Phase 1/2, Multicentre, Open-label, Multiple-cohort Study of Dato-DXd in Chinese Patients With Advanced Non-small-cell Lung Cancer, Triple-negative Breast Cancer, Gastric/Gastroesophageal Junction Cancer, Urothelial Cancer, and Other Solid Tumours (TROPION-PanTumor02)
Phase: PHASE1
Conditions: Carcinoma, Non-Small-Cell Lung, Triple Negative Breast Cancer
Sponsor: AstraZeneca

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Clinical Study Protocol 
Study Intervention
Datopotamab deruxtecan 
(Dato-DXd, DS-1062a)
Study Code
D9266C00001
Version
4.0
Date
29 May 2023
Phase 1/2, Multicentre, Open-label, Multiple-cohort Study of 
Dato-DXd in Chinese Patients With Advanced Non-small-cell 
Lung Cancer, Triple-negative Breast Cancer, 
Gastric/Gastroesophageal Junction Cancer, Urothelial Cancer, 
and Other Solid Tumours
Sponsor Name: AstraZeneca AB
Legal Registered Address: 151 85 Södertälje, Sweden
Regulatory Agency Identifier Number(s): NCT Number: NCT05460273
This CSP has been subject to a peer review according to AstraZeneca Standard procedures. 
The CSP is publicly registered and the results are disclosed and/or published according to the 
AstraZeneca Global Policy on Bioethics and in compliance with prevailing laws and 
regulations.
Protocol Number: D9266C00001
Amendment Number: 3
Study Intervention: Datopotamab deruxtecan (Dato-DXd, DS-1062a)
Study Phase: Phase 1/Phase 2
Short Title: Dato-DXd in Patients with Advanced Solid Tumours
Acronym: TROPION-PanTumor02 
Study Physician Name and Contact Information will be provided separately.
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Clinical Study Protocol - D9266C00001
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VERSION HISTORY
DOCUMENT HISTORY
Document
Date
Amendment 3 (Version 4.0)
29 May 2023
Amendment 2 (Version 3.0)
31 March 2022 
Amendment 1 (Version 2.0)
17 November 2021
Original Protocol (Version 1.0)
20 October 2021
Amendment 3 (Version 4.0; 29 May 2023) 
The overall rationale for this amendment is to accomplish the following: 

Update the protocol language to reflect new clinical data and external guidance and to 
provide clarification

Make minor adjustments to the text.  
List of Substantial Modifications
Section Number and 
Name
Description of Change
Brief Rationale
1.1 Synopsis; 1.3 Schedule 
of Activities; 4.1.1 Study 
Overview; 7.1.2 Follow-up 
for Survival; 8.2.4 Overall 
Survival
Updated the time windows for study 
activities and clarified the recording 
requirements for additional 
assessments during survival follow-
up.
To provide a wider window for data 
collection of subsequent progression 
status and overall survival
1.1 Synopsis; 3 Objectives 
and Endpoints; 8.6.2 
Immunogenicity 
Assessments; 9.4.4.4 
Immunogenicity Data
Clarified that neutralising antibodies 
may be tested when ADA is positive, 
as Dato-DXd is at low-risk of 
immunogenicity and the nAb 
evaluation could be optional for early 
studies.
To reflect that neutralising ADA may 
be determined when ADA is positive.
1.3 Schedule of Activities; 
8.3.5.5 Ophthalmologic 
Assessments; 8.4.11 
Adverse Events of Special 
Interest
Clarified that an Ophthalmologic 
Assessment Manual will be used 
instead of the previous form provided 
in the Appendices. Updated 
instructions for the use of artificial 
tears. Removed Appendix K 
Ophthalmologic Assessment Form.
To align with the latest 
recommendations from the external 
advisory board (ie, that artificial tears 
be used 4-8 times per day as opposed 
to “daily”) and clarify that the 
Ophthalmologic Assessment form is 
now included in the Dato-DXd Site 
Ophthalmologic Assessment Manual 
1.3 Schedule of Activities; 
6.5 Concomitant Therapy; 
7.1.1 Follow-up of 
Sections 1.3, 8.4.1, and 8.4.7; 
Appendix B2. Updated to specify the 
collection timeframe for AEs, SAEs, 
To clarify instructions and collect 
extra information on AESIs

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Section Number and 
Name
Description of Change
Brief Rationale
Participants Post 
Discontinuation of Study 
Intervention; 8.4.1 Time 
Period and Frequency for 
Collecting AE and SAE 
Information; 8.4.7 Disease 
Progression; 8.4.11 
Adverse Events of Special 
Interest; Appendix B2 
Definitions of Serious 
Adverse Event
all AESIs and AESIs of 
ILD/pneumonitis, and to clarify the 
types of events to be reported within 
24 hours of investigator awareness.
Clarification that pre-existing medical 
conditions identified through 
mandatory screening procedures are 
to be recorded as medical history.
Removed text about distinguishing 
between serious and severe AEs.
Sections 6.5, 7.1.1, and 8.4.11. Text 
added to state that all AESIs and 
concomitant medications 
administered as treatment for drug-
related AESIs should be followed 
until either event resolution, end of 
study, including any post-treatment 
follow-up, trial termination, 
withdrawal of consent, or participant 
death.
ILD/Pneumonitis:
•
Added text to state that all 
ILD/pneumonitis events should 
be reported beyond the specified 
safety follow-up period.
Infusion-related Reaction:
•
Amended text regarding 
collection of ≥Grade 3 AEs via a 
targeted questionnaire of IRR.
To collect extra information on AESIs 
and ensure that any AESIs are 
followed until resolution
1.3 Schedule of Activities; 
8.3.2 Vital Signs; 8.3.3 
Electrocardiograms; 8.3.5.2 
Pulmonary Assessments; 
8.3.5.3 ILD/Pneumonitis 
Investigation
Simplified the instructions for 
handling ECG readings, vital signs, 
and pulmonary assessments. 
Removed Appendix J Guidance for 
Management of Participants with 
Drug-Induced ILD/pneumonitis. 
Updated the evaluation procedures for 
ILD. All references to Appendix J 
were removed and replaced with 
references to the TMGs in the CSP 
Annex.
To simplify the instructions for 
assessments and remove redundant 
instructions for management of 
ILD/pneumonitis
1.3 Schedule of Activities
Removed the ECG assessment during 
the EoT visit.
To clarify that the requirements for 
ECG are reduced due to no cardiac 
safety signal noted for Dato-DXd
2.2.1 Dato-DXd; 2.3.1 Risk 
Assessment; 2.3.2 Benefit 
Updated the description of prior data, 
the description of risks and benefits, 
To reflect clinical data for Dato-DXd 
up to the DCO of 16Nov2022 (in 

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 of 1 6 5
Secti o n N u m ber a n d 
N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
Assess me nt; 2. 3. 3 O verall 
Be nefit/ Ris k C o ncl usi o n; 
4. 3 J ustificati o n f or D ose
a n d t he d ose j ustificati o n. Re m o ve d 
S ecti o ns 8. 3. 5. 5
 
 
. 
ali g n me nt wit h Dat o-D X d I B 
E diti o n 7 . 0) 
I n Ta ble 2 a n d Secti o n 2. 3. 3,  
 was 
d o w n gra de d fr o m a n i m p orta nt 
i de ntifie d ris k t o a n i de ntifie d ris k a n d 
was re m o ve d fr o m t he 
descri pti o n of t he ris k.
 
 
 
 
 
I n Ta ble 2, 
 
 
ris k.
T he c ha n ge t o 
 
was t o ma ke it a n i m p orta nt ris k, i n 
li ne wit h n o n-cli nical data a n d class 
effect i nf or mati o n.
5. 1 I n cl usi o n Criteria; 5. 2 
E xcl usi o n Criteria; 8. 3. 4 
Cli nical Safet y La b orat or y 
Assess me nts; A p pe n di x F 
C o ntrace pti o n 
Re q uire me nts
U p date d i nstr ucti o ns f or se x a n d 
c o ntrace pti o n. 
I ncl usi o n criteria 9-1 1 a n d 
A p pe n di x F: A d de d f urt her details of 
c o ntrace pti o n req uire me nts f or fe male 
a n d male partici pa nts a n d i nstr ucti o ns 
f or d onati n g or usi n g o va or freezi n g 
or  d o nati n g s per m, res pecti vel y. 
Clarificati o n
E xcl usi o n criteri o n 2 6 clarifie d t hat 
fe males s h o ul d refrai n fr o m 
br eastfee di n g fr o m scree ni n g
t hr o u g h o ut t he st u d y a n d f or  
 
 after t he last d ose of Dat o-
D X d. 
T o f oll o w F D A g ui da nce o n h o w l o n g 
partici pa nts s h o ul d refrai n fr o m 
br eastfee di n g i n cli nical st u dies 
( 5 half -li ves of st u d y 
i nter ve nti on + 6 m o nt hs)
Secti o n 8. 3. 4 re vise d pre g na nc y 
w or di n g t o clarif y t hat re peat 
pre g na nc y tests ( uri ne or ser u m test 
per i nstit uti o nal g ui deli nes) m ust be 
perf or me d wit hi n 7 2 h o urs bef ore t he 
first d ose of st u d y i nter ve nti o n a n d 
clarif y t h e ste ps t o be ta ke n if t he 
res ult is p ositi ve or a b n or mal.
C ha n ge d i n li ne wit h a pr o gra m -wi de 
decisi o n t o a d d clarificati o n f or t he 
ti mi n g f or c ollecti o n of t he scree ni n g 
ser u m pre g na nc y test
5. 2 E xcl usi o n Criteria; 
8. 3. 4 Cli nical Safet y 
La b orat o r y Assess me nts
Clarifie d criteria f or H B V a n d H C V 
i n criteri o n 7.
T o ali g n wit h F D A g ui da nce t o 
br oa de n eli gi bilit y criteria f or 
C CI
C CI
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
5 of 1 6 5
Secti o n N u m ber a n d 
N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
partici pa nts i nfecte d wit h H B V a n d 
H C V
6. 2. 2. 1 A d mi nistrati o n of 
Dat o -D X d; A p pe n di x G 2 
Restricte d, Pr o hi bite d, a n d 
Per mitte d C o nc o mita nt 
Me dicati o ns/ T hera pies 
( Ta ble 1 8)
Re vise d a d vice t hat partici pa nts 
recei ve 
 
a ge nts pri or t o i nf usi o n of Dat o -D X d 
a n d on s u bse q ue nt da ys as nee de d 
fr o m “rec o m me n de d” t o “ hi g hl y 
rec o m me n de d” a n d clarifie d t hat t he y 
s h o ul d re mai n o n site f or at least 1
h o ur p ost -i nf usi o n of e very d ose of 
Dat o -D X d.
T o e ns ure a n a de q uate d urati o n of 
m o nit ori n g f or I R R after Dat o -D X d 
i nf usi o ns a n d t o clarif y t he 
rec o m me n dati o ns f or pre-me dicati o n
6. 6 D ose M o dificati o n; 
6. 6. 1 D ose Dela ys; 
6. 6. 2 D ose Dela ys f or 
Reas o ns o t h er tha n 
Treat me nt -relate d T o xicit y; 
6. 6. 3 D ose Re d ucti o ns ; 
8. 4. 5 A d verse E ve nts Base d 
o n E xa mi nati o ns a n d Tests; 
8. 4. 1 1 A d verse E ve nts of 
S pecial I nterest
Te xt a me n de d t o sa y t hat 
2 c o nsec uti ve d oses of Dat o-D X d 
m ust be a d mi nistere d at least 1 8 da ys 
a part (rat her t ha n 1 9 da ys a part).
T o matc h t he ne w visit wi n d o w 
( ± 3 da ys).
Te xt a me n de d t o: “ A d ose of Dat o -
D X d ca n be dela ye d  
 
 fr o m 
t he pla n ne d date of a d mi nistrati o n (ie, 
 fr o m t he last i nf usi o n date).  
 
 
 
T o all o w m ore ti me f or a n y a d verse 
e ve nt t o res ol ve bef ore re q uiri n g 
per ma ne nt disc o nti n uati o n of 
Dat o -D X d 
Ne w s u bsecti o ns a d de d t o clarif y t he 
pr oce d ures f or d ose m o dificati o ns, 
i ncl u di n g a d di n g Fi g ure 3, o utli ni n g 
t he pr oce d ure if treat me nt wit h Dat o-
D X d is dela ye d f or c o n dit i o ns ot her 
t ha n t o xicit y res ol uti o n, a n d 
clarif yi n g t he pr oce d ure i n t he e ve nt 
t hat a d ose dela y occ urs pri or t o 
c o m pleti o n of P K bl o o d sa m pli n g. 
Als o, “ d ose i nterr u pti o n” was 
c ha n ge d t o “ d ose dela y” t o clarif y 
t hat t he w h ole d ose w o ul d be dela ye d. 
T o cla rif y a n d e ns ure c o nsiste nc y wit h 
T M Gs
6. 7 C o nti n ue d Access t o 
St u d y I nter ve nti o n After 
t he E n d of t he St u d y
Clarifie d t he strate g y f or pr o vi di n g 
Dat o -D X d after t he st u d y
U p o n c o m pleti o n of data c ollecti o n i n 
a trial, partici pa nts ma y still be 
be nefitti n g fr o m treat me nt i n t he 
o pi ni o n of t he i n vesti gat or. T his 
la n g ua ge has bee n a d de d f or 
tra ns pare nc y t o healt h a ut h orities, 
C CI
C CI
C CI
C CI

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Section Number and 
Name
Description of Change
Brief Rationale
regulators and ethics boards on how 
these participants may continue to 
receive that treatment.
6.8 Treatment of Overdose; 
8.5 Overdose; Appendix B4 
Medication Error, Drug 
Abuse, or Drug Misuse
Clarified the handling of drug misuse 
and overdose
Update required due to AstraZeneca
safety
8 Study Assessments and 
Procedures; 8.3.4 Clinical 
Safety Laboratory 
Assessments; 8.6 Human 
Biological Samples
Clarified the instructions for 
laboratory assessments and for 
handling human biological samples, 
including the timing of procedures, 
how abnormal test results will be 
handled, and how long samples will 
be stored.
Clarification
8.4.8 Disease Under Study
Clarified that events unequivocally 
due to Disease Under Study should 
not be reported as AEs during the 
study unless they meet SAE criteria 
(not those leading to study 
intervention discontinuation).
To clarify the reporting of events due 
to Disease Under Study
8.7.1 Collection of 
Mandatory Samples for 
Biomarker Analysis
Revised the time for biomarker 
sample retention to one year after 
final CSR publication.
Update for consistency with a 
company-wide policy and local 
regulations
9.3 Populations for 
Analyses; 9.4.1 General 
Considerations; 9.4.2.1.1.3 
Primary Endpoint: 
Confirmed ORR by ICR; 
9.4.4.1 Pharmacokinetics
Added “enrolled” population, general 
statistical considerations, and 
additional description of ORR 
analysis. Expanded the description of 
PK analysis procedures.
To clarify the analysis procedures
Appendix A Regulatory, 
Ethical, and Study 
Oversight Considerations
Added text about investigator 
oversight and reporting requirements 
for serious breaches. Added text 
about informed consent, data 
protection, and data quality assurance. 
Updated the minimum duration of 
record retention. 
Update required to comply with 
regulatory requirements and global 
company requirements
Appendix E Guidelines for 
Evaluation of Objective 
Tumour Response Using 
RECIST 1.1 Criteria
(Response Evaluation 
Criteria in Solid Tumours)
Table E14: changed “Non-PD or NE” 
to “Non-PD or NE or NA” in the 
“Non-Target Lesions” column for NE 
target lesions. Updated the 
instructions in RECIST 1.1 TL 
assessment at follow-up to clarify the 
description of TLs. 
Correction and clarification

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Section Number and 
Name
Description of Change
Brief Rationale
Appendix G Concomitant 
Medications
Clarified that corticosteroids can be 
used as clinically indicated, clarified 
the restrictions on the use of palliative 
radiotherapy, and clarified that anti-
resorptive/bone therapy is allowed for 
treatment of bone metastases and 
osteoporosis. 
Clarified the instructions for 
prohibition of chronic systemic 
corticosteroids/immunosuppressants.
Clarified the instructions for 
supportive medications/therapies.
To clarify instructions
Throughout
Removed various references to 
COVID-19 protocols, including 
removing Appendix I Instructions 
Related to COVID-19. Updated 
9.4.4.5 COVID-19 Impact (previously 
called COVID-19 Data)
To align with the current stage of the 
COVID-19 pandemic and because no 
adverse impacts have been identified 
between COVID-19 and the 
benefit/risk considerations for 
Dato-DXd
ADA, anti-drug antibody; AE, adverse event; AESI, adverse event of special interest; COVID-19, coronavirus 
2019-nCoV; CSP, clinical study protocol; CSR, clinical study report; Dato-DXd, datopotamab deruxtecan; DCO, 
data cutoff; ECG, electrocardiogram; EoT, end of treatment; FDA, Food and Drug Administration; HBV, 
hepatitis B virus; HCV, hepatitis C virus; IB, Investigator’s Brochure; ICR, independent central review; ILD, 
interstitial lung disease; IRR, infusion-related reaction; NA, not applicable; NE, not evaluable; ORR, objective 
response rate; PD, progression of disease; PK, pharmacokinetic; Q3W, every 3 weeks; RECIST, Response 
Evaluation Criteria in Solid Tumours; SAE; serious adverse event; TL, target lesion; TMG, toxicity management 
guideline.
List of Non-substantial Modifications
Section Number and 
Name
Description of Change
Brief Rationale
Title Page, 1.1 Synopsis
Added Clinicaltrials.gov number
Update with new registry information
1.1 Synopsis; 4.1 Overall 
Design
Clarified the meaning of “screened”
Minor clarification
1.3 Schedule of Activities
Simplified descriptions and moved 
the “Notes” column into the footnotes
Minor clarification
8.1 Administrative and 
General/Baseline 
Procedures
Added a section to clarify 
administrative and general/baseline 
procedures
To clarify the administrative/general 
procedures
Appendix A8 Source 
Documents
Revised the location of the definition 
of what constitutes source data. 
Correction.
Appendix C3 International 
Air Transport Association 
Updated the name of this section
Correction

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Section Number and 
Name
Description of Change
Brief Rationale
Guidance Document (62nd
Edition)
Appendix E Guidelines for 
Evaluation of Objective 
Tumour Response Using
RECIST 1.1 Criteria 
(Response Evaluation 
Criteria in Solid Tumours)
Updated the subheading numbers and 
added the word “alone” to “Special 
considerations regarding lesion 
measurability at baseline” to clarify 
that the indicated assessments alone 
are not considered adequate. 
Minor clarification.
Removed the section “Central 
Imaging” from “RECIST 1.1 
evaluation of overall visit response at 
follow-up”.
Reduce redundancy
Throughout
Minor updates to wording
Clarification
RECIST, Response Evaluation Criteria in Solid Tumours. 

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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
VERSION HISTORY........................................................................................................... 2
TABLE OF CONTENTS...................................................................................................... 9
1
PROTOCOL SUMMARY................................................................................ 14
1.1
Synopsis ........................................................................................................... 14
1.2
Schema............................................................................................................. 20
1.3
Schedule of Activities....................................................................................... 20
2
INTRODUCTION............................................................................................ 26
2.1
Study Rationale ................................................................................................ 26
2.2
Background ...................................................................................................... 27
2.2.1
Dato-DXd......................................................................................................... 27
2.2.2
Non-small-cell Lung Cancer ............................................................................. 28
2.2.3
Triple-negative Breast Cancer........................................................................... 29
2.2.4
Other Solid Tumours ........................................................................................ 30
2.2.4.1
Gastric or Gastroesophageal Junction Adenocarcinoma .................................... 30
2.2.4.2
Urothelial Carcinoma........................................................................................ 31
2.2.5
Other TROP2-directed Antibody-Drug Conjugate Therapies ............................ 31
2.3
Benefit/Risk Assessment................................................................................... 31
2.3.1
Risk Assessment............................................................................................... 31
2.3.2
Benefit Assessment........................................................................................... 33
2.3.3
Overall Benefit/Risk Conclusion....................................................................... 34
3
OBJECTIVES AND ENDPOINTS................................................................... 35
4
STUDY DESIGN ............................................................................................. 36
4.1
Overall Design.................................................................................................. 36
4.1.1
Study Overview ................................................................................................ 37
4.1.2
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis ................................................ 39
4.2
Scientific Rationale for Study Design ............................................................... 39
4.2.1
Rationale for Study Endpoints .......................................................................... 40
4.2.2
Rationale for Study Design in TNBC Cohort .................................................... 41
4.3
Justification for Dose........................................................................................ 41
4.4
End of Study Definition.................................................................................... 42
5
STUDY POPULATION ................................................................................... 43
5.1
Inclusion Criteria .............................................................................................. 43
5.2
Exclusion Criteria ............................................................................................. 48
5.3
Lifestyle Considerations ................................................................................... 52
5.3.1
Meals and Dietary Restrictions ......................................................................... 52
5.3.2
Tobacco............................................................................................................ 53

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5.4
Screen Failures ................................................................................................. 53
6
STUDY INTERVENTION............................................................................... 53
6.1
Study Intervention(s) Administered .................................................................. 53
6.2
Preparation/Handling/Storage/Accountability of Interventions.......................... 55
6.2.1
Storage of Dato-DXd........................................................................................ 55
6.2.2
Preparation of Dato-DXd.................................................................................. 56
6.2.2.1
Administration of Dato-DXd............................................................................. 56
6.2.2.2
Safety Monitoring............................................................................................. 57
6.3
Measures to Minimise Bias............................................................................... 57
6.3.1
Participant Enrolment ....................................................................................... 57
6.3.2
Procedures for Handling Incorrectly Enrolled Participants ................................ 58
6.3.3
Methods for Assigning Treatment Groups......................................................... 58
6.3.4
Methods for Ensuring Blinding......................................................................... 59
6.4
Study Intervention Compliance......................................................................... 59
6.5
Concomitant Therapy........................................................................................ 59
6.5.1
Drug-Drug Interactions..................................................................................... 60
6.6
Dose Modification ............................................................................................ 61
6.6.1
Dose Delays...................................................................................................... 61
6.6.2
Dose Delays for Reasons other than Treatment-related Toxicity ....................... 62
6.6.3
Dose Reductions............................................................................................... 62
6.6.4
Dose Modification for Toxicity Management.................................................... 63
6.7
Continued Access to Study Intervention After the End of the Study.................. 64
6.8
Treatment of Overdose ..................................................................................... 64
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.......................................................... 65
7.1
Discontinuation of Study Intervention............................................................... 65
7.1.1
Follow-up of Participants Post Discontinuation of Study Intervention............... 66
7.1.2
Follow-up for Survival...................................................................................... 66
7.2
Participant Discontinuation/Withdrawal From the Study................................... 67
7.3
Loss to Follow-up............................................................................................. 67
8
STUDY ASSESSMENTS AND PROCEDURES ............................................. 68
8.1
Administrative and General/Baseline Procedures.............................................. 69
8.2
Efficacy Assessments........................................................................................ 69
8.2.1
Imaging Tumour Assessments .......................................................................... 69
8.2.2
Central Reading of Scans.................................................................................. 71
8.2.3
Bone Scan or Skeletal Survey ........................................................................... 71
8.2.4
Overall Survival................................................................................................ 71
8.3
Safety Assessments........................................................................................... 71
8.3.1
Physical Examinations...................................................................................... 71
8.3.2
Vital Signs........................................................................................................ 72
8.3.3
Electrocardiograms........................................................................................... 72
8.3.4
Clinical Safety Laboratory Assessments............................................................ 73

