 5.5. 
 
 
Table 5.5: 
Administration Criteria for Irinotecan and Paclitaxel 
 
Administration Criteria 
l rinotecan Monotherapy 
Paclitaxel Monotherapy 
White blood cell count 
2':2 ,8 0 0 / mm3 and 
<15,000/mm3 
2':2 , 0 0 0/mm3 and 
<15,000/mm3 
Platelet count 
2':7 5 ,0 0 0/mm3 
2':7 5 ,0 00/mm3 
ALT/AST 
:S3 x ULN or baseline 
:S3 x ULN or baseline 
Total bilirubin 
:Sl. 5 mg/dL 
:Sl. 5 mg/dL 
Creatinine 
:Sl .5 mg/dL 
:Sl. 5 mg/dL 
Nausea/Vomiting/Stomatitis 
:<:::Grade 1 
:<:::G  rade 
1 
Di a rrhea 
:<:::Grade 1 
:<:::G rade 
2 
Neuropathy/Arthralgia/Myalgia 
:<:::Grade 2 
:<:::G rade 
2 
Non-inflammatory   Pulmonary 
Tox i c i t y 
:<:::Grade 1 
:<:::G  rade 
1 
 
 
5.3.3. 
Dose Reductions 
Dose levels in both treatments must be reduced to Level- 1 when any of the following AEs 
are observed after the previous drug administration. 
If a subject develops an acute onset of new or worsening pulmonary or other related 
signs/symptoms such as dyspnea, cough or fever, follow the indication of Pulmonary 
Toxicity described in Ta ble 5.2. 


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Table 5.6: 
Dose Reduction Criteria 
 
Dose Reduction Criteria 
Both Treatments (lrinotecan and Paclitaxel) 
White blood cell count decreased 
:=::Grade 3 
Pl atelet co unt decreased 
:=::Grade 3 
Neutrophil count decreased 
:=::Grade 3 
Infection 
Documented clinically, infection of unknown 
origin 
Diarrhea, stomatitis, neuropathy, arthralgia, 
m yalgia 
:=::Grade 3 
Increase in ALT/AST 
:=::Grade 3 
Others 
When administration criteria are not fulfilled 
and treatment delay for 2 consecut ive weeks 
was required because of AEs 
When the treating physician judged that dose 
reduction was required because of AEs 
If Grade 4 nonhematological toxicity occurred in subjects with anorexia or abnormal 
serum sodium and potassium levels are observed, treatment is discontinued at the treating 
physician's discretion. When paclitaxel monotherapy subjects experienced Grade 3 
allergic reactions, treatment is discontinued. 
Subjects experienced Grade 3 non-inflammatory pulmonary toxicity, treatment is 
discontinued. 
If subjects receiving irinotecan monotherapy are found to be homozygo us fo r the 
UGTJA1*6 or UGTJA1*28 allele (UGT JA1*6 /*6, UGTJ A1*28/*28) or heterozygousfor 
both alleles (UGTJAJ *6!*28), and if they meet the abovementioned criteria, dose 
reduction to Level - 2 (100 mg/m2 is allowed. 
 
5.4. 
Method of Assessing Treatment Compliance 
All drugs used for the study treatment will be administered by the investigator or other 
designated study personnel. Therefore, treatment compliance will be guaranteed as long 
as the subject attends each visit for administration of the study treatment. Start and stop 
date/time of injection, amount of drug administered, and reason for change or interruption 
(if applicable) must be recorded in medical record by clinical study personnel. 
 
5.5. 
Prophylactic Treatment and Concomitant Medications 
5.5.1. 
ProphylacticTreatment 
Base d on the currently avai lable clinical safety data, it is recommended that subjects 
receive prophylactic anti-emeticagents prior to infusion of DS-820la and on subseq uent 
days. Antiemetics such as 5- hydroxytryptamine receptor (5-HT3) antagonists or 
Neurokinin-1 (NKl) receptorantagonists and/or steroids (e.g. dexamethasone) should  be 
considered and administered in accordance with the prescribing information or 
institutional guidelines. 
)


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Hematopoietic growth factors may be used for prophylaxis or treatment based on the 
clinical judgment of the investigator. 
 
5.5.2. Concomitant Medications 
Medications used from the time the subject signs the informed consent for study 
participation to the follow-up 40 days visit (+7 days) after the last administration ofDS- 
820la/physician's choice treatment will be recorded. All concomitant medications will be 
recorded in the electronic case report form (eCRF). 
 
5.5.3. Prohibited Concomitant Medications/Activities 
For all subjects (DS-820l a and physician' s choice treatment): The following medications 
and products will be prohibited: 
• 
Other anticancer therapy, including cytotoxics, targeted agents, 
immunotherapy, antibodies, or surgery 
• 
Other investigatio nal therapeutic agents 
• 
Radiotherapy (except for palliative radiation to known metastatic sites as long 
as it does not affect assessment of response and it does not interrupt treatment 
for longer than the maximum time specified in the dose modification section) 
• 
Radiotherapy to the thorax 
 
For subjects receiving DS-820la: The following medications and products will also be 
prohibited: 
• 
Concomitant use of chronic systemic corticosteroids or other 
immunosuppressive medications except if it is standardpractice for managing 
specific adverse events. Inhaled steroids or intra articular steroid injections are 
permitted in this study. 
- 
Subjects with bronchopulmonarydisorders who require intermittent use of 
bronchodilators (such as al bu tero l) will not be excluded from this study. 
• 
Concomitant treatment with chloroquine or hydroxychloroquine is not allowed 
during the study treatment. Refer to Appendix 17.6 for further details. 
 
Restricted Therapies/Products 
• 
Use of e-cigarettes and vaping is strong ly discouraged but not prohibited. 
 
 
Concomitant use of dietary supplements, medication s not prescribed by the investigator, 
and alternative/complementarytreatments is discouraged, but not prohibited. 


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5.6. 
Subject Withdrawal/Discontinuation 
Any subject may withdraw their consent to participate in the study at any time without 
specifying a reason. It must also be documented (in the eCRF) whether the subject agrees 
to participate in post-treatment follow-up st udy assessments. 
5.6.1. 
Reasons for Discontinuation of Study Treatment 
Su bjects may be withdrawn from study treatment after signing the informed consent for 
the following reasons: 
l. Progressive disease per RECIST version l. l assessed by the investigator; 
2. Clinical progression (definitive clinical signs of disease progression, but a recent 
radiographicassessment did not meet the criteria for PD according to RECIST 
version l. l ); 
3. AE; 
4. Death; 
5. Withdrawal of consent by subject; 
6. Lost to follow-up; 
7. Physician Decision; 
8. Pregnancy; 
9. Study terminated by Daiichi Sankyo; 
l 0. Others, specify. 
If there is evidence that the subject is receiving benefit from treatment even though the 
subject has met a criterion for discontinuationas listed above, the subject may remain on 
study treatment after discussion with the Daiichi Sankyo's Clinical Study Lead or 
designee. 
All subjects who are withdrawn from the study treatment should complete protocol­ 
specified withdrawal procedures (Section 5.6.3) and follow-up procedures (Section 6.3). 
Record the reason for any subject who discontinues study treatment. Discontinued 
subjects will be followed for survival. 
5.6.2. 
Reasons for Discontinuation of Study Follow-up 
Subjects may be withdrawn from study follow-up after signing an informed consent for 
the following reasons: 
l. Withdra wal of consent to participate in study procedures; 
2. Death; 
3. Lost to follow-up; 
4. Study terminated by Daiichi Sankyo; 
5. Others, specify 


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5.6.3. Withdrawal Procedures 
If a subject is withdrawn from the stud y, the investigator will complete and report the 
observations as thoroughly as possible up to the date of withdrawal including the date of 
the last treatment and the reason for withdrawal. 
If the subject is withdrawn due to an AE, the investigator will follow the subject until the 
AE has resolved or stabilized, post cancer treatment, or lost to follow-up. 
All subjects who are withdrawn from the study should complete protocol-specified 
withdrawal p rocedures. Protocol-specified withdrawal procedures will be obtained during 
the EOT visit (+7 days) and the follow-up 40 days visit (+7 days) conducted after the last 
administration of DS-820la or the physician's choice treatment. 
When the investigator receive request of withdrawn from the study, the investigator also 
confirm the continuity of biomarker research. 
 
5.6.4. Subject Replacement 
Subjects that have been randomized will not be replaced in Primary Cohort. It is 
allowable to replace a subject that was enrolled but was not administered any study 
medication in Exploratory Cohort 1 or 2. 
 
5.6.5. Subject Re-screening Procedures 
Re-screening is permitted for any subject who failed to meet the eligibility criteria in the 
initial screening. The limit of re-screening is each 1 time in tissue screening (See Section 
6.1.1) and screening (See Section 6.1.2). Tissue sample for re-screening is the sample 
obtained after trastuzurnab (brand, approved biosimilar) treatment if ava ilable. Subjects 
that have been randomized will not be re-screened. The site subject identifier and the 
subject ID must remain the same at the time of re-screening. The initial screening 
information and the reason why the subject was ineligible for the initial evaluation will be 
recorded in the Screen ing Log. 


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6. 
STUDY PROCEDURES 
Obtain a signed and dated ICF before any study-related procedures or assessments are 
conducted . A separate tissue screening ICF may be used to obtain consent to send the 
sample to the central laboratory, if desired. 
After obtaining informed consent, the investigator or designee assign a site subject 
ident ifier and enter subject' s background data in the interactive web/voice response 
system (IXRS). 
Informed consent for pharmacogenomics study will be obtained separately. 
A study visit sc hedule in tabular format is provided below in Section 18. The following 
activities will be performed at each visit and recorded in the eCRF. 
Investigators will maintain a confidential screening log of all potential study candidates 
that includes limited information on the subjects, and the date and outcome of the 
screenmg process. 
 
6.1. 
Screening 
6.1.1. 
Tissue Screening 
To determine eligibility, subjects must meet the tumor biomarker criteria. The procedure 
for preparing tumor tissue is shown in the study laboratory manual for required tumor 
sample specifications and shippinginstructions. 
Note: A separate tissue sc reening ICF may be used to obtain consent to send the sample to 
the central laboratory, if desired. Subjects may continue on prior therapy while tissue 
testing takes place. 
The following activities will be performed: 
• 
Obtain adequate archived tumor sample for tissue screening to confirm HER2 
status. Archive tissue samples from surgery, endoscopy, or needle biopsy 
already collected and formalin-fixed paraffin-embedded will be used. If both 
of the arch ived and fresh samples are available for one pat ient, it is 
recommended to submit both samples to the centra l laboratory. If an archived 
tissue sample is not available or adequate, fresh sample is required. 
Registration is based on the HER2 status of archived sample, but in case 
archived sample could not detect HER2 status, fresh sample is utilized for 
enrollment. 
• 
Paraffin-embedded tissue blocks of forma lin-fixed tiss ue spec imens will be 
prepared by the standard procedure at the study site and submitted to the 
central laboratoryas soon as possible to determine HER2 status. 
• 
The central laboratory will assess the measured HER2 status and report it to the 
investigatorand Daiichi Sankyo. 
• 
If a tumor biopsy is needed, record any SAEs directly related to this tissue 
screening procedure. 
• 
For subjects who sign only the Informed Consent Form for tissue screening, 
report only serious adverse events (SAEs) directly related to tissue screening 


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procedure (ie, tumor biopsy). Unless documentation of other AEs is required 
by local law, only SAEs directly related to tumor biopsy will be recorded 
during tissue screening. 
 
6.1.2. 
Screening 
In this study, registration will be performed (See Section 5.1.1). If the subject is a 
screening failure, the subject is recorded as ineligible in the IXRS. 
The following activities and/or assessments will be performed during the screening period: 
 
 
Before registration 
• 
Record demographic information (eg, birth date, sex), primary cancer history, 
significant medical history information and prior treatment for cancer history 
information. 
• 
Review inclusion and exclusion criteria and confirm the subject' s eligibility 
when the results of all sc reening procedures have bee n obtained 
• 
Record the historical HER2 status. 
• 
Record the prior and concomitant medications. 
• 
Assess the subject for AEs. 
• 
Obtain fresh tumor biopsy, 
The subject who has a tumor is amenable to biopsy undergoes a fresh tumor 
biopsy. The investigator sends paraffin embedded and fixed tumor tissue to the 
central laboratory to assess the HER2 status exploratively. If not amenable, the 
investigatormust document why not amenable. 
If fresh tumor has been already submitted for this study and no chemotherapy 
or immunotherapy was conducted, re-submission is not necessary. 
Other biomarkers related to the activity of DS-820l a may be analyzed (eg, 
messenger RNA [mRNA] expression profile). These analyses are depending 
on tissue ava ilability. 
Further details will be provided in the laboratory manual. 
Within 14 days before registration 
• 
Perform a complete physical examination and record the weight and height. 
• 
Obtain vital sign measurements (systolic and diastolic blood pressure and pulse 
rate and body temperature and SpO2). 
• 
Assess ECOG PS Scale (Section 17.1). 
• 
Obtain blood samples for laboratory tests (Section 9.8) and troponin . 
• 
Perform urinalysis test 
• 
Perform a 12-lead ECG in triplicate•. 
*: ECGs will be taken in close success ion, approximate ly 3 minutes apart, after 
the subject has been in a supine/semi-recumbent position. 


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• 
Obtain a serum or urine sample for pregnancy testing in women of childbearing 
potential. For postmenopausal subjects (no childbearing potential, as indicated 
by the elapse of at least 12 months after the last menstruation) or fema le 
subjects who have no possibilityof pregnancy due to ste rilization surgery, etc., 
no pregnancy test will be required. Female subjects who have been 
amenorrheic for 12 months or longer for medical reasons other than 
sterilizationsurgery (eg, effect of medication) will be regarded as women of 
child-bearingpotential and are required to undergo the pregnancy test. 
Within 28 days before registration 
• 
Perform either ECHO or MUGA scan (LVEF). 
• 
Ophthalmologic assessments. 
The assessments will include visual acuity testing, slit lamp examination, and 
fundoscopy . 
• 
Perform tumor assessme nt by CT or magnetic resonance imaging (MRI) scans 
of the brain, chest, abdomen, pelvis, and any other sites of disease. The 
registration is based on local assessment of measurable disease. 
6.1.3. 
Registration 
The investigator or designeedetermines that all inclusion and exclusion criteria are 
satisfied, enter the subject registration data in the IXRS. A subject is considered to be 
enrolled in the study when registration is completed in the IXRS. 
The date of registration is defined as the date when the subject is registered as eligible in 
the IXRS. The date of screeningfailure is defined as the date when the subject is 
confirmed ineligible by the investigator. 
Investigators will be expected to maintain an Enrollment Log of all subjects enrolled in the 
study indicating their assigned Subject ID. The unique Subject ID will be assigned by 
IXRS. 
Investigators will maintain a confidential site subject identifier list. This confidential list 
of names of all subjects to whom Subject IDs have been allocated when they enrolled in 
the study, allows the investigator to reveal the identity of any subject when necessary. 
The drug number will be sequence number in DS-820la to identify the vial status. All 
vials of DS-820 l a will be numbered and traced. 
For screening failure subj ects, the inve stigator s will explain the reason of failure to the 
subject. 
 
6.1.4. 
Randomization 
Subjects in Primary Cohort will be randomized by IXRS into the two treatment groups in 
a 2:1 ratio (120 DS-820la group and 60 physician's choice group) and the randomization 
will be stratified by region, ECOG PS, and HER2 status. 
• 
Region (Japan or Korea) 
• 
ECOG PS (0 or 1) 


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• 
HER2 status (IHC 3+ or IHC 2+/ISH +) 
 
6.1.5. 
Discontinuation during the Screening Period 
If study entry is discontinued after the subject is assigned a unique subject ID, the reason 
for disco ntin uation is recorded in the eCRF from the categories listed below. 
• 
HER2 expression status is IHC O or not detected by the centra l laboratory. 
• 
Eligibility is not matched, except for HER2 expression 
• 
Withdrawa l by the subject 
• 
Others 
 
6.2. 
Treatment Period 
In considerat ion of the subject' s safety, additional safety assessments should be conducted 
as needed at the investigator' s discretion. If there are any non-scheduled data that are 
assessed, these are recorded in the eCRF when they are considered as an AE. 
 
6.2.1. 
Tumor Assessment 
The same imaging tumor assessment as at the time of screening by CT or MRI scans will 
be performed every 6 weeks (±7 days) from the first dosing (Cycle 1 Day l ) until PD, 
starting new anticancer treatment, or withdrawal of consent by subject to participate in 
study procedures regard less of a delay in dosing from the day of first administration, DS- 
820la or the control treatment. The assessment will be conducted before treatment of 
each cycle. CT or MR I scans of the chest, abdomen and pelvis are mandatory. Brain CT 
or MRI assessment is mandatory at baseline, in cases of pre-existing brain metastases or 
symptoms. The assessment should be co nducted in the same way during the study 
treatment. Instructions for the assessment are included in a separate manual. 
 
 
Handling of Images 
Copies of CT or MRI images should be provided to central review vendor. This is all 
images use d for tumor assessment in this study including unscheduled visits. However, 
images that were not scanned at baseline should be provided only in case the new lesion is 
detected. 
Copies of CT or MRI images should be immediately submitted to central vendor after the 
images taken, and they should be cond ucted within 2 weeks. 
Before the transfer of data, personal informatio n such as name should be masked. 
 
6.2.2. 
Patient Reported Outcomes (EQ-5D-5L and FACT-Ga) 
Qua lity of Life questionnaire s (EQ SD SL, FACT-Ga) will be completed in both groups of 
Primary Cohort on Day 1 before any study related procedures, including blood collection, 
Day 15 (±1), and every 6 weeks from the beginning of the study (eg, Day 43 (±7), 85 (±7), 
127 (±7), etc.), and EOT. EQ-5D-5L questio nnaire to be completed first and then FACT­ 
Ga questionnaire. 


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6.2.3. 
Safety Monitoring for suspected ILD/pneumonitis 
For suspected ILD/pneumonitis, study drug should be interrupted pending evaluation, 
which should include: 
high resolution CT 
pulmonologi st cons ultation (Infectious Disease consultation as clinically indicated) 
blood culture and CBC. Other blood tests could be considered as needed 
consider bronchoscopy and bronchoalveolar lavage if clinically indicated and feasible 
pulmonary function tests and pulse oximetry (SpO2) 
arterial blood gases if clinically indicated 
one blood sample collection for PK ana lysis as so on as ILD/pneumon itis is suspected, 
if feasible (for DS8201 group and exploratory cohort). 
Other tests could be considered, as needed. 
 
 
All events of ILD/pneumonitis regardle ss of sever ity or seriousness will be followed until 
resolution including after drug discontinuation. 
 
 
6.2.4. 
Schedule of Activity and Assessments for Subjects Receiving DS-8201a 
 
6.2.4.1. 
Cycle 1, Day 1 
 
6.2.4.1.1. 
Before administration 
The following procedures will be completed pre-dose on Day 1. If assessments at 
screening are performed within this period, they can be considered to be Day 1 data and 
there is no need to repeat them. 
• 
Assess subjects for AEs. 
• 
Record concomitant medications. 
• 
Obtain a blood sample for pharmacogenetic assessment. (This sample is not 
required for study participation and will be collected from subjects who have 
provided consent by signing the pharmacogenomic consent form.) 
Within 8 hours before administration 
• 
Obtain a PK blood sample (Section 8.1). 
• 
Obtain blood sample for ADA (Section 8.7). 
Latest data within 3 days before administration 
• 
Perform a complete physical examination and record the weight. 
• 
Obtain vital sign measurements(systolic and diastolic blood pressure and pulse 
rate, body temperature and SpO2). 


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• 
Assess the ECOG PS Scale (Section 17.1). 
• 
Obtain blood samples for laboratory tests (Section 9.8), HER2ECD (Section 
8.2.1), and cfDNA analysis. 
• 
Pe rform a 12-lead  ECG in triplicate. 
 