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8.3.5
Other Safety Assessments................................................................................. 75
8.3.5.1
Echocardiogram/Multigated Acquisition Scan .................................................. 75
8.3.5.2
Pulmonary Assessments.................................................................................... 75
8.3.5.3
ILD/Pneumonitis Investigation ......................................................................... 76
8.3.5.4
Eastern Cooperative Oncology Group Performance Status................................ 77
8.3.5.5
Ophthalmologic Assessments............................................................................ 77
8.3.5.6
Oral Care Plan .................................................................................................. 78
8.4
Adverse Events and Serious Adverse Events..................................................... 79
8.4.1
Time Period and Frequency for Collecting AE and SAE Information................ 79
8.4.2
Follow-up of AEs and SAEs ............................................................................. 80
8.4.3
Causality Collection.......................................................................................... 81
8.4.4
Adverse Events Based on Signs and Symptoms ................................................ 82
8.4.5
Adverse Events Based on Examinations and Tests............................................ 82
8.4.6
Hy’s Law.......................................................................................................... 83
8.4.7
Disease Progression.......................................................................................... 83
8.4.8
Disease Under Study......................................................................................... 83
8.4.9
New Cancers..................................................................................................... 83
8.4.10
Deaths .............................................................................................................. 83
8.4.11
Adverse Events of Special Interest.................................................................... 84
8.4.12
Safety Data to be Collected Following the Final Data Cut-off of the Study ....... 86
8.4.13
Reporting of Serious Adverse Events................................................................ 86
8.4.14
Pregnancy......................................................................................................... 87
8.4.14.1
Maternal Exposure............................................................................................ 87
8.4.14.2
Paternal Exposure............................................................................................. 88
8.4.15
Special Situations of Medication Error, Drug Abuse, or Drug Misuse ............... 88
8.4.15.1
Timelines.......................................................................................................... 88
8.4.15.2
Medication Error............................................................................................... 88
8.4.15.3
Drug Abuse ...................................................................................................... 89
8.4.15.4
Drug Misuse ..................................................................................................... 89
8.5
Overdose .......................................................................................................... 89
8.6
Human Biological Samples............................................................................... 89
8.6.1
Pharmacokinetics.............................................................................................. 90
8.6.1.1
Determination of Drug Concentration ............................................................... 91
8.6.2
Immunogenicity Assessments ........................................................................... 91
8.6.3
Pharmacodynamics........................................................................................... 91
8.7
Human Biological Sample Biomarkers ............................................................. 91
8.7.1
Collection of Mandatory Samples for Biomarker Analysis................................ 91
8.7.2
Collection of Optional Biomarker Samples ....................................................... 92
8.8
Optional Genomics Initiative Sample................................................................ 92
8.9
Health Economics............................................................................................. 92
8.10
Study Participant Feedback Questionnaire ........................................................ 92
9
STATISTICAL CONSIDERATIONS............................................................... 93
9.1
Statistical Hypotheses....................................................................................... 93
9.2
Sample Size Determination............................................................................... 93

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9.3
Populations for Analyses .................................................................................. 94
9.4
Statistical Analyses........................................................................................... 95
9.4.1
General Considerations..................................................................................... 95
9.4.2
Efficacy ............................................................................................................ 97
9.4.2.1
Primary Endpoint.............................................................................................. 97
9.4.2.2
Secondary Endpoint(s)...................................................................................... 98
9.4.2.3
Tertiary/Exploratory Endpoint(s) .................................................................... 103
9.4.3
Safety ............................................................................................................. 103
9.4.4
Other Analyses ............................................................................................... 105
9.4.4.1
Pharmacokinetics............................................................................................ 105
9.4.4.2
Biomarkers ..................................................................................................... 105
9.4.4.3
Optional Exploratory Genetic Sample............................................................. 105
9.4.4.4
Immunogenicity Data...................................................................................... 106
9.4.4.5
COVID-19 Impact .......................................................................................... 106
9.5
Interim Analyses............................................................................................. 106
9.6
Data Monitoring Committee ........................................................................... 106
9.6.1
ILD Adjudication Committee.......................................................................... 106
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS...................................................................................... 107
11
REFERENCES............................................................................................... 159
LIST OF TABLES
Table 1
Schedule of Activities.............................................................................. 21
Table 2
Risk Assessment...................................................................................... 31
Table 3
Objectives and Endpoints......................................................................... 35
Table 4
Study Intervention ................................................................................... 54
Table 5
Dose Reduction Levels of Dato-DXd....................................................... 63
Table 6
Laboratory Safety Variables..................................................................... 74
Table 7
Spirometry Component............................................................................ 75
Table 8
Pharmacokinetic Sampling Schedule ....................................................... 90
Table 9
Populations for Analysis .......................................................................... 94
Table 10
Summary of Outcome Variables and Analysis Populations ...................... 96
Table E11
Summary of Imaging Modalities for Tumour Assessment...................... 128
Table E12
RECIST 1.1 Evaluation of Target Lesions ............................................. 135
Table E13
RECIST 1.1 Evaluation of Non-Target Lesions ..................................... 136
Table E14
RECIST 1.1 Overall Visit Response ...................................................... 136
Table F15
Highly Effective Methods of Contraception (<1% Failure Rate) ............ 140

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Table G16
Restricted Medications/Therapies .......................................................... 141
Table G17
Prohibited Medications/Therapies.......................................................... 142
Table G18
Supportive Medications/Therapies......................................................... 143
LIST OF FIGURES
Figure 1
Study Design ........................................................................................... 20
Figure 2
Dosing Schedule...................................................................................... 54
Figure 3
Dose Delay Schema for Dato-DXd .......................................................... 62
LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations....................... 108
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...................................................................... 114
Appendix C
Handling of Human Biological Samples ................................................ 120
Appendix D
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law......................................................................... 122
Appendix E
Guidelines for Evaluation of Objective Tumour Response Using 
RECIST 1.1 Criteria (Response Evaluation Criteria in Solid Tumours).. 128
Appendix F
Contraception Requirements.................................................................. 138
Appendix G
Concomitant Medications ...................................................................... 141
Appendix H
Changes Related to Mitigation of Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis ............................ 145
Appendix I
Abbreviations ........................................................................................ 147
Appendix J
Protocol Amendment History................................................................. 152

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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: Phase 1/Phase 2, Multicentre, Open-label, Multiple-cohort Study of Dato-
DXd in Chinese Patients With Advanced Non-small-cell Lung Cancer, Triple-negative Breast 
Cancer, Gastric/Gastroesophageal Junction Cancer, Urothelial Cancer, and Other Solid 
Tumours.
Short Title: Dato-DXd in Patients With Advanced Solid Tumours.
Regulatory Agency Identifier Number(s):
Clinicaltrials.gov NCT05460273
Rationale:
Cancer is a major global health issue and the leading cause of death in China (Feng et al 2019, 
Zhang et al 2015, Zhou et al 2019) with 4.5 million new cases and 3 million deaths in 2020 
(GLOBOCAN 2020). The situation in China has been alarming partly due to the aging and 
growing population, as well as socioeconomic development. It is essential to develop new 
therapies for Chinese cancer patients who are refractory or intolerant to standard therapies, or 
for whom no standard therapy exists.
The Phase 1 first-in-human Study DS1062-A-J101 is evaluating Dato-DXd in 
TROP2-unselected participants with advanced NSCLC who have relapsed from or are 
refractory to SoC therapy as well as in participants with advanced TNBC who have relapsed 
from or are refractory to SoC therapy or for whom no SoC therapy is available. An additional 
cohort of participants with hormone receptor-positive, HER2-negative breast cancer is 
currently recruiting as of March 2021. Other tumour types may also be explored in the future. 
Clinical data from Study DS1062-A-J101 show efficacy of Dato-DXd with a manageable 
toxicity profile. However, none of the participants in Study DS1062-A-J101 are from China, 
and there is an unmet need for more information about the safety and efficacy of Dato-DXd in 
the adult Chinese population.
Given these encouraging preliminary safety and efficacy data, the current study is designed to 
further assess the efficacy, safety, PK, and immunogenicity of Dato-DXd in adult Chinese 
patients with selected advanced or metastatic solid tumours. This single-arm study consists of 
multiple cohorts, divided by indication. Cohort 1, which includes participants with advanced 
or metastatic NSCLC with or without AGAs who have received immune-oncology therapies 
and platinum-based chemotherapy (for participants with NSCLC without AGAs) or one or 
two prior lines of applicable targeted therapy and platinum-based chemotherapy (for 
participants with NSCLC with AGAs), and Cohort 2, which includes participants with
inoperable locally advanced or metastatic TNBC who have received at least 2 prior 
chemotherapy regimens for advanced breast cancer, counting the (neo)adjuvant therapy as a 

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prior chemotherapy regimen if progression occurred within 12 months after completion of the 
therapy, will be prioritised for enrolment. Additional cohorts will be added for future 
enrolment of participants with advanced or metastatic solid tumours and may include, but are 
not limited to, patients with advanced/unresectable or metastatic gastric or GEJ 
adenocarcinoma or urothelial carcinoma that is refractory or intolerant to SoC therapy or for 
which no SoC therapy is available.
Objectives and Endpoints:
The objectives and endpoints of this study for each cohort are shown below. 
Objectives
Endpoints
Primary
To estimate the effectiveness of Dato-
DXd by assessment of confirmed ORR by 
ICR 
Confirmed ORR is defined as the proportion of 
participants in each cohort who have a confirmed CR 
or confirmed PR, as assessed by ICR per RECIST 1.1. 
The measure of interest is the estimate of confirmed 
ORR.
Secondary
To estimate the effectiveness of Dato-
DXd by assessment of confirmed ORR by 
investigator assessment.
Confirmed ORR is defined as the proportion of 
participants in each cohort who have a confirmed CR 
or confirmed PR, as determined by investigator 
assessment per RECIST 1.1.
To estimate the effectiveness of Dato-
DXd by assessment of DoR.
Duration of response is defined as the time from the 
date of first documented response (which is 
subsequently confirmed) until date of documented 
progression per RECIST 1.1, as assessed by ICR and 
by investigator, or death due to any cause. 
To estimate the effectiveness of Dato-
DXd by assessment of DCR.
Disease control rate is defined as the percentage of 
participants who have a confirmed CR or PR or who 
have SD per RECIST 1.1, as assessed by ICR and by 
investigator. 
To estimate the effectiveness of Dato-
DXd by assessment of BOR. 
Best overall response is defined as participant’s best 
confirmed response during their participation in the 
study, but prior to starting any subsequent anticancer 
therapy, up until RECIST 1.1-defined progression or 
the last evaluable assessment in the absence of 
RECIST 1.1-defined progression. Best overall 
response will be assessed by ICR and by investigator 
per RECIST 1.1.

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Objectives
Endpoints
To estimate the effectiveness of Dato-
DXd by assessment of TTR.
Time to response is defined as the time from date of 
first dose of study intervention until the date of first 
documented objective response, which is subsequently 
confirmed per RECIST 1.1, as assessed by ICR and by 
investigator. 
To estimate the effectiveness of Dato-
DXd by assessment of PFS.
Progression-free survival is defined as time from date 
of first dose of study intervention until PD per 
RECIST 1.1, as assessed by ICR and by 
investigator, or death due to any cause.
To estimate the effectiveness of Dato-
DXd by assessment of OS.
Overall survival is defined as the time from the date of 
the first dose of study intervention to the date of death 
due to any cause.
To assess the safety and tolerability of 
Dato-DXd.
Safety and tolerability are evaluated in terms of 
TEAEs, AESIs including ILD evaluated by an 
independent adjudication committee, vital signs, 
clinical laboratory, ECG, ECHO/MUGA parameters, 
and ophthalmologic findings. 
To evaluate the PK of Dato-DXd.
Plasma concentrations and appropriate PK parameters
of Dato-DXd, total anti-TROP2 antibody, and MAAA-
1181a (DXd) will be calculated for participants with 
PK samples if data permit.
To investigate the immunogenicity of 
Dato-DXd.
The presence of ADAs against Dato-DXd will be 
evaluated.
Titre will be determined when ADA is positive.
For the exploratory objectives and endpoints, see Section 3 of the protocol.
Overall Design
Disclosure Statement: This is a Phase 1/Phase 2, multicentre, open-label, multiple-cohort 
study, which is designed to evaluate the efficacy, safety, PK, and immunogenicity of Dato-
DXd in adult Chinese participants with advanced or metastatic solid tumours. 
Participant Population: 
This study is divided into cohorts of participants with the same tumour type. The starting 
cohorts are Cohort 1 (NSCLC) and Cohort 2 (TNBC). Future cohorts will consist of other 
advanced or metastatic solid tumour types, including, but not limited to, 
advanced/unresectable or metastatic gastric or GEJ adenocarcinoma or urothelial carcinoma 
that is refractory or intolerant to SoC therapy or for which no SoC therapy is available. 
Cohort 1 and Cohort 2 will be prioritised for immediate enrolment, and the CSP will be 
amended as needed for the future cohorts. 

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Cohort 1: The target population of Cohort 1 is adult Chinese participants with advanced or 
metastatic NSCLC with orwithout AGAs (ie, alterations in genes with approved therapies, 
such as EGFR, ALK, or other known AGAs). Eligible participants without AGAs will have 
been previously treated with platinum-based chemotherapy and anti-PD-1/anti-PD-L1 
monoclonal antibody, either in combination or sequentially. Participants without AGAs who 
received anti-PD-1/anti-PD-L1 monoclonal antibody as frontline therapy may have received 
the combination of platinum-based chemotherapy and anti-PD-1/anti-PD-L1 monoclonal 
antibody in the second-line setting. Eligible participants with AGAs will have been previously 
treated with one or two prior lines of applicable targeted therapy that is approved for the 
participant’s genomic alteration and platinum-based chemotherapy as the only prior line of 
cytotoxic therapy. Participants with AGAs may have received up to one anti-PD-1/anti-PD-L1 
monoclonal antibody treatment alone or in combination with chemotherapy.
Cohort 2: The target population of Cohort 2 is adult Chinese participants with inoperable 
locally advanced or metastatic TNBC who have received at least 2 prior chemotherapy 
regimens for advanced breast cancer, counting the (neo)adjuvant therapy as a prior 
chemotherapy regimen if progression occurred within 12 months after completion of the 
therapy.
Number of Participants: 
Cohort 1: Approximately 40 eligible NSCLC participants in China will be enrolled.
Cohort 2: Approximately 78 eligible TNBC participants in China will be enrolled. 
For Cohort 1, approximately 6 participants with AGAs will be enrolled.  
An enrolment cap will be placed on Cohort 2: at most around 20% (approximately N=15) of 
enrolled participants with a DFI ≤12 months.
Note: ‘Screened’ means a participant’s, or their legally acceptable representative’s, agreement 
to participate in a clinical study following completion of the informed consent process. 
‘Enrolled’ means a participant’s, or their legally acceptable representative’s, agreement to 
participate in a clinical study following completion of the informed consent process and the 
participant is confirmed as eligible. Potential participants who are screened for the purpose of 
determining eligibility for the study, but are not enrolled, are considered ‘screen failures.’ 
Study Periods:
Screening Period: The Screening Period will start on the day of signing the ICF and have a 
maximum duration of 28 days. Rescreening is permitted one time. During the 28-day 
Screening Period, participants’ eligibility will be confirmed. 

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
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C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 8 of 1 6 5
T he st u d y  start date is t he date w he n t he first partici pa nt has si g ne d a n I C F. A partici pa nt is 
eli gi ble t o be e nr olle d i nt o t he st u d y w he n t he i n vesti gat or or desi g nee has o btai ne d writte n 
i nf or me d c o nse nt, has c o nfir me d all i ncl usi o n a n d e xcl usi o n cri teria ha ve bee n met b y t he 
parti ci pa nt, a n d all Scree ni n g pr oce d ures ha ve bee n c o m p lete d.
I nter ve nti o n Peri o d: Eli gi ble partici pa nts will e nter t he I nter ve nt i on Peri o d. T he I nter ve nt i on 
P eri o d starts o n C y cle 1 Da y  1 a n d c o nti n ues u ntil a partici pa nt per ma ne nt l y disc o nti n ues 
Dat o -D X d. 
D uri n g t h e I nter ve nt i on Peri o d, parti ci pa nts will recei ve Dat o -D X d. Partici pa nts will be 
treate d wit h Dat o-D X d at 6. 0 m g/ k g via a n i ntra ve n o us i nf usi o n o n Da y  1, Q 3 W u ntil t he y 
meet o ne of t he disc o nti n uati o n criteria. 
U p t o 2 d ose re d ucti o ns will be per mitte d f or partici pa nts recei vi n g Dat o -D X d. O nce t he d ose 
of  Dat o-D X d has bee n re d uce d beca use of t o xicit y, all s u bse q ue nt c y cles s h o uld be 
a d mi nistere d at t hat l o wer d ose le vel, u nless f urt her d ose re d ucti o n is re q uire d. O nce t he d ose 
of  Dat o-D X d is re d uce d, n o d os e re-escalat i on will be per mitte d. O ne a d diti o nal d ose 
re d uctio n m a y be p ossi ble o n a case - b y-case basis after disc ussi o n a n d a gree me nt bet wee n t he 
i n vesti gat or a n d s p o ns or. A d ose ca n be dela ye d f or 
 fr o m t he pla n ne d date of 
a d mi nistrati o n (ie, 
 fr o m t h e last i nf usi o n date). 
P arti cipa nts will u n der g o ra di o gra p hic assess me nt of t u m o ur res p o nse base d o n R E CI S T 1. 1 
e ver y 6 wee ks ( ± 7 da ys) fr o m t he date of t he first d ose of st u d y int er ve nt i on u nt il 
r a dio gra p hic P D as assesse d b y  in vesti g a t or. T he assess me nt m ust c o nti n ue u ntil P D as 
defi ne d per R E CI S T 1. 1, w het her or n ot t he partici pa nt is st ill o n treat me nt. F oll o wi n g P D 
assesse d b y in vest i gat or, o ne a d diti onal f oll o w-u p t u m o ur assess me nt s h o ul d be perf or me d at 
t he ne xt sc he d ule d i ma gi n g visit a n d n o less t ha n 4 wee ks after t he pri or assess me nt of P D. 
T he i nte nt of t his a d dit i onal f o ll ow- u p assess me nt is t o mi ni mise t he disc or da nce bet wee n 
i n vesti gat or a n d I C R assess me nts. T he sca ns fr om all assess me nts of t u m o ur res p o nse, 
i ncl u di n g t he f oll ow- u p assess me nt, will be se nt f or I C R re vie w. 
P ost -i nter ve nti o n F oll o w-u p Peri o d: After st u d y  int er ve nt i on di sc o nti n uatio n, all 
parti ci pa nts will u n der g o a n e n d-of -tr e at me nt visit ( wit hi n 7 da ys of t he decisi on t o st o p 
treat me nt) a n d will be f o ll owe d u p f or safet y  assess me nts 
 after t heir last d ose of 
st u d y int er ve ntio n (ie, t he Safet y F o ll ow- u p Visi t). If t he da y o n w hic h t he i n vesti gat or 
deter mi nes t hat t he patie nt s h o ul d disc o nt i n ue st u d y i nter ve nti on is o ver  
 after t he last 
d ose of s t u d y int er ve nt i on recei ve d b y t he patie nt, a n a d dit i onal safet y fol l ow- u p assess me nt is 
n ot nee de d.
P arti cipa nts w h o ha ve disc o nti n ue d st u d y  int er ve nti o n pri or t o o bjecti ve R E CI S T 1. 1 -defi ne d 
r a diol o gical  pr o gressio n  c o nfir me d b y in vest i gat or assess me nt, re gar dless of w het her or n ot 
t he y ha ve c o m me nce d s u bse q ue nt a ntica ncer t hera p y, will be f o ll owe d u p wi t h t u mo ur 
C CI
C CI
C CI
C CI

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assessments according to the SoA until RECIST 1.1-defined PD, regardless of whether or not 
the participant started a subsequent anticancer therapy, unless they have withdrawn all consent 
to study-related assessments. 
After discontinuation of study intervention, participants will then be followed up every 
3 months (± 14 days) for collection of information on survival, including the cause and date of 
death, and subsequent anticancer therapy. The Post-intervention Follow-up Period will 
continue until death, withdrawal of consent, or the end of the study. 
Statistical Methods:
The primary endpoint of the study is confirmed ORR by ICR, defined as the proportion of 
participants in each cohort with confirmed CR or PR as assessed by ICR based on 
RECIST 1.1. Objective response rate by ICR will be estimated with a 2-sided 95% exact CI 
using the Clopper-Pearson method based primarily on the RES population, who received at 
least one dose of study intervention and had measurable disease at baseline by ICR. The 
primary analysis and final analysis will be performed separately for each cohort.
The DCO for the primary analysis of ORR by ICR will occur approximately 6 months after 
the last participant for that cohort has initiated study intervention. Duration of response, DCR, 
BOR, TTR, PFS, OS, and available safety, immunogenicity, and PK data will also be 
summarised at this time. 
The DCO for the full final analysis of ORR by ICR will occur approximately 12 months after 
the last participant for that cohort has initiated study intervention. The full final analysis will 
report the analyses of all primary and secondary endpoints, including updated ORR and DoR, 
DCR, BOR, TTR, PFS, OS, PK, immunogenicity, and safety.
Safety data will be summarised descriptively.
Pharmacokinetic parameters of each participant with intensive PK samples will be estimated 
using non-compartmental analysis methods. Descriptive statistics will be provided for all 
plasma concentration data at each time point and PK parameters. The plasma concentration 
data will also be presented graphically as appropriate. The PK data generated in this study will 
be used for PopPK and E-R analyses, if data permit, to characterise the relationships of dose, 
exposure, efficacy, and safety endpoints. The results of the PopPK and E-R analyses will be 
reported separately from the clinical study report. Immunogenicity will be assessed through 
characterisation of incidence and titre of ADA. 

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1.2
Schema
Figure 1
Study Design
a
Additional cohorts may include, but are not limited to, advanced/unresectable or metastatic gastric or 
gastrointestinal junction adenocarcinoma or urothelial carcinoma that is refractory or intolerant to SoC 
therapy or for which no SoC therapy is available.
b
Study intervention will be delivered via intravenous infusion and continue until one of the criteria for 
discontinuation is met.
AGA, actionable genomic alteration; BOR, best overall response; CT, computed tomography; Dato-DXd, 
datopotamab deruxtecan; DCR, disease control rate; DoR, duration of response; ECOG PS, Eastern Cooperative 
Oncology Group performance status; EGFR, epidermal growth factor receptor; ICR, independent central review; 
MRI, magnetic resonance imaging; ORR, objective response rate; OS, overall survival; PFS, progression-free 
survival; PK, pharmacokinetics; Q3W, every 3 weeks; TNBC, triple-negative breast cancer; TROP2, tumour-
associated calcium signal transducer 2; TTR, time to response. 
1.3
Schedule of Activities
The procedures for this study are presented in the SoA (Table 1). Procedures and/or 
assessments are required from screening until data collection ends (inclusive of follow-up 
periods). Following the final DCO date, participants will be managed per SoC assessments at 
Investigator discretion.