6.2.4.1.2. 
Administration and after Infusion 
• 
Administer DS-820la as per Section 5.2.4. 
The following procedures will be completed post-dose on Day 1. 
• 
Obtain vital sign measurements (systolic and diastolic blood pressure and pulse 
rate and body temperature). 
• 
Obtain PK blood samples at the followi ng time points: within 15 minutes after 
end of infusion (EOI), at 4 and 7 hours (±15 minutes) after the start of 
administration (Section 8.1). 
• 
Collect blood samples for troponin (preferably high-sensitivity tropo nin-T) 2-3 
hours after end of infusion (EOI). An additional sample should be submitted 
for central lab troponin-T testing. 
- 
If troponin level is consistent with myocardial infarction as defined 
accord ing to manufacturer (CTCAE Grade 3), perform ECG testing in 
trip licate, repeat troponin testing 6 ± 1 hou rs and 12 ± 1 hours after initial 
troponin test was drawn, and follow institutional guidelines. 
- 
If troponin level is above the upper lim it of normal and below the level of 
myocardial infarction as defined by the manufacturer (CTCAE Grade 1), 
repeat troponin testing 3 + lhours after initial troponin test was drawn. If 
troponin level is above upper limit of normal and below the level of 
myocardial infarction as defined by the manufacturer (CTCAE Grade 1) at 
baseline, no repeat testing is required if the troponin level is not CTCAE 
Grade 3. 
- 
If repeat troponin level at 3 ± 1 hours rises significantl y per institutional 
guide lines, 
perform ECG in triplicate; 
repeat troponin testing at 6 ± 1 hours after initial troponin test; 
follow institutional guidelines for management of detectable troponin 
testing. 
- 
If repeat troponin level at 3 ± 1 hours does not rise significant! y per 
institutional gu idelines, 
repeat troponin testing at 6 ± 1 hours or at 24 ± 2 hours after initial 
troponin test. 
• 
Record concomitant medications. 
• 
Assess subjects for AEs. 


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6.2.4.2. 
Cycle 1, Day 8 
The following procedures will be performed on Day 8 (±1 day). 
• 
Obtain vital sign measurements (systolic and diastolic blood pressure and pulse 
rate and body temperature). 
• 
Obtain blood samples for laboratory tests (Section 9.8). 
• 
Obtain a PK blood sample on Day 8 (Section 8.1). 
• 
Record concomitant medications. 
• 
Assess subjects for AEs. 
 
6.2.4.3. 
Cycle 1, Day 15 
The following procedures will be performed on Day 15 (±1 day). 
• 
Obtain vital sign measurements (systolic and diastolic blood press ure and pulse 
rate and body temperature). 
• 
Obtain blood samples for laboratory tests (Section 9.8). 
• 
Obtain a PK blood sample on Day 15 (Section 8.1). 
• 
Record concomitant medications. 
• 
Assess subjects for AEs. 
• 
Quality of Life questionnaires (EQ SD SL, FACT-Ga) 
 
6.2.4.4. 
Cycle 1, Day22 
If the schedule on Day 1 of the next cycle is delayed for 3 days or more, including if the 
subject cannot continue onto the next cycle, the following procedures will be performed 
on Day 22 (±2 days). 
• 
Obtain a PK blood sample on Day 22 (Section 8.1). 
• 
Record concomitant medications. 
• 
Assess subjects for AEs. 
 
6.2.4.5. 
Cycle 2, Day 1 
 
6.2.4.5.1. 
Before Infusion 
The following procedures will be completed pre-dose on Day 1. 
• 
Record concomitant medications. 
• 
Assess subjects for AEs. 
Within 8 hours before administration 
• 
Obtain a PK blood sample (Sect ion 8.1). 
• 
Obtain a blood sample for ADA (Section 8.7). 
Latest data within 3 days before administration 


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• 
Perform a complete physical examination and record the weight. 
• 
Obtain vital sign measurements (systolic and diastolic blood pressure and pulse 
rate, body temperature and SpO2). 
• 
Assess the ECOG PS Scale (Section 17.1). 
• 
Obtain blood samples for laboratory tests (Section 9.8). 
• 
Ophthalmologic assessments. 
The assessments will include visual acuity testing, slit lamp examination, and 
fundoscopy. If the planned date of study drug administration is delayed after 
examination of Ophthalmologic assessments, and there are no abnormal 
findings on the examination, Ophthalmologic assessments may not be repeated 
at the investigator's judgment. 
• 
Perform a 12-lead ECG in triplicate. 
 
6.2.4.5.2. 
Administrationand  after Infusion 
• 
Administer DS-820la as per Section 5.2.4. 
The following procedures will be completed post-dose on Day 1: 
• 
Obtain vital sign measurements (systolic and diastolic blood pressure and pulse 
rate and body temperature). 
• 
Obtain a PK blood sample at the end of administration within 15 minutes after 
EOI (Section 8.1). 
• 
Collect blood samples for troponin (preferably high-sensitivity troponin-T) 2-3 
hours after end of infusion (EOI). An additional sample should be submitted 
for central lab troponin-T testing. 
- 
If troponin level is consistent with myocardial infarction as defined 
according to manufacturer (CTCAE Grade 3), perform ECG testing in 
triplicate, repeat troponin testing 6 ± 1 hours and 12 ± 1 hours after initial 
troponin test was drawn, and follow institutional guidelines. 
- 
If troponin level is above the upper limit of normal and below the level of 
myocardial infarction as defined by the manufacturer (CTCAE Grade l), 
repeat troponin testing 3 ± 1hours after initial troponin test was drawn. 
- 
If troponin level is above upper limit of normal and below the level of 
myocardial infarction as defined by the manufacturer (CTCAE Grade l) at 
baseline, no repeat testing is required if the troponin level is not CTCAE 
Grade 3. 
- 
If repeat troponin level at 3 ± 1 hours rises significantlyper institutional 
guidelines, 
perform ECG in triplicate; 
repeat troponin testing at 6 ± 1 hours after initial troponin test; 
follow institutional guidelines for management of detectable troponin 
testing. 


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- 
If repeat troponin level at 3 ± 1 hours does not rise significant!y per 
institutional guidelines, 
repeat troponin testing at 6 ± 1 hours or at 24 ± 2 hours after initial 
troponin test. 
• 
Record concomitant medications. 
• 
Assess subjects for AEs. 
 
6.2.4.6. 
Cycle 2, Day22 
If the schedule on Day 1 of the next cycle is delayed for 3 days or more, including if the 
subject cannot continue onto the next cycle, the following procedures will be performed 
on Day 22 (±2 days). 
• 
Obtain a PK blood sample on Day 22 (Section 8.1). 
• 
Record concomitant medications. 
• 
Assess subjects for AEs. 
 
6.2.4.7. 
Cycle 3, Day 1 
 
6.2.4.7.1. 
Before Infusion 
The following procedures will be completed at pre-dose on Day 1. 
• 
Record concomitant medications. 
• 
Assess subjects for AEs. 
Within 8 hours before administration 
• 
Obtain a PK blood sample (Section 8.1) 
Latest data within 3 days before administration 
• 
Perform a complete physical examinationand record the weight. 
• 
Obtain vital sign measurements (systolic and diastolic blood pressure and pulse 
rate, body temperature and SpO2). 
• 
Assess the ECOG PS Scale (Section 17.1). 
• 
Obtain blood samples for laboratory tests and HER2ECD (Section 8.2.1). 
• 
Perform a 12-lead ECG in triplicate. 
 
6.2.4.7.2. 
Administration and after Infusion 
• 
Administer DS-8201a as per Section 5.2.4. 
The following p rocedures will be completed post-dose on Day 1: 
• 
Obtain vital sign measurements (systolic and diastolic blood pressure and pulse 
rate and body temperature). 
• 
Obtain PK blood samples at the followi ng time points: within 15 minutes after 
EOI, 4 and 7 hours (± 15 minutes) after the start of administration (Section 8.1). 


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• 
Collect blood samples for troponin (preferably high-sensitivity troponin-T) 2-3 
hours afte r end of infusion (EOI). An additional sample should be submitted 
for central lab troponin-T testing. 
- 
If troponin level is consistent with myocardial infarction as defined 
according to manufacturer (CTCAE Grade 3), perform ECG testing in 
triplicate, repeat troponin testing 6 ± l hours and 12 ± l hours after initial 
troponin test was drawn, and follow institutional guidelines. 
- 
lftroponin level is above the upper limit of normal and below the level of 
myocardial infarction as defined by the manufacturer (CTCAE Grade 1), 
repeat troponin testing 3 ± l hours after initial troponin test was drawn. 
- 
If troponin level is above upper limit of normal and below the level of 
myocardial infarction as defined by the manufacturer (CTCAE Grade 1) at 
baseline, no repeat testing is required if the troponin level is not CTCAE 
Grade 3. 
- 
If repeat troponin level at 3 ± 1 hours rises significantlyper institutional 
guide lines, 
perform ECG in triplicate; 
repeat troponin testing at 6 ± 1 hours after initial troponin test; 
follow institutional guidelines for management of detectable troponin 
testing. 
- 
If repeat troponin level at 3 ± 1 hours does not rise significant!y per 
institutional guidelines, 
repeat troponin testing at 6 ± 1 hours or at 24 ± 2 hours after initial 
troponin test. 
• 
Record concomitant medications. 
• 
Assess subjects for AEs. 
 
6.2.4.8. 
Cycle 3, Day 8 
The following procedures will be performed on Day 8 (±3 days). 
• 
Obtain a PK blood sample on Day 8 (Section 8.1). 
• 
Record concomitant medications. 
• 
Assess subjects for AEs. 
6,2.4.9, 
Cycle 3, Day 15 
The following procedures will be performed on Day 15 (±3 days). 
• 
Obtain a PK blood sample on Day 15 (Section 8.1). 
• 
Record concomitant medications. 
• 
Assess subjects for AEs. 


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6.2.4.10. Cycle 3, Day22 
If the schedule on Day 1 of the next cycle is delayed for 3 days or more, including if the 
subject cannot continue onto the next cycle, the following procedures will be performed 
on Day 22 (±2 days). 
• 
Obtain a PK blood sample on Day 22 (Section 8.1). 
• 
Record concomitant medications. 
• 
Assess subjects for AEs. 
6.2.4.11. Cycle 4 and Subsequent Cycles, Day 1 
6.2.4.11.1. Before Infusion 
The following procedures will be completed pre-dose on Day 1. 
• 
Record concomitant medications. 
• 
Assess subjects for AEs. 
Within 8 hours before administration 
On Day 1 of Cycle 4, 6, and 8 
• 
Obtain a PK blood sample (Section 8.1). 
On Day 1 every 4 cycles from Cycle 4 to the EOT (eg, Day 1 of Cycle 4, 8,12,...) 
• 
Obtain a blood sample for ADA (Section 8.7) 
Latest data within 3 days before administration 
• 
Perform a complete physical examination and record the weight. 
• 
Obtain vital sign measurements (systolic and diastolic blood pressure and pulse 
rate, body temperature and SpO2). 
• 
Assess the ECOG PS Scale (Section 17.1). 
• 
Obtain blood samples for laboratory tests (Section 9.8). 
On Day 1 every 2 cycles from Cycle 3 to the EOT (eg, Day 1 of Cycle 3, 5, 7, 9, 
lLJ 
• 
Obtain blood samples for HER2ECD (Section 8.2.1). A portion of this 
HER2ECD blood sample from each subject who provides consent will be used 
for future central lab analysis for SARS-CoV-2 testing. SARS-CoV-2 testing 
will be conducted every 4 cycles from Cycle 5 (Cycles 5, 9, 13, etc). 
On Day 1 of Cycle 4 and the EOT 
Obtain blood samples for exploratory biomarkers, such as cfDNA analysis in 
plasma. 
Others 
On Day 1 every 4 cycles (±7 days) from Cycle 5 to the EOT (eg, Day 1 of Cycle 5, 
9,13,...) 


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• 
Perform either ECHO or MUGA scan (LVEF). If the planned date of study 
drug administration is delayed after examination of ECHO or MUGA scan, and 
there are no abnormal findings on the examination, ECHO or MUGA scan may 
not be repeated at the investigator' s judgment. 
• 
Perform a 12-lead  ECG in triplicate. 
 
6.2.4.11.2. Administration and after Infusion 
• 
Administer DS-820l a as per Section 5.2.4. 
The following procedures will be completed post-dose on Day 1. 
• 
Record concomitant medications. 
• 
Assess subjects for AEs. 
 
 
On Day 1 of Cycle 4, 6, and 8 
• 
Obtain a PK blood sample at the end of administration within 15 minutes after 
EOI (Section 8. l). 
6.2.4.12. End of Treatment 
The date of discontinuation of treatment is defined as the date of the decision by the 
investigator. The following assessments will be performed at the EOT visit (within 7 days 
after the date of discontinu ation ). 
• 
Perform a complete physical examination and record the weight. 
• 
Obtain vital sign measurements (systolic and diastolic blood pressure and pulse 
rate, body temperature and SpO2). 
• 
Assess the ECOG PS Scale (Section 17.1). 
• 
Obtain blood samples for laboratory tests and troponin test (Section 9.8), 
HER2ECD (Section 8.2.1) and cfDNA analysis. A portion of this HER2ECD 
blood sample from each subject who provides consent will be use d for future 
central lab analysis for SARS-CoV-2 testing. 
• 
Obtain a serum or urine sam ple for pregnancy testing in women of childbearing 
potential. For postmenopausal subjects (no childbearing potential, as indicated 
by an elapse of at least 12 months after the last menstruation) or female 
subjects who have no possibility of pregnancy due to sterilization surgery, etc., 
no pregnancy test will be required. Fe male subjects who have been 
amenorrheic for 12 months or longer for medical reasons other than 
sterilization surgery(eg, effect of medication) will be regarded as women of 
child-bearing potential and are required to undergo the pregnancy test. 
• 
Perform a 12-lead ECG in triplicate. 
• 
Perform either ECHO or MUGA scan (LVEF). 
• 
Ophthalmologic assessments. 


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The assessments will include visual acuity testing, slit lamp examination, and 
fundoscopy. 
Perform the same imaging tumor assessment as at the time of screening by CT 
or MRI scans. CT or MRI sca ns of the chest, abdomen and pelvis are 
mandatory.If the previous scan was within the last 3 weeks, this assessment 
does not need to be performedat the EOT Visit. 
• 
Record concomitant medications. 
• 
Assess subjects for AEs. 
• 
Record the reason for treatment discontinuation. 
• 
Quality of Life questionnaires (EQ 5D 5L, FACT-Ga) 
• 
Obtain fresh tumor biopsy 
Perform the post-treatment biopsy: perform a biopsy from EOT visit to the 
follow up visit and the investigator sends paraffin embedded and fixed tumor 
tissue to the central laboratory to assess post-treatment HER2 status 
exploratively. If the subject can not be performed a post-treatment biopsy, the 
investigatormust document why not performed. 
Other biomarkers related to the activity of DS-8201a may be analyzed (eg, 
mRNA expression profile). These analyses are depending on tissue 
ava ilability. 
Furtherdetails will be provided in the laboratory manual. 
 
6.2.5. 
Schedule of Activity and Assessments for Subjects Receiving Physician's 
Choice Treatment 
Treatment and procedures performedon treatment period and EOT are specified in 
Section 18.2. Procedures including physical examination, weight, ECOG PS assessment, 
12-lead ECG, hematology, blood chemistry, and vital sign (including SpO2) are to be 
performed within 3 days before each treatment. Troponin is performed at after 
administration. 
 
6.3. 
Follow-up 
The Follow-up (F/U) visit should occur 40 days (+7 days) after the last administration. If 
the subject begins another anticancer therapy before the end of  the 40 days (+7 days), 
every effort will be made  to complete all the F/U assessments prior to commencing the  
new therapy. In case of unresolved AEs, the investigator will follow the AEs until the 
event has resolved or the condition has stabilized as far as possible. If assessments at EOT 
or the treatment period are performed within this period, they can be considered to be the 
F/U data and there is no need to repeat them. If  discontinuation of treatment is decided 
later than 40 days after the last administration of DS-820la, there is  no need to perform  
the F/U assessments except for obtaining a blood sample for ADA. 
The following information will be collected at this F/U visit: 
• 
Obtain vital sign measurements (systolic and diastolic blood pressure and pulse 
rate and body temperature and SpO2). 


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• 
Perform a complete physical examination and record the weight. 
• 
Assess the ECOG PS Scale (Section 17.1). 
• 
Obtain blood samples for laboratory tests (Section 9.8) and ADA (only for 
subjects with DS-820la treatment, Section 8.7). 
• 
Record concomitant medications. 
• 
Assess subjects for AEs. 
 
6.4. 
Survival Status and New Treatment Follow-up 
After completing the post treatment follow-up period, subjects will be followed by visit or 
telephone contact approximately every 3 months (±14 days) to assess survival and new 
cancer treatment until death or the data cut-off date , wh ichever comes first. Even if a 
subject moves to another hospital, the investigator must confirm surv ival and anticance r 
therap y as far as po ssible. If survival status is lost to fo llow- up, the last contact date will 
be recorded. The following data are recorded in the eCRF. 
• 
New treatment for cancer and the start date 
• 
Subject outcome: Alive/dead/lost to follow-up 
• 
Date of death/ date of last contact to be known alive 
 
6.5. 
Follow-up of Anti-Drug Antibodies 
For subjects with positive ADA at F/U visit, additional serum ADA samples may be 
collected every 3 months (±14 days) up to I year from the last dose of the study d rug, or if 
the ADA becomes negative, or if the ADA titer becomes less than the baseline value 
(app lica ble when pre-existing ADA is observed), or if the subject starts another therapy 
for cancer, or withdraws consent from the study, whichever occurs first. This test is only 
for subjects in the DS-820l a treatment group. 


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7. 
EFFICACY ASSESSMENTS 
7.1. 
Assessments of Efficacy Endpoint(s) 
Efficacy assessments will be based on tumor assessments to be performed at screening and 
every 6 weeks from the day of first dosing (Cyclel Dayl ) while the subject remains in this 
study. The primary efficacy endpoint is ORR assessed by independent central imaging 
facility review based on RECIST version 1.1. Refer to Section 17.3 for details regarding 
RECIST version 1.1 for radiological tumor assessments. All CT or MRI scans should be 
sent to the central imaging CRO selected by Daiichi Sankyo to confirm the existence of a 
measura ble lesion by RECIST version 1.1. 
CT or MRI scans of the chest, abdomen and pelvis are mandatory. Brain CT or MRI is 
requiredonly in cases of pre-existing brain metastases or symptoms. The assessment 
should be conducted in the same way during the study treatment. 
The following efficacy variables will be assessed. 
• 
Primary Endpoint 
- 
ORR (the sum of Complete Response [CR] rate and Partial Response [PR] 
rate) assessed by independent central imaging facility review based on 
RECIST version 1.1 (For Primary Cohort) 
• 
Secondary Endpoints (based on central review unless otherwise stated) 
- 
OS (not central review) 
- 
PFS 
- 
DoR 
- 
DCR 
- 
TTF 
- 
ORR assessed by the investigator based on RECIST version 1.1 
- 
ORR (for each Exploratory Cohort 1 and 2) 
 
 
• 
Exploratory Endpoints (based on central review unless otherwise stated) 
- 
Time to response 
- 
Best percent changein the sum of diamete rs of measurable tumors 
- 
PFS based on investigator assessment 


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8. 
PHARMACOKINETIC/PHARMACODYNAMIC 
ASSESSMENTS 
8.1. 
Pharmacokinetic (PK) Assessment(s) 
The serum PK parameters listed in Table 8. l of DS-820l a, total anti-HER2 antibody and 
MAAA-118 la for each subject will be estimated us ing standard noncompartmental 
methods. The details of PK analysis will be specified in the Statistical Analysis Plan. 
 
 
Table 8.1: 
Pharmacokinetic Parameters 
 
PK parameters 
DS-8201a, total anti-HER2 
antibody and MAAA-118l a 
Cmax, Tmax, AUClast, A UC2 1d 
 
Blood samples for DS-820 la PK analyses will be obtained at the time points specified in 
Table 8.2. Instructions for the handling of blood samples and shipping of serum samples 
for DS-820 la PK analyses are included in a separate document (eg, the laboratory 
manual). The actual time of study drug administration and the exact time of blood 
sampling for DS-820la PK analysis must be recorded in the CRF. 
 