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
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T a ble 1
Sc he d ule of Acti viti es
Pr oce d ure
Scree ni n g a
I nter ve nti o n peri o d ( d a ys ± visit wi n d o w)
P ost- i nter ve nti o n peri o d
Det ails i n C S P secti o n or 
a p pe n di x
C 1
C 2  
C 3
C 4 + 
u ntil P D
E o T or 
E/ D b
F oll o w -u p
S afet y c S ur vi v al d
D a y
D a y -2 8 t o - 1
D a y 1  
D a y 8
D a y 1 5
D a y 1  
D a y 1  
D a y 1
Visit wi n d o w ( ± d a ys) 
N/ A
± 3 
± 3 
± 3 
± 3 
± 3 
± 3
-3, + 7
+ 7
± 1 4
I nf or me d c o nse nt: mai n st u d y e
X
Secti o n  5. 1
Inf or me d c o nse nt: i nte nsi ve P K 
sa m pli n g ( o pti o nal) e
X
Secti o n  5. 1
St u d y Pr oce d ures a n d S afet y Assess me nts
I ncl usi o n a n d e xcl usi o n criteria
X  
X
f
Secti o ns  5. 1 a n d 5. 2
Treat me nt assi g n me nt i n I R T
X g
Secti o n  6. 2. 2
De m o gra p h y
X
Secti o n  5. 1 a n d 8. 1
Me dical hist or y 
X
X f
Secti o ns  5. 1 , 5. 2 a n d 
8. 1
C urre nt me dical c o n diti o ns
X
X f
Secti o ns  5. 1 a n d 5. 2
F ull p h ysical e xa mi nati o n
X
Secti o n  8. 3. 1
Tar gete d p h ysical e xa mi nati o n
X 
X h
X h
X h
X  
X
Secti o n  8. 3. 1
Hei g ht
X
Secti o n  8. 3. 1
Wei g ht
X
X f
X h
X h
X h
X  
X
Secti o n  8. 3. 1
E C O G perf or ma nce stat us
X
X f
X h
X h
X h
X  
X
Secti o n  8. 3. 5. 4
1 2- lea d E C G
X
As cli nicall y i n dicate d
Secti o n  8. 3. 3
E C H O/ M U G A ( L V E F)
X
As cli nicall y i n dicate d
Secti o n  8. 3. 5. 1
Vital si g ns 
X
X f,h, j
X h, j
X h, j
X h, j
X  
X
Secti o n  8. 3. 2
 i
X
X f,h,j
X h,j
X h,j
X h,j
X  
X
Secti o n  8. 3. 5. 2
P ul m o nar y f u ncti o n tests
If I L D/ p ne u m o nitis is s us pecte d
Secti o n  8. 3. 5. 2 a n d 
8. 3. 5. 3
I L D/ p ne u m o nitis i n vesti gati o n
If I L D/ p ne u m o nitis is s us pecte d
Secti o n  8. 3. 5. 3
C CI

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Procedure
Screening a
Intervention period (days ±visit window)
Post-intervention period
Details in CSP section or 
appendix
C1
C2
C3
C4 + 
until PD
EoT or 
E/Db
Follow-up
Safety c Survival d
Day
Day -28 to -1
Day 1
Day 8
Day 15
Day 1
Day 1
Day 1
Visit window (± days) 
N/A
±3
±3
±3
±3
±3
±3
-3,+7
+7
±14
Chest CT
(HRCT preferred if
feasible)
If ILD/pneumonitis is suspected
Section 8.3.5.2 and 
8.3.5.3
Ophthalmologic assessments k
X
As clinically indicated
X
Section 8.3.5.5
Oral care plan l
Daily before dosing, throughout treatment, and up to the safety follow-up visit
Section 8.3.5.6
AE review
X
At every visit and may be conducted via phone if not tied to a 
visit
X
X
X 
(SAEs)
Sections 6.6 and 8.4
Prior and concomitant 
medication review
X
At every visit and may be conducted by phone if not tied to a 
visit
X
X
Sections 5.2 and 6.5
Subsequent anticancer therapy m
X
X
Section 7.1.2
Laboratory Assessments
Serum or urine pregnancy test 
(FOCBP only)
X n
X n
X n
X n
X n
X n
X n
Sections 5.1, 5.2, and 
8.4.14
Hepatitis B and C and HIV o
X
Sections 5.2 and 8.3.4
Clinical safety laboratory 
assessments (clinical chemistry, 
haematology)
X 
X f
X h
X h
X h
X
X
Sections 5.1 and 8.3.4
Coagulation
X
As clinically indicated.
Section 8.3.4
Urinalysis
X
As clinically indicated
Section 8.3.4
Biomarker Assessments
Tumour sample collection 
(archived or newly acquired 
biopsy) subject to all required 
approvals. p
X
Section 8.7.1
PK Testing

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Procedure
Screening a
Intervention period (days ±visit window)
Post-intervention period
Details in CSP section or 
appendix
C1
C2
C3
C4 + 
until PD
EoT or 
E/Db
Follow-up
Safety c Survival d
Day
Day -28 to -1
Day 1
Day 8
Day 15
Day 1
Day 1
Day 1
Visit window (± days) 
N/A
±3
±3
±3
±3
±3
±3
-3,+7
+7
±14
Pre-dose blood sample for 
Dato-DXd, total anti-TROP2 
antibody, and DXd (MAAA-
1181a) sparse PK testing (within 
8 hours)
X
X
X 
(C4 and 
C8)
Section 8.6.1
Post-dose blood sample for 
Dato-DXd, total anti-TROP2 
antibody, and DXd sparse PK 
testing
X q
X 
(C4 and 
C8) r
Section 8.6.1
Additional post-dose blood 
sample for Dato-DXd PK testing 
(only required for participants in 
the intensive PK cohort) s 
X t
X
X
Section 8.6.1
Additional blood sample for 
Dato-DXd PK testing (if 
feasible) 
As soon as ILD/pneumonitis is suspected
Sections 8.3.5.3 and 
8.6.1
Immunogenicity Testing
Pre-dose blood sample for 
immunogenicity testing (within 
8 hours) 
X
X
X (C4, 
C8, and 
every 4 
cycles 
thereafte
r) 
Section 8.6.2
Post-dose blood sample for 
immunogenicity testing 
X
X
Section 8.6.2
Imaging and Efficacy Assessments

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 4 of 1 6 5
Pr oce d ure
Scree ni n g a
I nter ve nti o n peri o d ( d a ys ± visit wi n d o w)
P ost- i nter ve nti o n peri o d
Det ails i n C S P secti o n or 
a p pe n di x
C 1
C 2  
C 3
C 4 + 
u ntil P D
E o T or 
E/ D b
F oll o w -u p
S afet y c S ur vi v al d
D a y
D a y -2 8 t o - 1
D a y 1  
D a y 8
D a y 1 5
D a y 1  
D a y 1  
D a y 1
Visit wi n d o w ( ± d a ys) 
N/ A
± 3 
± 3 
± 3 
± 3 
± 3 
± 3
-3, + 7
+ 7
± 1 4
T u m o ur i ma gi n g ( R E CI S T 1. 1) u
X
E ver y  6 wee ks ( ± 7 da ys) fr o m t he date of t he first d ose of st u d y i nter ve nti o n u ntil 
R E CI S T 1. 1 -defi ne d ra di ol o gical P D b y i n vesti gat or assess me nt, w het her or n ot t he partici pa nt 
is still o n treat me nt. 
 
 
Secti o ns  8. 2. 1 a n d 8. 2. 2
Brai n sca n v
X
Partici pa nts 
 m ust ha ve t he lesi o ns rec or de d as part of t he 
R E CI S T assess me nt a n d m ust ha ve a brai n sca n 
 
Secti o ns  8. 2 . 1 a n d 8. 2. 2
B o ne i ma gi n g w
X
Secti o ns  8. 2. 1 a n d 8. 2. 2
S ur vi val stat us
X
Secti o ns  7. 1. 2 a n d 8. 2. 4
St u d y I nter ve nti o n A d mi nistr ati o n
St u d y  i nter ve nti o n a d mi nistere d 
(I V i nf usi o n) 
X 
Dat o -D X d at 6. 0 m g/ k g will be a d mi nistere d via I V i nf usi o n 
o n Da y 1 of eac h 3 -wee k c ycle
Secti o n  6
a
U p t o 2 8 da ys bef ore t he first d ose of st u d y i nter ve nti o n. It is str o n gl y rec o m me n de d t hat scree ni n g assess me nts be c o n d ucte d as cl ose as p ossi ble t o Da y 1. 
b
Wit hi n 7 da ys after t he decisi o n t o st o p treat me nt. A -3, + 7 -da y wi n d o w is all o wa ble. If t he reas o n f or disc o nti n uati o n is P D, t he n b ot h “ E o T/ disc o nti n uati o n” a n d “ P D” 
visits ca n be c o n d ucte d at t he sa me visit. 
c
T he Safet y F oll o w -u p Visit will be perf or me d  
 after t he last st u d y i nter ve nti o n a d mi nistrati o n. If t he da y o n w hic h t he i n vesti gat or deter mi nes t hat t he patie n t 
s h o ul d disc o nti n ue st u d y i nter ve nti o n is o ver  
 after t he last d ose of st u d y i nter ve nti o n recei ve d b y t he patie nt, a n a d dit i o nal safet y f oll o w-u p assess me nt is n ot nee de d.
d
E ver y  3 m o nt hs ± 1 4 da ys.
e
Writte n i nf or me d c o nse nt a n d a n y l ocall y re q uire d pri vac y act d oc u me nt a ut h orisati o n m ust be o btai ne d pri or t o perf or mi n g a n y
C S P -s pecific pr oce d ures, i ncl u di n g 
scree ni n g/ baseli ne eval uati o ns. 
f
If scree ni n g assess me nts ha ve bee n perf or me d wit hi n 7 2 h o urs pri or t o starti n g st u d y i nter ve nti o n, t he y d o n ot ha ve t o be re peate d at C 1 Da y 1 if t he partici pa nt’s c o n diti o n 
has n ot c ha n ge d. 
g
E ver y  eff ort s h o ul d be ma de t o mi ni mise t he ti me bet wee n  treat me nt assi g n me nt i n I R T a n d starti n g treat me nt (ie, wit hi n 3 b usi ness da ys of treat me nt assi g n me nt). 
h
Wit hi n 7 2 h o urs pri or t o i nf usi o n. 
i
If  
 is meas ure d o n t he da y of i nf usi o n, it s h o ul d be meas ure d 
 
j
Assess me nt s h o ul d als o be c o n d ucte d at t he e n d of i nf usi o n.
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

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k
Ophthalmologic assessments including but not limited to visual acuity testing, slit lamp examination, intraocular pressure measurement, fundoscopy, and fluorescein staining 
will be performed at screening, as clinically indicated, and at the EoT visit by an ophthalmologist, or if unavailable, another licensed eye care provider. Please refer to the 
Dato-DXd Site Ophthalmologic Assessment Manual for further details.
l
Participants will be provided an OCP prior to and during study treatment. Daily before dosing, throughout treatment, and up to the safety follow-up visit.
m
Subsequent anti-cancer drug treatment may commence following discontinuation of study intervention, including at PD.
n
A negative serum pregnancy test must be documented during screening for all FOCBP. If a serum pregnancy test is collected greater than 72 hours prior to the first dose of 
study intervention, perform a repeat pregnancy test (urine or serum per institutional guideline) within 72 hours before the first dose of study intervention. Perform repeat 
pregnancy tests (urine or serum per institutional guideline) within 72 hours before each infusion at each cycle, at EoT, and the first follow-up visit. A positive urine 
pregnancy test result must immediately be confirmed using a serum test. 
o
As required by local regulations or IRB/EC. Prior HBV surface antigen, HCV antibody test, and HIV antibody test results can be used if performed within 120 days before 
screening. If an HIV infection meets the criteria outlined in Section 5.2, monitoring of viral RNA load and CD4+ cell count is recommended and should be performed per 
local SoC (eg, every 3 months). 
p
Tumour samples collected from the primary tumour or from a metastatic site before treatment with Dato-DXd should be provided for all enrolled participants in this study 
based on local regulatory approval. A fresh tumour sample collected during screening is preferred if clinically feasible in the form of an FFPE tissue. For the FFPE tissues, a 
minimum of 5 slides of freshly prepared, unstained, 4- to 5-micron sections are required. If such a de novo collection is not feasible, an archival tumour sample collected as 
close to screening as possible must be provided, in the form of a minimum of 5 slides of freshly prepared, unstained, 4 to 5-micron sections from the archival FFPE tumour 
block. As uncontrolled oxidation processes affect tumour sections, tumour tissue blocks are preferred, if local regulation permits.
q
Within 30 minutes after end of infusion. One additional sample at 5 hours (± 15 minutes) after start of infusion for C1 will be collected.
r
Within one hour after end of infusion. 
s
Additional samples will be collected only for participants enrolled in selected sites. 
t
Collect samples at 7 (± 15 minutes) and 24 (± 2 hours) hours after start of infusion for C1.
u
The baseline tumour assessment must be performed within 28 days before the start of study intervention and as close as possible to the start of study intervention.
v
A brain scan must be performed at baseline within 28 days before the start of study intervention and as close as possible to the start of study intervention. Participants with 
brain metastases at baseline must have the lesions recorded as part of the RECIST assessment and must have a brain scan performed every 6 weeks (±7 days) from the date of 
the first dose of study intervention until radiological progression per RECIST. Otherwise, follow-up brain imaging is required only if new brain metastases are suspected.
w
All participants should have a baseline bone scan or skeletal survey performed no more than 12 weeks before, and as close as possible to, the start of study intervention. 
Note: All assessments on treatment days are to be performed prior to study intervention administration, unless otherwise indicated. Data collection following study analysis until 
the end of the study is described in Section 8.
AE, adverse event; HBV, hepatitis B virus; HCV, hepatitis C virus; C, cycle; CD, cluster of differentiation; CSP, Clinical Study Protocol; Dato-DXd, datopotamab deruxtecan; EC,
Ethics Committee; ECG, electrocardiogram; ECHO, echocardiogram; ECOG, Eastern Cooperative Oncology Group; E/D, Early Study Intervention/Discontinuation; EoT, end of 
treatment; FFPE, formalin fixed and paraffin embedded; FOCBP, female of child-bearing potential; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human 
immunodeficiency virus; HRCT, high-resolution computed tomography; ICF, informed consent form; ILD, interstitial lung disease; IRB, Institutional Review Board; IRT, 
interactive response technology; IV, intravenous; LVEF, left ventricular ejection fraction; MUGA, multigated acquisition; OCP, oral care plan; PD, progression of disease;
PK, pharmacokinetic; QXW, every X weeks; RECIST 1.1, Response Evaluation Criteria in Solid Tumours, Version 1.1; SAE, serious adverse event; SoC, standard of care; SpO2,
peripheral capillary oxygen saturation

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2
INTRODUCTION
Datopotamab deruxtecan (Dato-DXd, DS-1062a) is an ADC that binds to trophoblast cell 
surface protein 2 (TROP2), also known as tumour-associated calcium signal transducer 2. 
Dato-DXd is in development as a candidate therapy for cancer.
2.1
Study Rationale
Cancer is a major global health issue and the leading cause of death in China (Feng et al 2019, 
Zhang et al 2015, Zhou et al 2019) with 4.5 million new cases and 3 million deaths in 2020 
(GLOBOCAN 2020). The situation in China has been alarming partly due to the aging and 
growing population, as well as socioeconomic development. It is essential to develop new 
therapies for Chinese cancer patients who are refractory or intolerant to standard therapies, or 
for whom no standard therapy exists.
The Phase 1 first-in-human Study DS1062-A-J101 is evaluating Dato-DXd in 
TROP2-unselected participants with advanced NSCLC who have relapsed from or are 
refractory to SoC therapy as well as in participants with advanced TNBC who have relapsed 
from or are refractory to SoC therapy or for whom no SoC therapy is available. An additional 
cohort of participants with hormone receptor-positive, HER2-negative breast cancer is 
currently recruiting as of March 2021. Other tumour types may also be explored in the future. 
Clinical data from Study DS1062-A-J101 show efficacy of Dato-DXd with a manageable 
toxicity profile. However, none of the patients in Study DS1062-A-J101 are from China, and 
there is an unmet need for more information about the safety and efficacy of Dato-DXd in the 
adult Chinese population.
Given these encouraging preliminary safety and efficacy data, the current study is designed to 
further assess the efficacy, safety, PK, and immunogenicity of Dato-DXd in adult Chinese 
patients with selected advanced or metastatic solid tumours. This single-arm study consists of 
multiple cohorts divided by indication. Cohort 1, which includes participants with advanced or 
metastatic NSCLC with or without AGAs who have received immune-oncology therapies and 
platinum-based chemotherapy (for participants with NSCLC without AGAs), or one or two 
prior lines of applicable targeted therapy and platinum-based chemotherapy (for participants 
with NSCLC with AGAs), and Cohort 2, which includes participants with inoperable locally 
advanced or metastatic TNBC who have received at least 2 prior chemotherapy regimens for 
advanced breast cancer, counting the (neo)adjuvant therapy as a prior chemotherapy regimen 
if progression occurred within 12 months after completion of the therapy, will be prioritised 
for enrolment. Future cohorts may include, but are not limited to, participants with 
advanced/unresectable or metastatic gastric or GEJ adenocarcinoma or urothelial carcinoma 
that is refractory or intolerant to SoC therapy or for which no SoC therapy is available.

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2.2
Background
2.2.1
Dato-DXd
Antibody-drug conjugates are payload delivery systems that have been developed to overcome 
the challenges of delivering cytotoxics and cytostatics specifically into cancer cells by 
targeting cells that express the preferred marker.
As of 27 July 2020, AstraZeneca and Daiichi Sankyo Company, Limited (Daiichi Sankyo) 
entered into a joint global development and collaboration agreement for Dato-DXd, a TROP2 
targeting ADC that is being developed as a therapeutic candidate for cancer.
Dato-DXd is an ADC comprising a recombinant humanised anti-TROP2 immunoglobulin G1 
monoclonal antibody, MAAP-9001a, which is covalently conjugated via a cleavable 
drug-linker, MAAA-1162a (the complex of MAAA-1181a, hereafter referred to as DXd, and a 
maleimide tetrapeptide linker), using thioether bonds to the topoisomerase I inhibitor DXd. 
This tumour-selective cleavable drug-linker is stable in the systemic circulation. Dato-DXd 
binds to the transmembrane glycoprotein TROP2, which is highly expressed on the cell 
surface of epithelial tumours and is internalised. The drug component of Dato-DXd, DXd (a 
DNA topoisomerase I inhibitor), is released by enzymatic processes after internalisation, 
leading to inhibition of tumour growth and apoptosis of the target tumour cells and 
neighbouring tumour cells via the inhibition of DNA topoisomerase I.
TROP2 is highly expressed in various epithelial tumours, including oesophageal squamous 
cell carcinoma (Nakashima et al 2004), breast cancer (Lin et al 2013), and NSCLC 
(Kobayashi et al 2010). Its expression correlates with aggressive tumour behaviour and has 
been used as a prognostic marker in several types of cancer (Fong et al 2008, Kobayashi et al 
2010, Lin et al 2013, Mühlmann et al 2009).
In vitro studies indicate that Dato-DXd exhibits TROP2 expression-dependent cell growth 
inhibitory activity, and in vivo studies using a tumour-bearing mouse model indicate that 
administration of Dato-DXd results in the regression of TROP2-positive tumours. The 
biodistribution and antitumour activity of the ADC are expected to depend on the expression 
level of the target antigen in tumour tissue. The targeted indications of the Dato-DXd 
programme have high expression of TROP2 (Cubas et al 2009, Shvartsur et al 2015). 
There are currently no TROP2-directed therapies approved for the treatment of NSCLC. A 
detailed description of the chemistry, pharmacology, mechanism of action, efficacy, and 
safety of Dato-DXd is provided in the IB.
2.2.2
Non-small-cell Lung Cancer
As of 2020, lung cancer was the most common cause of death worldwide, accounting for 
1.8 million annual deaths (https://www.who.int/news-room/fact-sheets/detail/cancer). In 
China, lung cancer is also the malignant tumour with the highest incidence rate and mortality 

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rate (Sung et al 2021, Chen et al 2016). Advances in early detection of lung cancer have been 
slow, and more than half of lung cancers are still diagnosed at an advanced stage (Siegel et al 
2019). Only 18.6% of all patients with lung cancer are alive 5 years or more after diagnosis 
(Howlader et al 2017). Non-small-cell lung cancer accounts for 80% to 85% of all lung 
cancers (American Cancer Society 2020). The introduction of targeted therapies and 
checkpoint inhibitors in recent years has improved the treatment landscape, and patients with 
metastatic NSCLC are now surviving longer (Paz-Ares et al 2018, Ricciardi et al 2014, NCCN 
Practice Guidelines in Oncology 2021). A number of genomic alterations that have an impact 
on therapy selection have been identified in NSCLC, and molecular testing is part of the SoC 
in the evaluation of NSCLC (NCCN Practice Guidelines in Oncology 2021). These include, 
but not limited to, EGFR gene mutations, ALK gene rearrangements, ROS1 rearrangements, 
NTRK gene fusions, BRAF point mutations, RET gene rearrangements, and METex14 skipping 
variants. For the subset of patients with NSCLC whose tumours have AGAs, targeted 
therapies (eg, EGFR, ALK, ROS1, METex14 skipping, or RET kinase inhibitors) are 
recommended during the course of treatment as systemic treatments. However, once patients 
have developed acquired resistance to the various targeted therapies and progressed after 
platinum-based chemotherapy, therapeutic options are generally limited to cytotoxic agents 
deployed as monotherapy, and median survival times are less than one year.
For patients with metastatic NSCLC and negative test results for AGAs, the NCCN and 
CSCO guidelines recommend an immune checkpoint inhibitor with or without chemotherapy 
as first-line therapy. The expression of PD-L1 is often assessed to select patients for immune 
checkpoint inhibitors. For patients with PD-L1 levels of 1% or more, especially with 50% or 
more, immune checkpoint inhibitor monotherapy is recommended based on the results from 
the KEYNOTE 042 study (Cho et al 2021). Platinum-based chemotherapy with or without 
immune checkpoint inhibitors is recommended for patients with metastatic NSCLC and 
negative test results for AGAs regardless of PD-L1 status, based on the results from the 
KEYNOTE-189 (Gray et al 2020), KEYNOTE 407 (Paz-Ares et al 2018), CameL (Zhou et al 
2021), ORIENT-11 (Yang et al 2020), ORIENT-12 (Zhou et al 2020a), RATIONALE 304 
(Lu et al 2020), RATIONALE 307 (Wang et al 2020), and GEMSTONE 302 study (Zhou et al 
2020b). 
Among patients relapsing or progressing after frontline platinum-containing doublet 
chemotherapy, the Checkmate-017 and Checkmate-057 studies demonstrated superior OS of 
nivolumab over docetaxel monotherapy in patients with squamous and non-squamous 
NSCLC, respectively (Brahmer et al 2015, Borghaei et al 2015). For patients relapsing or 
progressing after frontline immune checkpoint inhibitor monotherapy, chemotherapy is 
recommended by NCCN and CSCO guidelines.
As a result of these and similar studies, patients with NSCLC and without AGAs generally 
receive platinum doublets and immune checkpoint inhibitors, either in combination or in 

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sequence, as the first one or two lines of therapy. None of these therapies, however, are 
considered curative in the advanced setting, and once patients have progressed after them, 
therapeutic options are generally limited to cytotoxic agents deployed as monotherapy, and 
median survival times are less than one year. 
Docetaxel monotherapy remains perhaps the most widely used treatment for patients whose 
NSCLC has progressed after platinum-based chemotherapy and immune checkpoint inhibitors 
(for patients with NSCLC without AGAs) or target therapies (for patients with NSCLC with 
AGAs), consistent with NCCN and CSCO guidelines. The INTEREST (Kim et al 2008), 
Checkmate 078 (Wu et al 2019), KEYNOTE-010 (Herbst et al 2016), and OAK (Rittmeyer et 
al 2017) studies suggest that the NSCLC patients who received docetaxel as second-line 
therapy have median PFS of 2.0 months to 4 months and median survival of 8.0 months to 
9.6 months. Consequently, novel treatments for patients who have advanced or metastatic 
NSCLC after receiving platinum-based chemotherapy and immune-oncology therapies (for 
patients with NSCLC without AGAs), or targeted therapies (for patients with NSCLC with 
AGAs), are still needed to improve prognosis, control disease, and prevent symptoms while 
minimising toxicity; this represents an area of considerable unmet medical need. A new class 
of therapy with better efficacy and fewer side effects would therefore be a preferred option in 
this treatment setting.
2.2.3
Triple-negative Breast Cancer
Triple-negative breast cancer accounts for approximately 15% of invasive breast cancers (Li 
et al 2018, Si et al 2015) and is a subgroup that is not amenable to hormonal-based 
therapeutics available for the larger group of breast cancer that express oestrogen and/or 
progesterone, or anti-HER2 therapeutics for those that have elevated HER2 production. 
Compared with other subtypes of breast cancer, the survival time of TNBC patients is shorter, 
and the mortality rate is 40% within the first 5 years after diagnosis (Dent et al 2007). Triple-
negative breast cancer is highly invasive, and approximately 46% of TNBC patients will have 
distant metastasis. The median survival time after metastasis is only 13.3 months, and the 
recurrence rate after surgery is as high as 25%. Metastasis often involves the brain and 
visceral organs. Distant metastasis mostly occurs in the third year after diagnosis (Lin et al 
2008). The average time to relapse in non-TNBC patients is 35 to 67 months, while that in 
TNBC patients is only 19 to 40 months. The mortality rate of TNBC patients within 3 months 
after recurrence is as high as 75% (Gluz et al 2009, Zhang et al 2015). In China, therapeutic 
options are currently limited to sequential chemotherapies. Sequential single chemotherapy 
agents (given until PD or unacceptable toxicity) are recommended in preference to 
chemotherapy combinations except in patients with a need for rapid symptom and/or disease 
control. The most commonly used agents in the metastatic setting are taxanes, anthracyclines, 
platinum agents, vinorelbine, capecitabine, and eribulin. Although chemotherapy significantly 
improves clinical outcomes for TNBC patients, recurrence rates remain relatively high and 
TNBC tumours often develop resistance to chemotherapeutic agents (Carey et al 2007, 

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Foulkes et al 2010). The limited treatment options and aggressive phenotypes of TNBC 
highlight the need for advances in more effective therapeutic treatment options for 
TNBC patients, especially in treated patients who are refractory to chemotherapy or who 
relapse to multiple lines of chemotherapy agents. 
A TROP2 ADC sacituzumab govitecan-hziy (IMMU-132; Trodelvy™), was recently 
approved by the US FDA, but is not currently approved in China, for the treatment of adult 
patients with unresectable locally advanced or metastatic TNBC who have received 2 or more 
prior systemic therapies, with at least one of them for metastatic disease based on the results 
from the Phase 3 IMMU-132-05 study (Bardia et al 2021a). Thus, there remains an unmet 
medical need for treatment options for Chinese patients with advanced TNBC.
Dato-DXd has shown promising preliminary efficacy in TNBC patients in 
Study DS1062-A-J101, but this study did not include participants from China (Bardia 2021). 
The current study intends to fill a crucial knowledge gap by evaluating Dato-DXd in Chinese 
participants with advanced TNBC. 
2.2.4
Other Solid Tumours
2.2.4.1
Gastric or Gastroesophageal Junction Adenocarcinoma
Gastric adenocarcinoma is the fifth most common cancer worldwide. In 2020, there were over 
one million newly diagnosed cases and 768 thousand deaths annually worldwide, making 
gastric cancer the fourth leading cause of cancer-related deaths in the world (GLOBOCAN 
2020b, Torre et al 2015). Globally, the highest incidence of GC is reported in East Asian 
countries, particularly China (with nearly half of global cases), Japan, and South Korea. In 
China, gastric adenocarcinoma is now the second most commonly diagnosed cancer and is the 
second leading cause of cancer-related death (Chen et al 2016). GLOBOCAN statistics 
estimate that there were over 478 thousand new cases of gastric adenocarcinoma and over 
373 thousand deaths caused by gastric adenocarcinoma in China in 2018 (GLOBOCAN 
2020). Worldwide, approximately 65% of gastric adenocarcinoma patients present with 
locally advanced or metastatic disease with a poor outcome (Meza-Junco and Sawyer 2012). 
In China, this figure is higher, with approximately 80% of patients presenting with advanced 
disease and likely to have a poor outcome: the 5-year relative survival rate was 35.9% in 
patients with GC in the period from 2010 to 2014 (Yang et al 2018). In patients with GC who 
are refractory to standard therapies, the median life expectancy is approximately 6 months, 
underlining the high unmet medical need.
2.2.4.2
Urothelial Carcinoma
Urothelial cancer is the ninth most common cancer worldwide (Torre et al 2015). The SoC in 
patients with advanced bladder cancer has been platinum-based combination therapy 
regimens. Despite initial high response rates, most patients inevitably progress; in the second 

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
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Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 1 of 1 6 5
li ne setti n g, i m m u n ot hera p y wit h c hec k p oi nt i n hi bit ors is utilise d with O R Rs a p pr o xi matel y i n 
t he 2 0 % ra n ge (Bal ar et al 2 0 1 7).
Saci t u z u ma b g o viteca n -hzi y is a p pr o ve d b y t he U S F D A, b ut n ot i n C hi na, f or use i n patie nts 
wi t h locall y a d va nce d or metastatic ur ot helial ca ncer w h o ha ve pre vi o usl y  recei ve d a 
pl at i n u m-c o ntai ni n g c he m ot hera p y a n d eit her a P D -1 or P D -L 1 i n hi bit or base d o n t he P hase 2 
T R O P H Y st u d y  (Ta ga wa et al 2 0 2 1 ).
2. 2. 5
Ot her T R O P 2 -directe d A nti b o d y -Dr u g C o nj u g ate T her a pies 
Saci t u z u ma b g o vit e c a n-hzi y, a T R O P 2 -di recte d A D C, is a p pr o ved b y  t he U S F D A t o use i n 
certai n patie nts wit h metastatic T N B C or l ocall y a d va nce d or metastatic ur ot helial ca ncer (see 
Secti o n  2. 2. 3 a n d Secti o n 2. 2. 4. 2 ). 
T here are n o a p pr o ve d T R O P 2 -directe d A D C t hera pies f or ot her t u m o ur t y pes. H o we ver, 
sacit uz u ma b g o viteca n-hzi y has de m o nstrate d a ntit u m o ur efficac y a n d acce pta ble t olera bilit y 
i n a P hase 1/ P hase 2 m ul tice ntre St u d y (I M M U- 1 3 2-0 1) i n patie nts wit h a d va nce d e pit helial 
ca ncers (Bar di a et al 2 0 2 1 b). T his bas ket trial s ho we d t hat O R R was 3 1. 5 % ( 1 7 of 5 4 
parti ci pa nts) f or h or m o ne rece pt or -p osit i ve metastatic breast ca ncer, 1 6. 7 % ( 9 of 5 4 
parti ci pa nts) f or N S C L C, 1 7. 7 % ( 1 1 of 6 2 partici pa nts) f or S C L C, 5. 3 % ( 1 of 1 9 partici pa nts) 
f or oes o p ha geal carci n oma, 3. 2 % ( 1 of 3 1 partici pa nts) f or c ol orectal ca ncer, 2 2. 2 % ( 4 of 1 8 
parti ci pa nts) f or e n d o metrial ca ncer, a n d 9. 1 % ( 1 of 1 1 partici pa nts) f or castrate -resista nt 
pr ostate ca ncer.
2. 3
Be nefit/ Ris k Assess me nt
T he st u d y  will be perf or me d i n acc or da nce wit h et hical pri nci ples t hat ha ve t heir ori gi n i n t he 
Declarati o n of Helsi n ki a n d are c o nsiste nt wit h I C H G C P a n d a p plica ble re g ulat or y  
re q uire me nts.
M ore detaile d i nf or mat i on a b o ut t he k n o w n a n d e x pecte d be nefits a n d p ote ntial ris ks of 
Dat o -D X d ma y be f ou n d i n t he I B. A ris k assess me nt is i ncl u de d i n Ta ble 2 .
2. 3. 1
Ris k Assess me nt
A ris k assess me nt is i ncl u de d i n  Ta ble 2.
T a ble 2
Ris k Assess me nt
P ote nti al Ris k of 
Cli nic al Si g nific a nce
S u m m ar y of D at a/ R ati o n ale f or 
Ris k
Miti g ati o n Str ate g y
St u d y i nter ve nti o n: D at o -D X d
 
 is 
c o nsi dere d a n i m p orta nt 
Base d o n data fr o m o n g oi n g 
St u d y D S 1 0 6 2 - A-J 1 0 1 
( T R O PI O N-Pa n T u m or 0 1) i n 
T hese i de ntifie d a n d p ote ntial ris ks are 
ge nerall y ma na gea ble t hr o u g h d ose 
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Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 2 of 1 6 5
i de ntifie d ris k ass ociate d 
wit h a d mi nistrati o n of 
Dat o -D X d. 
Ot her i de ntifie d ris ks f or 
Dat o -D X d are  
 
 
 
 
 
 
 
 
 
 
 
 
 are 
c o nsi dere d p ote ntial ris ks 
f or Dat o-D X d.
 is 
c o nsi dere d a n i m p orta nt 
p ote ntial ris k.
 
 
i m pair me nt.
I nf or mati o n o n A Es is 
prese nte d i n Secti o n  8. 4 .
partici pa nts wit h N S C L C ( N =
) as 
of 
 
partici pa nts were n ote d t o ha ve 
p ote ntial I L D/ p ne u m o nitis e ve nts. Of 
t he 
partici pa nts wit h p ote ntial 
I L D/ p ne u m o nitis e ve nts, 
 
ha d I L D/ p ne u m o nitis e ve nts 
a dj u dicate d as dr u g -relate d, i ncl u di n g 
 partici pa nts  
 i n t he 6 m g/ k g
d ose gr o u p. T hree cases of 
Dat o -D X d -relate d I L D/ p ne u m o nitis 
wit h a fatal o utc o me ha ve bee n 
re p orte d, all i n t he 8 m g/ k g d ose 
gr o u p. N o fatal cases of 
I L D/ p ne u m o nitis were o bser ve d i n t he 
6 m g/ k g d ose gr o u p.
As of t he D C O date of 
 
f or all i n dicati o ns, 
 of 
partici pa nts treate d wit h 
Dat o -D X d e x perie nce d seri o us I R R 
e ve nts. All 
e ve nts were re p orte d as 
 a n d relate d t o Dat o-D X d.
Base d o n a c u m ulati ve re vie w of 
safet y data, i ncl u di n g a vaila ble 
n o ncli nical, cli nical, a n d 
e pi de mi ol ogic i nf or mati o n a n d 
scie ntific literat ure ( p u blis he d a n d 
u n p u blis he d), re p orte d t o xicities f or 
t he sa me class of a ge nts of t he m A b 
a n d pa yl oa d as Dat o-D X d, a n d ta ki n g 
i nt o c o nsi derati o n bi ol o gical 
pla usi bilit y, t he i m p orta nt i de ntifie d 
ris k is 
 
 is c o nsi dere d 
a n i m p orta nt p ote ntial ris k.
N o c o nfir me d cases of H y’s La w or 
DI LI ha ve bee n o bser ve d.
Please see t he c urre nt versi o n of t he 
I B f or a detaile d a n d u p-t o-date 
s u m mar y of data i ncl u di n g A Es, 
S A Es, a n d C T C A E Gra de 3 t o 5 
e ve nts re p orte d acr oss t he Dat o -D X d 
pr o gra m me.
m o dificati o n ( Secti o n  6. 6 ) a n d r o uti ne 
cli nical practice.
 
 
 
 
 
S pecific i ncl usi o n/e xcl usi o n criteria 
( Secti o n 5 ) a n d T M Gs (see t he T M G 
A n ne x) are c urre ntl y i n place t o 
miti gat e t he ris ks a n d A E SIs.
A E, a d verse e ve nt; A E SI, a d verse e ve nt of s pecial i nterest; A L T, ala ni ne a mi n otra nsferase; A S T, as partate 
a mi n otra nsferase; C T C A E, C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts; Dat o -D X d, dat o p ota ma b 
der u xteca n; D C O, data c ut off; DI LI, dr u g -i n d uce d li ver i nj ur y; I B, i n vesti gat or’s br oc h ure; I L D, i nterstitial 
l u n g disease; I R R, i nf usi o n-relate d reacti o n; m A b, m o n ocl o nal a nti b o d y; N S C L C, n o n-s mall-cell l u n g ca ncer; 
S A E, seri o us a d verse e ve nt; T M G, t o xicit y ma na ge me nt g ui deli nes
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2.3.2 Benefit Assessment
Dato-DXd is under development for the treatment of lung and breast tumours. In vitro studies 
indicate that Dato-DXd exhibits TROP2 expression-dependent cell growth inhibitory activity, 
and in vivo studies using a tumour-bearing mouse model indicate that administration of Dato-
DXd results in the regression of TROP2-positive tumours.
Supportive preliminary clinical data on Dato-DXd monotherapy are available from ongoing 
Phase I first-in-human study, DS1062-A-J101 (TROPION-PanTumor01), evaluating 
escalating doses of Dato-DXd (0.27 mg/kg to 10 mg/kg) in participants with heavily 
pre-treated advanced NSCLC and TNBC, relapsed or refractory to SoC therapy. These data 
have demonstrated efficacy across dose groups, with tumour responses observed at doses of 4, 
6, and 8 mg/kg and an acceptable and manageable toxicity profile (see Section 4.3). The 
patient populations tested to date include TROP2-unselected patients with advanced NSCLC 
with or without AGAs who have relapsed from or are refractory to SoC therapy and patients 
with advanced TNBC who have relapsed from or are refractory to SoC therapy or for whom 
no SoC therapy is available. As of the DCO date of 06 April 2021, 34 NSCLC participants 
with AGA were treated with Dato-DXd at doses of 4.0, 6.0, or 8.0 mg/kg and were evaluable 
for response assessment. The ORR by ICR was 35.3% (12/34 [95% CI, 19.7-53.5]). The 
overall DCR was 82.4%, and the median DoR was 9.5 mo (95% CI, 3.3-NE). The efficacy 
and safety profile of Dato-DXd as a late-line treatment in advanced NSCLC patients with or 
without AGA was comparable. These results from Study DS1062-A-J101, which has sites in 
the US and Japan, support the evaluation of benefit for patients in China in the present study. 
TROP2, the molecular target of Dato-DXd, is associated with increased tumour growth and 
enhanced proliferation, cell migration, and anchorage-independent growth. TROP2 is 
overexpressed in the majority of human epithelial cancers (including oral, head-and-neck, 
thyroid, lung, oesophageal, gastric, colorectal, pancreatic, breast, renal, uterine, cervical, 
ovarian cancers, and glioma) (Goldenberg et al 2018) but with lower expression in certain 
normal tissues. Thus, a TROP2-directed ADC strategy is likely to benefit patients with 
multiple cancer types, including those not yet tested in Study DS1062-A-J101. 
2.3.3 Overall Benefit/Risk Conclusion
There is an unmet medical need for efficacious and safe therapies in treatment of patients with 
advanced or metastatic solid tumours, especially tumours that are relapsed or refractory to 
SoC therapy. Preliminary results from Study DS1062-A-J101 have shown promising efficacy 
of Dato-DXd at a dose of 6.0 mg/kg Q3W and support further evaluation of Dato-DXd in the 
Chinese population and for Chinese patients with other advanced solid tumours. In this cohort, 
the most frequent TEAEs were nausea/vomiting, stomatitis, fatigue, alopecia, decreased 
appetite, and constipation. The toxicity profile of the 6.0 mg/kg dose regimen of Dato-DXd 
was acceptable and manageable.

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 4 of 1 6 5
T he 2 m ost rel e v a nt ris ks c o nsi dere d f or t he be nefit/ris k assess me nt are t he i m p orta nt 
i de ntifie d ris k of 
 a n d t he i de ntifie d ris k of  
, b ot h of w hic h ca n be  
. 
T o s pecificall y mit i gate t hese ris ks, strict i ncl usi o n/e xcl usi o n criteria ha ve bee n i ncl u de d i n 
t his C S P. Partici pa nts will also b e m o ni t ore d closel y  t hr o u g h o ut t he st u d y a n d cli nical a n d 
la b orat or y assess me nts will be perf or me d bef ore e ver y c ycle. T o xicit y ma na ge me nt g ui deli nes 
will assist wit h t he ma na ge me nt of t he m ost c o m m o nl y see n A Es (see t he T M G A n ne x). 
O verall, Dat o -D X d i s a p ote nt a ntica ncer t hera p y wit h t he p ote ntial t o pr o vide a n i m pr o ve d 
mea ni n gf ul cli nical be nefit a n d a m ore fa v o ura ble safet y pr ofile c o m pare d wi t h t he c urre nt 
S o C f or pati e nts wit h a d va nce d or metastatic s o li d t u m o urs. It is t heref ore of ke y i m p orta nce
t o e val uate t he r ole of Dat o-D X d i n C hi nese pat ients wi t h a d va nce d or metastatic s o li d 
t u mo urs. F urt her m ore, Dat o -D X d ma y pr o vi de be nefit t o C hi nese patie nts wit h ot her 
a d va nce d or metastatic s o li d t u m o urs w h o are refract or y or i nt olera nt t o S o C t hera p y, or f or 
w h o m n o S o C t hera p y  is a vaila ble, a n d t h ose patie nts will be part of f ut ure c o h orts of t his 
st u d y. Co nsi deri n g t he m eas ures t o mi ni mise ris ks t o partici pa nts, t he ris ks ide nt ifie d i n 
ass ociat i on wi t h Dat o-D X d are j ust ifie d b y t he a ntici pate d be nefits t hat ma y be aff or de d t o 
parti ci pa nts wit h a d va nce d or metastatic s oli d t u m o urs. T he be nefit/ris k assess me nt s u p p orts 
t he pr o p ose d st u d y. 
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3
OBJECTIVES AND ENDPOINTS
The objectives and endpoints of this study for each cohort are shown in Table 3. 
Table 3
Objectives and Endpoints
Objectives
Endpoints
Primary
To estimate the effectiveness of Dato-DXd by 
assessment of confirmed ORR by ICR.
Confirmed ORR is defined as the proportion of 
participants in each cohort who have a confirmed 
CR or confirmed PR, as assessed by ICR per 
RECIST 1.1. 
The measure of interest is the estimate of 
confirmed ORR.
Secondary
To estimate the effectiveness of Dato-DXd by 
assessment of confirmed ORR by investigator 
assessment.
Confirmed ORR is defined as the proportion of 
participants in each cohort who have a confirmed 
CR or confirmed PR, as determined by investigator 
assessment per RECIST 1.1. 
To estimate the effectiveness of Dato-DXd by 
assessment of DoR.
Duration of response is defined as the time from 
the date of first documented response (which is 
subsequently confirmed) until date of documented 
progression per RECIST 1.1, as assessed by ICR 
and by investigator, or death due to any cause. 
To estimate the effectiveness of Dato-DXd by 
assessment of DCR.
Disease control rate is defined as the percentage of 
participants who have a confirmed CR or PR or 
who have SD per RECIST 1.1, as assessed by ICR 
and by investigator. 
To estimate the effectiveness of Dato-DXd by 
assessment of BOR. 
Best overall response is defined as participant’s 
best confirmed response during their participation 
in the study, but prior to starting any subsequent 
anticancer therapy, up until RECIST 1.1-defined 
PD or the last evaluable assessment in the absence 
of RECIST 1.1-defined progression. Best overall 
response will be assessed by ICR and by 
investigator per RECIST 1.1.
To estimate the effectiveness of Dato-DXd by 
assessment of TTR.
Time to response is defined as the time from the 
date of the first dose of study intervention until the 
date of first documented objective response, which 
is subsequently confirmed per RECIST 1.1, as 
assessed by ICR and by investigator. 
To estimate the effectiveness of Dato-DXd by 
assessment of PFS.
Progression-free survival is defined as time from 
the date of the first dose of study intervention until 
progression per RECIST 1.1, as assessed by ICR 
and by investigator, or death due to any cause.