 
Table 8.2: 
Pharmacokinetic Sampling Time Points 
 
Cycle 
Day 
Sampling Time Point (Acceptable Range) 
Cycle 1 
Day 1 
Before infusion (Bl) (-8 hours) 
EOI: Within 15 minutes after EOI 
4 hours afte r the start of administration (±15 minutes) 
7 hours afte r the start of administration (±15 minutes) 
Day 8 
7 days after the start of administration (±1 day) 
Day 15 
14 days after the start of administration (±1 day) 
Day 22 
If the schedu le on Day I of the next cycle is delayed for 3 
days or longer, or the subject is discontinued, collect a blood 
sample 21 days after the start of drug administration (±2 
days) 
Cycle 2 
Day 1 
Bl (-8 hours) 
If a blood samp le is collected on Day 22 of Cycle 1, the 
blood sample will be collected at Bl on Day 1 of Cycle 2. 
EOI: Within 15 minutes after EOI 


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Table 8.2: 
Pharmacokinetic Sampling Time Points (Continued) 
 
Cycle 
Day 
Sampling Time Point (Acceptable Range) 
Cycle 2 
Day 22 
lf the schedule on Day 1 of the next cycle is delayed for 3 
days or longer, or the subject is discontinued, collect a blood 
sample 21 days after the start of drug administration (±2 
days) 
Cycle 3 
Day 1 
Bl (-8 hours) 
lf a blood sample is collec ted on Day 22 of Cycle 2, the 
blood sample will be collected at Bl on Day 1 of Cycle 3. 
EOI: Within 15 minutes after EOI 
4 hours afte r the start of administration(±15 minutes) 
7 hours after the start of administration (±15 minutes) 
Day 8 
7 days after the start of administration (±3 days) 
Day 15 
14 days after the start of administration (±3 days) 
Day 22 
lf the schedule on Day 1 of the next cycle is delayed for 3 
days or longer, or the subject is disco ntinued, collect a blood 
samp le 21 days after the start of drug administration (±2 
days) 
Cycle 4, 6, 8 
Day 1 
Bl (- 8 hours) 
lf a blood sample is collected on Day 22 of Cycle 3, the 
blood sample will be collected at Bl on Day 1 of Cycle 4. 
EOI: Within 15 minutes after EOI 
 
 
In case of chloroquine or hydroxychloroquine administration for SARS-CoV-2 infection, 
additional PK serum samples should be collected at the time points specified in Table 8.3. 
The chloroquine or hydroxychloroquine administration time and the exact time of blood 
sampling for DS-820la PK analysis must be recorded in the CRF. 
 
Table 8.3: 
Schedule of PK Sample Collection for Subjects Administered 
Chloroquine or Hydroxychloroquine 
 
Day of CQ or HCQ Administration 
Sampling Time Point (Acceptable Ranges) 
Day 1 
Prior to CQ/HCQ dose 
Day 3 or Day 4 
Prior to CQ/HCQ dose (within 4 hrs) 
End of CQ or HCQ treatment 
Prior to CQ/HCQ dose (within 4 hrs) 
Prior to resumption of DS-8201a (afte r 
CQ/HCQ wash-out period)" 
Before infusion of study treatment (within 
8 hrs) 
CQ = chloroquine; HCQ = hydroxychloroquine. 
a Washout period ofno less than 14 days is required before resumption of DS-8201a. 


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8.2. 
Biomarkers 
In this study, biomarker analyses will be used to investigate the effect of the DS-820la at 
the molecular and cellular level as well as to determine how changes in the markers may 
relate to exposure and clinical outcomes. The sample collection information as required 
should be recorded on the eCRF page(s) and central laboratory requisition form(s). 
Detailed instructions for the collection, handling, and shipping of biomarker samples are 
outlined in the laboratory manual. 
8.2.1. 
Pharmacodynamic Assessments 
 
8.2.1.1. 
Pharmacodynamic Assessments in Blood Samples 
Pharmacodynamic biomarkers will be analyzed with the intent of monitoring the anti­ 
tumor impact of treatment with DS-820la. The pharmacodynamic biomarkers are 
HER2ECD and cfDNA. Blood samples will be collected for HER2ECD analysis at the 
time points specified in Table 8.4 and cfDNA analysis at the time points specified in 
Table 8.5. 
Biomarker samples will be shipped to a central laboratory. Sample collection, 
preparation, handling,storage, and shipping instructions are provided in the laboratory 
manual. 
Table 8.4: 
Extracellular Domain of HER2 Sampling Time Points 
 
Cycle 
Sampling Time Point (Acceptable Range) 
Cycle 1 Day I 
Within 3 days before administration 
Every 2 cycles from Cycle 3 
(eg, Cycle 3, 5, 7, 9, 11...) 
Within 3 days before administration 
EOT 
The date when the investigator decides on 
discontinuation of the study treatment 
(+7 days). 
 
 
Table 8.5: 
Cell Free DNA Sampling Time Points 
 
Cycle 
Sampling Time Point (Acceptable Range) 
Cycle 1 Day I 
Within 3 days before administration 
Cycle 4 Day I 
Within 3 days before administration 
EOT 
The date when the investigator decides on 
discontinuation of the study treatment 
(+7 days). 
 
 
8.2.1.2. 
Pharmacodynamic Assessments in Newly Obtained Tumor Specimen s 
Collection of paired tumor specimens is critical to assess the pharmacodynamic effect of 
DS-820la. Tumor specime ns will be used to assess the HER2 status using IHC and/or 
ISH, and mRNA expression profile using NGS technology and or other methods. The 


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detailed instructions for the handling of tumor samples and shipping of tumor samples are 
included in the laboratory manual. Timing of sample collection is baseline (before 
registration) and EOT. 
 
8.2.1.3. 
Additional Biomarker Assessments 
During the study, in addition to the biomarkers specified above, exploratory biomarker 
research may be conducted on any samples. These studies would extend the search for 
other potential biomarkers relevant to the effects of DS-820la 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 cl inica l outcome, reagent and 
sample availability. If the patient agrees, the remaining samples (tumor tissues, blood and 
plasma) may be stored for up to 15 years. 
8.2.1.4. 
Disclosure of the Results of Additional Biomarker Assessments 
Becau se the nature and value of future additional biomarker assessments is unknown at 
this time, any results obtained from research involving samples will not be disclosed to the 
subject or investigators now or in the future. 
 
8.3. 
SARS-CoV-2 Serum samples collection 
Portion of HER2ECD blood sample from each subject who provides consent will be used 
for future central lab analysis for SARS-CoV-2 testing. Samples will be sent to the central 
laboratory and stored until the tests will become available. 
 
8.4. 
Pharmacogenomic Analysis 
8.4.1. 
Genomic or Genetic Banking Analysis 
A single blood sample for pharmacogenornics analysis will be collected from each subject 
who has consented to this test on Day 1. Participation in this part of the study is optional 
for all subjects. 
The following procedures will be used for the long-term preservation (banking) of DNA 
specimens extracted from subjects' blood samples. Pharmacogenomic samples may be 
analyzed for genes involved in absorption, distribution, meta bolism, elimination, safety, 
and efficacy of DS-820l a. Additionally, samples may be analyzed for genes involved in 
DS-820l a related signaling pathways, or to examine diseases or physiologic processes 
related to DS-8201a. 
DNA samples will not be immortalized or sold to anyone. This information may be useful 
to increase knowledge about differences between indiv id uals in the way they respond to 
the study drug. 
Specimen shipping and handling details will be included in the laboratory manual. 
 
8.4.1.1. 
Disclosure of the Results of Genomic or Genetic Analysis 
Becau se the nature and value of future pharmacogenomic research is unknown at this 
time, any results obtained from research involving pharmacogenomic samples will not be 
disclosed to the subject or investigators now or in the future. 


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8.5. 
Anonymization of Samples 
The samples should be submitted to the courier without any personal information such as 
name that can be used to identify individuals. The samples should be identified by the 
'S ubject ID'. 
The correspondence list which can link the Subject ID and the personal information 
should be kept strictly at the study center and the linkage between the Subject ID and 
personal information should not be informed the courier or the central laboratory. 
8.6. 
Sample Storage and Disposal 
The samples and any other components from the cells collected for the additional 
biomarker assessment and pharmacogenomicanalysis will be stored in the central 
laboratory up to 15 years. 
[Only for the Korean Study Sites] 
The investigator should ask subject how long samples can be stored when given informed 
consent. The storage period should be written by subject in the ICF. 
If the subject withdra ws consent, samples should be disposed of by the following 
procedure depending on the location of the tumor samples. Obtained data will not be 
discarded if the assessments have already been performed before consent was withdrawn. 
If samples are temporarily stored at the study site 
The investigator will identify the samples of the relevant subject and dispose of them. 
If samples are stored at the central laboratory 
The investigator will notify Daiichi Sankyo about the identification number of the subject 
who withdrew consent. Daiichi Sankyo will instruct the central laboratory to dispose of 
the relevant samples. Eventually, after the end of the sample storage period, the central 
laboratory will dispose of all samples as instructed by Daiichi Sankyo. 
8.7. 
Immunogenicity 
Blood samples will be collected for ADA analysis at the time points specified in 
Table 8.6. Serum concentrations of DS-820la and/or total anti-HER2 antibody may be 
measured using the same ADA samples for the purpose of anti-drug antibody assessment. 
Instructions for the handling and shippingof serum samples are included in a separate 
document (eg, the laboratory manual). 
The immunogenicity testing will be performed using validated ADA assay following 
tiered assay steps including sc reening, and confirmatory as well as titer determination. 
Samples confirmed positive will be banked until ava ilability of the neutralizing anti-drug 
antibody (NAB) assay. 


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Table 8.6: 
Anti-Drug Antibodies (ADA) Sampling Time Points 
 
Cycle 
Day 
Sampling Time Point (Acceptable Range) 
Cycle 1 
Day 1 
Bl (- 8 hours) 
Cycle 2 
Day 1 
Bl (- 8 hours) 
Every4 cycles from Cycle 4 
(eg, Cycle 4, 8, 12...) 
Day 1 
Bl (- 8 hours) 
F/ U 
- 
40 da ys (+7 days) after the last stud y drug 
administration or before starting new 
anticancer treatment, whichever comes first 
Q3F/U* 
- 
Every 3 months (±14 days). 
* For subjects with positive ADA at the F/U visit, additional serum ADA samples may be collected every 3 
months (±14 days) up to l year from the last dose of study drug, or if the ADA becomes negative, or if the 
ADA titer becomes less than at baseline (applicable when pre-existing ADA is observed), or if the subject 
starts another therapy for cancer, or withdraws consent for the study, whichever occurs first. 


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9. 
SAFETY EVALUATION AND REPORTING 
9.1. 
Assessment of Safety Endpoint(s) 
Safety endpoints will include SAEs, TEAEs, AESI, discontinuation due to AE, 
discontinuationdue to AESI, physical examination findings (including ECOG PS), vital 
sign measurements, standard clinical laboratory parameters, elevated troponin levels, ECG 
parameters, ECHO/MUGA findings, and ophthalmologic findings. TEAEs will be graded 
according to NCI-CTCAE version 4.03. Safety analyses in general will be descriptive and 
will be presented in tab ular format with the appropriate summary statistics. 
9.2. 
Adverse Event Collection and Reporting 
All clinical AEs occurring after the subject signs the main ICF for study participatio n and 
up to 40 (+ 7) days after last treatment (ie, the follow-up period), whether observed by the 
investigator or reported by the subject, will be recorded on the AE CRF page. All SAEs 
occurring after the subject signs the main ICF for study participation and up to 40 (+ 7) 
days after last treatment will be recorded on CRF. For subjects who sign only the 
Informed Consent Form for tissue sc reening, report only serious adverse events (SAEs) 
directly related to tissue screening procedure (ie, tumor biopsy). Unless documentation of 
other AEs is required by local law, only SAEs directly related to tumor biopsy will be 
recorded during tissue screening . Medical conditions (including laboratory values/vital 
signs that are out of range) that were diagnosed or known to exist prior to informed 
consent will be recorded as part of the medical history. 
All AEs, SAEs are to be reported according to the procedures in Section 9.5 SAE 
Reporting Procedure for Investigators. 
All clinical laboratory results, vital signs, and ECG results or findings should be assessed 
by the investigator to determine their clinical significance. Isolated abnorma l clinical 
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, or if they 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 of the subj ect at each study visit. Subjects should be questioned 
in a genera l way, without asking about the occurrence of any specific symptoms. The 
investigator must assess all AEs to determine their seriousness, severity, and causa lity in 
accordance with the definitions in Section 9.4. The investigator's assessment must be 
clearly documented in the site' s source documentation with the investigator's signature. 
Always report the diagnosis as the AE or SAE term. When a diagnosis is not available; 
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 
AEs or SAEs. 
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 


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an AE or SAE, but the reason for the procedure may be an AE or SAE. Pre-planned (prior 
to signing the ICF) procedures or treatments requiring hospitalization for pre-existing 
conditions that do not worsen in severity should not be reported as SAEs (see Section 
9.4.2 for Definitions). 
In case of death, the unde rlying or immediate cause of death should a lways be reported as 
a SAE. 
Progressive disease is a study endpoint and should therefore not be reported as an 
AE/SAE. However, when a subject dies from PD without other immediate causes, 
"Progressive disease" should be repo1ted as a SAE. 
Any serious, untowa rd event that may occur subsequent to the reporting period that the 
investigator assesses as related to the study drug should also be reported and managed as a 
SAE. 
If any AEs occur, the investigator will take appropriate actions and report the event to 
Daiichi Sankyo if necessary. The AEs should be followed until they resolve if possible, 
even beyond the post treatment follow-up period. Howeve r, if the AEs are not expected to 
recover, then follow-up during the clinical study is terminated. Even if follow-up during 
the clinical study is terminated, treatment of the event will be continued. Once post 
anticancer treatment is started, follow-up of the AE is terminated. 
9.3. 
Adverse Events of Special Interest 
Additional relevant info rmation regarding the AESis ILD/pne umonitis,QT prolongation, 
and LVEF decrease, for the DS-8201a clinical program regardless of seriousness is to be 
collected through the targeted questio nnaires within eCRF. Additional relevant 
information regarding the AESI Infusion related reaction is to be collected through the 
narrative form within eCRF. In the event that eCRF is unavailable, report AESis on a 
paper form. Once eCRF becomes available, please enter AESis reported on the paper 
form into eCRF as soon as possible. 
For broad surveillance of ILD/pneumonitis, relevant AEs under the MedDRA Standard 
MedDRA Query (SMQ) ofl nterstitial Lung Disease as well as preferred terms {PTs) of 
respiratory failure and acute respirato ry failure are included for enhanced data collections. 
For broad surveillance of LVEF decrease, relevant AEs under the MedDRA SMQs of 
Cardiac Failure is included for enhanced data collection; additional data for these AEs are 
collected via targeted questionnaires of heart failure. 
 
 
9.3.1. 
QT prolongation and LVEF decrease 
QT prolongation and LVEF decrease in association with DS-8201a are considered to be 
important potential risks based on the available pre-clinical data, literature and available 
safety info rmation for drugs of similar class. Refer to the current IB for a summary of 
preliminary clinical trial data. 
LVEF will be measured by either ECHO or MUGA scan. All ECHOs/MUGAs will be 
evaluated by the investigator or delegated physician for monitoring cardiac function. 
Troponin will be measured at screening and EOT and as needed based on subject reported 


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cardiac symptoms. Triplicate ECGs will be performed and standard ECG parameters will 
be measured, including RR, PR, QT intervals, and QRS duration. All ECGs must be 
evaluated by investigator or delegated physician for the presence of abnormalities. 
Whether or not meas urement is performed, date performed, res ults, and findings for each 
parameter will be recorded in the eCRF. 
9.3.2. 
Interstitial Lung Disease/Pneumonitis 
Clinical Summary 
ILD/pneumonitis is considered an important identified risk based on a comprehens ive 
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 
Adjudication Committee (AC), available data from recent epidemiology/literature, 
biological plausibilit y, and safety information from drugs of similar class. Refer to the 
current 1B for a summary of preliminary clinical study data. 
Management Guidance: 
ILD/pneumonitis should be ruled out if a subject develops radiographic changes 
potentially consistent with ILD/pneumonitis or develops an acute onset of new or 
worsening pulmonary or other related signs/symptoms such as dyspnea, cough or fever. 
If the AE is confirmed to have an etiology other than ILD/pneumonitis, follow the 
manageme nt guidance outlined in the designated "Other Non-Laboratory Adverse Events" 
dose modification section of the study protocol. 
If the AE is suspected to be ILD/pneurnonitis, treatment with study drug should be 
interrupted pending further evaluations. Evaluation s should incl ude high resolution CT, 
pulmonologi st consultat ion (infectious disease consultation as clinically indicated), blood 
culture and CBC (other blood tests could be considered as needed), bronchoscopy and 
bronchoalveolar lavage if clinically indicated and feasible should be considered, 
pulmonary function tests and pulse ox imetry (SpO2), arte rial blood gases if clinically 
indicated, and one blood sample collection for PK ana lysis as soon as ILD/pneurnonitis 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 " Pulmonaiy Toxicity" dose modification section of the study protocol. 
All events of ILD/pneumonit is regard less of sever ity or seriousness will be followed until 
resolution including after drug discontinuation. 
9.3.2.1. 
Interstitial Lung Disease Adjudication Committee 
An independent ILD Adjudication Co mmittee for the DS-820l a program is responsible 
for reviewing all cases of potential ILD/pneumonitis. To ensure adequate and relevant 
independentevaluation, systematic additional data collection will be conducted for all 
cases that will be brought for adjudication. These additional data collection will cover a 
more in-depth relevant medical history (eg smoking, radiation, COPD and other chronic 
lung conditions), diagnostic evaluation, treatment and outco me of the event. This data 
collection will be triggered for adverse events reported using MedDRA preferred terms 
(PT) from the current ILD SMQ. Please refer the guideline for the additional data 
collection and submission to ILD Adjudication Committee. 


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9.3.3. 
Infusion-related Reactions 
As with any therape utic antibodies, there is a possibility of infusion-related reactions, and 
immune respo nses ca using allergic or anaphylactic reactions following the administration 
of DS-820 l a. Immune respo nses causing allergic or anaphylactic reactions are considered 
to be an adverse event of special interest for the DS-820l a clinical program. Subjects 
receiving DS-820 la should be monitored vital signs, physical examination, and signs and 
symptoms of infusion related reaction: chills, fever, hypotension, skin rash, etc. Refer to 
the current 1B fo r a summary of preliminary clinical trial data. 
 
 
9.3.4. 
Independent Data Monitoring Committee (IDMC) 
IDMC will be established for this study. Details on the membership, responsibilities, and 
working procedures of the co mmittee will be described in its own charter. 
 
 
9.4. 
Adverse Events 
9.4.1. 
Definition of Adverse Events 
An AE is any untoward medical occurrence in a subject signing the main ICF for study 
participation, and that does not necessarily have to have a causal relationship with the 
treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated 
with the use of a medicinal product, whether considered related to the medicinal product 
(ICH E2A Guideline. Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting, Oct 1994). 
It is the responsibility of investigators, based on their knowledge and experience, to 
determine those circumstances or abnormal clinical laboratory findings that should be 
considered AEs. 
Definition of worsening of the underl ying tumor is described below. 
• 
Tumor progression including new lesion is not AE. However, if outcome of 
tumor progression is death during observation period of AE, it must be SAE. 
(Name of SAE is tumor progression, and outcome is death.) 
• 
If sign and worsening of symptoms along with tumor progression are detected, 
it is AE. 
• 
Rising of tumor maker is not AE. 
 
9.4.2. 
Serious Adverse Events 
A SAE is any untoward medical occurrence that at any dose: 
• 
Results in death, 
• 
Is life threatening, 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization, 


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• 
Results in persistent or significant disability/incapacity, 
• 
ls a congenital anomaly/birth defect, or 
• 
ls an important medical event. 
Note: The te1m " life threatenin g" in the definition of " serious" refers to an event in which 
the subject was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe (ICH E2A Guideline. 
Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, 
Oct 1994). 
Medical and scientific judgment should be exe rcised when deciding whether expedite d 
reporting is appropriate in other situations, such as impo rtant medical events that may not 
be immediate ly life threatening or result in death or hospitalization but may jeopardize the 
subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. Examples include allergic bronchospasm, convulsions, and blood 
dyscrasias or development of drug dependency or drug abuse. 
Note: 
• 
Procedures are not AEs or SAEs, but the reason for the procedure may be an 
AE or SAE. 
• 
Pre-planned (prior to signing the ICF) procedures or treatments requiring 
hospitalization for pre-existing conditions that do not worsen in severity are not 
SAEs. 
 
9.4.3. 
Severity Assessment 
All AEs will be graded (1 to 5; see below) according to the NCI-CTCAE version 4.03: 
• 
Grade 1 Mild AE 
• 
Grade 2 Moderate AE 
• 
Grade 3 Severe AE 
• 
Grade 4 Life-threatening co nsequences; urgent intervention indicated 
• 
Grade 5 Death related to AE 
Severity vs. Seriousness: Severity is used to describe the intensity of a specific event while 
the event itself, however, may be of relatively minor medical significance (such as severe 
headache). Serio usness of an event is based upon a universal and global Regulatory 
definition for reporting SAEs to regulatory agencies. For example, the NCI-CTCAE 
Grade 4 (life-threatening consequences; urgent intervention indicated) is assessed  based 
on unique clinical descriptions of severity for each AE, and these criteria may be different 
from those used for the assessment of AE seriousness. An AE assessed as Grade 4 based 
on the NCI-CTCAE grades may or may not be assessed as serious based on the 
seriousness crite ria. Overall, the severity of an event may be graded by the Investigator as 
Grade 1 or 2, but if the sub ject presents to the emergency facility for evaluatio n and is 
hospitalized overnight for observation that immediately makes the event serious based 
upon hospitalization without regard to the investigator assessment of severity. 