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Objectives
Endpoints
To estimate the effectiveness of Dato-DXd by 
assessment of OS.
Overall survival is defined as the time from the 
date of the first dose of study intervention to the 
date of death due to any cause.
To assess the safety and tolerability of Dato-DXd.
Safety and tolerability are evaluated in terms of 
TEAEs, AESIs including ILD evaluated by an 
independent adjudication committee, vital signs, 
and clinical laboratory, ECG, ECHO/MUGA 
parameters, and ophthalmologic findings. 
To evaluate the PK of Dato-DXd.
Plasma concentrations and appropriate PK 
parameters of Dato-DXd, total anti-TROP2 
antibody, and DXd will be calculated for 
participants with PK samples if data permit.
To investigate the immunogenicity of Dato-DXd.
The presence of ADAs against Dato-DXd will be 
evaluated.
Titre will be determined when ADA is positive.
Exploratory
To investigate the association of a biomarker (TROP2) 
with response (ORR, PFS, and OS) to Dato-DXd.
Expression of TROP2 will be measured in tumour 
samples.
4
STUDY DESIGN
4.1
Overall Design
This is a Phase 1/Phase 2, multicentre, open-label, multiple-cohort study, which is designed to 
evaluate the efficacy, safety, PK, and immunogenicity of Dato-DXd in adult Chinese 
participants with advanced or metastatic solid tumours. It is a single-arm study with no 
blinding.
This study is divided into cohorts of participants with the same tumour type. The starting 
cohorts are Cohort 1 (NSCLC) and Cohort 2 (TNBC). Future cohorts will consist of other 
advanced or metastatic solid tumour types, including, but not limited to, 
advanced/unresectable or metastatic gastric or GEJ adenocarcinoma or urothelial carcinoma 
that is refractory or intolerant to SoC therapy or for which no SoC therapy is available. 
Cohort 1 and Cohort 2 will be prioritised for immediate enrolment and the CSP will be 
amended as needed for the future cohorts.
Cohort 1: The target population of Cohort 1 is adult Chinese participants with advanced or 
metastatic NSCLC with or without AGAs (ie, alterations in genes with approved therapies, 
such as EGFR, ALK, or other known AGAs). Eligible participants without AGAs will have 
been previously treated with platinum-based chemotherapy and anti-PD-1/anti-PD-L1 
monoclonal antibody either in combination or sequentially. Participants without AGAs who 
received anti-PD-1/anti-PD-L1 monoclonal antibody as frontline therapy may have received 

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 7 of 1 6 5
t he c o m bi nati o n o f pl at i n u m-base d c he m ot hera p y  a n d a nti-P D -1/a nt i-P D -L 1 m o n o cl o nal  
a nt i b o d y in t he sec o n d -li ne setti n g. Eli gi ble partici pa nts wit h A G As will ha ve bee n pre vi o usl y 
treate d wit h o ne or t w o pri or li nes of a n a p plica ble tar gete d t hera p y t hat is a p pr o ve d f or t he 
parti ci pa nt’s ge n o mic alterat i on a n d plat i n u m-base d c he m ot hera p y  as t he o nl y pri or li ne of 
c yt ot o xic t hera p y. P artici pa nts wit h A G As ma y ha ve recei ve d u p t o o ne a nt i-P D -1/a nt i-P D -L 1 
m o n ocl o nal a nti b o d y  tr e at me nt alo ne or i n c o m bi nati o n wit h c he m ot hera p y . A t otal of 
a p pr o xi matel y 4 0 eli gi ble part ici pa nts i n C hi na will be e nr olle d i n t his c o h ort. C o h ort 1 will 
e nr o l a p pr o xi matel y  p artici pa nts wit h A G As.
C o h ort 2: T he tar get p o p ulat i on of C o h ort 2 is a d ult C hi nese partici pa nts wit h i n o pera ble 
l ocall y a d va nce d or metastatic T N B C w h o ha ve recei ve d at least 2 pri or c he m ot hera p y  
re gi me ns f or a d va nce d breast ca ncer, c o u nti n g t he ( ne o)a dj u va nt t hera p y as a prior 
c he m ot hera p y re gi me n if pr o gressi o n occ urre d wit hi n 1 2 m o nt hs after c o m plet i on of t he 
t hera p y ( D FI ≤1 2 m o nt hs ). A t otal of a p pr o xi matel y 7 8 eli gi ble partici pa nts i n C hi na will be 
enr o lle d i n t his c o h ort. C o h ort 2 will e nr ol at most ar o u n d 2 0 % (a p pr o xi matel y  N = 1 5) of 
e nr o lle d partici pa nts wit h a D FI ≤1 2 m o nt hs .
E nr olle d partici pa nts will be treate d wit h Dat o -D X d at 6. 0 m g/ k g via a n I V i nf usi o n o n Da y  1, 
Q 3 W. 
N ote: ‘ Scree ne d’ mea ns a partici pa nt’s, or t heir le gall y acce pta ble re prese ntati ve’s, a gree me nt 
t o partici pate i n a cli nical st u d y fol l owi n g c o m plet i o n of t he i nf or me d c o nse nt pr ocess. 
‘ E nr olle d’ mea ns a partici pa nt’s, or t heir le gall y acce pta ble re prese ntati ve’s, a gree me nt t o 
p artici pate i n a cli nical st u d y fol l owi n g c o m plet i on of t he i nf or me d c o nse nt pr ocess a n d t he 
parti ci pa nt is c o nfir me d as eli gi ble. P ote nti al p artici pa nts w h o are scree ne d f or t he p ur p ose of 
deter mi ni n g eli gi bilit y f or t he st u d y, b ut are n ot e nr olle d, are c onsi dere d ‘scree n fail ures.’ 
T he pri mar y  o bjecti ve of t he st u d y is t o esti mate t he effecti ve ness of Dat o-D X d b y  assess me nt 
of  c o nfir me d O R R b y I C R.
A st u d y -le vel fl o w dia gra m is prese nte d i n Secti on  1. 2 .
4. 1. 1
St u d y O ver vie w
T he st u d y  will be di vi de d i nt o 3 perio ds: t he Scree ni n g Peri o d, I n ter ve nti on Peri o d, a n d 
P os t-i nter ve nti o n F o ll ow- u p Peri o d.
Scree ni n g Peri o d: T he Scree ni n g Peri o d will start o n t he da y  of si g ni n g t he I C F a n d ha ve a 
ma xi m u m d urat i on of 2 8 da ys. Rescree ni n g is per mitte d o ne ti me. D uri n g t he 2 8 -d a y  
Scree ni n g Peri o d, partici pa nts’ eli gi bilit y will  be c o nfir me d. Partici pa nts will u n der g o t he 
assess me nts descri be d i n t he S o A (see Secti o n  1. 3 ).
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T he st u d y  start date is t he date w he n t he first partici pa nt has si g ne d a n I C F. A partici pa nt is 
eli gi ble t o be e nr olle d i nt o t he st u d y w he n t he i n vesti gat or or desi g nee has o btai ne d writte n 
i nf or me d c o nse nt, has c o nfir me d all eli gi bilit y crit eria ha ve bee n met b y t he partici pa nt, a n d 
all Scree ni n g pr oce d ures ha ve bee n c o m plete d.
I nter ve nti o n Peri o d: Eli gi bl e partici pa nts will e nter t he I nter ve nt i on Peri o d. T he I nter ve nt i on 
P eri o d starts o n C y cle 1 Da y 1 a n d c o nti n ues, as descri be d i n t he S o A (see Secti o n 1. 3 ), u ntil a 
parti ci pa nt per ma ne nt l y disc o nti n ues Dat o-D X d. D uri n g t he I nter ve nt i on Peri o d, parti ci pa nts 
will recei ve Dat o -D X d at 6. 0 m g/ k g via a n I V i nf usi o n Q 3 W u ntil t he y meet o ne of t he 
di sc o nti n uati on cri t eria (see Sect i on 6. 2. 2. 1 a n d Secti o n 7. 1 ). See Secti o n 6. 6 f or t he d ose 
m o dificati o n cri t eria.
P arti cipa nts will u n der g o ra di o gra p hic assess me nt of t u m o ur res p o nse base d o n R E CI S T 1. 1 
e ver y 6 wee ks ( ± 7 da ys) fr o m t he date of t he first d ose of st u d y int er ve nt i on u nt il ra di o gra p hic 
P D as assesse d b y i n vest i gat or. F oll o wi n g P D assesse d b y i n vesti gat or, o ne a d diti onal f oll o w-
u p t u m o ur assess me nt s h o ul d be perf or me d at t he ne xt sc he d ule d i ma gi n g visit a n d n o less 
t ha n 4 wee ks after t he p rior assess me nt of P D. T he i nte nt of t his a d dit i onal f oll o w- u p 
assess me nt is t o mi ni mise t he disc or da nce bet wee n i n vesti gat or a n d I C R assess me nts.
P ost -i nter ve nti o n F oll o w-u p Peri o d: T he P ost -i nter ve nti on F o ll ow- u p Peri o d will start u p o n 
p er m a ne nt disc o nt in uat i on of Dat o -D X d. After st u d y  int er ve nt i on disc o nt i n uati on, all 
parti ci pa nts will u n der g o a n e n d-of -tr e at me nt visit ( wit hi n 7 da ys of t he decisi on t o st o p 
treat me nt) a n d will be f o ll owe d u p f or safet y  assess me nts  
 after t heir last d ose of 
st u d y i nter ve ntio n (ie, t he Safet y F o ll ow- u p Visi t), as descri be d i n t he S o A (see Secti o n 1. 3 ). 
If t he da y o n w hic h t he i n vesti gat or deter mi nes t hat t he pati e nt s h o uld disc o nt i n ue st u d y 
i nter ve nt i on is o ver 
 after t he last d ose of st u d y int er ve nt i on recei ve d b y t he patie nt, a n 
a d ditio nal  foll o w -u p assess me nt i s n ot nee de d.
P arti cipa nts w h o ha ve disc o nti n ue d treat me nt wit h o ut o bjecti ve R E CI S T 1. 1 -defi ne d 
r a diol o gical  pr o gressio n  c o nfir me d b y in vest i gat or assess me nt, re gar dless of w het her or n ot 
t he y ha ve c o m me nce d s u bse q ue nt a ntica ncer t hera p y, will be f o ll owe d u p wi t h t u mo ur
assess me nts as i n dicate d i n t he S o A (see Secti o n  1. 3 ) u ntil R E CI S T 1. 1-defi ne d P D re gar dless 
of  w het her or n ot t he partici pa nt starte d a s u bse q ue nt a ntica ncer t hera p y, u nless t he y ha ve 
wi t hdra w n all c o nse nt t o st u d y -r elate d assess me nts. 
After di sc o nti n uati on of st u d y  int er ve nt i on, parti ci pa nts will t he n be f o ll owe d u p e ver y  
3 m o nt hs ( ± 1 4 da y s) for c ollecti o n of  inf or m at i on o n s ur vi val, i ncl u di n g t h e ca use a n d date of 
deat h, a n d s u bse q ue nt a nt ica ncer t hera p y. T he P ost-i nter ve nt i on F oll o w -u p Peri o d will 
c o nti n ue u ntil deat h, wit h dra wal o f c o nse nt, or t he e n d of t he st u d y (ie, pr o gressi o n/s ur vi val 
f oll ow -u p), as per t he S o A (see Secti o n  1. 3 ). 
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The DCO for the primary analysis of ORR by ICR will occur approximately 6 months after 
the last participant for that cohort has initiated study intervention, and the DCO for the full 
final analysis of ORR by ICR will occur approximately 12 months after the last participant for 
that cohort has initiated study intervention. 
4.1.2
Study Conduct Mitigation During Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis
The guidance given below supersedes instructions provided elsewhere in this CSP and should 
be implemented only during cases of civil crisis, natural disaster, or public health crisis (eg, 
during quarantines and resulting site closures, regional travel restrictions, and considerations if 
site personnel or study participants become infected with COVID-19 or a similar pandemic 
infection), which would prevent the conduct of study-related activities at study sites, thereby 
compromising the study site staff or the participant’s ability to conduct the study. The 
investigator or designee should contact the study sponsor to discuss whether the mitigation 
plans below should be implemented.
To ensure continuity of the clinical study during a civil crisis, natural disaster, or public health 
crisis, changes may be implemented to ensure the safety of study participants, maintain 
compliance with GCP, and minimise risks to study integrity. 
Where allowable by local health authorities, ECs, health care provider guidelines (eg, hospital 
policies), or local government, these changes may include the following options: 

Obtaining reconsent for the mitigation procedures (note: in the case of verbal reconsent, 
the ICF should be signed at the participant’s next contact with the study site).

Rescreening: Additional rescreening for screen failure and to confirm eligibility to 
participate in the clinical study can be performed in previously screened participants. The 
investigator should confirm this with the designated study physician. 

Home or remote visit: Performed by a site qualified HCP or HCP provided by a TPV.

Telemedicine visit: Remote contact with the participants using telecommunications 
technology including phone calls, virtual or video visits, and mobile health devices. 
For further details on study conduct during civil crisis, natural disaster, or public health crisis, 
refer to Appendix H. 
4.2
Scientific Rationale for Study Design
This is a Phase 1/Phase 2, multicentre, open-label, multiple-cohort study of Dato-DXd, which 
is designed to evaluate the efficacy, safety, PK, and immunogenicity of Dato-DXd in adult 
Chinese participants with advanced NSCLC, TNBC, gastric or GEJ cancer, urothelial cancer, 
and other solid tumours. It is a single-arm study with no blinding.

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There is an unmet need for treatments for many patients with advanced or metastatic solid 
tumours. Thus, the Phase 1 first-in-human Study DS1062-A-J101 is evaluating Dato-DXd in 
TROP2-unselected participants with advanced NSCLC who have relapsed from or are 
refractory to SoC therapy as well as in participants with inoperable locally advanced or 
metastatic TNBC. An additional cohort of participants with hormone receptor-positive, 
HER2-negative breast cancer is currently recruiting as of March 2021. Other tumour types 
may also be explored in the future. Clinical data from Study DS1062-A-J101 show efficacy of 
Dato-DXd with a manageable toxicity profile. However, none of the participants in 
Study DS1062-A-J101 are from China and there is an unmet need for more information about 
the safety and efficacy of Dato-DXd in the adult Chinese population.
Given these encouraging preliminary safety and efficacy data for patients with advanced 
NSCLC and TNBC, the current study will prioritise these patient groups to further assess the 
efficacy, safety, PK, and immunogenicity of Dato-DXd in adult Chinese participants. Thus, 
the study will immediately enrol participants in Cohort 1 (NSCLC) and Cohort 2 (TNBC). 
The single-arm study design will provide new efficacy and safety information on an important 
patient population and will support the global therapeutic development for Dato-DXd.
4.2.1
Rationale for Study Endpoints
The primary endpoint is confirmed ORR assessed by ICR, defined as the proportion of 
participants in each cohort with confirmed CR or confirmed PR, as assessed by ICR based on 
RECIST 1.1. Confirmed ORR by ICR represents the percentage of participants in each cohort 
whose disease decreases in size or disappears and provides an early signal for clinical benefit 
since it is a direct measure of the drug’s antitumour activity. It is an appropriate and 
reasonable efficacy endpoint for single-arm studies considering the unmet medical needs and 
the encouraging efficacy data in terms of ORR by ICR observed in Study DS1062-A-J101, in 
accordance with the requirements of the National Medical Products Administration’s Center 
for Drug Evaluation. 
Additional secondary efficacy endpoints for each cohort (ORR assessed by investigator; DoR, 
DCR, BOR, TTR, and PFS by investigator assessment and ICR; and OS) will be used to 
further evaluate efficacy and to corroborate the benefits of antitumour effects demonstrated by 
confirmed ORR as assessed by ICR.
As part of the secondary endpoint assessment, blood samples will be taken to allow for 
research into the PK and immunogenicity of Dato-DXd. The safety and tolerability of 
Dato-DXd will be assessed by the standard safety endpoints. Careful consideration has been 
given to the mitigation of risks related to the mode of action and the nature of the target, 
which will be closely monitored during the study.

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 1 of 1 6 5
4. 2. 2
R ati o n ale f or St u d y Desi g n i n T N B C C o h ort
T he efficac y of sacit uz u ma b g o viteca n -hzi y was relat i vel y p o orer i n T N B C patient s wit h brai n 
metastasis base d o n t he p u blis he d data fr o m I M M U - 1 3 2-0 5 st u d y , wit h a n O R R of 3. 1 % a n d 
cli nical be nefit rate of 9. 4 % (Bar dia et al 2 0 2 1a ). Dat o-D X d has de m o nstrate d pr o misi n g 
a nt itu m o ur efficac y  in St u d y  D S 1 0 6 2- A-J 1 0 1 i n patie nts wit h a d va nce d/ metastatic N S C L C 
re gar dless of br ai n metastasis. H o we ver, beca use t here is o nl y li mite d data fr o m t he St u d y 
D S 1 0 6 2 - A-J 1 0 1 T N B C c o h ort t o assess t he efficac y a nd safet y of  Dat o-D X d i n T N B C 
pati e nts wit h brai n metastasis, t he T N B C c o h ort will e xcl u de partici pa nts wit h brai n 
metastases.
T he D FI fr o m t he c o m p leti o n of ( ne o)a dju va nt c he m ot h era p y is c o nsi dere d t o be o ne of t he 
k e y  fact ors wit h pr o g n ostic i m pact i n T N B C (Del uc he et al  2 0 2 0). D FI pla ys a n i m p orta nt r ole 
i n t he pr o g n osis f or patie nts wit h rela pse d breast ca ncer, as l o n ger D FI is ass ociate d wit h 
s u perior pr o g n osti c o utc o me c o mpare d wi t h s h orter D FI (Da w o o d et al 2 0 1 0 ). Partici pa nts 
wi t h in o pera ble l ocall y  a d va nce d or metastatic breast ca ncer wit h a D FI ≤1 2 m o nt hs will  b e 
ca p pe d at ar o u n d 2 0 %. T his distri b uti o n o f parti ci pa nts is s u p p orte d b y t he real-w orl d 
pre vale nce a n d t he K E Y N O T E -3 5 5 st u d y  (C ortes et al 2 0 2 0 ).
4. 3
J u stific ati o n f or D ose
T he 6 m g/ k g I V d ose of Dat o -D X d was selecte d base d o n res ults fr om t he o n g oi n g P hase I, 
2- part ( d ose escalat i on a n d d ose e x pa nsi o n), m ult ice ntre, n o nra n d omise d, o pe n -label, m ul tiple 
d ose, first -i n-h u ma n st u d y  ( St u d y D S 1 0 6 2 - A-J 1 0 1 [ T R O PI O N-Pa n T u m or 0 1]) i n partici pa nts 
wi t h a d va nce d sol i d t u mo urs. I n t his st u d y , Dat o-D X d s h o we d a ge nerall y t olera ble safet y 
pr ofile i n part ici pa nts wit h N S C L C acr oss a d ose ra n ge of 0. 2 7 m g/ k g t o 8 m g/ k g. D uri n g t he 
d ose escalat i on p hase, t he n o n -t olerate d d ose f or Dat o -D X d was 1 0. 0 m g/ k g a n d t he 
ma xi m u m t olerate d d ose ( 8 m g/ k g) was deter mi ne d.
As of
, data are a vaila ble f or 2 1 0 partici pa nts wit h N S C L C w h o were treate d wit h 
Dat o -D X d i n t he 0. 2 7 m g/ k g t o 1 0. 0 m g/ k g Q 3 W c o h orts. 
O ut of 1 8 0 res p o nse-e val ua ble partici pa nts (treate d wit h Dat o -D X d at d oses of 4 m g/ k g 
[ 5 0 partici pa nts], 6 m g/ k g [ 5 0 partici pa nts], a n d 8 m g/ k g [ 8 0 partici pa nts ]), t he O R R b y 
bli n de d i n de pe n de nt ce ntral re vie w was 2 2. 0 % ( 1 1 P Rs i n 5 0 parti ci pa nts) i n t he 4 m g/ k g d ose 
gr o u p, 2 6. 0 % ( 1 3 P Rs i n 5 0 parti ci pa nts) i n t he 6 m g/ k g d ose gr o u p a n d 2 3. 8 % ( 1 8 P Rs a n d 
1 C R i n 8 0 partici pa nts) i n t he 8 m g/ k g d ose gr o u p. T he D C R was 7 6. 0 % ( 1 1 P Rs a n d 2 6 S Ds 
i n 5 0 partici pa nts) i n t he 4 m g/ k g d ose gr o u p, 7 0. 0 % ( 1 3 P Rs a n d 2 0 S Ds i n 5 0 parti ci pa nts) 
i n t he 6 m g/ k g d ose gr o u p, a n d 7 8. 8 % ( 1 C R, 1 8 P Rs a n d 4 2 S Ds i n 8 0 parti ci pa nts) i n t he 
8 m g/ k g d ose gr o u p.
Dat o -D X d has a n i m p orta nt i de nt ifie d 
 t hat ca n ha ve a life t hreate ni n g 
or fatal  o ut c o me. As of  
, 
 
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Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 2 of 1 6 5
 ha ve bee n re p orte d i n partici pa nts with N S C L C i n St u d y  D S 1 0 6 2- A-J 1 0 1; 
( T R O PI O N-Pa n T u m or 0 1), all i n t he 8 m g/ k g d ose gr o u p. 
 of I L D/ p ne u m onit is 
were o bser ve d i n t he 6 m g/ k g d ose gr o u p (see Ta ble 2 ). T o xicit y ma na ge me nt g uideli nes are 
i n place t o a d dress t o xicity (see t he A n ne x d oc u me nt t o t his C S P f or Dat o-D X d). D ose -
de pe n de nt effects a n d tre n ds were o bser ve d wit h a lar ger pr o p or tio n of  participa nts i n t he 
hi g her d ose gr o u ps e x perie nci n g T E A Es t hat were se vere, seri o us, a n d w hic h res ulte d i n d ose 
d el a y, re d uctio n, a n d disc o nt i n uati on, c o m pare d wi t h partici pa nts i n lo wer d ose gr o u ps.
A n E -R a nal ysis o f t he St u d y D S 1 0 6 2- A-J 1 0 1 (T R O P I O N-Pa n T u m or 0 1 ) st u d y data, 
i ncl u di n g res p o nse, s u m of di a meters, P F S, a n d ke y AE (e g, st o m at itis/ m uc osal i nfla m mati on) 
e n d p o i nts, s u g geste d t hat t he 6 m g/ k g Q 3 W d ose ha d better efficac y t ha n t he 4 m g/ k g q 3 w 
d ose of Dat o -D X d a n d t he 8 m g/ k g Q 3 W d ose ( ma xi m u m  t olerate d d ose) ha d a d dit i onal 
safety lia bility wi t h n o sig nifica nt i m pr o ve me nt i n efficac y  relati ve t o t he 6 m g/ k g q 3 w d ose 
of  Dat o-D X d. He nce, t he 6 m g/ k g d ose is t he o pti mal m o n ot hera p y  d os e for f urt her 
de vel o p me nt of Dat o -D X d i n cli nical st u dies. 
T he pr o p ose d d ose s h o ul d als o be a p pr o priate f or t he C hi nese patie nts i n t his st u d y si nce n o 
cli nicall y rele va nt et h nic differe nce i n Dat o -D X d e x p os ure is e x pecte d wit h t he treat me nt of 
Dat o -D X d i n C hi nese patie nts base d o n t he preli mi nar y data fr o m t he D S 1 0 6 2- A- J 1 0 1 st u d y. 
N o n ota bl e differe nces were o bser ve d i n e x p os ure of Dat o -D X d, t otal a nti -T R O P 2 a nti b o d y , 
a n d D X d ( A U C ta u a n d C ma x ) bet wee n Ja pa nese a n d n o n-Ja pa nese p o p ulati ons.
4. 4
E n d of St u d y Defi niti o n
A partici pa nt is c o nsi dere d t o ha ve c o m p lete d t he stu d y if he/s he has c o m p lete d all p hases of 
t he st u d y, i ncl u di n g t he last visit s h o w n i n t he S o A ( Secti o n 1. 3 ) a n d u n der g o ne deter mi nati on 
of O S.
T he st u d y  ma y be st o p pe d if, i n t he j u d g me nt of Astra Ze neca, st u d y partici pa nts are place d at 
u n d ue ris k beca use o f cli nicall y si g nifica nt fi n di n gs. 
T he e n d o f t he st u d y is defi ne d as t he ti me of t he D C O f or t he fi nal a nal ysis. T he fi nal 
a nal ysis will be p erf or m e d a p pr o xi matel y 1 2 mo n t hs after t he last partici pa nt has i nitiate d 
st u d y int er ve ntio n. Parti ci pa nts ma y b e wit hdra w n fr o m t he st u d y at t his ti me; h o we ver, 
parti ci pa nts ma y re mai n o n st u d y int er ve ntio n be y o n d cl os ure of t he data base if, i n t he o pi ni o n  
of  t he i n vesti gat or, t he y c o nti n ue t o recei ve be nefit fr o m st u d y int er ve nt i on a n d ha ve n o 
e vi de nce of P D.
See Secti o n  6. 7 f or details o n partici pant  ma na ge me nt f o ll owi n g t he fi nal D C O as well as 
f oll owi n g st u d y  c o mplet i on.
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5
STUDY POPULATION
This study is divided into cohorts of participants with the same tumour type. The starting 
cohorts are Cohort 1 (NSCLC) and Cohort 2 (TNBC). Future cohorts will consist of other 
advanced or metastatic solid tumour types, including, but not limited to, gastric or GEJ cancer, 
urothelial cancer, and other solid tumours. Cohort 1 and Cohort 2 will be prioritised for 
immediate enrolment and the CSP will be amended as needed for the future cohorts.
Cohort 1: The target population of Cohort 1 is adult Chinese participants with advanced or 
metastatic NSCLC with or without AGAs (ie, alterations in genes with approved therapies, 
such as EGFR, ALK, or other known AGAs). Eligible participants without AGAs will have 
been previously treated with platinum-based chemotherapy and anti-PD-1/anti-PD-L1 
monoclonal antibody, either in combination or sequentially. Participants without AGAs who 
received anti-PD-1/anti-PD-L1 monoclonal antibody as frontline therapy may have received 
the combination of platinum-based chemotherapy and anti-PD-1/anti-PD-L1 monoclonal 
antibody in the second-line setting. Eligible participants with AGAs will have been previously 
treated with one or two prior lines of applicable targeted therapy that is approved for the 
participant’s genomic alteration and platinum-based chemotherapy as the only prior line of 
cytotoxic therapy. Participants with AGAs may have received up to one anti-PD-1/anti-PD-L1 
monoclonal antibody treatment alone or in combination with chemotherapy. 
Cohort 2: The target population of Cohort 2 is adult Chinese participants with inoperable 
locally advanced or metastatic TNBC who have received at least 2 prior chemotherapy 
regimens for advanced breast cancer, counting the (neo)adjuvant therapy as a prior 
chemotherapy regimen if progression occurred within 12 months after completion of the 
therapy.
Future cohorts are anticipated to enrol other target populations of adult Chinese participants 
with advanced or metastatic solid tumours, including, but not limited to, 
advanced/unresectable or metastatic gastric or GEJ adenocarcinoma, or urothelial carcinoma 
that is refractory or intolerant to SoC therapy or for which no SoC therapy is available. 
Prospective approval of CSP deviations to recruitment and enrolment criteria, also known as 
CSP waivers or exemptions, is not permitted.
Participants who do not meet the eligibility criteria requirements are screen failures; refer to 
Section 5.4.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply: 

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 4 of 1 6 5
I ncl usi o n Criteri a f or All P artici p a nts
A ge
1
P arti cip a nt m ust be ≥ 1 8 years at t he ti me of scree ni n g. 
P artici p a nt a n d Dise ase C h ar acteristics
2
Easter n C o o perati ve O nc ol o g y  Gr o u p perf or ma nce stat us of 0 or 1. 
3
T he e nr o lle d partici pa nts s h o ul d ma ke a vaila ble a n arc hi val F F P E t u m o ur sa m ple or ne wl y 
ac q uire d F F P E t u mo ur sa m pl e f or i m m u n o hist oc he mistr y  stai ni n g t o ce ntrall y deter mi ne 
T R O P 2 e x pressi o n, base d o n l ocal re g ulat or y  a p pr o val. 
4
At  least o ne lesi on n ot pre v i ousl y  irra diate d t hat q ualifies as a R E CI S T 1. 1 tar get lesi on at 
baseli ne a n d ca n be acc uratel y meas ure d at baseli ne as ≥ 1 0 m m i n t he l o n gest dia meter 
(e xce pt l y m p h n o des, w hic h m ust ha ve s h ort a xis ≥ 1 5 m m) wit h C T or M RI a n d is 
s uita ble f or acc urate repeate d m eas ure me nts.
N ote: Partici pa nts wit h b o ne o nl y metastases i n t he a bse nce of ot her meas ura ble disease 
are n ot per mitte d. 
5
Has L V E F ≥
 b y eit her a n E C H O or M U G A sca n wit hi n 2 8 da ys bef ore e nr o l me nt.
6
A de q uate b o ne marr o w reser ve a n d or ga n f u nct i on wit hi n 7 da ys bef ore e nr ol me nt defi ne d 
as f o ll ows:
-
Hae m o gl o bi n ≥9. 0 g/ d L (re d bl o o d cell/ plas ma tra nsf usi o n is n ot all o we d wit hi n o ne 
wee k pri or t o Scree ni n g assess me nt).
-
A bs ol ute ne utr o p hil c o u nt ≥1. 5 × 1 0 9/ L ( gra n ul oc yte c ol on y sti m ulati n g fact or 
a d mi n istratio n is n ot all o we d wit hi n o ne wee k pri or t o Scree ni n g assess me nt).
-
Pl at elet c o u nt ≥1 0 0 × 1 0 9/ L ( platelet tra nsf usi on is n ot all o we d withi n o ne wee k 
pri or t o Scree ni n g assess me nt).
-
I nter nati o nal n or malise d rati o/ pr ot hr o m bi n ti me a n d eit her partial t hr o m b o plasti n 
ti me or acti vate d partial t hr o m b o plasti n ti me ≤1. 5 × t he U L N.
-
T ot al  bilir u bi n ≤1. 5 × U L N if n o li ver metastases or < 3 × U L N i n t he prese nce of 
d oc u m e nte d Gil bert’s s y n dr o me ( u nc o nj u gate d h y per bilir u bi ne mia) or li ver 
metastases at baseli ne.
-
As partate a mi n otra nsferase/ A L T ≤3 × U L N or A S T/ A L T < 5. 0 × U L N i n t he 
prese nce of li ver metastases at baseli ne. 
-
Calc ulate d creati ni ne cleara nce ≥
m L/ mi n as deter mi ne d b y t he C oc kcr oft -Ga ult 
e q uatio n ( usi n g act ual b o d y  wei g ht). 
o
Males:
Cr C L = 
Wei g ht ( k g) × ( 1 4 0 – A ge [ years])
( mL/ mi n)
7 2 × ser u m creati ni ne ( m g/ d L)
o
Fe males:
C CI
C CI

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 5 of 1 6 5
Cr C L = 
Wei g ht ( k g)
× ( 1 4 0 – A ge [ years])
× 0. 8 5
( mL/ mi n)
7 2 × ser u m creati ni ne ( m g/ d L)
7
Has a mi ni m u m life e x pecta nc y  of 1 2 wee ks
Se x a n d C o ntr ace pti ve/ B arrier Re q uire me nts
8
Male a n d/ or fe male
C o ntrace pti ve use b y me n or w o me n s h o ul d be c o nsiste nt wit h l ocal re g ulat i ons re gar di n g 
t he met h o ds of c o ntrace pti o n f or t h ose partici pat i n g i n cli nical st u dies; 
9
All F O C B P m ust ha ve a ne gat i ve ser u m pre g na nc y test d oc u me nte d d uri n g scree ni n g; see 
A p pe n di x F f or furt her details a n d f or a defi nit i on of fe males n ot of c hil d -beari n g 
p ote nti al.
1 0
F O C B P m ust use o ne hi g hl y effecti ve f or m of birt h c o ntr ol or a v oi d i nterc o urse fr o m 
scree ni n g t hr o u g h o ut st u d y a n d for 
after t he last d ose of Dat o-D X d; see 
A p pe n di x F f or fur t her details. Starti n g at t he ti me of first d ose of Dat o -D X d, fe male 
parti ci pa nts must n ot d o nate, or retrie ve f or t heir o w n use, o va at a n y  time d uri n g t his 
st u d y a n d for 
 after t he last d ose of Dat o -D X d. Preser vati o n of o va 
s h o uld be c o n si dere d prior t o e nr ol me nt i n t his st u d y . Fe males recei vi n g H R T a n d w h ose 
me n o pa usal stat us is i n d o u bt will be re q uire d t o use o ne of t he c o ntrace pti o n met h o ds 
o utli ne d f or F O C B P if t he y wis h t o c o nti n ue usi n g H R T d uri n g t he st u d y. Ot her wise, 
H R T m ust be di sc o nti n ue d t o all o w c o nfir mati on of p ost -me n o pa usal stat us pri or t o 
e nr o l me nt; see A p pe n di x F f or furt her details. 
1 1
Male parti ci pa nts must use a c o n d o m plus a n a d di tio n al c o ntrace pti ve met h o d (see 
A p pe n di x F ), or a v oid i nterc o urse, fr o m  t he ti me of scree ni n g t hr o u g h o ut t he t otal 
d urati o n of  the st u d y a n d t he dr u g was h o ut peri o d (
 after t he last d ose of 
st u d y int er ve ntio n), i n a d di tio n t o t he fe male part ner usi n g a hi g hl y  effecti ve 
c o ntrace pti ve met h o d. Male part ici pa nts must n ot d o nate or ba n k s per m d uri n g t his sa me 
ti me peri od. Preser vati o n of s per m s h o ul d be c o nsi dere d pri or t o e nr ol me nt i n t he st u d y .
I nf or me d C o nse nt
1 2 Ca pa ble of gi vi n g si g ne d i nf or me d c o nse nt as descri be d i n  A p pe n di x A , w hic h i ncl u des 
c o mplia nce wi t h t he re q uir e me nts a n d restrict i ons liste d i n t he I C F a n d i n t his C S P.
A d diti o n al I ncl usi o n Criteri a f or C o h ort 1 ( N S C L C)
P artici p a nt a n d Dise ase C h ar acteristics
1 3 Hi st olo gi call y or c yt olo gi call y d oc u me nte d Sta ge III B or III C N S C L C disease n ot 
a me na ble f or s ur gical resect i on or defi nit i ve c he m ora diati on or Sta ge I V N S C L C disease 
at t he be gi n ni n g of st u d y int er ve nt i on ( base d o n t he A merica n J o i nt C o m mittee o n Ca ncer, 
Ei g ht h E di tio n).
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 6 of 1 6 5
F or t he s u bset of parti ci pa nts wit ho ut A G As:
-
D oc u m e nte d ne gat i ve test res ults f or E G F R a n d A L K ge n o mic alterati o ns. If test 
res ults for E G F R a n d A L K are n ot a vaila ble, partici pa nts are re q uire d t o u n der g o 
testi n g perf or me d l ocall y for t hese ge n o mic alterati o ns.

N o k n o w n ge n o mic alterat i ons i n R O S 1 , R E T , M E Tex 1 4 ski p pi n g, or ot her A G As 
wi t h a p pr o ve d t hera pies.
N ote: Tests f or A G As ot her t ha n E G F R a n d A L K are n ot ma n dat or y. K n o w n stat us 
f or R O S 1 , R E T , M E Tex 1 4 ski p pi n g , or ot her A G As (e xce pt E G F R a n d A L K ) is n ot 
re q uir e d for e nr ol me nt a n d partici pa nts wit h u n k n o w n stat us f or t hese ge n o mic 
alt er atio ns will be classifie d as wit h o ut A G As f or e nr o l me nt. 
F or t he s u bset of partici pa nts wit h A G As:

D oc u m e nte d p ositive test res ults f or o ne or m ore acti o na ble ge n o mic alterati o n: 
E G F R, A L K, R O S 1, M E Tex 1 4 ski p pi n g, R E T or ot her A G As wit h a p pr o ve d t hera pies .
1 4 Has d oc u me ntati o n of ra di o gra p hic disease pr o gressi o n w hile o n or after recei vi n g t he 
m o st rece nt treat me nt re gi me n f or a d va nce d or metastatic N S C L C.
1 5 P arti cip a nts m u st meet O N E of t he f o ll owi n g pri or t hera p y  re q uire me nts f or a d va nce d or 
metastati c N S C L C:
F or t he s u bset of partici pa nts wit h o ut A G As:
-
Recei ve d plati n u m -base d c he m ot hera p y  in c o m bi nati o n wit h a nt i-P D -1/a nt i-P D -L 1 
m o n ocl o nal a nti b o d y  as t he o nl y prior li ne of t hera p y .
-
Recei ve d pri or plat i n u m-base d c he m ora di ot hera p y wit h mai nte na nce a nt i-P D -1/ a nti -
P D -L 1 m o n ocl o n al a nti b o d y for Sta ge III disease a n d rela pse d/ pr o gresse d wit hi n 6 
m o nt hs fr om t he last d ose of plat i n u m-base d c he m ot hera p y .
-
Recei ve d pri or plat i n u m-base d c he m ora di ot hera p y 
 
 for Sta ge III disease a n d s u bse q ue nt l y 
recei ve d a nti-P D -1/ a nti -P D -L 1 m o n o cl o n al  a nti b o d y t hera p y 
 
 f or recurre nt di sease.
-
Recei ve d plati n u m -base d c he m ot hera p y  a n d a nti-P D -1/ a nti -P D -L 1 m o n o cl o nal 
a nt i b o d y 
 se q ue ntiall y as t he o nl y 2 prior li nes of t hera p y .
N O T E: 
o
P arti cipa nts w h o recei ve d a nt i-P D -1/ a nti -P D -L 1 m o n ocl o nal a nti b o d y  as first 
li ne t hera p y ma y ha ve recei ve d t he c o m bi nati on of plati n u m -base d 
c he m ot hera p y a n d a nti-P D -1/a nti -P D -L 1 m o n ocl o n al a nt i b o d y as sec o n d li ne 
t hera p y. 
o
P arti cip a nts wi t h k n o w n 
m ut atio n, i n t he a bse nce of ot her A G A, w h o 
recei ve d 
 as a se parate li ne of 
t hera p y in a d dit i on t o t he pri or t hera p y  re q uire me nts descri be d a b o ve, are n ot 
eli gi ble.
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 7 of 1 6 5
F or t he s u bset of partici pa nts wit h A G As:
-
Recei ve d o ne or t w o pri or li nes of a p plica ble tar gete d t hera p y f or t he partici pa nt’s 
ge n o mic alterati o n at t he ti me of scree ni n g:
o
P arti cipa nts w h o ha ve t u m o urs wi t h E G F R L 8 5 8 R or E x o n 1 9 deleti on m ut atio ns 
m ust ha ve recei ve d pri or osi mert i ni b.
o
T h ose w h o recei ve d a tar gete d a ge nt as a dj u va nt t hera p y  for earl y -sta ge disease 
m ust ha ve rela pse d or pr o gresse d w hile o n t he treat me nt or wit hi n  m o nt hs o f 
t he last d ose O R recei ve d at least o ne a d dit i onal c o urse of tar gete d t hera p y f or 
t he sa me ge n o mic alt er atio n 
 
 f or rela pse d/ pr o gressi ve disease.
o
P arti cipa nts w h o ha ve bee n treate d wit h a pri or T KI m ust recei ve a d dit i on al  
a p pr o ve d tar gete d t hera p y, if locall y  a vaila ble a n d cli nicall y a p pr o priate, f or t he 
a p plica ble ge n o mic alterati o n, or t he partici pa nt will n ot be all o we d i n t he st u d y .
-
Recei ve d plati n u m -base d c he m ot hera p y  as t he o nl y prior li ne of c y t ot o xic t hera p y:
o
O ne plat i n u m-c o ntai ni n g re gi me n f or a d va nce d disease.
o
T h ose w h o recei ve d a plat i n u m-c o ntai ni n g re gi me n as a dj u va nt t hera p y for 
earl y-sta ge disease m ust ha ve rela pse d or pr ogresse d w hile o n t he treat me nt or 
wi t hi n  mo n t hs of t he last d ose O R recei ve d o ne a d dit i onal c o urse of plat i n u m-
c o ntai ni n g t hera p y 
 f or 
r ela pse d/ pr o gressi ve disease.
-
Ma y  ha ve recei ve d  
 a nti-P D -1/a nti -P D -L 1 m o n o cl o n al  a nti b o d y treat me nt 
alo ne or i n c o m bi nat i on wi t h c he m ot hera p y.  
A d diti o n al I ncl usi o n Criteri a f or C o h ort 2 ( T N B C)
P artici p a nt a n d Dise ase C h ar acteristics
1 6 Pat h ol o gi call y d oc u me nte d oestr o ge n a n d pr o gester o ne rece pt or-ne gati ve ( < 1 % of cells 
e x pressi n g h or m o nal rece pt ors via i m m u n o hist oc he mical a nal ysis) a n d H E R 2 -ne gati ve 
e x pressi o n acc or di n g t o t he A merica n S ociet y  of Cli nical O nc ol og y  – C olle ge of 
A merica n Pat h ol o gists g ui deli nes. If a partici pa nt ha d m ult i ple res ults, t he m ost rece nt test 
res ult will be use d t o c o nfir m eli gi bility.
1 7 I n o pera ble l ocall y a d va nce d or metastatic breast ca ncer.
1 8 Recei ve d at least 2 pri or c he m ot hera p y  re gi me ns f or locall y a d va nce d or metastatic breast 
ca ncer a n d pre vi o usl y treate d wit h a ta xa ne i n a n y setti n g. Partici pa nt must ha ve 
d oc u m e nte d pr o gressio n o n t hei r most rece nt c he m ot hera p y  re gi me n.
-
F or parti ci pa nts wit h a d oc u me nte d ger mli ne B R C A 1/ B R C A 2 m utati o n w h o 
recei ve d a P A R P i n hi bit or rec o m me n de d i n C hi na g ui deli nes, t he P A R P i n hi bit or ca n 
be use d t o meet t he criteria f or o ne of 2 pri or c he m ot hera pies.
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 8 of 1 6 5
-
F or parti ci pa nts wit h disease pr o gressio n d uri n g ne oa dj u va nt treat me nt or rela pse 
wi t hi n 1 2 mo n t hs after t he c o m pleti on of ( ne o)a dj u va nt t hera p y , t he ( ne o)a dju va nt 
t hera p y ca n be c o u nte d as a pri or c he mot h era p y re gi me n.
-
If a c he m ot hera p y dr u g is c ha n ge d wit hi n 2 8 da ys of use t o a n ot her dr u g, t he first 
dr u g i s n ot c o u nte d as a prior c he m ot h era p y re gi me n. 
-
Tar gete d a ge nts (e g, P D -1/ P D -L 1 i n hi bit ors) o n t heir o w n d o n ot c o ntri b ute t o t he 
c o u nt of pri or c he mot h era p y re gi me ns; h o we ver, use of s uc h a ge nts i n c o m bi nati on 
wi t h c he mot h era p y s h o uld be classifie d as o ne pri or c he m ot hera p y  re gi me n. 
5. 2
E xcl usi o n Criteri a 
P arti cipa nts are e xcl u de d fr o m  t he st u d y if a n y of t he f o ll owi n g cri t eria a p pl y: 
E xcl usi o n Criteri a f or All P artici p a nts
Me dic al C o n diti o ns
1
As j u d ge d b y  t he i n vesti gat or, has a n y e vi de nce of diseases (s uc h as se vere or 
u nc o ntr olle d s yste mic diseases, i ncl u di n g hist or y  of all o ge neic or ga n tra ns pla nt a n d acti ve 
blee di n g diseases or si g nifica nt car diac or ps yc h o l o gical c o n diti ons), w hic h, i n t he 
i n vesti gat or’s o pi ni o n, ma kes it u n desira ble f or t he partici pa nt t o partici pate i n t he st u d y 
or t hat w o ul d j e o par dis e c o mplia nce wi t h t he C S P.
2
Has hist or y  of a n ot her pri mar y mali g na nc y, e xce pt f or a de q uatel y resecte d basal cell 
carci n o ma of t he s ki n or s q ua m o us cell carci n o ma of t he s ki n, i n sit u disease t hat has 
u n der g o ne p ote ntiall y c urat i ve t hera p y, or ot her s oli d mali g na nc y treate d wit h c urati ve 
i nte nt wit h no k n o w n acti ve disease wit hi n 
y ears bef ore e nr ol me nt a n d of 
 
 
3
Has persiste nt t o xicit ies ca use d b y pre vio us a nti ca ncer t hera p y, e xcl u di n g alo pecia, n ot 
yet i m pr o ve d t o Gra de ≤ 1 or baseli ne. N ote: partici pa nts ma y be e nr o lle d wit h s ome 
c hr o nic, sta ble Gra de 2 t o xicit ies ( defi ne d as n o w orse ni n g t o > Gra de 2 f or at least 
3 m o nt hs pri or t o e nr ol me nt a n d ma na ge d wit h S o C treat me nt), w hic h t he i n vest i gat or 
dee ms rel ate d t o pre vio us a nt ica ncer t hera p y, i ncl u di n g ( b ut n ot li mite d t o):
-
C he m ot h era p y-i n d uce d ne ur o pat h y
-
Fat i g ue
-
Resi d ua l t o xicities fr o m prior i m m u n ot hera p y  treat me nt: Gra de 1 or Gra de 2 
e n d ocri n o pat hies, w hic h ma y i ncl u de:
o
H y p ot h y r oidis m/ h y pert h y r oidis m
o
T y pe 1 di a betes
o
H y per gl ycae mia
o
A dre nal i ns ufficie nc y
o
A dre nalit is
C CI
C CI