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9.4.4. 
Causality Assessment 
The investigator should assess the causal relat ionship between an AE and the study drug 
based on his/her clinical judgment and the following definitions. The causality assessment 
must be made based on the available information and can be updated when 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 , conc urrent diseases, and 
concomitant medications). 
or 
- 
The AE follows a reasonable temporal sequence from study drug 
administration, and is a known reaction to the drug under study or its 
chemical group, or is predicted by known pharmacology. 
• 
Not Related: 
- 
The AE does not follow a reasonable sequence from study drug 
administration, or can be reasonably explained by the subject's clinical 
state or other factors (eg, disease under study, concurrent diseases, and 
concomitant medications). 
 
9.4.5. 
Actions Taken Regarding Study Drug(s) 
• 
Dose Not Changed: No change in study drug dosage was made. 
• 
Drug Withdrawn: The study drug was permanently stopped. 
• 
Dose Reduced: The dosage of the study drug was reduced. 
• 
Drug Interrupted: The study drug was temporarily stopped. 
 
9.4.6. 
Other Actions Taken for Events 
• 
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, independent of 
whether medication was required or not. 
• 
Others 
 
9.4.7. 
Adverse Event Outcomes 
• 
Recovered/Resolved 
- 
The subject fully recovered from the AE and no residual effect is observed. 


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• 
Recovering/Resolving 
- 
The AE improved but has not fully resolved. 
• 
Not Recovered/Not Resolved 
- 
The AE itself is still present and observable. 
• 
Recovered/Resolved with Sequelae 
- 
The residual effects of the AE are still present and observable. 
- 
Include sequelae/resid ual effects. 
• 
Fatal 
- 
Fatal should be used when death is a direct outcome of the AE. 
• 
Unknown 
9.5. 
Serious Adverse Events and Adverse Events of Special Interest 
Reporting-Procedure For Investigators 
All AEs, AESI, SAEs and medication errors including overdose, will be reported in the 
CRF. 
Serious events that are also efficacy endpoints (eg, PD) will be exempted from SAE 
processing and expedited reporting. Disease progression should not be reported as an 
AE/SAE. However, when a subject dies from PD with no other immediate causes, 
"disease progression" should be repo1ted as a SAE and captured on designated eCRF. 
These events are clinically anticipated events in the target treatment population, and will 
be periodically reviewed by the Daiichi Sankyo safety teams to ensure prompt 
identification of any clinically concerning safety issues. 
The following types of events should be reported by the investigator in electronic data 
capture (EDC) within 24 hours of becoming aware of it: 
• 
SAEs (see Section 9.4.2 for definition) 
• 
All potential ILD/pneumonitiscases should be reported within 24 hours; 
including both serious and non-serious potent ial ILD/pne umonitis cases. 
• 
Hepatic events (both serious and non-serious) which meet the potential Hy's 
Law criteria defined as an elevated (ALT or AST) 2: 3 x ULN and an elevated 
TBL > 2 x ULN that may occur either at different time points or  
simultaneous ly 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 conside red both excessive and medica lly important. An 
"excessiveand medically important" overdose includes any overdose in which 
either a serious adverse event, a non-serious adverse event, or no adverse event 
occurs and is considered by the Investigator as clinically relevant, i.e. poses an 
actua l 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 overdo se includin g DS-820la dosage, 
clinical course, assoc iated AEs, and outcome must be captured in the 
Narrative form of the CRF within eCRF. 
If any SAEs occur, the investigator should also immediately report the event to the heads 
of the study sites. An SAE report will be submitted to the heads of the study sites in 
accordance with the procedures and format of the study site. 
All events (serious and non-serious) must be reported with the investigator's assessment of 
the event's seriousness, severity, and ca usality to the study drug. A detailed narrative 
summarizing the course of the event, including its evaluation, treatment, and outcome 
should be provided. Specific or estimated dates of the event onset, treatment, and 
resolution should be included when available. Medical history, concomitant medications, 
and laboratory data that are relevant to the event shouldalso 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 Daiichi Sankyo 
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 unava ilable, report SAEs on a Serious Adverse Event Report 
(SAVER) form (Supplement 5). All completed SAVER forms must be signed by the 
investigator,and e-mailed or faxed to the CRO using the provided SAVER form and the 
appropriate fax number provided. Once eCRF becomes available, please enter SAEs 
reported on the SAVER Form into eCRF as soon as possible. Once eCRF becomes 
available, please enter SAEs reported on the SAVER Form into eCRF as soon as possible. 
See Section 15.12.5 for contact information for SAE reporting. Please call the local SAE 
Hotline (see Study Manual) or your study monitor for any questions on SAE reporting. 
9.6. 
Notifying Regulatory Authorities, Investigators, and the 
Institutional Review Board/Ethics Committee 
Daiichi Sankyo and/or the CRO will inform investigators, Institutional Review 
Boards/Ethics Committees (IRBs/ECs), and regulatory authorities of any Suspected 
UnexpectedSerious Adverse Reactions (SUSARs) that have occurred at other study sites 
or in other studies of the study drug, as appropriate per local reporting requirements. 
Daiichi Sankyo and/or the CRO will comply with any additional local safety reporting 
requirements. 


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9.7. 
Exposure In Utero During Clinical Studies 
Daiichi Sankyo must be notified of any subject or their female partner who becomes 
pregnant while receiving or within 7 months of discontinuing the study drug. 
Although pregnancy is not technically an AE, all pregnancies must be followed to 
concl usion to determine their outcome. This information is important both for drug safety 
and public health concerns. It is the responsibility of the investigator, or designee, to 
report any pregnancy of a female subject using the Expos ure In Utero (EIU) Reporting 
form (Supplement 6). 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 informat ion, including normal delivery or induced abortion. 
The adve rse pregnancy outcome, either se rious or non-serious, should be reported in 
accordance with the study procedures. If the outcome of the pregnancy meets the criteria 
for immediate classification as a SAE (ie, post-partum complications, spontaneous or 
induced abortion, stillbirth, neonatal death, or congenital anomaly, including that in an 
aborted fetus), the invest igato r shou ld follow the procedures for reporting SAEs outlined 
in Sectio n 9.5. 


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9.8. 
Clinical Laboratory Evaluations 
The following clinical laboratory tests will be performed: 
 
Laboratory test 
Parameters 
Hematology 
Red blood cell count, hemoglobin, hematocrit, platelet count, 
white blood cell count, differential white blood cell count 
(neutrophils, lymphocytes, monocytes, eosinophils, basophils) 
Blood Chemistry 
Total protein, albumin, ALP, ALT, AST, total bilirubin, BUN, 
Ca, Cl, serum creatinine, LDH, K, Na, Mg, ln temational 
nonnalized ratio (INR)/Prothrombin time (PT) and activated 
partial thromboplastin time (aPTT) 
Urinalysis test 
Protein, glucose, blood, microscopy assessments (if indicated), 
and specific gravity 
The following parameters will also be analyzed at the visits indicated in Section 18. 
• 
Pregnancy test (serum or urine) for all female subjects of childbearing potential 
must be performed during the Screening Period. A positive urine pregnancy 
test result must immediately be confirmed using a serum test. 
• 
Troponin (preferably troponin-T) test must be performed at the visits indicated 
in Section 18. Additional troponin testing should be performed if subject 
reports cardiac symptoms. Same assay should be used for the subject thro ugh 
o ut their stud y participat ion. 
 
 
All clinical laboratory values must be assesse d by the investigator for clinical sign ifi cance 
a nd used to take appropriate clinical manage ment measures. All abnormal clinical 
laboratory values considered clinically significant by the investigator should be recorded 
on the AE page of the eCRF. If the abnormal laboratory value constitutes a SAE, the 
event should be reported on the AE page of the eCRF as an SAE and other relevant 
procedures must be followe d (see Section 9.5). Abnormal laboratory values (NCI­ 
CTC AE Grade 3 or 4) occ urrin g durin g the clini ca l study will be followed until repeat test 
results return to normal (or base line), stabilize, or are no longer clini ca lly sign ificant. 
 
9.9. 
Vital Signs 
Vital sign meas urements will include systolic and diastolic blood pressure and pulse rate 
and body temperature. Additionally, SpO2 w ill be meas ured before administration on Day 
1 of each cycle and EOT. 
 
9.10. 
Electrocardiograms 
Standard supine 12-lead ECGs in triplicate will be performed in the schedule of eve nts. 
Standard ECG parameters will be measured,  incl uding  Hea rt rate,  RR, PR, QT intervals, 
and QRS duration. All ECGs must be eva luated by the investigator or delegated  physician 
for the presence of abnormalities 


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9.11. 
Physical Examinations 
Physical examination findings including ECOG PS will be used to evaluate the following 
body systems/organs: general appearance; dermatological; head and eyes; ears, nose, 
mouth, and throat; pulmonary; cardiovascular; abdomina l; genitourinary (optional); 
lymphatic; musc uloske leta l/extremities; and neurological. Weight and height will also be 
recorded in kilograms and centimeters, respectively. 
 
9.12.  
ECOGPS 
Other Examinations 
Cardiac Assessments 
Either ECHO or MUGA scan will be performed as described in the schedule of events. 
LVEF will be measured by either ECHO or MUGA scan. 
Ophthalmic Assessments 
Ophthalmic assessments will include visual acuity testing, slit lamp examination and 
fundoscopy 
Pulmonary Assessments 
Pulmonary assessment will include CT or MRI of the chest, SpO2 and will be performed 
as described in scheduleof events. For more details please refer to Section 6 of the 
protocol. 
An ILD AC will review all cases of potential ILD/pneumonitis on an ongoing basis. 
Description of the ILD AC is available in Section 9.3.2.1. 


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10. 
OTHER ASSESSMENTS 
10.1. 
Patient Reported Outcomes 
Patient reported outcomes (PRO) will be used in both groups of Primary Cohort to 
evaluate study treatment and comparator and will be measured on the sa me days as well as 
EOT. The impact of gastric cancer symptoms will be assessed based upon the FACT-Ga 
(Version 4.0) and EQ-5D-5L questionna ires (Section 17.5). FACT-Ga and EQ-5D-5L are 
completed on Day 1 before any tests/seeing Investigator, Day 15 (±1), the every 6 weeks 
from the beginning of the study (eg, Day 43 (±7), 85 (±7), 127 (±7), etc.), and EOT. EQ- 
5D-5L questionnaire to be completed first and then FACT-Ga questionnaire. 
10.1.1. 
EQ-5D-SL 
The EQ-5D-5L is a widely used generic health-related quality of life (QoL) instrument 
that allows for estimation of health utility. 
The EQ-5D-5L is self-administered and consists of 2 parts, the EQ-5D-5L descriptive 
system, and the EQ Visual Analogue Scale (VAS) (Herdman M, Gudex C, Lloyd A, 
Janssen MF, Kind P, Parkin D, Bonsel G, Badia X. Development and preliminary testing 
of the new five-level version ofEQ-5D (EQ-5D-5L). Quality of Life Research.(2011) 20: 
1727). The descriptivesystem comprises 5 dimensions (mobility, self-care, usual 
act ivities, 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 
cardin al 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 use d as a q uantitative measure of health as judged by 
the individual respondents. 
10.1.2. 
FACT-Ga 
The FACT-Ga is one of several instruments developed to assess QOL in patients with 
gastric cancer. The FACT-Ga is a 46-item Likert-scaled questionnaire, with response 
scores ranging from Oto 4. The response categories include ' Not at all', ' A little bit', 
'Somewhat', 'Quite a bit' , and 'Very much' . Negatively worded items  are reverse-scored 
so that all participants who experience a higher severity of symptoms  receive a lower 
score (FACT-Ga: a new international measure of QOL in gastric cancer, Eremenco SL, 
Cashy J, Webster K, J Clin Oncol, 2004). The measure is based on the Functional 
Assessment of Cancer Therapy-General (FACT-G) (The Functional Assessment of Cancer 
Therapy scale: development and validation of the general measure, Cella DF, Tulsky DS, 
Gray G, J Clin Oncol, 1993), which is composed of four unid imensional factors (physical, 
social/family, emotional, and functional well-being), and includes a 19-item 
multidimensional ' Additional Concerns' subscale composed of items specifically 
pertaining to a wide range of symptoms related to gastrointestinal cancer. 


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10.1.3. 
Health Care Resource Utilization. 
Time to SAE related hospitalization will be assessed for the Primary Cohort only. Each 
hospitalization event will prompt the completion, by the site, of a detailed hospitalization 
eCRF containing the following components: 
1. 
Date of SAE related admiss ion to hospital. 
11. Date of SAE related dischargefrom hospital. 
111. Primary reason for SAE related hospitalization. 
1v. Disc hargestatus from SAE related hospital (died, discharged home, discharged to 
home health care, discharged to nursing home care, dischargedto long-term care, 
other). 
v. 
Use of intensive care unit (ICU) services in hospital (Yes/No). 
a. If yes, date of admission to ICU. 
b. If yes, date of discharge from ICU. 


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11. 
STATISTICAL METHODS 
11.1. 
General Statistical Considerations 
The primary analysis for ORR and formal interim analysis for OS will be performed when 
all subjects have completed tumor assessment approximatelyat 24 weeks (or discontinued 
the study) in Primary Cohort. The final OS analysis will be performed when about 133 
OS events are observed in Primary Cohort. 
Summary statistics will be presented by cohort/treatment group. Cont inuous varia bles will 
be summarized by the number of observations, mean, standard deviation, median, 
minimum, and maximum values (as well as geometric means and geometric coefficient of 
variation for Cmax and AUC PK parameters). Categorical variables will be summarized 
using frequency counts and percentages. 
Assessment of change from baseline to post-treatment or the ratio of post-treatment to 
baseline will include only those subjects with both baseline and post-treatment 
measurements. The last non-missing value of a variable taken before the first dose of the 
study drug will be used as the base line value, unle ss otherwise specified. In general, 
missing or dropout data will not be imputed for the purpose of data analysis, unless 
otherwise specified. 
Analyses of ORR and DCR will be performed on the Response Evaluable Set. The other 
efficacy analyses will be performed on the full analysis set (FAS). Safety analyses will be 
performed using the Safety Analysis Set. Analysis of PK parameters will be based on the 
PK Analysis Set. All other exploratory analyses will be performed based on the FAS and 
the availability of assessments. 
 
11.2. 
Analysis Sets 
11.2.1. 
Full Analysis Set 
TheFAS for the Primary Cohort will include all randomized subjects who received at least 
1 dose of the study treatment. The FAS for the each of the Exploratory Cohorts will 
include all subjects who received at least 1 dose of the study treatment. 
 
11.2.2. 
Response Evaluable Set 
The Response Evaluable Set for the Primary Cohort will include all randomized subjects 
who received at least 1 dose of study drug and had measurable tumors based on central 
review at baseline. The Response Evaluable Set for the each of the Exploratory Cohorts 
will include all subjects who received at least 1 dose of the study treatment and had 
measurable tumors based on central review at baseline. 
 
11.2.3. 
Safety Analysis Set 
The Safety Analysis Sets for the Primary and each of the Exploratory Cohorts will include 
all subjects who received at least one dose of the study treatment. Subjects will be 
summarized according to treatment actually received. 


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11.2.4. 
Pharmacokinetic Set 
The PK Analysis Sets for the Primary and each of the Exploratory Cohorts will include all 
subjects who received at least one dose of DS-820l a and had measura ble serum 
concentrations of DS-820la. 
11.3. 
Study Population Data 
Subject disposition will be summarized for the enrolled subjects in each cohort. The total 
number of subjects for each defined analysis set will also be tabulated for each cohort. 
The demographic and baseline characteristics will be summar ized descriptively for the 
FAS, Response Evaluable Set, and the Safety Analysis Set for each cohort. Study drug 
exposure, treatment duration, and comp liance with study therapy as well as prior and 
concomitant medications will be summarized us ing descriptive statistics for the Safety 
Analysis Set for each cohort. 
 
11.4. 
Statistical Analyses 
11.4.1. 
Efficacy Analyses 
 
11.4.1.1. 
Primary Efficacy Analyses 
The primary endpoint is ORR (the proportion of subjects who achieved a best overall 
response of CR or PR) assessed by independent central imaging facility review based on 
RECIST version 1.1. The primary efficacy analysis will be performed for the Response 
Evalua ble Set in the Primary Cohort. A Cochran-Mantel-Haenszel (CMH) test with 
region as a stratification factor will be used to compare ORR between the treatment 
groups. The primary efficacy analysis for ORR will be assessed for statistical significance 
at 2-sided alpha= 0.05. 
The estimate of ORR and its 2-sided 95% exact CI will be provided for each 
cohort/treatment group. In addition, ORR by each fixed time point (eg, 3, 6, 9, 12 months) 
along with their 2-sided 95% exact Cls will be provided for each cohort/treatment group. 
 
11.4.1.2. 
Secondary Efficacy Analyses 
The secondary efficacy endpoints include OS, PFS, DoR, DCR (the proportion of subjects 
who achieved a best overall response of CR or PR or Stable Disease [SD]), TTF, and ORR 
assessed  by independent central imaging facility review (for each Exploratory Cohort 1 
and 2) and the investigator based on RECIST version 1.1. 
OS is defined as the time from the date ofr andomization (the date of the registration for 
Exploratory Cohorts) to the date of death from any cause. If the death of a subject is not 
reported before the data cut-off for OS analysis, OS will be censored at the last contact 
date at which a subject was known to be alive. 
PFS is defined as the time from the date of randomization (the date of the registration for 
each of the Exploratory Cohorts) to the earlier of the dates of the first radiographic PD via 
independent central imaging facility review based on RECIST version l. l or death due to 
any cause. If the PD (eg, clinical diagnosis of PD) is not confirmed  by central imaging, 
PFS will be censored at the last day of imaging assessment. Detailed censoring rules for 
PFS will be specified in the statistical analysis plan (SAP). 


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DoR is defined as the time from the date of the first objective response (CR or PR) to the 
date of the first disease progression or death due to any cause. DoR will be measured for 
respo nding subjects (CR or PR) only. Detailed censoring rules for DoR will be specified 
in the SAP. 
TTF is defined as the time from the date ofr andomization (the date of the registration for 
Exploratory Cohorts) to the earliest date of the first radiographic PD, death due to any 
cause, or treatment discontinuation. Detailed censoring rules for TTF will be specified in 
the SAP. 
OS and PFS will be compared between the treatment groups using stratified log-rank tests 
with region as a stratification factor in Primary Cohort. To control the family-wise type I 
error rate (FWER) for primary and secondary efficacy endpoints, a serial hierarchically 
ordered gatekeeping strategy will be applied. The tests will be performed in the followi ng 
order: ORR, OS. The sequence of tests will continue until the test does not meet the 
significancelevel of 2-sided alpha = 0.05. The testing procedure will follow the steps 
below: 
l. Test the primary endpoint, ORR, at a 2-sided 5% significance level. If positive, 
continue to step 2; otherwise,stop. 
2. Test OS (interim and final analyses) at an overall 2-sided 5% significance level. 
The first analysis of OS will occur at the time of the primary analys is for ORR only if 
ORR meets the significance level of 2-sided alpha 0.05. The final analysis of OS will 
occur when about 133 OS events are observed in the Primary Cohort. A Lan-DeMets 
alpha-spending function with the O'Brien-Fleming stopping boundary will be used to 
determine the significance level at the first and final analysis of OS. The HRs and their 
95% CI will be estimated using stratifiedCox proportional hazardsregression models with 
region as a stratificationfactor. Kaplan-Meier estimates and survival curves will also be 
presented for each cohort/treatmentgroup. 
OS , PFS , DoR , and TTF will be summarized with median event times and their 2-sided 
95% CI for the median using Brookmeyer and Crowley methods for each cohort/treatment 
group. In addition, Kap lan-Meier estimates at each fixed time point (eg, 3, 6, 9, 12 
months) along with their 2-sided 95% Cis will be provided for each cohort/treatment 
group. 
DCR will be analyzed in the same manner as ORR analysis. 
 
11.4.1.3. 
Exploratory Efficacy Analyses 
 
11.4.1.3.1. 
Analyses of Exploratory Efficacy Endpoints 
 
 
Duration of SD, time to response, time to SAE related hospitalization, best percent change 
in the sum of diameters of measurable tumors, and PFS based on investigator assessment 
will be evaluated and considered as exploratory efficacy endpoints. 
Duration of SD is defined for subjects whose best response is SD as the time from the date 
of the first dose to the date of the first documentation of PD. Detailed censoring rules for 
duration of SD will be specified in the SAP. 


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Time to response is defined as the time from the date of the first dose to the date of the 
first documentation of objective response (CR or PR). Time to response will be measured 
for responding subjects (CR or PR) only. 
Duration of SD, time to response, and time to SAE related hospitalization will be 
summarized with median event times and their 2-sided 95% CI for the median by 
cohort/treatment group using Kaplan-Meier methods. 
Time to SAE related hospitalization, and PFS based on investigator assessment will be 
analyzed in the same manner as OS and PFS analyses. 
Descriptive statistics for the best (minimum) percent change from baseline in the sum of 
diameters will be provided by cohort/treatment group. A waterfall plot of the best 
(minimum) percent change in the sum of diameters for each subject will be presentedfor 
each cohort/treatment group with vertical lines representing the sorted values of percent 
changes. A spider plot of the percent change in the sum of diameters for each subjec t will 
be also presented for each cohort/treatment group. 
11.4 .2. 
Pharmacokinetic /Pharmacodynamic/Biomarker Analyses 
 
11.4.2.1. 
Pharmacokinetic Analyses 
Serum concentrations for DS-820l a, total anti-HER2 antibody and MAAA- l 18la will be 
listed, plotted, and summarized using descriptive statistics by cohort/treatment arm at each 
time point. PK param ete rs will be listed and summarized using desc riptive stat istics by 
coho rt/treatment arm. 
The population pharmacok.inetic (pop-PK) analysis to evaluate the effect of intrinsic and 
extrinsic factors of DS-8201a, and if appropriate, total anti-HER2 antibody and MAAA- 
1181a will be characterized,  including available  PK data from the Phase 1 (DS8201-A- 
Jl Ol ) study. After establishment of the pop-PK model, a population 
pharmacokinetics/pharmacodynamics (pop-P K/PD) model will be developed to evaluate 
the relationship between exposure and efficacy and tox icity. The pop-PK and pop-PK/PD 
will be reported in a separate report from the clinical study report 
11.4.2.2. 
Pharmacodynamic Analyses 
Not applicable 
 
11.4.2.3. 
Biomarker Analyses 
Biomarkers will be listed and summarized using desc riptive stat istics. 
 
11.4 .2.4. 
Pharmacogenomic Analyses 
Not applicable 
 
11.4.3. 
Safety Analyses 
Safety analyses in general will be descriptive and will be presented in tabular format with 
the appropriate summary statistics. 
Safety analysis will be performed using the Safety Analysis Set for each cohort and 
subjects will be analyzed according to their actual treatment received. 


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) 
11.4.3.1. 
Adverse Event Analyses 
A TEAE is defined as an AE that emerges during the treatment period (from date of first 
dose unti l the F/U visit after the last dose of the study drug), having been absent at pre­ 
treatment; or reemerges during treatment, having been present at baseline but stopped 
prior to treatment; or worsens in severity after starting treatment related to the pre­ 
treatment state, when the AE is continuous. TEAEs will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA) and assigned grades based on version 
4.03 of NCI-CTCAE . The number and percentage of subjects reporting TEAEs will be 
tabulated by System Organ Class (SOC), Preferred Term (PT), relationship to the study 
treatment, and the worst CTCAE grade. Similarly, the number and percentage of subjects 
reporting serious TEAEs will be tabulated by cohort/trea tment group, as well as TEAEs 
leading to disco ntinuation of the study treatments. 
A by-subject AE (including TEAE) data listing including but not limited to the verbatim 
terms, SOC, PT, NCI-CTCAE grade, and relationship to study treatment will be provided. 
Deaths, other SAEs, and other significant AEs, including those leading to discontinuation 
of the study treatments, will be listed. 
 
11.4.3.2. 
Clinical Laboratory Evaluation Analyses 
Descriptive statistics will be provided for the clinical laboratory test results and changes 
from baseline by cohort/treatment group at each scheduled time of evaluation, including 
the EOT visit, maximum post-treatment value, and minimum post-treatment value. 
Abnormal clinical laboratory results will be graded according to NCI-CTCAE version 
4.03, if applicable, and the grade will be presented in a by-subject data listing. A shift 
table, presenting 2-way frequency tabulation for baseline and the worst post-treatment 
value acco rdin g to NCI-CTCAE grade, will be provided for clinical laboratory tests. 
All clinical laboratory test results and abnormal clinical laboratory test results deemed of 
clinical significanceor of Grade 3 or 4 will be listed. 
11.4.3.3. 
Vital Sign Analyses 
Descriptive statistics will be provided by cohort/treatment group for the vital sign 
measurements and changes from baseline by scheduled time of evaluatio n, including the 
EOT visit and the maximum and minimum post-treatment values. All vital sign data will 
also be listed. 
11.4.3.4. 
Electrocardiogram Analyses 
Descriptive statistics will be provided by cohort/treatment group for ECG parameters and 
changes from baseline by scheduledtime of evaluation, includin g the EOT visit and the 
maximum post-treatment value. In add ition, the numb er and percentage of subjects with 
ECG interval values meeting the criteria will be tabulated (eg, QTc 450 ms, >450 to 
80 ms, >480 ms to 500 ms, and >500 ms). The QT intervals will be corrected for 
hea1trate by Fridericia's f01mula (QTcF = QT/[RR]'/3 
ECG data will also be listed. 


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11.4.3.5. 
Anti-Drug Antibodies Analyses 
A shift table, presenting the 2-way freq uency tabulation for base line and all sc hedule 
times, incl uding the EOT Visit, will be provided for each cohort/treatment group the 
incidence of ADA. 
11.4.3.6. 
Other Safety Analyses 
All other safety endpoints (eg, physical examination findings including EC OG PS, 
ECHO/MUGA, and ophthalmologic findings) will be listed. 
11.4.4. 
Other Analyses 
 
11.4.4.1. 
Subgroup Analyses 
Subgro up analyses for ORR, OS, PFS, DoR, and DCR will be performed. TEAEs will be 
also summarized by cohort/treatment group for eac h subgro up. Subgroups will include: 
• 
Region (Japan, Korea) 
• 
Lines of prior systemic therapy (2, 3, 24). 
• 
Age (<65, 265 years). 
• 
Sex (female, male). 
• 
ECOG PS (0, l ). 
• 
HER2 status (Primary Cohort: IHC 3+ or IHC 2+/ISH +) 
• 
Primary tumor locat ion (Gastric/GE]) 
• 
Histological subt ype(Intestinal or Diffuse or Others) 
• 
Number of metastatic sites (<2, 22) 
• 
Previous total gastrectomy (Yes or No) 
• 
Prior adjuvant/ neoadjuvant therapy (Yes or No) 
• 
Prior Ramcirumab contained treatment (Yes or No) 
• 
Prior treatment with irinotecan or other topoisomerase I inhibitors (Yes or No) 
• 
Most recently treatment with irinoteca n or other topoisomerase I inhibitors (Yes or 
No) 
• 
Prior treatment with checkpoint inhibitor or other immuno-o ncology therapy (Yes 
or No) 
• 
Most recently treatment with trastuzumab or trastuzumab similar treatment 
including study drug (Yes or No) 
• 
Presence of liver metastasis at baseline (Yes or No) 
• 
Renal impairment at baseline (within normal range, and mild/moderate 
impairment) 
• 
Physician's choice treatment (DS-820l a vs irinotecan or paclitaxel in physician's 
choice group) 


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In each subgroup defined above, the analysis will be carried out using the same type of 
methodology as described for the overall analysis of the corresponding endpoint. 
 
11.4.4.2. 
Analyses of Exploratory HEOR Endpoints 
HEOR endpoints (eg, EQ-5D-5L, FACT-Ga, health care resource utilization) will be 
summarized using standard methods of analysis for the corresponding questionnaires and 
descriptive statistics for the actual value and change from baseline will be computed for 
the summarized index scores for all subjects and by treatment group for the FAS in the 
Primary Cohort. Further details will be provided in the SAP. 
 
11.5. 
Interim Analyses 
One formal interim OS analysis will be conducted  when all subjects have completed 
tumor assessment approximately at 24 weeks (or discontinued the st udy) in Primary 
Cohort assumi ng the OS events observed thus far do not reach the target number of OS 
events (i.e., 133 OS events in Primary Cohort). The interim OS will be tested only if ORR 
shows the statistical significance at 2-sided alpha  = 0.05.  The overall 2-sided alpha is to 
be controlled at 0.05 for the interim OS analysis and final OS analysis using the Lan­ 
DeMets alpha-spending function with an O' Brien-Flemingboundary.  The boundary used 
at the  interim and final OS analysis depends on the actual number of observed deaths at 
the interim analysis. 
 
 
11.6. 
Sample Size Determination 
A total of approximately 220 (Primary Cohort: approximately 180, Exploratory Cohort 1: 
approximately 20, and Exploratory Cohort 2: approximately 20) will be enrolled. 
Primary Cohort 
Combined analysis of ORR from Phase 2 and 3 studies (a total of 13 studies) of second- or 
subsequent-line chemotherapyin patients  with gastric cancer was conducted. 32 As a 
result, the combined ORR was 9.4% (95% confidence interval [CI]: l. l% to 
17.7%).3, 3 3, 4 3, 5 3, 6 3,7 3, 8 3, 9 4, 0 4, 1 4, 2 4, 3 4, 4 45   The ORR in the physician' s choice  gro up was 
conservatively assumed to be 15%, which exceeded the above-mentioned combined mean 
estimate of ORR. The ORR in DS-820 la monotherapy group was also assumed to be 
40%. The sample size of 180 subjects (120 subjects to DS-820la monotherapy group and 
60 subjects to the physician's choice group) provides a 92.9% power to detect this 
magnitude of difference using a Fisher's exact test at 2-sided alpha = 0.05 level of 
significance. 
Approximately 133 OS events will be needed to detect a HR of 0.61 for OS (a 64% 
improvement in median OS from 5.5 months in the physician's choice group to 9.0 
months in DS-820 la monotherapy group) with an 2-sided alpha = 0.05 level of 
significanceand 80% power. The sample size of 180 subjects also provides an 80.8% 
power to detect this magnitude of OS difference, ass uming a 10-month long enrollment 
period and a 12-month follow-up period after the last subject is randomized. 
Exploratory Cohort (l and 2) 


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The probability that more than 4 responders out of 20 subjects (ORR >20%) are observed 
will be less than 20% under the lower reference value of ORR= 15%, but more than 75% 
under the expected ORR = 30%. 
The power computation is performed using the POWER procedure of SAS® Vers io n 9.3. 
 
11.7. 
Statistical Analysis Process 
The clinical study will be analyzed by Daiichi Sankyo or its agent/CRO followed by this 
protoco l, and the SAP which will demonstrate all methodologies and disp lays/shells for 
statistical analyses. 
The SAP will provide the statistical methods and definitions for the analysis of efficacy 
and safety data, and will describe the approaches to be taken to summarize other clinical 
study information such as subject disposition,demographic and baseline characteristics, 
stud y drug exposure, and prior and concomitant medications. The SAP will also include a 
description of how missing, unused, and spurio us data will be addressed. 
To preserve the integrity of the statistical analysis and clinical study conclusions, the SAP 
will be finalized prior to database lock. 
All statistical analyses will be performed using SAS® Ve rs io n 9.3 or higher (SAS Institute, 
Cary, NC 27513). 
 
12. 
DATA INTEGRITY AND QUALITY ASSURANCE 
For the purpose of monitoring and auditing by Daiichi Sankyo and inspection by the 
regulatory authoriti es and/or the IRB, the study site should provide direct access to all 
documents and records related to this study, includin g the source documents. To verify 
the proper conduct of the study and the absolute reliability of the study data, Daiichi 
Sankyo should perform monitoring and auditing by reviewing the source documents and 
other relevant documents directly. Daiichi Sankyo should arrange the procedures for 
direct access to these documents in advancewith the investigator. Direct access includes 
permission to examine, analyze, verify, and reproduce any records and reports that are 
important for evaluation of a clinical study. 
 
12.1. 
Monitoring and Inspections 
Daiichi Sankyo or CRO monitor and the regulatory authority inspectors are responsible for 
contacting and visiting the  investigator for the purpose  of inspecting the facilities, and 
upon reque st, inspecting the various record s of the study (eg, CRFs, source data, and other 
pertinent documents). 
The verification of adherence to the protocol; completeness, accuracy, and consistency of 
the data; and adherence to ICH GCP and local regulations on the conduct of clinical 
research will be accomplished through a combination of onsite visits by the monitor and 
remote review of study data. The frequency of the monitoring visit will vary based on the 
activity at each study site. The monitor is responsible for inspecting the CRFs and 
ensuring completeness of the essential study documents. The monitor should have access 
to subject medical records and other study-related records needed to verify the entries on 
the CRFs. Detailed information is provided in the monitoring plan. 


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The monitor will communicate deviations from the protocol, SOPs, GCP and applicable 
regulations to the investigator and will ensure that appropriate action(s) designed to 
prevent recurrence of the detected deviations are taken and documented. 
The investigator agrees to cooperate with the monitor to ensure that any problems detected 
in the course of these monitoring visits are addressed to the satisfaction of Daiichi Sankyo 
and are documented. 
In accordance with ICH GCP and the Daiichi Sankyo's audit plans, this study site may be 
selected for audit by representatives of Daiichi Sankyo. Audit of study site facilities (eg, 
pharmacy, drug storage areas, laboratories) and review of study-related records will be 
performed to eva luate the study conduct and compliance with the protocol, ICH GCP, and 
app lica ble regulatory requirements. The investigator should respon d to the audit finding s. 
In the event that a regulatory authority informs the investigator that it  intends to conduct 
an inspection, Daiichi Sankyo will be notified immediately. 
12.2. 
Data Collection 
An eCRF must be completed for each subject who signs an ICF (including a se parate 
tiss ue screening ICF) . The investigator, sub-investigator, or study site staff will enter the 
data in the CRF in accordance with the CRF Completion Guidelines that are provided by 
Daiichi Sankyo. 
CRF completion should be kept cmTentto enable the monitor to review the subject' s status 
throughout the course of the study.  CRFs will be completed, reviewed, and e-signed by 
the investigator. 
The investigator e-signs according to the study data flow. 
Any clinical data entered in the CRF will be subject to these data management procedures 
and will be included in the final study data sets according to CDISC standards. 
Daiichi Sankyo or a designee will supply eCRFs. 
All data collected during the study will 
be recorded in this individual, subject-specific eCRF. Instructions will be provided for the 
completion of the eCRF and any corrections made will be automatically documented via 
the EDC software's "audit trail." 
Data for all study visits will be recorded on the eCRF for subjects who have received the 
study drug. Only minimal data will be recorded as screening failures on the eCRF for 
subjects who do not meet eligibility and/or do not receive the study drug. Further data, 
such as AEs, will not be collected from subjects once they are considered screening 
failures or have decided to withdraw prior to receiving the study drug. 
Data will be electronically recorded using the EDC {Table 12.l) system, which enables the 
preparation of eCRF. The CRF and audit trail will be prepared using the EDC system. 
The signed eCRF will be treated as an original report. The EDC system should be 
validated before use. 


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Table 12.1: 
EDC System 
 
Name of EDC system 
Medidata Rave® 
E D C s ystem developer 
Medidata Solutions lnc. 
Entry method 
Web-based data entry 
Input tenninal 
Des ktop/laptop computer at the study site 
Incompatible operating 
systems 
None 
Recommended browsers The Medidata Rave® s upports any browser which is HTML 5 and CSS2 
compliant. Browsers must have JavaScript enabled. 
Screen Resolution 
The minimum screen resolution required to properly display Medidata 
Rave applications is 1024 x 764. 
Connection Speed 
128kbps is the minimum connection speed recommended for using 
Medidata Rave. 
Othe r 
Adobe Flash Player : ver. 10 or above is required 
 
 
12.3. 
Data Management 
Each subject will be identified in the database by a unique subject ID as defined by 
Daiichi Sankyo. 
To ensure the quality of clinical data across all subjects and study sites, a Clinical Data 
Manage ment review will be performed on subject data according to specifications given to 
Daiichi Sankyo or CRO. Data will be vetted both electronically and manua lly for CRFs 
and the data will be electronically vetted by programmed data rules within the applicatio n. 
Queries generate d by rules and raised by reviewers will be generate d 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 ce ntral labs will be reconciled with the 
clinical database. 
SAEs in the clinical database will be reconciled with the safety database. 
All AEs will be coded using MedDRA. All prior cancer therapy and prior/concomitant 
medications entered into the database will be coded using the latest version of the World 
Health Organization Drug Dictio nary. 
12.4. 
Study Documentation and Storage 
The investigator will maintain a Signature List of appropriately qualified persons to whom 
he/she has delegated study duties. All persons authorized to make entries and/or 
corrections on CRFs will be included on the Signature List. 
Investigators will maintain a confidential screening log of all potential study candidates 
that includes limited information of the subjects, data and the outcome of the screening 
process. 


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Investigators will be expected to maintain an Enrollment Log of all subjects enrolled in the 
study indicating their assigned study number. 
Investigators will maintain a confidential site subj ect identifier list. This confidential list 
of names of all subjects allocated to study numbers when enrolling in the study allows the 
investigator to reveal the identity of any subject when necessary. 
Source documents are original documents, data, and records from which the subject's CRF 
data are obtained.  These include,  but are not limited to, hospital records, clinical and 
office charts, laboratory and pharmacy records, diaries, microfiches, X-rays, and 
correspondence. 
Record s of subjects, source documents, data correction forms, CRFs, inventory of the 
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 evaluat io n and reconstruction of the 
clinical study. These records will be retained in a secure file for the period required by the 
institution or study site policy. Prior to transfer or destruction of these records, Daiichi 
Sankyo 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 to maintain a comprehensive and 
centralized filing system (Trial Master File) of all study-related (essential) documentation, 
suitable for inspection at any time by representatives of Daiichi Sankyo and/or the 
applicable regulatory authorities . Essent ial documents contained in the Trial Master File 
include: 
• 
Subject files containing completed CRFs, ICFs, and suppo rting copies of 
source documentation (if kept). 
• 
Study files containing the protocol with all amendments, Investigator' s 
Brochure (IB), copies of relevant essential documents required prior to 
commencing a clinical study, and all correspondence to and from the EC/IRB 
and Daiichi Sankyo. 
• 
Records related to the study drug(s) including acknowledgment ofreceipt at 
the study site, accountabi lity records and final reconciliation and applicable 
correspondence. 
In addition, all original source documents suppo rting entries in the CRFs must be 
maintained and be readily available. 
All study-relatedessential documentation will be retained by the institution for at least 15 
years after completion of the study (for a longer period if needed to comply with other 
applicable requirement s), or until the institution is instructed otherwise by Daiichi Sankyo. 
It is the responsibility of Daiichi Sankyo to inform the investigator/institution when these 
documents no longer need to be retained. 


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Subjects' medical files will be retained in accordance with the applicable legislation and in 
accordance with the maximum period of time permitted by the hospital, institution or 
private practice. 
No study documents will be destroyed without the prior written agreement of Daiichi 
Sankyo and the investigator. Should the investigato r wish to assign the study records to 
another party or move them to another location, he/she must notify Daiichi Sankyo in 
writing of the new responsible person and/or the new location. 


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


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14. 
PUBLICATION POLICY 


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15. 
ETHICS AND STUDY ADMINISTRATIVE INFORMATION 
15.1. 
Compliance Statement, Ethics, and Regulatory Compliance 
This study will be conducted in comp liance with the protocol, the ethical principles that 
have their origin in the Declaration of Helsinki, the International Council for 
Harmonisation (ICH) consolidated Guideline E6 for Good Clinical Practice (GCP) 
(CPMP/ICH/135/95), and applicable regulatory requirement(s) including the following: 
• 
Japanese Ministry of Health, Labour and Welfare Ordinance No. 28 of27 
March, 1997 and/or; 
• 
The Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical 
Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, 
and Cosmetics of25 November, 2014; 
• 
Other applicable local regulations. 
 
15.2. 
Subject Confidentiality 
The investigators and Daiichi Sankyo will preserve the confidentiality of all subjects 
taking part in the study, in accordance with GCP and local regulations. 
The investigator must ensure that the subject's anonymity is maintained. On the CRFs or 
other documents submitted to Daiichi Sankyo or the CRO, subjects must be identified by a 
unique subject identifier as designated by Daiichi Sankyo. Documents that are not for 
submission to Daiichi Sankyo or the CRO (eg, signed ICF) must be kept in strict 
confidence by the investigator. 
In compliance with ICH GCP Guidelines, it is required that the investigator and institution 
permit authorized representatives of the company, of the regulatory agency(s), and the 
IRB/EC direct access to review the subject's original medical records for verification of 
study-related procedures and data. The investigator is obligated to inform the subject that 
his/her study-related records will be reviewed by the above-named representati ves without 
violating the confidentiality of the subject. 
 