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 9 of 1 6 5
o
S ki n h y p o pi g me ntati o n ( vit ili g o)
P arti cip a nts wi t h irre versi ble t o xicit y t h at is n ot reas o na bl y e x pecte d t o be e xacer bate d b y 
st u d y int er ve ntio n ma y  be i ncl u de d (e g, heari n g l oss) after c o ns ultati o n with t he 
Astra Ze neca st u d y  cli nical lea d.
4
Has l e pt o me ni n geal carci n omat osis or metastasis.
5
Has si g nifica nt t hir d -s pace fl ui d rete nti o n (e g, ascites or ple ural eff usi o n) a n d i s n ot 
a me na ble t o re q uire d re peate d drai na ge.
6
Has cli nicall y si g nifica nt c or neal disease.
7
Has k n o w n act i ve he pat itis or u nc o ntr olle d he patitis B or C vir us i nfecti on or i s p osi tive 
f or he patitis B or C vir us base d o n t he e val uati on of tests f or he patit is B ( he patitis B vir us 
s urface a nti ge n, a nti-he pat itis B vir us s urface a nti b o d y, a nti-he pat itis B vir us c ore 
a nt i b o d y, or he patitis B vir us D N A) or he patitis C ( p ositive he pat itis C a nti b o d y or 
he pat itis C vir us R N A). Partici pa nts are eli gi ble if t he y : 
a)
Ha ve bee n c urat i vel y treate d f or H C V i nfecti on as de m o nstrate d cli nicall y  a nd b y  viral 
ser olo gi es.
b)
Ha ve recei ve d H B V vacci nat i on wi t h o nl y a nti-H Bs p osi ti vity a n d n o cli nical si g ns of 
he pat itis 
c)
Are H Bs A g - a n d a nt i-H B c + (i e, t h ose w h o ha ve cleare d H B V after i nfect i on) a n d meet 
c o n ditio ns i -iii of crit erio n “ d” bel o w:
d)
Are H Bs A g + wit h c hr o nic H B V i nfect i on (l ast i n g 6 m o nt hs or l o n ger) a n d meet 
c o n ditio ns i -iii b el o w:
i)
H B V D N A viral l oa d <  
.
ii) Ha ve n or m al tra nsa mi nase val ues, or, if li ver metastases are prese nt, 
a b n or mal tra nsa mi nases, wit h a res ult of AS T/ A L T < 3 × U L N, w hic h are n ot 
attri b uta ble t o H B V i nfect i on.
iii) Start or mai ntai n a nti viral treat me nt if cli nicall y i n dicate d as per t he 
i n vesti gat or
8
Has u nc o ntr olle d i nfect i on re q uiri n g I V a nt i bi otics, a nti virals, or a ntif u n gals; s us pecte d 
i nfecti ons (e g, pr o dr o mal s y m pt o ms); or i na bilit y t o r ule o ut i nfect i ons ( partici pa nts wit h 
l ocalise d f u n gal i nfect i ons of s ki n or nails are eli gi ble).
9
Has k n o w n HI V i nfect i on t hat i s n ot well c o ntr olle d. All of t he fol l owi n g criteria are 
re q uire d t o defi ne a n HI V i nfecti on t hat i s well c o ntr olle d: u n detecta ble viral R N A l oa d, 
C D 4 + c o u nts > 2 5 0 cells/ m m 3, n o hist or y of AI D S-defi ni n g o p p ort u nist ic i nfecti on wi t hi n 
, a n d sta ble f or 
 o n sa me a nti-HI V m e dicat i ons. If a n 
HI V i nfect i on meets t he a b o ve criteria, m o nit ori n g of viral R N A l oa d a n d C D 4 + c o u nt is 
rec o m me n de d.
C CI
C CI
C CI

Clinical Study Protocol - D9266C00001
AstraZeneca
Datopotamab deruxtecan (Dato-DXd, DS-1062a)
CONFIDENTIAL AND PROPRIETARY
50 of 165
10 Has known active tuberculosis infection (clinical evaluation that may include clinical 
history, physical examination and radiographic findings, or tuberculosis testing in line 
with local practice).
11 Any other medical conditions, including cardiac disease or psychological disorders, 
and/or substance abuse, that may, in the opinion of the investigator, interfere with the 
participant’s participation in the clinical study or evaluation of the clinical study results. 
12 Has a mean resting QTcF > 470 ms, regardless of sex, obtained from triplicate 12-lead 
ECGs performed at screening OR 
-
Investigator judgment of one or more of the following:
o
History of QT prolongation associated with other medications that required 
discontinuation of that medication, or any current concomitant medication 
known to prolong the QT interval and cause Torsades de Pointes.
o
Congenital long QT syndrome, family history of long QT syndrome, or 
unexplained sudden death under 40 years of age in first-degree relatives.
13 Has uncontrolled or significant cardiac disease including any of the following: 
-
Myocardial infarction or uncontrolled/unstable angina within 6 months before 
enrolment.
-
Congestive heart failure (New York Heart Association Class II to IV).
-
Cardiac arrhythmia (multifocal premature ventricular contractions, bigeminy, 
trigeminy, ventricular tachycardia), which is symptomatic or requires treatment 
(CTCAE 5.0 Grade 3), symptomatic or uncontrolled atrial fibrillation despite 
treatment, or asymptomatic sustained ventricular tachycardia. Participants with atrial 
fibrillation controlled by medication or arrhythmias controlled by pacemakers may 
be permitted upon discussion with the study clinical lead. 
-
Uncontrolled hypertension (resting systolic blood pressure > 180 mmHg or diastolic 
blood pressure > 110 mmHg) 
14
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.
15 Clinically severe pulmonary function compromise resulting from intercurrent   
       pulmonary illnesses including, but not limited to, any underlying pulmonary 
       disorder (eg, pulmonary emboli within 3 months of the study enrolment, severe asthma, 
       severe COPD, restrictive lung disease, pleural effusion, etc) or any autoimmune, 
       connective tissue, or inflammatory disorders (eg, rheumatoid arthritis, Sjögren’s 
       syndrome, sarcoidosis, etc).

Clinical Study Protocol - D9266C00001
AstraZeneca
Datopotamab deruxtecan (Dato-DXd, DS-1062a)
CONFIDENTIAL AND PROPRIETARY
51 of 165
Prior/Concomitant Therapy
16 Has prior exposure to any of the following:
-
Chloroquine/hydroxychloroquine without an adequate treatment washout period of 
> 14 days prior to enrolment 
-
Any agent including an ADC-containing a chemotherapeutic agent targeting 
topoisomerase I.
-
TROP2-targeted therapy.
17 Prior exposure to the following anti-cancer therapies without an adequate treatment 
washout period prior to enrolment:
-
Chemotherapy, immunotherapy (non-antibody-based therapy), retinoid therapy: ≥2 
weeks or 5 times the terminal elimination t½ of the chemotherapeutic agent, 
whichever is longer; ≥6 weeks for nitrosoureas or mitomycin C.
-
Antibody-based anti-cancer therapy: ≥4 weeks
18 Any concurrent anti-cancer treatment. Concurrent use of hormonal therapy for 
non-cancer-related conditions (eg, HRT) is acceptable.
19 Palliative radiotherapy with a limited field of radiation within ≤2 weeks or with wide 
field of radiation to the chest or to more than 30% of the bone marrow within ≤4 weeks 
before the first dose of study intervention. 
20 Major surgical procedure or significant traumatic injury within ≤3 weeks of the first dose 
of study intervention or an anticipated need for major surgery during the study. 
Prior/Concurrent Clinical Study Experience
21 Previous treatment in the present study 
22 Participation in another clinical study with a study intervention or investigational 
medicinal device, randomisation into a prior Dato-DXd study regardless of treatment 
assignment, or concurrent enrolment in another clinical study, unless it is an observational 
(non-interventional) clinical study or during the follow-up period of an interventional 
study
23 Has a history of severe hypersensitivity reactions to either the drug substance or inactive 
ingredients (including, but not limited to, polysorbate 80) of Dato-DXd or to other 
monoclonal antibodies.
Other Exclusions
24 Involved in the planning and/or conduct of the study (applies to both AstraZeneca staff 
and/or staff at the study site).
25 Judgment by the investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions, and requirements.
26 For females only: is pregnant (confirmed with positive pregnancy test), breastfeeding, or 
planning to become pregnant. Female participants should refrain from breastfeeding from 

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
5 2 of 1 6 5
scree ni n g t hr o u g h o ut t he st u d y a n d for 
 after t he last d ose of st u d y 
i nter ve nt i on.
A d diti o n al E xcl usi o n Criteri a f or C o h ort 1 ( N S C L C)
Me dic al C o n diti o ns
2 7
Has mi xe d S C L C a n d N S C L C hist ol o g y .
2 8
Pri or e x p os ure t o t he f oll o wi n g a nt i-ca ncer t hera p y wit h o ut a n a de q uate treat me nt 
was h o ut peri o d pri or t o e nr ol me nt:
-
≥1 wee k f or t yr osi ne ki nase i n hi bit ors a p pr o ve d f or t he treat me nt of N S C L C; 
baseli ne C T sca n m ust be c o m plete d after disc o nti n uat i on of t y r osi ne ki nase 
i n hi bit ors.
2 9
Has s pi nal c or d c o m pressi o n or brai n metastases u nless treate d, as y m pt o mat ic, sta ble, a n d 
n ot re q uir i n g ster oi ds f or 
 pri or t o t he start of st u d y int er ve nt i on. 
P arti cip a nts wi t h treate d brai n metastases w h o are n o l o n ger s y m pt o matic a n d w h o 
re q uire n o treat me nt wit h c ortic oster oids or a nti c o n v ulsa nts must ha ve rec o vere d fr o m t he 
ac ute t o xic effect of ra di ot hera p y. A mi ni m u m of 
 must ha ve ela pse d bet wee n t he 
e n d of w h o le brai n ra di ot hera p y a n d st u d y e nr ol me nt. 
A d diti o n al E xcl usi o n Criteri a f or C o h ort 2 ( T N B C)
Me dic al C o n diti o ns
3 0
P arti cip a nts wi t h a hist or y of or c urre nt brai n metastases.
5. 3
Lifest yle C o nsi der ati o ns
T he f o ll owi n g restri ct i ons a p pl y w hile t he partici pa nt is recei vi n g st u d y  int er ve ntio n a n d f or 
t he s pecifie d ti mes bef ore a n d after:
1
P arti cipa nts m ust f ol l ow t he c o ntrace pti o n re q uire me nts o utli ne d i n  A p pe n di x F.
2
P arti cipa nts s h o ul d n ot d o nate bl o o d or bl o o d c o m p o ne nts w hile partici pat i n g i n t his 
st u d y a n d t hr o u g h 
 da ys after t he last d ose of st u d y int er ve nt i on. 
3
Prese r vati on of o va a n d s per m s h o ul d be c o nsi dere d pri or t o e nr ol me nt i n t his st u d y .
Restricti o ns relat i n g t o c o nc o mita nt t hera pies are descri be d i n A p pe n di x G.
5. 3. 1
Me als a n d Diet ar y Restricti o ns
I n ge neral, t here are n o dietar y r estrict i ons f or t he st u d y assess me nts or treat me nt wit h 
Dat o -D X d. C o nc o mita nt use of dietar y s u p ple me nts, me dicat i ons n ot prescri be d b y t he 
i n vesti gat or, a n d alter nati ve/c om p le me ntar y treat me nts is disc o ura ge d b ut n ot pr o hi bite d.
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
5 3 of 1 6 5
5. 3. 2
T o b acc o
Use of t o bacc o pr o d ucts, e -ci g arettes, a n d va pi n g is str o n gl y disc o ura ge d, b ut n ot pr o hi bite d. 
A n y pri or or c urre nt use of t hese pr o d ucts s h o ul d be rec or de d i n t he e C R F.
5. 4
Scree n F ail ures
Scree n fail ures are defi ne d as part ici pa nts w h o c o nse nt t o partici pate i n t he cli nical st u d y b ut 
are n ot s u bse q ue nt l y assig ne d t o t he st u d y . A mi ni mal s et of scree n fail ure i nf or mati on is 
re q uire d t o e ns ure tra ns pare nt re p orti n g of scree n fail ure partici pa nts t o meet t he C O N S O R T 
p u blis hi n g re q uire me nts a n d t o res p o n d t o q ueries fr o m re g ulat or y a ut h orities. Mi ni mal 
i nf or mat i on i ncl u des de m o gra p h y, scree n fail ure details, eli gi bility crit eria, a n d a n y S A E 
d uri n g t he Scree ni n g Peri o d.
I n di vi d uals w h o d o n ot meet t he criteria f or partici patio n i n t his st u d y  (scree n fail ure) ma y b e 
rescree ne d a si n gle ti me. Rescree ne d partici pa nts s h o ul d be assi g ne d t he sa me partici pa nt 
n u m ber (i e, E -c o de) as f or t he i nit ial scree ni n g. H o we ver, rescree ni n g s h o ul d be d oc u me nte d 
s o t hat its effect o n st u d y res ults, if a n y, ca n be assesse d. All assess me nts m ust be re peate d f or 
rescree ni n g u nless t he y are wit hi n 2 8 da ys of t he first d ose of st u d y int er ve nt i on. E xce pt i ons 
will be c o nsi dere d i n c o ns ultat i on wi t h t he s p o ns or o n a case- b y-case basis. A 
scree ni n g/ baseli ne b o ne sca n d oes n ot nee d t o be re peate d if it is wit hi n 1 2 wee ks of 
e nr o l me nt. 
T hese partici pa nts s h o ul d ha ve t he reas o n f or st u d y wit h dra wal rec or de d i n t he e C R F as 
‘eli gi bility cri t eria n ot f ulfille d’ (ie, partici pa nt d oes n ot meet t he re q uire d i ncl usi on/e xcl usi o n 
criteria). T his reas o n f or st u d y wit hdra wal is o nl y vali d f or scree n fail ures (ie, partici pa nts 
w h o are n ot e ntere d i n t he st u d y ). 
P arti cipa nt e nr ol me nt is descri be d i n Secti o n  6. 2. 2 .
6
S T U D Y I N T E R V E N TI O N
St u d y  int er ve nt i on is defi ne d as a n y i n vesti gati onal i nter ve nt i on(s), m ar kete d pr o d uct(s), 
pl ace b o, or me dical de vice(s) i nte n de d t o be a d mi nistere d t o a st u d y  partici pa nt acc or di n g t o 
t he C S P.
6. 1
St u d y I nter ve nti o n(s) A d mi nistere d
Dat o - D X d will be s u p plie d b y Astra Ze neca as a  
 m g/ vial l y o p hilise d p o w der f or 
c o nce ntrate f or s ol ut i on f or i nf usi on. F o ll owi n g rec o nstit uti o n wit h sterile water f or i nject i on, 
t he s olut i on c o ntai n s 
 mg/ m L Dat o -D X d i n 
 m M hist i di ne/ histi di ne H Cl, % ( w/ v) 
s ucr ose a n d  
 ( w/ v) p ol ys or bate 8 0; it has a p H of  
. T he fi nal v ol u me o f Dat o -D X d is 
m L w he n rec o nstit ute d. See  Ta ble 4.
C CI
C CI
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Dat o p ota ma b der u xteca n ( Da t o-D X d, D S -1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
5 4 of 1 6 5
T he rec o nstit ute d dr u g pr o d uct is a 
 
T a ble 4
St u d y I nter ve nti o n
I nter ve nti o n n a me
Dat o -D X d
T y pe 
A D C
D os a ge f or m
L y o p hilise d p o w der f or c o nce ntrate f or s ol uti o n f or 
i nf usi o n i n a si n gle-use vial.
U n it d ose stre n gt h(s)
 m g/ vial (
m g/ m L)
D os a ge re gi me n
6. 0 m g/ k g Q 3 W
R o ute of a d mi nistr ati o n
I V i nf usi o n
Use
E x peri me ntal
I M P a n d NI M P
I M P
S o urci n g 
Pr o vi de d ce ntrall y b y t he s p o ns or
P ac k a gi n g a n d l a belli n g
Dat o -D X d will be pr o vi de d i n  
 m g vials i n cart o n. 
Eac h vial a n d cart o n will be la belle d i n acc or da nce wit h 
G M P A n ne x 1 3 a n d per c o u ntr y re q uire me nts a
C u rre nt/ F or mer n a me(s) or ali as(es)
D S -1 0 6 2a
a
La bel te xt f or Dat o -D X d ( D S -1 0 6 2a) ma y s h o w ‘ D S -1 0 6 2’ de pe n di n g o n t he a gree d pr o d uct na me use d i n 
t he res pecti ve a p pr o ve d st u d y master la bel d oc u me nt. All na mi n g c o n ve nti o ns f or t hese c o m p o u n ds are 
c orrect d uri n g t his tra nsi ti onal peri o d.
A D C, a nti b o d y - dr u g c o nj u gate; Dat o-D X d, dat o p ota ma b der u xteca n; G M P, G o o d Ma n ufact uri n g Practice; I M P, 
i n vesti gati o nal me dici nal pr o d uct; I V, i ntra ve n o us; NI M P, n o n-i n vesti gati o nal me dici nal pr o d uct; Q 3 W, e very 
3 wee ks.
All parti ci pa nts will recei ve a 6. 0 m g/ k g Dat o -D X d as a n I V i nf usi o n Q 3 W o n Da y 1 of eac h 
2 1 -d a y  c ycle. See Sectio n  6. 2. 2. 1 f or detaile d i nstr ucti o ns a b o ut a d mi nistrati o n of Dat o -D X d. 
T he dr u g f or m ulati o n use d i n t his st u d y  will be L y o -D P.
Fi g ure 2
D osi n g Sc he d ule
Dat o -D X d, dat o p ota ma b der u xteca n; Q 3 W, e ver y 3 wee ks
C CI
C CI
C CI
C CI

Clinical Study Protocol - D9266C00001
AstraZeneca
Datopotamab deruxtecan (Dato-DXd, DS-1062a)
CONFIDENTIAL AND PROPRIETARY
55 of 165
Duration of Treatment
All participants in this study will receive 6.0 mg/kg Dato-DXd as an IV infusion Q3W on 
Day 1 of each 21-day cycle. Participants will continue to receive Dato-DXd until PD occurs as 
judged by investigator assessment or until any other discontinuation criterion is met, as 
defined in Section 7.1. 
Intervention beyond RECIST 1.1-defined PD is not permitted in this study.
6.2
Preparation/Handling/Storage/Accountability of Interventions
The investigator or designee (eg, pharmacist) must confirm appropriate temperature 
conditions have been maintained during transit for all study intervention received at the site 
and throughout the entire study duration until authorisation is provided for on-site destruction 
or removal of the study intervention, reflecting completion of the study. In the event of a 
temperature excursion detected at any time during the study, sites will follow the reporting 
procedures for notifying the sponsor (or designated party); release of study intervention for 
clinical use can only occur once the event has been reviewed and approval is provided by the 
sponsor (or designated party).
Only authorised site staff may prepare, dispense and administer study intervention. All study 
intervention must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labelled storage conditions with access limited to 
authorised site staff (and investigator, where applicable).
The investigator is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records) reflecting destruction or 
return of all unused study intervention); this task may be delegated to study staff members 
identified on the site delegation log. 
Further guidance and information for the final disposition of unused study interventions are 
provided in the Pharmacy Manual.
6.2.1
Storage of Dato-DXd
The investigator, or an appropriate delegate, will ensure that all study intervention is stored in 
a secure, limited access storage area, at appropriate temperatures and as specified on the label, 
and in accordance with applicable regulatory requirements. A calibrated 
temperature-monitoring device will be used to record the temperature conditions in the drug 
storage facility. A temperature log will be used to record the temperature of the storage area. 
Temperature excursions outside the permissible range listed in the clinical supply packaging 
are to be reported to the study monitor upon detection. Storage conditions stated in the 
respective IBs may be superseded by the label storage instructions.

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
5 6 of 1 6 5
Dat o -D X d vials are t o be st ore d at 
 
Dat o -D X d m ust be ke pt i n ori gi nal pac ka gi n g u nt il use t o pre ve nt pr ol o n ge d li g ht e x p os ure.
6. 2. 2
Pre p ar ati o n of D at o -D X d
T he d ose of Dat o -D X d m ust be pre pare d b y t he i n vesti gat or’s or site’s desi g nate d st u d y  
i nter ve nt i on ma na ger usi n g ase pt ic tec h ni q ue i n c o m plia nce with l ocal re g ulatio ns a n d si t e 
re q uire me nts. 
 
F o ll owi n g pre parati o n a n d d uri n g a d mi nistrati o n, t he pre pare d I V ba g 
 
.
6. 2. 2. 1
A d mi nistr ati o n of D at o -D X d
Dat o -D X d will be a d mi nistere d as a 6. 0 -m g/ k g I V i nf usi o n Q 3 W o n Da y 1 of  eac h 2 1-d a y  
c ycle.
Pr e m e dicat i on t o mit i gate t he ris k of I R Rs is re q uire d pri or t o a n y d ose of Dat o-D X d a n d m ust 
i ncl u de a nti hista mi nes a n d aceta mi n o p he n with or wit h o ut gl uc oc ortic o i ds. 
Base d o n t he c urre ntl y a vaila ble cli nical safet y data, i t is hi g hl y rec o m me n de d t hat 
parti ci pa nts recei ve 
 a ge nts pri or t o i nf usi o n of Dat o -D X d a n d o n 
s u bse q ue nt da ys as nee de d. 
 a n d 
 s h o ul d be c o nsi dere d a n d a d mi nistere d i n acc or da nce wit h t he 
prescri bi n g i nf or mati o n or i nst ituti o nal  g ui deli nes. 
 ca n be 
use d, if nee de d.
Dat o -D X d will be a d mi nistere d usi n g a n I V ba g c o ntai ni n g 
 a n d 
deli vere d t hr o u g h a n I V a d mi nistrati o n set wit h a 
. T he sta n dar d i nf usi o n 
ti me f or Dat o-D X d is a p pr o xi matel y 
 f or t he first i nf usi on. If t he 
i nf usio n  is well t olerate d a n d t he partici pa nt d oes n ot e x perie nce a n I R R, t he n t he 
mi ni m u m i nf usi o n ti me f or s u bse q ue nt c y cles is  
. H o we ver, if t here are 
i nterr u ptio ns d uri n g t he i nf usi o n, 
 
 
.
T he I V li ne will be fl us he d wit h 5 % de xtr ose f or i nject i on acc or di n g t o l ocal practices t o 
e ns ure t he f ull d ose is a d mi nistere d. I nf usi o n t i me d oes n ot i ncl u de t he fi nal fl us h ti me.
Refer t o t he P har mac y Ma n ual f or detaile d i nf or mati o n a b o ut pre parati o n a n d a d mi nistrati o n 
of  Dat o-D X d.
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
5 7 of 1 6 5
T he parti ci pa nt s h o uld r e m ai n at t he sit e for at l east  
 p ost-i nf usi on of e ver y  d ose of 
Dat o -D X d f or cl ose o bser vat i on f or p ossi ble aller gic reacti ons a n d I R Rs at eac h treat me nt 
c ycle.
T he parti ci pa nt’s wei g ht at scree ni n g ( baseli ne) will be use d t o calc ulate t he i nit ial d ose. If, 
d uri n g t he c o urse of treat me nt, t he partici pa nt’s wei g ht c ha n ges b y  
, t he partici pa nt’s 
d ose will be recalc ulate d base d o n t he partici pa nt’s u p date d wei g ht. After t he re calc ulat i on, 
t he u p date d partici pa nt’s wei g ht will be use d as t he ne w baseli ne wei g ht. T he site ma y f o ll ow 
l ocal i nst ituti o nal  p olic y for r e -calc ulat i n g d ose base d o n wei g ht c ha n ges 
6. 2. 2. 2
S afet y M o nit ori n g
P arti cipa nts will be m o ni t ore d d uri n g a n d after i nf usio n of  Dat o-D X d. Vital si g ns will be 
meas ure d acc or di n g t o t he S o A.
Ma na ge me nt of st u d y  int er ve nt i on- relate d t o xicities are descri be d i n t he T M Gs f or Dat o -D X d, 
(see t he T M G A n ne x). As wit h a n y biol o gic pr o d uct, aller gic reacti o ns t o d ose a d mi ni str atio n 
are p ossi ble. T heref ore, a p pr o priate dr u gs a n d me dical e q ui p me nt t o treat ac ute a na p h ylact ic 
reactio ns m ust be i m me diatel y a vaila ble, a n d st u d y pers o n nel m ust be trai ne d t o rec o g nise a n d 
treat a na p h yla xis.
6. 3
Me as ures t o Mi ni mise Bi as
6. 3. 1
P artici p a nt E nr ol me nt 
All partici pa nts will be ce ntrall y assi g ne d t o t he o pe n -la bel st u d y int er ve nt i on usi n g a n I R T. 
P arti cipa nts s h o ul d be gi n treat m e nt o n t he da y of treat me nt assig n me nt i n I R T. 
Bef ore t he st u d y  is i nitiate d at a site, t he call/l o g-i n directi ons a n d u ser g uid es f or t he I R T will 
be pr o vi de d t o t he site. T he I R T will pr o vi de t he kit i de nt ificati on n u m ber t o be all ocate d t o 
t he partici pa nt at eac h dis pe nsi n g visit. St u d y int er ve nt i on will be dis pe nse d at t he st u d y  visits 
s u m marise d i n t he S o A (see Secti o n 1. 3 ).
Ret ur ne d st u d y  int er ve nt i on s h o ul d n ot be re -dis pe nse d t o t he partici pa nts.
If a partici pa nt wit h dra ws fr om t he st u d y, t he n his/ her E-c o de ca n n ot be re use d. Wit h dra w n 
parti ci pa nts will n ot be re place d.
I n vesti gat ors s h o ul d kee p a rec or d (ie, t he partici pa nt scree ni n g l o g) of partici pa nts w h o 
e ntere d scree ni n g.
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
5 8 of 1 6 5
At  scree ni n g/ baseli ne (Da ys -2 8 t o - 1), t he i n vesti gat ors or s uita bl y trai ne d dele g ate will 
perf or m  t h e fol l owi n g:

O btai n si g ne d i nf or me d c o nse nt bef ore a n y st u d y -s pecific pr oce d ures are perf or me d. If 
la b orat or y or i ma gi n g pr oce d ures were perf or me d f or alter nate reas o ns pri or t o si g ni n g 
c o nse nt, t hese ca n be use d f or scree ni n g p ur p oses w ith c o nse nt of t he partici pa nt. 
H o we ver, all scree ni n g la b orat or y  a n d i ma gi n g res ults must ha ve bee n o btai ne d wit hi n 
2 8 d a y s of  t he first d ose of st u d y int er ve nt i on E xce pt f or vir us a nt i b o d y test res ults, w hic h 
ca n be use d if perf or me d wit hi n 1 2 0 da ys bef o re scree ni n g.