15.3. 
Informed Consent 
Before a subject participates 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 
specificprocedures or any study drugs are administered. Subjects must be given the 
opportunity to ask questions and receive satisfactory answers to their inquiries, and must 
have adequate time to decide whether or not to participate in the study. The written ICF 
must be prepared in the local language(s) of the potential subject pop ulation. 
When obtaining and documenting informed consent, the investigator must comply with 
the applicable regulatory requirements, and must adhere to GCP and to the ethical 
principles that have their origin in the Declaration of Helsinki. The consent form and any 
revision(s) must be approved by the EC or IRB before they are provided to potential 
subjects. 


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The subject' s written infmmed consent must be documented in the subject' s medical 
records. The ICF must be signed and personally dated by the subject and by the person 
who conducted the informed consent disc ussion. The origina l signed ICF must be retained 
in accordance with institutional policy, and a copy of the signed consent form must be 
provided to the subject. The date and time (if applicable) when informed consent was 
given must be recorded in the CRF. 
If the subject cannot read, then according to ICH GCP Guideline, Section 4.8.9, an 
impartial witness must be present during the entire informed consent discussion . This 
witness must sign the ICF after the subject has consented to the subject's pa1ticipation and 
if possible, sign the ICF. By signing the ICF, the witness attests that the information in the 
ICF and any other written information was adequate ly exp lained to and apparently 
understood by the subject and that informed consent was freely given by the subject. 
Suggested model text for the ICF for the study and any app licable subparts (genomic, PK, 
etc.) are provided in the Daiichi Sankyo's ICF template for the investigator to prepare the 
documents to be used at his or her study site. Updates to applicable forms will be 
communicate d in writing by Daiichi Sankyo. 
 
15.4. 
Informed Consent for Pharmacogenomic Analysis 
Before obtaining samples for pharmacogenomic analysis, the investigator is responsible 
for obtaining freely given consent, in writing, from the subject, after giving an explanation 
of the pharmacogenomic analysis in intelligible terms. Before obtaining the informed 
consent, the investigator should provide the subjects with adequate time to have the 
opportunity to inquire abo ut the detail s of the study, and should answer all questions 
properly. This analysis is an optional analysis for whom agreed to join clinical study, and 
another written informed consent document is prepared, separately from informed consent 
for clinical study. 
 
15.5. 
Regulatory Compliance 
The stu dy protocol, subject informat ion and consent form, the Investigator ' s Broch ure, 
any written instruction s 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 
qualificat ions must be submitted to the EC or IRB for ethical review and approval 
according to the local regulations, prior to the study start. The written approval must 
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. 
Daiichi Sankyo will appoint a Coordinating Investigator. The Coordinating Investigator 
will be responsible for testifying to the accurac y of the description of the study cond uct. 
The investigator and/or Daiichi Sankyo must subm it and, where necessary, obtain 
approval from the EC or IRB for all subse quent protocol amendments and changes to the 
ICF. The investigator must notify the EC or IRB of deviations from the protocol or SAEs 
occurring at the study site and other AE reports received from Daiichi Sankyo/CRO, in 
accordance with local procedures. 


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As required by local regulations, the Daiichi Sankyo's local Regulatory Affairs group or 
representative to whom this responsibility has been delegated will ensure that all legal 
aspects are covered, and that approval from the appropriate regulatory bodies has been 
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 the regulatory authorities and that these changes 
are implemented only after approval by the relevant regulatory bodies, as required . 
In the event of any prohibition or restrictions imposed (eg, clinical hold) by any applicable 
Regulatory Authority(ies) in any area of the world, or if the investigator is aware of any 
new information that may influence the evaluation of the benefits and risks of the study 
drug, Daiichi Sankyo should be informed immediately. 
In addition, the investigator will inform Daiichi Sankyo immediately of any urgent safety 
measures taken by the investigator to protect study subjects against any immediate hazard, 
and of any suspected/actual serious GCP non-compliance that the investigator becomes 
aware of. 
 
15.6. 
Protocol Deviations 
The investigator should cond uct the st udy in compl iance with the protocol agreed to by 
Daiichi Sankyo and, if required, by the regulatory authority( ies), and which were given 
approval/favorable opinion by the IRBs/ECs. 
A deviation to any protocol procedure or waiver to any stated criteria will not be allowed 
in this study except where necessary to eliminate an immediate hazard(s) to the subject. 
Daiichi Sankyo must be notified of all intended or unintended deviations to the protocol 
(eg, inclusion/exclusion criteria, dosing, misse d 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 an incorrect dose or stud y treatment, and had at least 
1 administration of study drug, data should be collected for safety purposes. 
If applicable, the investigator must notify the EC or IRB of deviations from the protocol in 
accordance with local procedures. 
 
15.7. 
Supply of New Information Affecting the Conduct of the Study 
When new information becomes available that may adversely affect the safety of subjects 
or the conduct of the study, Daiichi Sankyo will inform all investigators involved in the 
clinical study, ECs/lRBs, and regulato ry authorities of such information, and when 
needed, will amend the protocol and/or subject information. 
The investigator should immediately inform the subjects whenever new information 
becomes available that may be relevant to the subjects' consent or may influence the 
subjects' willingness to continue pa1ticipation in the stud y. The communication should be 
documented on the 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 IEC/IRB. The 
investigator shouldobtain written informed consent to continue participation with the 


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revised written information even if subjects have already been informed of the relevant 
information. The investigator or other responsible personnel who provided explanations 
and the subject must sign and date the revised ICF. 
15.8. 
Protocol Amendments 
Any amendments to the study protoco l that seem to be appropriate as the study progresses 
will be communicated to the investigator by Daiichi Sankyo or the CRO. 
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 protocol amendment may be implemented after it has been approved by the IRB/EC and 
by regulatory authoritie s where appropriate, unless immediateimplementation of the 
change is necessary for subject safety. 
15.9. 
Study Termination 
In case any of the following conditions apply, and Daiichi Sankyo judge s that it is difficult 
to continue the study, Daiichi Sankyo will prematurely terminate or suspend the study. 
Daiichi Sankyo should then decide whether or not to terminate or suspe nd the study, and 
document the decision. 
1. In case new safety information or SAE information on the study drug is obtained. 
2. In case of a significantGCP violation or protocoldeviation on the part of Daiichi 
Sankyo, study site, or the investigator. 
3. In case other new information is obtained during the study. 
If the  study is  prematurely terminated  or suspended by Daiichi Sankyo in consultation 
with the medical advisor, Daiichi Sankyo must  promptly inform  the investigators/study 
sites of the termination or suspension and the reaso n(s) for the termination or suspension 
in written form. The IRB should also be informed promptly and provided reason(s) for the 
termination or suspension by Daiichi Sankyo or by the investigator/study site, as specified 
by the applicable regulato ry requirement(s). 
If the study is terminated or suspended, for whatever reason, the investigator must 
promptly inform the subjects and take appropriate measures (eg, conducting examinations) 
to ensure the safety of the subjects. 
15.10. 
Steering Committee 
A steer ing committee will be established for this study. Details on the membership, 
responsibilities,and working procedures of the committee will be described in its own 
charter. 
 
 
15.11. 
Data and Safety Monitoring Board 
Not applicable 


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PD 
PD 
PD 
PD 
PD 
15.12. 
Address List 
A list of key study personnel (including personnel at Daiichi Sankyo, CRO, laboratories, 
and other vendors) and their contact information (address, telephone, fax, email) will be 
kept on file and regularly updated as necessary. 
 
15.12.1. 
Sponsor 
Daiichi Sankyo Co., Ltd 
3-5-1, Nihonbashi-honcho.Chuo-ku, Tokyo I03-8426 Japan 
 
15.12.2. 
Medical Officer / External Medical Monitor/ Internal Medical Monitor 
Medical Officer / External Medical Monitor: 
PD 
Natio nal Cancer Center Hospital East 
6-5-1, Kashiwanoha. Kashiwa-shi, Chiba-ken, 277-8577 Japan 
PD 
PD 
Internal Medical Monitor: 
15.12.3 . 
Coordina ting Investigator 
 
The Cancer Institute Hospital of Japanese Foundation for Cancer Research 
3-8-31, Ariake, Koto-ku, Tokyo 135-8550, Japan 
 
 
 
15.12.4. 
Sponsor's Clinical Study Lead 
15.12.5. 
Spon sor's Clinical Operations Delivery Lead 
 
15.12.6. 
Spon sor's Safe ty Contacts 
PD 
PD 
PD 


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PU 
 
 
PD 
 
15.12.7. 
ARO 
Not applicab le 
 
15.12.8. 
CROs 
CMIC Co., Ltd. (Japan) 
1-1-1, Shibaura, Minato-ku, Tokyo, 105-0023, Japa­ 
PD 
 
CMIC Korea Co., Ltd. (Korea) 
lOF, 129, Teheran-ro, Gangnarn-gu, Seoul, Republi c of Korea (06133) 
PD 
 
 
DAIICHI SANKYO RD NOVARE CO., LTD. 
1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan 
PD 
 
 
15.12.9. 
EDC Vendor 
Medidata Solutions, Inc. 
350 Hudson Street, 9th Floor, New York, NY 10014, USA 
 
 
 
15.12.10. EDC System Support 
Fujitsu Limited 
TOKYU REIT Kamata Building 5-13-23, Kamata, Ota-ku, To kyo 144-0052 Japan 
PD 
15.12.11. IXRS Vendor 
Almac group 
25 Fretz Road Souderton, PA 18964 
PD 


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-po 
15.12.12. Centra l Laboratory 
Covance Central Laboratory Services 
8211 SciCor Drive 
4 
 
 
 
G uardant Health, Inc. 
505 Penobscot Drive 
Redwood City, CA 94063 U.S.A. 
PD 
 
Daiichi Sankyo RD Novare Co., Ltd. 
1-16-13 Ki takasa i, Edogawa, Tokyo 134-8630, JAPAN 
PD 
15.12.13. 
Central Imaging 
Bioclinica Inc. 
211 Carnegie Center, Princeton, NJ 08540 
 
 
 
15.12.14. Bioanalytical Laboratory (Pharmacokinetics and Anti-Drug Antibodies) 
PPD 
2244 Dabney Road 
Richmond VA 23230, USA 
PD 
 
 
15.12.15. Sponsor's Biostatistician 
PD 
1-2-58 Hirom achi, Shinagawa-ku, Tokyo 140-8710, Japan 
PD 
 
 
15.12.16. 
Data Safety Monitoring Board 
CMIC Co., Ltd. Academia Clinical Research Division 
Osaka branch, Nakanoshima Central Tower, 2-2-7 Nakanoshima, Kita-ku 
Osaka 530-0005, Japan 
Indianapolis, IN 4621 
PPD 
I 
PD 


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16. 
REFERENCES 
l.  Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, Cancer 
Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, 
France: International Agency for Research on Cancer; 2013. Available from: 
http://globocan.iarc.fr, accessed on 09/05/2015. 
2. Park JM, Kim YH. Current approaches to gastric cancer in Korea. Gastrointest 
Cancer Res. 2008;2(3):137-44. 
3. Inoue M, Tsugane S. Ep idemio logy of gastr ic cancer in Japan. Postgrad Med J. 
2005;81(957):419-24. 
4. Minashi K, Hironaka S. Advances in secondary che motherapy for gastric cancer. 
Gan To Kagaku Ryoho. 2015;42(4):398-402. 
5. Park DI, Yun JW, Park JH, et al. HER-2/neu amp lification is an independent 
prognostic factor in gastric cancer. Dig Dis Sci 2006;51(8):1371-9. 
6. Kim KC, Koh YW, Chang HM, et al. Evaluation ofHER2 protein expression in 
gastric carcinomas: comparative analysis of l,414 cases of whole-tissue sec tions 
and 595 cases of tissue m icroarray s. Ann Surg Oncol. 2011;18(10):2833-40. 
7. Cho EY, Park K, Do I, et al. Heterogeneity ofERBB2 in gastric carcinomas: a 
study of tissue microarray and matched primary and metastatic carcinomas. Mod 
Pathol. 2013;26(5):677-84. 
8. Shan L, Ying J, Lu N. HER2 expression and relevant clinicopathological features 
in gastric and gastroesophagealjunction adenocarcinoma in a Chinese population. 
Diagn Pathol. 2013;8:76-82. 
9. Yano T, Doi T, Ohtsu A, et al. Comparison ofHER2 gene amplication assessed by 
fluoresce nce in s itu hybridization and HER2 protein expression assessed by 
immunohistochemistry in gastric cancer. Oncol Rep. 2006;15(1): 65-71. 
10. Yoon HH, Shi Q, Sukov WR, et al. Assoc iation of HER2/ErbB2 expression and 
gene amplication with pathological features and prognosis in esophageal 
adenocarcinomas. Clin Cancer Res. 2012;18(2):546-54. 
11. Yan M, Parker BA, Schwab R, et al. HER2 aberrations in cancer: implications for 
therapy. Cancer Treat Rev. 2014;40(6):770-80. 
12. Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines 
Version 4 (May, 2014). 
13. Japanese Gastric Cancer Association. Preliminary Figures for Ramucirumab, 
Japanese gastric cancer treatment guidelines Version 4 (October, 2015). 
14. Nishimura T, Iwasa S, Nagashima K, et al. lrinotecan monotherapy as third-line 
treatment for advanced gastric cancer refractory to fluorop yrimidine s, platinum, 
and taxanes. Gastric Cance r. 2017;20(4):655-662. 
15. Shimoyama R, Yasui H, Boku N, et al. Weekly paclitaxel for heavily treated 
advanced or recurrent gastric cancer refractory to fluoro uracil, irinotecan, and 
cisplatin. Gastric Cancer. 2009;12(4):206-11. 


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16. Kang YK, Boku N, Satoh T, et al. Nivolumab in patients with advanced gastric or 
gastro-oesophageal junction cancer refractory to, or intolerant of, at least two 
previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a 
randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017; 390: 
2461-2471 
17. Seyoung S, Min-HR, Ji YA, et al. Loss of HER2 positivity after anti-HER2 
chemotherapyin HER2-positive gastric cancer patients: Results of GASTric 
cancer HER2 reassessment study 3 (GASTHER3) [abstract]. J Clin Oncol. 
2017;35(Suppl 4):27. 
18. Abou-Alfa GK, Letourneau R, Harker G, et al. Randomized phase III study of 
exatecan and gemcitabine compared with gemcitabine alone in untreated advanced 
pancreatic cancer. J Clin Oncol. 2006;24(27):4441-7. 
19. Cheverton P, Friess H, Andras C, et al. Phase III results of exatecan (DX-8951£) 
versus gemc itabine (Gem) in chemotherapy-naivepatients with advanced 
pancreatic cancer (APC) [abstract]. J Clin Oncol. 2004;22(Suppl 14):4005. 
20. De Jager R, Cheverton P, Tamanoi K, et al. DX-895lf: summary of phase I clinical 
trials. Ann NY Acad Sci. 2000;922:260-73. 
21. Ogitani Y, Aida T, Hagihara K, et al. DS-820 la, a nove l HER2-targeting ADC 
with a novel DNA topoiso merase I inhibitor, demonstrates a promising antitumor 
efficacy with differentiation from T-DMl. Clin Cancer Res. 2016;22(20):5097- 
108. 
22. Ogitani Y, Hagihara K, Oitate M, et al. Bystander killing effect of DS-8201a, a 
novel anti-human epidermal growth factor receptor 2 antibody-drug conjugate, in 
tumors with human epidermal growth factor receptor 2 heterogeneity. Cancer Sci. 
2016;107(7):1039-46. 
23. Archer SG, Eliopoulos A, Spandidos D, et al. Expression of ras p21, p53 and c­ 
erbB-2 in advanced breast cancer and response to first line hormonal therapy. Br J 
Cancer. 1995;72(5):1259-66. 
24. Esteva FJ, Guo H, Zhang S, et al. PTEN , PIK3CA, p-AKT, and p-p70S6K status: 
association with trastuzumab response and survival in patients with HER2-positive 
metastatic breast cance r. Am J Pathol. 2010;177(4):1647-56. 
25. Ross JS, SlodkowskaEA, Symmans WF, et al. The HER-2 receptor and breast 
cancer: ten years of targeted anti-HER-2 therapy and personalized medicine. 
Oncologist. 2009;14(4):320-68. 
26. Hofmann M, Stoss 0, Shi D, et al. Assessment of a HER2 scoring system for 
gastric cancer: results from a validation study. Histopathology. 2008;52(7):797- 
805. 
27. Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a 
novel therapeutic target. Ann Oncol. 2008;19(9):1523-9. 
28. Harder J, Ihorst G, Heinemann V, et al. Multicentre phase II trial of trastuzumab 
and capecitabine in patients with HER2 overexpressing metastatic pancreatic 
cancer. Br J Cancer. 2012;106(6):1033-8. 


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29. Yoshizawa A, Sumiyoshi S, Sonobe M, et al. HER2 status in lung 
adenocarcinoma: a comparison of immunohistochemistry, fluoresce nce in s itu 
hybridization (FISH), dual-ISH, and gene mutations. Lung Cance r. 
2014;85(3) :373-8 . 
30. Blok EJ, Kuppen PJ, van Leeuwen JE, et al. Cytoplasmic overexpression ofHER2: 
a key factor in colorectal cancer. Clin Med Insights Oncol. 2013;7:4l -51. 
31. Verri E, Guglielmini P, Puntoni M, et al. HER2/neu oncoprotein overexpression in 
epithelial ovarian cancer: evaluation of its prevalence and prognostic significance. 
Clinical study. Oncology. 2005;68(2-3):154-61. 
32. Fleiss JL, Levin B, Paik MC. Statistical methods for rates and proportions, 3rd 
edition. John Wiley & Sons, Inc. New Jersey; 2003. p. 209-26. 
33. Hartmann JT, Pintoffl JP, Al-Batran SE, et al. Mitomycin C plus infusional 5- 
fluoro uracil in platinum-refractory gastric adenocarcinoma: an extended 
multicenter phase II study. Onkologie. 2007;30(5):235-40. 
34. Zhang XT, Li J, Bai Y, et al. A phase II study of triweekly paclitaxel and 
capecitabine combination therap y in patients with fl uorop yrimidine-platinum­ 
resistant metastatic gastric adenocarcinoma. J Cancer Res Ther. 2013;9 
Suppl:S l 53-7. 
35. Bang YJ, Im SA, Lee KW, et al. Randomized, Double-blind phase II trial with 
prospective classification by ATM protein level to evaluate the efficacy and 
tolerabi lity of olapari b plus pac litaxe l in patients with recurrent or metastatic 
gastric cancer. J Clin Oncol. 2015;33(33):3858-65. 
36. Tanabe K, Fujii M, Nishikawa K, et al. Phase II/III study of second-line 
chemotherapy comparing irinotecan-alone with S-1 plus irinotecan in advanced 
gastric cancer refractory to first-line treatment with S-1 (JACCRO GC-05). Ann 
Oncol. 2015;26(9):1916-22. 
37. Wainberg ZA, Soares HP, Patel R, et al. Phase II trial of everolimus in patients 
with refractory metastatic adenocarc inoma of the esophagus, gastroesophageal 
junction and stomach: poss ible role fo r predictive biomarker s. Ca nce r C hemother 
Pharmacol. 2015;76(1):61-7. 
38. Zheng Y, Fang W, Mao C, et al. Biweekly S-1 plus paclitaxe l (SPA) as second-line 
chemotherapy after failure from fluoropyrimidine and platinum in advanced gastric 
cancer: a phase II study. Cancer Chemother Pharmacol. 2014;74(3):503-9. 
39. Fuchs CS, Tomasek J, Yong CJ, et al. Ramucirumab monotherapy for previously 
treated advanced gastric or gastro-oesophageal junction adenocarc inoma 
(REGARD ): an international, randomised, multicentre, placebo-controlled, phase 3 
trial. Lancet. 2014;383(9911):31-9. 
40. Martin-Richard M, Gallego R, Pericay C, et al. Multicenter phase II study of 
oxaliplatin and sorafenib in advanced gastric adenocarcinoma after failure of 
cisplatin and fluorop yrimid ine treatment. A GEMCAD study. Invest New Drugs. 
2013;31(6):1573-9. 


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41. Ohtsu A, Ajani JA, Bai YX, et al. Everolimus for previo usly treated advanced 
gastric cancer: results of the randomized, double-bl in, d 
study. J Clin Oncol. 2013;31(31):3935-43. 
phase III GRANITE- I 
42. Kato K, Chin K, Yoshikawa T, et al. Phase II study ofNK105, a paclitaxel­ 
incorporating micellar nanoparticle, for previously treated advanced or recurrent 
gastric cancer. Invest New Drugs. 2012;30(4):1621-7. 
43. Kim SG, Oh SY, Kwon HC, et al. A Phase II study of irinotecan with bi-weekly, 
low-dose leucovorin and bolus and continuous infusion 5-fiuorouracil (modified 
FOLFIRI) as salvage therapy for patients with advanced or metastatic gastric 
cancer. Jpn J Clin Oncol. 2007;37(10):744-9. 
44. Barone C, Basso M, Schinzari G, et al. Docetaxel and oxaliplatin combination in 
second-line treatment of patients with advanced gastric cancer. Gastric Cancer. 
2007;10(2):104-11. 
45. Lim JY, Cho JY, Paik YH, et al. Salvage chemotherapy with docetaxel and 
epirubicin for advanced/metastatic gastric cancer. Oncology. 2007;73(1-2):2-8. 


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17. 
APPENDICES 
17.1. 
Cockcroft-GaultEquation 
The estimated creatinine clearance (CrCl; rnL/min) will be calculated using the 
Cockcroft-Gault equation based on actual weight in kilograms (1 kilogram = 2.2 pounds): 
Conventional- serum creatinine in mg/dL: 
Male: 
CrCl (mL/min) = [140- age(in years)] x weight (in kg) 
sennn creatinine (in mgldL) x 72 
Female: 
CrCl (mL/min) =  [140- age(in years)] x weight   (in  kg)   x 0_85 
sen.nu crea tinine (in mg/dL) x 72 
 
 
International System of Units (SI) - serum creatinine in pmol/L: 
Male: 
CrCl (mL/min) = 
[140 - age (in year s)] x weight (in kg) 
sennn creatinine (in µrnoVL) x 72 x 0.0113 
Female: 
CrCl (mL/min) =    
[1_4_0_-_age  (i_n  y_e_ar_s)]_x_w_e_igh_t_(in_ kg)_ 
x  0.85 
sennn creatinine (in µmoVL) x 72 x 0.0 113 
 
 
Source: Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum 
creatinine. Nephron. 1976;16(1):31-41. 


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


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17.3.1.1.2. Non-Measurable 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph 
nodes with 2'.:10 to < 15  mm short axis), as well as truly non-measura ble lesions. Lesions 
considered truly non-measura ble include: leptomeningeal disease, ascites, pleural  or 
pericardia! effusion, inflammatory  breast  disease,  lymphangiticinvolvement  of  skin  or 
lung, and abdominal masses/abdominal  organomegaly  identified  by physical exam that  is 
not measurab le by reproducible imaging techniques. 
 
17.3.1.1.3. Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment. 
17.3.1.1.3.1. Bone Lesions 
• 
Bone scan, positron emission tomography (PET) scan or plain films are not 
considered adequate imaging techniques to measure bone lesions. However, these 
techniques can be used to confirm the presence or disappearance of bone lesions. 
• 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as 
CT or MRI can be considered as measurable lesions if the soft tissue component 
meets the definition of measurability described above. 
• 
Blastic bone lesions are non-measurable. 
 
17.3.1.1.3.2. Cystic Lesions 
• 
Lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant les ions (neither measurable nor non-measurabel ) since 
they are, by definition, simple cysts. 
• 
"Cystic lesions" thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if noncystic lesions are present in the same subject, these are preferred 
for selection as target lesions. 
 
17.3.1.1.3.3. Lesions with Prior Local Treatment 
• 
Tumor lesions situated in a previous ly irradiated area, or in an area subjected to 
other loco-regional therapy, are not considered measurable unless there has been 
demonstra ted progression in the lesion. 
17.3.1.2. 
Specifications by Methods of Measurements 
17.3.1.2.1. Measurement of Lesions 
All measuremen ts should be recorded in metric notatio n, using cal ipers if clinically 
assessed. All baseline evaluations should be performed as close as possible to the 
treatment start and NEVER more than 28 days of the first dose of study drug 
administration. 


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17.3.1.2.2. Method of Assessment 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during F/U. Imaging based evaluation 
should always be performed rather than clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of lesions on 
CT scan based on the assumption that CT slice thickness is 5 mm or less. When CT scans 
have slice thickness greater than 5 mm, the minimum size for a measurable lesion should 
be twice the slice thickness. MRI is also acceptable in certain situations (eg, for body 
scans). 
 
17.3.2. 
Tumor Response Evaluation 
 
17.3.2.1. 
Assessment of Overall Tumor Burden and Measurable Disease 
To assess objective response or future progression, it is necessary to estimate the overall 
tumor burden at baseline and use this as a comparator for subsequent measureme nts. 
In this study, only subjects with measurab le disease at baseline should be included in the 
study. 
17.3.2.2. 
Baseline Documentation of"Target"and "Non-targe"t Lesions 
Target lesions are all measurable lesions up to a maximum of two lesions per organ and 5 
lesions in total, and will be recorded and measured at baseline (this means in instances 
where subjects have only 1 or 2 organ sites involved a maximum of 2 and 4 lesions 
respect ively will be recorded). 
Target lesions should be se lected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be 
selected. 
Lymph nodes merit special mention since they are normal anatomical structures which 
may be visible by imaging even if not involved by tumor. As noted above, pathologica l 
nodes which are defined as measurable and may be identified as target les ions must meet 
the criterion of a sh01i axis of 2':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 qualifi es 
as a malignant, measurable node. In this example, 20 mm should be recorded as the node 
measurement. All other pathological nodes (those with sho1i axis 2':10 mm but <15 mm) 
should be considered non-target lesions. Nodes that have a short axis <10 mm are 
considered non-pathological and should not be recorded or followed. 


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A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters . If lymph 
nodes are to be included in the sum, then as noted above, only the short axis is added into 
the sum. The baseline sum diam eter s wi ll be used as reference to further characterise any 
objective tumor regression in the measura ble dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes sho uld be 
identified as non-target lesions and should also be recorded at baseline. Measurements are 
not required and these lesions should be followed as "present," "absent," or in rare cases 
"unequivocalprogression." In addition, it is possible to record multiple non-target lesions 
involving the same organ as a single item on the case record form (eg, "multiple enlarged 
pelvic lymph nodes" or "multiple liver metastases"). 
 
17.3.2.3. 
Response Criteria 
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions. 
17.3.2.3.1. Evaluation of Target Lesions 
CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to < l 0 mm. 
PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference 
the baseline sum diam eters. 
PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference 
the smallest sum on study (this includes the baseline sum if that is the smallest on study). 
In addition to the relative increase of 20%, the sum must also demon strate an absolute 
increase of at least 5 mm (Note: the appearance of 1 or more new lesions is also 
considered progression). If investigator makes a clinical diagnosis that there has been 
progression, imaging examinations should be performed as promptly as possible, and 
effo rt should be made to obtain an imagebased assessment of PD. 
SD: Neither sufficie nt shrink age to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum diameters while on study. 
 
17.3.2.3.2. Special Notes on the Assessment of Target Lesions 
Lymph nodes: Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (meas ured in the same an atom ica l p lan e as the baseline 
examination), even if the nodes regress to below 10 mm on study. This means that when 
lymph nodes are included as target lesions, the "sum" of lesions may not be zero even if 
CR criteria are met, since a normal lymph node is defined as having a short axis of 
<10 mm. For PR, SD, and PD, the actual short axis measurement of the nodes is to be 
included in the sum of target lesions. 
Target lesions that become "too small to measure": While on study, all lesions (nodal and 
non-nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (eg, 2 mm). However, sometimes lesions or 
lymph nodes which are recorded as target lesions at baseline become so faint on CT scan 
that the radiologist may not feel comfortable assigning an exact measure and may report 
them as being "too small to measure".  When this occurs, it is impo1tant that a value be 


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recorded on the eCRF. If it is the opinion of the radiologist that the lesion has likely 
disappeared, the measurement should be recorded as O 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 surround ed by fat such as in 
the retroperitoneum ; ho wever,if a lymph node is believed to be present and is faintly seen 
but too small to meas ure, 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 erro r. 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 "frag ment," the 
longestdiameters of the fragmented portions should be added together to calc ulate the 
target les ion sum. Similarly, as lesions coalesce, a plane between them may be maintained 
that would aid in obtaining maximal diameter measurements of each individual lesion. If 
the lesions have truly coalesced such that they are no longer separable, the vector of the 
longest diameter in this instance should be the maximal longest diameter for the 
"coalesced lesion." 
 
17.3.2.3.3. Evaluation of Non-target Lesions 
This section provides the definitions of the criteria used to determine the tumor response 
for the group of non-target lesions. While some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only qualitatively 
at the time points specified in the protocol. 
CR: Disappearanceof all non-target lesions and normalization of tumor marker level. All 
lymph nodes must be non-pathological in size (<10 mm short axis). 
Non-CR/Non-PD: Persistence of 1 or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
PD: Unequivocal progression (see comments below) of existing non-target lesions (Note: 
the appearance of 1 or more new lesions is also considered progression). Overall tumor 
burden increases significantly enough to require a change in therapy. 
If investigator makes a clinical diagnosis that there has been progression, imaging 
examinations should be performed as promptly as possible, and effort should be made to 
obtain an imagebased assessment of PD. 
17.3.2.3.4. Special Notes on Assessment of Progression of Non-target Disease 
The concept of progression of non-target disease requires additional exp lanation as 
follows: 
When the subject also has measurable disease: In this setting, to achieve "unequivocal 
progression" on the basis of the non-target disease, there must  be an overall level of 
substa ntial 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 


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of therapy. A modest " increase" in the size of 1 or more non-target lesions is usually not 
suf ficient to qualit y for unequivocal progression status. The designation of overall 
progression solely on the basis of change in non-target disease in the face of SD or PR of 
target disease will therefore be extremely rare. 
 
17.3.2.3.5. New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: ie, not attributable to differences in scanning tec hnique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some 
"new" bone lesions may be simply healing or flare of preexisting lesions). This is 
pa1ticularly imp01iant when the subject' s baseline lesions show PR or CR. For example, 
necrosis of a liver lesion may be repo1ted on a CT scan rep01i as a " new" cystic lesion, 
which it is not. 
A lesion identified on a F/U study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of 
this is the subject who has visceral disease at baseline and while on study has a CT or MRI 
brain ordered which reveals metastases. The subject' s brain metastases are considered to 
be evidence of PD even if he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
F/U evaluation will clarify if it represents truly new disease. If repeat scans confirm there 
is definitely a new lesion, then progression should be declared using the date of the initial 
scan. 
 
17.3.2.4. 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the study 
treatment until the EOT. Confirmatory measurement for CR, PR, or SD in Primary 
Cohort is not required. In Exploratory Cohort l and 2, confirm ato ry measureme nt for CR, 
PR, or SD is required in the study. 
The subject' s best overall response assignment will depend on the findings of both target 
and non-target disease and will also take into consideration the appearance of new lesions. 
 
17.3.2.4.1. Time Point Response 
It is assumed that at each protocol-specified time point, a response assessment occurs. 
Table 17.2 provides a summary of the overall response status calculation at each time 
point for subjects who have measurable disea se at base lin e. 


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Table 17.2: 
Overall Response: Subjects with Target (±Non-target) Disease 
 
Target lesion 
Non-target lesion 
New lesion 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all Evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = Complete Response, PR= Partial Response, SD = Stable Disease, PD= Progressive Disease, and 
NE = Not Evaluable. 
 
 
 
17.3.2.4.2. Missing Assessments and Inevaluable Designation 
When no imaging/measurement is performed at all at a partic ular time point, the subject is 
No t Evaluable (NE) at that time point. If only a subset of lesion measurements are made 
at an assessment, usually the case is also considered NE at that time point, unless a 
con vincing argument can be made th at the co ntribution of the individual missing lesion(s) 
would not change the assigned time point response. This would be most likely to happen 
in the case of PD. For example, if a subject had a baseline sum of 50 mm with 3 measured 
lesions and at F/U only 2 lesions were assessed, but those gave a sum of 80 mm, the 
subject will have achieved PD status, regardless of the co ntribution of the missing lesion. 
 
17.3.2.4.3. Best Overall Response: All Time Points 
The best overall response is determined once all the data for the subject is known. 
As for Primary Cohort, confirmation is not needed. But, as for Exploratory Cohorts 1 and 
2 is needed. Best response in this study is defined as the best response across all time 
points (eg, a subject who has SD at first assessment, PR at second assessment, and PD on 
last assessment has a best overall response of SD). When SD is believed to be best 
response, it must also meet the protocol specified minimum time from baseline, 6 wee ks 
(±7 days). If the minimum time is not met when SD is otherwise the best time point 
response, the subject's best response depends  on the subsequent assessments.  For 
example, a subject who has SD at first assessment, PD at second and does not meet 
minimum duration for SD, will have a best response of PD. The same subject lost to 
follow-up after the first SD assessment would be considered inevaluable. 


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17.3.2.4.4. Special Notes on Response Assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to 
"norm al " size (<l 0 mm), they may still have a meas urement reported on scans. This 
measurements hould be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes. As noted earlier, 
this means that subjects with CR may not have a total sum of "zero" on the eCRF. 
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
"symptomaticdeterioration." Every eff01t should be made to document objective 
progression eve n after discontinuation of treatment. Symptomatic deterioration is not a 
descriptor of an objective response: it is a reason for stopping study therapy. The 
objective response status of such subjects is to be dete rmined by evaluation of target and 
non-target disease. 
For equivocal findings of progression (eg, very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment. If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progress ion was suspecte d. 
17.3.2.5. 
Frequency of Tumor Re-evaluation 
In this study, tumor measure ment will be conducted every 6 weeks (±7 days) after Day 1 
of Cycle 1 while the subject remains on study until progression of disease, withdrawal of 
consent, death, or loss to F/U. Scan dates should not be adjusted or rescheduled due to 
dose interruption of any type. 
Baseline tumor assessments must be performed within 28 days of the first dose of stud y 
drug administration. 
All efforts should be made to ensure consistency between the baseline measurements and 
all subsequent measurements in reference to utilization of scanning method, equipment, 
technique (including slice thickness and field of view), and radiographic interpreter. 
The radiographic evaluation must include CT or MRI scanning of the brain, chest, 
abdomen, and pelvis at screening period. Any additional suspecte d sites of disease should 
also be imaged. Every effort should be made to use the same assessment modality for all 
assessments for each subject. How ever, if there is no brain metastasis at the time of 
screening, CT or MRI should only be done when symptoms associated with brain 
metastasis occur during study period. If no clinical symptoms are observed, brain CT or 
MRI is not mandatory during st udy period. All evaluations should meet the standard of 
care for imaging of lesions in the respective organ(s) and should conform to the image 
acquisition guidelines according to institutional standards. 
All target and non-target sites are evaluated at each time point of tumor assessment. 


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17.4. 
New York Heart Association Functional Classification 
Table 17.3: 
New York Heart Association Functional Classification 
 
Functio11a l Ca p acity 
O bj ective 
Assess 
m e nt 
Class I. Patients with cardiac disease but 
without resulting limitation of physical 
activity. Ordinary physical activity does not 
cause undue fatigue, palpitation, dyspnea, or 
angina/ pain. 
A. No objective evidence of cardiovascular 
disease. 
Class JI. 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 angina/ pain. 
B. Objective evidence of minimal 
cardiovascular disease. 
Class Ill. 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 angina/ pain. 
C. Objective evidence of moderately severe 
cardiovascular disease. 
Class JV. Patients with cardiac disease 
resulting in inability to carry on any physical 
activity without discomfort. Symptoms of heart 
failure or the angina! syndrome may be 
present even at rest. If any physical activity is 
undertaken, discomfort is increased. 
D. Objective evidence of severe cardiovascular 
disease. 
Source: American Heart Association, Inc. Classification of Functional Capacity and Objective Assessment. 
Available from: 
http://my.americanheart.org/profess ional/Statemen tsG uide lines/B yPublicationDate/PreviousYears/Classifica 
tion-of-Functional-Capacity-and-Objective-Assessment_UCM_423811_Article.jsp 


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17.5. 
 
17.5.1. 
Quality of Life Questionnaires 
 
FACT-G 
 
 
 
f /\CT-Ga (Version 4) 
 
Below is a lis t of statemen ts that other people witb your illness bavc said are important. Please 
cir cle or ma r k one nu mber Iler line to indi ca te yo ur respons e as it a pplies to t he nast 7 da ys. 
 
 
  
PIIYSICAL WELL-BEING 
Nol 
A lillle 
om e•     Quite 
Ver) 
Ill 1111 
bit 
"""' 
n bit 
mu ch 
 
" 
I have a lack of energy ....................................................... 0 
2 
3 
-I 
C11"! 
1have nausea .................................................................. 0 
2 
3 
4 
GP-\ 
Because of my physical condition,  I hnvc trouble 
meeting the needs of my family......................................... 
0 
2 
3 
4 
c., , 
1 have pain........................................................................... 
0 
2 
3 
4 
(Ip>\ 
I am bothered by side effects of treatment ......................... 0 
2 
3 
4 
""' 
..,, 
I feel ill.............................................................................. 
0 
2 
3 
4 
1am forced 10 spend t ime in bed ........................................ 
0 
2 
3 
4 
  SOCIAL/FAMl LYWELL-BEING 
Not 
A little    Some-   Qu ite 
Very 
at all 
bit 
wha t 
a bit 
mu ch 
,,,., 
1feel  close to my friends.................................................... 
0 
2 
3 
4 
,..... 
1gel emotional support from rny family ............................ 
0 
2 
3 
4 
"'' 
Iget support from my friends............................................. 
0 
2 
3 
4 
""' 
ly family has accepted my illness.................................. 
0 
2 
3 
4 
 
 
 
 
 
""' 
 
 
 
please mark111/s box D and o ro r/Je ne .rrseer/on. 
I am satisfied with my sex life ............................................   0 
2 
3 
4 
1,if,1,.li,il  111,(  n.tlj 
(' 1\JII J ' lQIOl 
\II,11"'-':0" 
P•   l.tt 
,.... 
1am satisfied with fomily communication about my 
illness ........... ......................... .......... .................. .................. 
0 
2 
3 
4 
c.v. , 
I feel close to my partner (or the person who is my main 
support) .............................................................................. 
0 
2 
3 
4 
1)1 
!l<!ganlless of your cwre/11 level of :,·e.rnal acrlrfly, please 
answer tlr l! followln[!. q111?s r1011. lfyo11 prefer 110 1ro a11swer Ir. 


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FACT-Ga (Ve rsion 4) 
 
Pl eas e ci r cl e o r m a r k o ne nu m b er pe r li ne to ind ica te yo ur re spo nse as it a p11lies to the pa st 7 
da vs. 
 
 
  
EMOT IO NAL W ELL-BE ING  
 
 
'"" 
I feel sad ..............................................................................     0 
2 
3 
4 
 
 
 
 
 
 
 
 
 
 
"" 
"'' 
(ifj 
 
Gr.I 
I have accepted my illness 
................ ...........................     0 
2 
3 
4 
(if< 
Iamsleep
ngi well ............................................................... 
0 
2 
3 
4 
Gr6 
I am enjoying the things I usually do for fun ...................... 
0 
2 
3 
4 
(jf' 
Ia content with the quality ofmy life right now.............. 
0 
2 
3 
4 
 
 
 
 
 
 
 
 
 
 
f.np;;h(t ,a[) 
C'C'l'}TIJht q1    7. l'rr.' 
 
J9A st:OO? 
fl,'11c2 (111 
Not 
A little Some- 
Quite 
Very 
at all 
bit 
what 
a bit 
much 
GC1 
I am satisfied with how I am coping with my illness. 
0 
2 
3 
4 
(j(l 
Iamlosngihope in the fight against my illness......... 
0 
2 
3 
4 
GU 
I feel nervous ....................................................................... 
0 
2 
3 
4 
Co£< 
I worry about dying ................................................ 
0 
2 
3 
4 
GU 
I worry that my condition will get worse ............... 
0 
2 
3 
4 
  
FUNCTIONAL WELL-BEING 
Not 
A lit tle So me- Quite 
Very 
at all 
bit 
what 
a bit 
much 
I am able10 work (include work at home).......................... 
0 
2 
3 
4 
My work (include work at home) is fulfilling..................... 
0 
2 
3 
4 
Ia able to enjoy life.......................................................... 0 
2 
3 
4 


Protocol DS820l-A-1202 
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FACT-Ga (Version 4) 
 
Please circle or mark one numb er per line to indicate your response as it a1Jp lies to the past 7 
davs. 
 
  
AD DITIONAL CONCERNS 
 
 
c, 
I am losing weight ............................... ..
....
..  .......·•········· 
0 
2 
3  
4 
"'I 
I havea loss of appetite....................................................... 
0 
2 
3 
4 
(',a'.! 
I am bothered by reflux or heartburn ................................. 
0 
2 
3 
4 
H.'1 I a m able to eat the foods that I like .................................... 0 
2 
3 
4 
..... 
T have discomfort or pain when I eat.................................. 0 
2 
3 
4 
"" 
I have a feeling of fullness or heaviness in my stomach 
area...................................................................................... 
0 
2 
3 
4 
C l 
I have swelling or cramps in my stomach area ·············-···· 
0 
2 
3 
4 
Go 
, 1 
I have rrouble swallowing food....................... .................. 
0 
2 
3 
4 
".
".
' 
Go 
19 
My digestive problems interfere with my usual activities.. 0 
2 
3 
4 
c•• 
T a void going out to eat because of my illness 
0 
2 
3 
4 
""' 
"'"' 
c.. 
u 
 
cs 
ram bothered  by gas ( natulence) 
0 
2 
3 
4 
I have diarrhea (diarrhoea).......... ········••····························      0 
2 
3 
4 
4 
4 
""' 
Beca use of my illness, I have difficulty planning for the 
future ...................................................................................  0 
2 
3 
4 
E {\.i:u 'd.sil) 
ccsin31  1981.1w 
Not 
A lit1le 
Some- 
Quite 
Ve , 
at all 
bit 
what 
a bit 
mu ch 
"'1 
I feel tired........................................................................... 0 
2 
3 
.. 
1, 
I feel weak all over .
.. .
....
...
..  .. .
.....
.. ... .................. .
.. .... 
0 
2 
3 
I a m bothered by a change in my eating habits................... 0 
2 
3 
4 
I am able to enjoy meals with family or friends.................. 
0 
2 
3 
4 
I  have stomachproblems  that worry me ············· •• ·· 
0 
2 
3 
4 
I havediscomfort or pain in my stomach area .................... 0 
2 
3 
4 


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17.5.2. 
EQ-5D-5L 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Health Questionnaire 
 
 
English version for the UK 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
UK (English) v.2 <Cl 2009 E.uroQol Group . E.Q-5D" ' is a trade marl< of the E.uroQol Group 


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Under each heading, please tick the ONE box that best describes your health TODAY 
 
MOBILITY 
I have no problems in walking about 
D 
I have slight problems in walking about 
D 
I have moderate problems in walking about 
D 
I have severe problems in walking about 
D 
I am unable to walk about 
D 
SELF-CARE 
I have no problems washing or dressing myself 
D 
I have slight problems washing or dressing myself 
D 
I have moderate problems washing or dressing myself 
D 
I have severe problems washing or dressing myself 
D 
I am unable to wash or dress myself 
D 
USUAL ACTIVITIES(e.g. work, study, housework, 
family or leisure activities) 
I have no prob lems  doing  my usual activities 
D 
I have slight problems doing my usual activities 
D 
I have moderate problems doing my usual activities 
D 
I have severe problems doing my usual activities 
D 
I am unable to do my usual activities 
D 
PAIN / DISCOMFORT 
I have no pain or discomfort 
D 
I have slight pain or discomfort 
D 
I have moderate pain or discomfort 
□ 
I have severe pain or discomfort 
D 
I have extreme pain or discomfort 
□ 
ANXIETY / DEPRESSION 
I am not anxious or depressed 
D 
I am slightly anxious or depressed 
D 
I am moderately anxious or depressed 
D 
I am severely anxious or depressed 
D 
I am extremely anxious or depressed 
D 
 
 
 
 
2 
UK (English) v.2 © 2009 EuroQo/ Group. EQ-5D'" isa trade marl< of the EuroQo/ Group 


Protocol DS820l-A-1202 
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• 
We would like to know how good or bad your health is 
TODAY. 
• 
This scale is numbered from Oto 100. 
 
• 
100 means the best health you can imagine. 
0 means the worst health you canimagine. 
• 
Mark an X on the scale to indicate how your health is TODAY. 
 
• 
Now, please write the number you marked on the scale in the 
box below. 
 
 
 
YOUR HEALTH TODAY= D 
The best heaIth 
you can imagine 
100 
 
95 
 
90 
 
85 
 
80 
 
75 
 
70 
 
65 
 
60 
 
55 
 
50 
 
45 
 
40 
 
35 
 
30 
 
25 
 
20 
 
15 
 
10 
 
5 
 
0 
T he   worst health 
youcan imagine 
 
1 
UK (English) v.2 © 2009 EuroQo/ Group. EQ-5D"' is a trade mark of the EuroQo/ Gro up 


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17.6. 
Instructions Related to SARS-CoV-2 
Due to the potential impact of SARS-CoV-2, ie COVID-19, on subject safety, the Sponsor 
recommends the following dose modification and management plan for subjects with 
confirmed or suspecte d SARS-CoV-2 while being treated with DS-820l a. Dose 
modifications will be based on the worst CTCAE grade. Use CTCAEversion 4.03 
general grading criteriato evaluate SARS-CoV-2.  All dose modifications 
(discontinuation, interruptions or reductions) must be recorded on the AE and drug 
administration eCRFs. 
 
 
17.6.1. 
Dose Modification Criteria for Suspected or Confirmed SARS-CoV-2 
If SARS-CoV-2 infection is suspected, interrupt DS-820 l a and rule out SARS-CoV-2 per 
local guidance. 
- If SARS-CoV-2 is ruled out, follow study protocol. 
- If SARS-CoV-2 is confirmed or is still suspected after eva luation fo llow dose 
modification as outlined in Tab le 17.4 below and manage SARS-CoV-2 per local 
guidance until recovery of SARS-CoV-2. SARS-CoV-2 recovery is defined as no 
signs/symptoms of SARS-CoV-2, at least 1 negative real-time reverse transcription 
polymerase chain reaction (RT-PCR) test result, and nearly or completely resolved 
chest CT findings. 
 
Table 17.4: 
SARS-CoV-2Dose Modification Criteria 
 
SARS-CoV-2 Worst Toxicity 
NCI-CTCAE Version 4.03 
Grade 
Schedule Modification for DS-8201a 
Grade 1 
Resume study drug at the same dosea 
Grade 2 
Resume study drug at the same dose if chest CT findings are 
completely resolved" 
Reduce by 1 dose level if chest CT findings are nearly 
resolved 
Grade 3 
Reduce by 1 dose level if chest CT findings are completely 
resolved 
Discontinue study drug if chest CT findings are not 
complete ly resolved 
Grade 4 
Discontinue study drug 
SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); CT = computed 
tomography 
a 
Closely monitor signs/symptoms after resuming DS-8201a, initially with a phone call every 3 days for 
the first week, and then with a weekly phone call thereafter, for a total of 6 weeks. 
In addition to the recommendations outlined in Table 17.4, investigators may consider 
dose modifications of the study drng according to the subject' s condition and after 
discussion with the study Medical Monitor or designee. 


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If an event is suspected to be drug-related ILD/pneumonitis, manage per protocol 
ILD/pneumonitis management guideline 
 
 
17.6.2. 
Prior and Concomitant Medications- Prohibited Therapies/Products 
• 
Chloroquine or hydroxychloroquine; 
- Concomitant treatment is not allowed during the study treatment (Section 5.5.3). 
- If treatment is absolutely required for SARS-CoV-2, DS-820la must be 
interrupted. 
- If administered, then a washout period ofno lessthan 14 days is required before 
resumption of DS-8201a. 
 
 
17.6.3. 
PK Assessment(s) if Chloroquine or Hydroxychloroquine is Administered 
Additional PK serum samples should be collected, if chloroquine or hydroxychloroquine 
is administered for SARS-CoV-2 infection, at the time points specified in the Schedule of 
Events (Table 8.3). 
The chloroquine or hydroxychloroquine administration time and the exact time of blood 
sample collection for PK analysis must be recorded on the eCRF. 
 
 
17.6.4. 
SARS-CoV-2 Assessment(s) 
All confirmed or suspec ted SARS-CoV-2 infection events must be recorded in the eCRF. 
If a subject presents to the clinic with symptoms suggestive of SARS-CoV-2, but the real­ 
time RT-PCR test is not available at the site, a sample kit will be provided for sample 
collection to be tested at a central laboratory. The results will be provided to the site from 
the central laboratory. 
Serum samp les will be used for SARS-CoV-2 testing from each subject who provides 
consent. Samples will be collected prior to the study drug infusion, shipped to a central 
laboratory, and stored there until the tests become available. 
If subjects consent, the remaining serum samples will also be stored for future analysis. 
 
 
17.6.5. 
Statistical Analysis - Assessment of the Impact of SARS-CoV-2 
If deemed appropriate, analyses will be performed to explore the impact of SARS-CoV-2 
on the safety, efficacy, and any other endpoints, as appropriate, reported for the study. 
As a result of the impact of SARS-CoV-2 on study cond uct, adj ustment s to the statistical 
analysis and interpretation will be made, if required. These will be described in the 
statistical analysis plan. 


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18. 
SCHEDULE OF EVENTS 
18.1. 
Schedule of Events for Subjects Receiving DS-8201a 
This safety monitoring is also applied if suspected ILD/pneumonitis occurs at EOT and during Follow-up. 
 
Tissue 
Screen 
SC R 
Cycle I 
Cycle 2 
Cycle 3 
Cycle 4 and 
subsequent 
cycles Day 1 
EOT 
(a) 
F/U 
(b) 
Q3M 
F/U 
(±14 
days) 
Day I 
Day 
8 
Day 
15 
Day 
22 
Day I 
Day 
22 
Day I 
Day 
8 
Day 
15 
Day 
22 
Bl 
EOI 
(± 1 
day) 
(± 1 
day) 
(±2 
days) 
Bl 
EOI 
(±2 
days) 
Bl 
EOI 
(±3 
days) 
(±3 
days) 
(±2 
days) 
Bl 
EOI 
Informed Consent 
• • 
Tumor sample for 
tissue screenin" 
• 
Fresh biopsy tumor 
sample for HER2 
Status, RNA 
expression, addional 
biomaker assessment 
(c) 
• 
• 
Administer 
DS-820 la (d) 
• 
• 
• 
• 
Contact IXRS (e) 
• • • 
• 
• 
• 
• 
Medical 
history 
/Primary 
Cancer 
historv/Demograohic 
• 
Vital Signs 
• ct) • cg
• 
• 
• 
• cg>
• 
• <g) 
• 
• cg)
• • 
Physical Examination 
• cQ 
• cg
• <g>
• <g) 
• cgl 
• • 
SpO 2 
• cQ 
• cg
• cg>
• <g) 
• cgl
• • 
H e ight 
• cQ 
Weight, ECOG PS 
• ct) . 
(g) 
• cg>
• <g) 
• cg)
• • 
Laboratory Tests 
• cQ 
• cg
• 
• 
• <g>
. 
(g) 
• cgl 
• • 


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) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCR: screening, F/U: follow-up, BI: before infusion, EOI: end of infusion, EOT: end of treatment 
a The date when the investigator decides to discontinue study treatment (+7 days) 
b 40 days (+7 days) after the last study drug administration or before startingnew anticancer treatment, whichever comes first 
Tissue 
Screen 
SCR 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 and 
subseq uent 
cycles Day I 
EOT 
(a) 
F/U 
(b) 
Q3M 
F/U 
(±14 
days) 
Day I 
Day 
8 
Day 
IS 
Day 
22 
Day 1 
Day 
22 
Day I 
Day 
8 
Day 
IS 
Day 
22 
BI 
EOI 
(±1 
da y) 
(±1 
day) 
(±2 
days) 
Bl 
EOI 
( ±2 
days)
BI 
EOI 
(±3 
da ys ) 
(±3 
d a ys) 
(±2 
days) 
BI 
EOI 
Tro p on in(h ) 
• <I) 
• 
• 
• 
• (h>
Blood Samples 
cfDNA 
for 
• <g
• <g,i) 
• 
Pharmacogenomics 
Blood Sample 
. 
(j) 
PK Blood Sample (x) 
. 
(k)
e (l,m) • • 
e (n) 
• 0c) • o> 
e ( o) 
e (k) 
e (l,m) • • 
e (n) 
e (k) 
. 
(I) 
ADA Blood Sample 
e (o 
e (o) 
e (o) 
• . 
(p) 
Blood Sample 
HER2ECD(y) 
for 
. (g) 
• <gq, ) 
• <g,v 
• 
Urinalysis 
• <I) 
EC HO o r MUGA 
(L VEF) (r) 
e (s) 
• <t) 
• 
12-lead ECG in 
triplicate (u) 
• <I) . (g) 
• <gl 
• <g) 
. 
(g) 
• 
Ophthalmologic 
Assessments(v) 
e (s) 
e (v) 
Pregnancy Test 
• <I) 
• 
EQ -5 D-SL, 
FACT- 
Ga(w) 
e (w) 
• 
Tumor Assessment 
• cs) 
E very 6  weeks  (±7  days)from Cycle  I  Day  I  until PD,  starting new anticancer treatment, or withdrawal of consent by subject regardless 
of Post Treatment Follow-up period 
• 
Concomitant 
Medications 
• 
AEs 
• 
Survival Follow-up 
I 
I 
• 


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c The subject who has a tumor amenable to biopsy undergo a fresh tumor biopsy. If not amenable, the investigator must document why not a menable. If fresh tumor 
has been already submitted for this study and no chemotherapy or immunotherapy was conducted, re-submission is not necessary. 
d DS-820la is to be administered every 3 weeks (Cycle allowance is ±3 days)  unless discontinuation criteria are required. 
e Eligible subjects will be registered using IXRS. The subject is recorded as ineligible in the IXRS if a screen failure 
f Within 14 days before registration 
g Within 3 daysbefore administration 
h Collect blood samples for troponin (preferably high-sensitivity troponin-T) at Screening, EOT and if at any time a subject reports signs or symptoms suggesting 
congestive heart failure, myocardial infarction, or other causes of myocyte necrosis (Refer to section 6.2.4). 
i  Samples will be collected at  BI on Day 1 of Cycle 1,  Cycle 4, and EOT for ctDNA in plasma 
j Participation in this part of the study is optional for all subjects. 
k Within 8 hours BI on Day l of each cycle until Cycle 4 and then every 2 cycles until Cycle 8 (eg, Cycle l, 2, 3, 4, 6, 8). 
1 Within 15 minutes ofEOI on Day 1 of each cycle until Cycle 4 (eg, Cycle 1, 2, 3 and 4) and then on Day 1 of Cycle 6 and Cycle 8. 
m4 h and 7 h after the start of administration(±15 minutes) 
n If treatment of the next cycle is delayed for 3 days or longer, or the subject is discontinued, collect a PK blood sample on this day (±2 days) 
o Within 8 hours BI on Day 1 of Cycle l, 2 and 4, and then every 4 cycles 
p For subjects with positive ADA at the F/U visit, additional serum ADA samples may be collected every 3 months (±14 days) up to l year after the last dose of the 
study drug, or until the ADA becomes negative, or until the ADA titer becomes less than the baseline (applicable when pre-existing ADA was observed), or until the 
subject starts another therapy for cancer, or withdraws consent from the study, whichever occurs first. 
q Before administration at every 2 cycles from Cycle 3 (eg, Cycle 3, 5, 7, 9...) 
r If meet dose reduction criteria, additional test is required within 3 weeks 
s Within 28 days before registration. 
t ECHO or MUGA scan assessments (note: the same test must be used for the subject throughout the study) will be performed at Screening and Day l of Cycle 5 and 
then every 4 cycles (±7 days) (eg, Cycle 5, 9, 13... ) 
u ECG will be taken in triplicate in close succession at screening. Subsequent ECGs in triplicate will be performed at Day l of Cycle 5 and then every 4 cycles (±7 
days) (eg, Cycle 5, 9, 13...), EOT and if an abnormality is noted. ECGs will be taken while in a supine/semi-recumbent position. 
v Ophthalmologic assessments will be performed at Screening and EOT and as clinically indicated 
wTo be completed on Day l before any tests/seeing Investigator, Day 15 (±1), the every 6 weeks from the beginning of the study (eg, Day 43 (±7), 85 (±7), 127 (±7), 
etc.), and EOT. EQ-5D-5L questionnaire to be completed first and then FACT-Ga questionnaire. PRO could be collected in only Primary Cohort. 
x: In case of administration of chloroquine/hydroxychloroquine, perform PK sampling according to the following schedule: pre-dose on Day I of 
chloroquine/hydroxychloroquine administration,pre-dose on Day 3 or Day 4 (within 4 hours), end of chloroquine/hydroxychloroquine treatment (within 4 hours), 
and after washout period pre-dose on the day of restarting study treatment (within 8 hours) 
y: A portion ofHER2ECD blood sample from each subject who provides consent will be used for future central lab analysis for SARS-CoV-2 testing. SARS-CoV-2 
testing will be conducted every 4 cycles from Cycle 5 (Cycles 5, 9, 13, etc) and EOT. 
For suspected ILD/pneumonitis, treatment with study drug should be interruptedpending evaluation. Evaluations should include: 
• high resolution CT 
• pulmonologist consultation(Infectious Disease consultationas clinically indicated) 
• blood culture and CBC. Other blood tests could be considered as needed 


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• consider bronchoscopy and bronchoalveolar lavage if clinically indicated and feasible 
• pulmonary function tests and pulse ox ime try (Sp02) 
• arterial blood gases if clinically indicated 
• one blood sample collection for PK and analysis as soon as ILD/pneumonitis is suspected, if feasible. 
Other tests could be considered, as needed. 


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18.2. 
Schedule of Events for Subjects Receiving the physician's choice treatment 
This safety monitoring is also applied if suspected ILD/pneumonitis occur at EOT and during Follow-up. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
Tissue 
Screen 
SC R 
Treatment Period 
EOT (a) 
F/ U (b) 
QJM F/U 
(±14 days) 
Informed Consent 
• • 
• 
Tumor sample for tissue screening 
Fresh biopsy tumor sample for HER2 Status, RNA 
expression, addional biomaker assessment (c) 
• 
Contact IXRS (d) 
• 
• 
• 
• 
Administer the physician' s choice treatment 
• 
e (e) 
Medic.al history!Primary Cancer history/Demographic 
Height 
e (f) 
Vital Signs 
. 
(f) 
At administration of physician's choice treatment • 
• 
Physical Examination 
SpO2 
Weight, ECOG PS 
• 
Laboratory Tests 
• 
12-lead ECG in triplicate (g) 
Urinalysis 
• 
<f) 
Tropon in 
• 
<f) 
e (h) • 
Pregnancy Test 
• <f) 
ECHO or MUGA (LVEF) 
• <i) 
Ophthalmo logic Assessments 
• <i) 
EQ - 5 D- S L, FACT-Ga 
• 
u) 
• u) 
Tumor Assessment 
• <i) 
Every 6 weeks (±7 days) from the day of fisrt dosing until PD, 
starting new anticancer treatment, or withdrawal of consent by 
subject regardless of Post Treatment Follow-up period 
• 
• 
Concomitant Medications 


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Tissue 
Screen 
SCR I 
Treatment Period 
I EOT(a) I F/U (b) 
QJM F/U 
(±14 days) 
AEs 
• 
Survival Follow-up 
I 
I 
I 
• 
SCR: screening, F/U: follow-up, BI: before infusion, EOI: end of infusion, EOT: end of treatment 
a The date when the investigator decides to discontinue study treatment (+7 days) 
b 40 days (+7 days) after the last study drug administration or before starting new anticancer treatment, whichever comes first 
c The subject who has a tumor amenable to biopsy undergo a fresh tumor biopsy. If not amenable, the investigator must document why not amenable. If  fresh tumor 
has been already submitted for this study and no chemotherapy or immunotherapy was conducted, re-submission is not necessary. 
d Eligible subjects will be registered using IXRS. The subject is recorded as ineligible in the IXRS if a screen failure. 
e Subjects receive the physician's choice treatment irinotecan monotherapy or paclitaxel  monotherapy 
f Within 14 days before registration 
g ECG will be taken in triplicate in close succession at screening, EOT, and if an abnormality is noted. ECGs will be taken while in a supine/semi-recumbent position. 
h Collect blood samples for troponin (preferably high-sensitivity troponin-T) at Screening, EOT and if at any time a subjectreports signs or symptoms suggesting 
congestive heart failure, myocardial infarction, or other causes ofmyocyte necrosis (Refer to section 6.2.4). 
i Within 28 days before registration. 
j To be completed on Day l before any tests/seeing Investigator, Day 15 (±1), the every 6 weeks from the beginning of the study (eg, Day 43 (±7), 85 (±7), 127 (±7), 
etc.), and EOT. EQ-5D-5L questionnaire to be completed first and then FACT-Ga questionnaire. 
 
For suspected ILD/pneumonitis, treatment with study drug should be interrupted pending evaluation. Evaluations sho uld include: 
• high resolution CT 
• pulmonologist consultation(Infectious Disease consultation as clinically indicated) 
• blood culture and CBC. Other blood tests could be considered as needed 
• consider bronchoscopy and bronchoalveolar lavage if clinically indicated and feasible 
• pulmonary function tests and pulse ox ime try (SpO2) 
• arterial blood gases if clinically indicated 
Other tests could be considered, as needed.