O btai n a u ni q ue 
 E-c o de, t hr o u g h t he I R T i n t he f o ll owi n g f or m at
 
T his n u m ber is t he partici pa nt’s u ni q ue
i de ntifier a n d is use d t o i de ntif y t he partici pa nt o n t he e C R Fs.

Deter mi ne partici pa nt eli gi bilit y (see Sect i ons  5. 1 a n d 5. 2 ).

E nr ol  eli gi ble partici pa nt i nt o t he st u d y a n d o btai n  treat me nt assi g n me nt. Treat me nt 
assi g n me nt s h o ul d be o btai ne d fr o m t he I R T o n t he sa me da y t he partici pa nt’s eli gi bilit y 
is c o nfir me d a n d t he y are e nr olle d i n t he st u d y. T he date of e nr ol me nt is defi ne d as t he 
date t he partici pa nt is c o nfir me d as eli gi ble i n t he I R T.
If t he partici pa nt is i neli gi ble, t he I R T will be accesse d t o ter mi nate t he participa nt i n t he 
s yste m.
P arti cipa nts will be gi n treat me nt o n C ycle 1 Da y 1. Parti cipa nts m ust n ot be e nr olle d a n d 
treate d u nless all eli gi bility crit eria ha ve bee n met.
6. 3. 2
Pr oce d ures f or H a n dli n g I nc orrectl y E nr olle d P artici p a nts
P arti cipa nts w h o fail  t o meet all of t he eli gi bility criteria s h o uld n ot, u n der a n y  circ u msta nces, 
be e nr olle d or recei ve st u d y  int er ve ntio n. T here ca n be n o e xce pt i ons t o t his r ule. Partici pa nts 
w h o are e nr olle d b ut s u bse q ue nt l y f ou n d n ot t o m eet all t he eli gi bility cri t eria must n o t be 
starte d o n st u d y int er ve nt i on a n d m ust be wit h dra w n fr o m t he st u d y.
W he n a partici pa nt d oes n ot meet all t he eli gi bilit y criteria b ut is e nr olle d i n err or, or 
i nc orrectl y starte d o n treat me nt, t he i n vest i gat or s h o ul d i nf or m t he Astra Ze neca st u d y cli nic al 
lea d i m me diatel y, a n d a disc ussi on s h o ul d occ ur bet wee n t he Astra Ze neca st u d y  cli nical lea d 
a n d t he i n vest i gat or re gar di n g w het her t o c o nti n ue or disc o nti n ue t he partici pa nt fr o m 
treat me nt. T he Astra Ze neca st u d y cli nical lea d must e ns ure all decisi o ns are a p pr o priatel y 
d oc u m e nte d a n d t hat t he p ote nti al be nefit/ris k pr ofile re mai ns p ositiv e f or t he partici pa nt.
6. 3. 3
Met h o ds f or Assi g ni n g Tre at me nt Gr o u ps
N ot a p plica ble.
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Astra Ze neca
Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
5 9 of 1 6 5
6. 3. 4
Met h o ds f or E ns uri n g Bli n di n g
N ot a p plica ble.
6. 4
St u d y I nter ve nti o n C o m pli a nce
Si tes will f oll ow l o c al  practices f or verificati on of st u d y  int er ve ntio n d oses pre pare d a n d 
a d mi nistere d t o st u d y p artici pa nts. 
W he n partici pa nts are d ose d at t he site, t he y  will ha ve st u d y int er ve nt i on pre pare d, dis pe nse d, 
a n d a d mi nistere d b y t he i n vesti gat or or desi gnee u n der me dical s u per visi o n. T he date, a n d 
ti me if a p plica ble, of t he a d mi nistere d st u d y int er ve nt i on will be rec or de d i n t he s o urce 
d oc u m e nts a n d rec or de d i n t he e C R F. T he d ose of st u d y  int er ve ntio n a n d st u d y  partici pa nt 
i de ntificati on will be c o nfir me d at t he ti me of d osi n g i n acc or da nce wit h l ocal treat me nt 
verificati o n pract ices.
De viat i on(s) fr o m t he prescri be d d osa ge re gi me n s h o ul d be rec or de d i n t he e C R F.
6. 5
C o nc o mit a nt T her a p y
A n y c o nc o mit a nt treat me nt, pr oce d ure, or ot her me dicat i on c o nsi dere d neces sar y b y t he 
i n vesti gat or f or t he partici pa nt’s safety a n d well bei n g, or vacci ne (i ncl u di n g o ver -t he- c o u nter 
or prescri pt i on me d ici nes, vita mi ns, a n d/ or her bal s u p ple me nts, or ot her s pecific cate g ories of 
i nterest) t hat t he partici pa nt is recei vi n g fr o m t he ti me of scree ni n g or recei ves d uri n g t he 
st u d y, i ncl u di n g t he 
fol l ow- u p peri o d f ol l owi n g t he l ast d ose of st u d y int er ve nt i on, 
m ust be rec or de d i n t he e C R F al o n g wit h t he f o ll owi n g:

Reas o n f or use

Dates of a d mi nistrati o n i ncl u di n g start a n d e n d da tes

D osa ge i nf or mati o n i ncl u di n g d ose a n d fre q ue nc y
C o nc o mita nt me dicat i ons a d mi nistere d as treat me nt f or dr u g -relate d A E SIs s h o ul d be 
rec or de d u ntil eit her e ve nt res ol uti on, e n d of st u d y , trial ter mi nat i on, wi t hdra wal  of c o nse nt, or 
parti ci pa nt deat h. 
T h e st u d y p h ysicia n s h o ul d be c o ntacte d if t here are a n y q u estio ns re gar di n g c o nc o mit a nt or 
pri or t hera p y .
If a n y c o nc omit a nt t hera p y is a d mi nistere d d ue t o ne w or u nres ol ve d A E, it s h o ul d be 
rec or de d.
P arti cipa nts m ust be i nstr ucte d n ot t o ta ke a n y  me dicat i ons, i ncl u di n g o ver -t he- c o u nter 
pr o d ucts, wit h o ut first c o ns ult i n g wit h t he i n vesti gat or.
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Datopotamab deruxtecan (Dato-DXd, DS-1062a)
CONFIDENTIAL AND PROPRIETARY
60 of 165
Restricted, prohibited, and permitted concomitant medications/therapies are described in more 
detail in Appendix G 2.
Guidance regarding potential interactions with concomitant medications is provided in 
Appendix G. 
6.5.1
Drug-Drug Interactions
In vitro DDI studies indicated that DXd, the drug component of Dato-DXd, is a substrate of P-
gp, MATE2-K, OATP1B1, OATP1B3, BCRP, MRP1, and CYP3A4. No human DDI study of 
Dato-DXd has been conducted. Since DDI is primarily driven by DXd, DDI study results for 
fam-trastuzumab deruxtecan-nxki (ENHERTU®), which has the same DXd payload, are 
relevant and described below:

Coadministration of itraconazole, a strong CYP3A inhibitor, with multiple doses of fam-
trastuzumab deruxtecan-nxki increased steady state AUC from 0 to 17 days (AUC0-17d) of 
fam-trastuzumab deruxtecan-nxki by 11% and DXd by 18%. The impact of these changes 
is not clinically meaningful.

Coadministration of ritonavir, a dual inhibitor of OATP1B/CYP3A, with multiple doses 
of fam-trastuzumab deruxtecan-nxki increased steady state AUC0-17d of fam-trastuzumab 
deruxtecan-nxki by 19% and DXd by 22%. The impact of these changes is not clinically 
meaningful.
Based on the information above, the effect of CYP3A/OATP1B on DXd is not considered to 
be clinically meaningful, and as a result, concomitant use of CYP3A/OATP1B inhibitors with 
Dato-DXd is permitted. However, participants should be closely monitored when Dato-DXd is 
concomitantly used with drugs that inhibit CYP3A, OATP 1B1, and OATP1B3.
Concomitant use of drugs that inhibit MATE2-K, P-gp, BCRP, and MRP1 is permitted, 
although participants should be closely monitored for adverse reactions. As urinary excretion 
of DXd is expected to be low, MATE2-K, which is involved in the excretion of substrates into 
urine, is expected to have minimal impact on the exposure of DXd. In addition, multiple 
efflux transporters such as P-gp and BCRP are involved in the excretion of DXd; therefore, 
the risk of interactions with these inhibitors is also expected to be low. Likewise, because the 
expression of MRP1 in the liver is low, the inhibition of MRP1 is expected to have little 
impact on the exposure of DXd.
Concomitant use of drugs that are substrates of OAT1 and OATP1B1 is permitted. As the 
exposure of DXd is expected to be low with Dato-DXd at doses administered in clinical 
studies, the inhibition of OAT1 and OATP1B1 by DXd is expected to have little impact on 
drugs that are substrates of OAT1 and OATP1B1.
There is a hypothetical interaction between Dato-DXd and hydroxychloroquine and/or 
chloroquine; therefore, concomitant treatment with hydroxychloroquine or chloroquine is not 

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2 a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
6 1 of 1 6 5
all o we d w hilst a partici pa nt is o n Dat o- D X d, a n d > 1 4 da y s of was h o ut is re q uire d bef ore 
starti n g Dat o-D X d a d mi nistrati o n. If treat me nt wit h c hl or o q ui ne or h y dr o x yc hl or o q ui ne 
treat me nt is a bs o l utel y re q uire d, st u d y int er ve nt i on m ust be i nterr u pte d. If c hl or o q ui ne or 
h y dr o x yc hl or o q ui ne is a d mi nistere d f or a n y  reas o n, t he st u d y int er ve nt i on m u st be i nterr u pte d, 
a n d a was h o ut peri o d of at least 1 4 da ys is re q uire d bef ore restarti n g st u d y  int er ve ntio n.
G ui da nce re gar di n g p ote ntial i nteracti o ns wit h c o nc o mita nt me dicat i ons is pr o vi de d i n 
A p pe n di x G .
6. 6
D ose M o dific ati o n
D osi n g m o dificati o n g ui deli nes a n d T M Gs are i n t he T M G A n ne x.
D ose dela ys are per mitte d f or Dat o- D X d treat me nt.
All d ose re d ucti o ns a n d dela ys (incl u di n g a n y misse d d oses), a n d t he reas o ns f or t he 
re d uctio ns/ dela ys are t o be rec or de d i n t he e C R F.
6. 6. 1
D ose Del a ys
T he d osi n g i nter val f or t he ne xt Dat o -D X d c y cle ma y be s h orte ne d, as cli nicall y feasi ble, t o 
gra d uall y  ali g n wit h t he sc he d ule of t u m o ur efficac y assess me nt. T w o c o nsec uti ve d oses m ust 
be a d mi nistere d at least 1 8 da y s a part. 
A d ose of Dat o -D X d ca n be dela ye d f or u p t o 
 fr om t he pla n ne d 
date of a d mi nistrati o n (ie, 
 fr o m t h e last i nf usi o n date).
 
 
.
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Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Dat o p ota ma b der u xteca n ( Dat o -D X d, D S -1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
6 2 of 1 6 5
Fi g ure 3
D ose Del a y Sc he m a f or D at o -D X d
I n t he e ve nt of a d ose dela y occ urri n g prior t o c o m pl et i on of P K bl o o d sa m pli n g i n t he st u d y , 
i n vestig at ors s h o uld c o ntact t he st u d y  cli nical lea d f or g ui da nce re gar di n g sc he d uli n g of t hese 
pr oce d ures.
6. 6. 2
D ose Del a ys f or Re as o ns ot her t h a n Tre at me nt -rel ate d T o xicit y
St u d y  treat me nt d ose dela y for c o n di tio n s ot her t ha n t o xicity res o l uti on s h o ul d be ke pt as 
s h ort as p ossi ble. 
 
Treat me nt c y cl es for a parti cip a nt f or w h o m  Dat o-D X d d osi n g is te m p oraril y  wit hhel d f or a n y  
reas o n ma y ha ve f ut ure c ycles sc he d ule d base d o n t he date of t he last Dat o -D X d d ose.
6. 6. 3
D ose Re d ucti o ns
I n case a d ose re d ucti o n is necessar y, Dat o-D X d will be m o difie d as f o ll ows. U p t o
d o se 
re d uctio n s will be per mitt e d for parti ci pa nts recei vi n g Dat o -D X d. O nce t he d ose of Dat o -D X d 
has bee n re d uce d beca use of t o xicit y,  all s u bse q ue nt c ycles s h o uld be a d mi nistere d at t hat 
l ower d ose le vel u nless f urt her d ose re d ucti o n is re q uire d (Ta ble 5 ). O nce t he d ose of 
Dat o D X d i s re d uce d, n o d ose re-escalat i on will be per mitte d. 
 d ose re d ucti o n 
ma y be p ossi ble 
 after disc ussi on a n d a gree me nt bet wee n t he 
i n vestigat or a n d s p o ns or.
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Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
6 3 of 1 6 5
T a ble 5
D ose Re d ucti o n Le vels of D at o -D X d
St arti n g d ose
D ose le vel - 1
D ose le vel - 2
6. 0 m g/ k g
 m g/ k g
 m g/ k g
Dat o -D X d, dat o p ota ma b der u xteca n.
I n vesti gat ors s h o ul d c o nsi der d ose re d ucti o ns or disc o nti n uati o ns of Dat o -D X d acc or di n g t o 
t he partici pa nt’s c o n dit i on a n d after disc ussi o n wi t h t he st u d y p h ysicia n or desig nee (see t he 
T M G A n ne x). F or ma na ge me nt of d ose dela ys d ue t o Dat o -D X d -relate d e ve nts, t he T M Gs 
(see t he T M G A n ne x) s h o ul d be f oll ow e d, as a p plica ble.
6. 6. 4
D ose M o dific ati o n f or T o xicit y M a n a ge me nt
F ull T M Gs f or Dat o -D X d are i ncl u de d i n t he T M G A n ne x. T he m ost c urre nt versi o n of t he 
T M Gs f or Dat o -D X d is pr o vi de d t o t he i n vest i gati ve site as a n A n ne x d oc u me nt t o t he C S P 
a n d is mai ntai ne d wit hi n t he Site Master File.
S pecific criteria f or dela y, i nterr u pti o n, re -i nitiati o n, d ose re d ucti o n a n d/ or disc o nti n uati on of 
Dat o -D X d are liste d i n t he A n ne x d oc u me nt t o t his C S P, w hic h is a p plica ble o nl y t o T E A Es 
t hat are assesse d as relate d t o use of Dat o- D X d b y  t he i n vesti gat or(s). F or n o n-dr u g -relate d 
T E A Es, f o ll ow sta n dar d cli nical practice. A p pr o priate cli nical e x perts s h o ul d be c o ns ulte d as 
dee m e d necessar y.
T he i n vest i gat or ma y c o nsi der d ose dela ys or disc o nti n uati ons of Dat o -D X d base d o n ot her 
e ve nts n ot liste d i n t he T M Gs (see t he A n ne x d oc u me nt t o t his C S P) acc or di n g t o t he 
parti ci pa nt’s c o n dit i on a n d after disc ussi o n wi t h t he st u d y cli nical lea d or desig nee.
O n i m pr o ve me nt of a n A E f or w hic h Dat o-D X d was te m p oraril y dela ye d, Dat o -D X d ma y be 
restarte d at t he sa me d ose at t he discreti o n of t he i n vesti gat or. If a f urt her e pis o de of t he sa me 
A E s u bse q ue nt l y re q uires d ose dela y, or if a differe nt A E s u bse q ue ntl y re q uires d ose dela y, 
Dat o -D X d ma y be restarte d at a o ne -d ose -level re d ucti o n o n i m pr o ve me nt of  t he A E or 
di sc o nti n ue d if t he partici pa nt is recei vi n g t he l o west C S P-s pecifie d d ose le vel.
A p pr o priate a n d o pti mal treat me nt of t he t o xicit y s h o uld be atte m pte d pri or t o c o nsi deri n g 
d ose m o dificat i ons. Pri or t o disc o nt i n uati on of st u d y  int er ve nt i on d u e t o t o xicit ies, please 
c o ns ult wit h t he st u d y cli nical lea d.
If a partici pa nt e x perie nces a cli nicall y si g nifica nt a n d/ or u nacce pta ble t o xicity,  d osi n g will be 
d el a ye d or per ma ne nt l y disc o nti n ue d i n acc or da nce wit h t he T M Gs a n d s u p p orti ve t hera p y 
a d mi nist ere d as re q uire d.
All d ose m o dificat i ons ( dela y , i nterr u ptio n, re d ucti o n, a n d/ or disc o nt i n uatio n) s h o ul d be base d 
o n t he w orst prece di n g t o xicit y ( C T C A E versio n  5. 0).
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Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
6 4 of 1 6 5
6. 7
C o nti n ue d Access t o St u d y I nter ve nti o n After t he E n d of t he 
St u d y
As descri be d i n Secti o n 4. 4 , t he st u d y will re mai n o pe n u ntil t he fi nal D C O.
At  t he ti me of fi nal a nal ysis c om p leti on f or eac h c o h ort, a n u m ber of partici pa nts ca n still be 
o n st u d y  dr u g wit hi n t he c urre nt st u d y. T hese partici pa nts are t o c o nti n ue treat me nt  
 
.
P arti cipa nts s h o ul d b e f ol l owe d acc or di n g t o t he i nstit uti o n’s S o C assess me nts. N o f urt her 
data c ollect i on is re q uired, e xce pt f or 
Astra Ze neca will c o nti n ue t o s u p pl y  Dat o-D X d after c o m plet i on of t his st u d y  w hile, i n t he 
o pi ni o n of t he i n vest i gat or, t he partici pa nt is be nefitti n g. 
I n t he e ve nt t hat pr o d uct de vel o p me nt reac hes a p oi nt w here alter nati ve pr o d uct s u p pl y  
o pti o ns bec o me a vaila ble, t he n t hese alter nat i ve pr o d uct s u p pl y o pti o ns will be disc usse d b y 
Astra Ze neca wit h t he i n vesti gat or. Astra Ze neca will w or k wit h t he i n vest i gat or t o tra nsiti on 
t he partici pa nt(s) t o alter nat i ve s u p pl y, w here p ossi ble.
I n t he e ve nt t hat 
 is a vaila ble at t he ti me of t he fi nal D C O
a n d data base cl os ure, partici pa nt(s) c urre ntl y recei vi n g treat me nt wit h Dat o -D X d ma y t he n be 
tra nsitio ne d t o s uc h a st u d y , a n d t he c urre nt st u d y ma y reac h its e n d. T he 
 
 w o uld e ns ure treat m e nt c o nti n uat i o n wit h visit assess me nts per its pr ot oc ol, as 
a p plica ble. A n y p artici pa nt w h o w o uld be eli gi ble t o m o ve t o s uc h a st u d y  w o uld be gi ve n a 
ne w i nf or me d c o nse nt, as a p plica ble.
6. 8
Tre at me nt of O ver d ose
Use of Dat o -D X d i n d oses e xcee di n g t hat s pecifie d i n t he C S P is c o nsi dere d t o be a n 
o ver d ose. T here is c urre nt l y n o s pecific treat me nt i n t he e ve nt of o ver d ose of Dat o- D X d, a n d 
p ossi ble s y m pt o ms of o ver d ose are n ot esta blis he d. 
I n t he e vent  of a n o ver d ose, t he i n vesti gat or s h o ul d:

E val uate t he partici pa nt t o deter mi ne, i n c o ns ultat i o n wit h t he st u d y cli nical lea d, if 
p ossi ble, w het her st u d y  int er ve nt i on s h o ul d be i nterr u pte d/ dela ye d or w het her t he d ose 
s h o uld be re d uce d.

Cl os el y  mo ni t or t he partici pa nt f or a n y A E/ S A E a n d la b orat or y a b n or malities as 
me dicall y a p pr o priate a n d at least u ntil t he ne xt sc he d ule d f o ll ow -u p. Refer t o Secti o n  8. 5
f or details of A E/ S A E re p orti n g relate d t o o ver d ose.

D oc u m e nt t he q ua ntit y of t he e xcess d ose as well as t he d urati o n of t he o ver d ose.
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AstraZeneca
Datopotamab deruxtecan (Dato-DXd, DS-1062a)
CONFIDENTIAL AND PROPRIETARY
65 of 165
7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Intervention
It may be necessary for a participant to permanently discontinue (definitive discontinuation) 
study intervention. If study intervention is permanently discontinued, the participant will 
remain in the study to be evaluated for safety, subsequent anticancer therapy, and survival. 
The investigator should instruct the participant to contact the site before or at the time if study 
intervention is stopped. A participant that decides to discontinue study intervention will 
always be asked about the reason(s) and the presence of any AEs. The reason for 
discontinuation should be documented in the source document and the appropriate section of 
the eCRF.
Participants who have permanently discontinued from further receipt of study intervention 
will need to be discontinued from the IRT. 
Participants may be discontinued from study intervention in the following situations: 

RECIST 1.1-defined radiological progression as assessed by the investigator (refer to 
Section 8.2.1 and Appendix E). 

Investigator determination that the participant is no longer benefiting from study 
intervention.

An AE that, in the opinion of the investigator or AstraZeneca, contraindicates further 
dosing. 

Any AE that meets criteria for discontinuation defined in the dose modification guidelines 
for management of study intervention-related toxicities (see the TMG Annex). 

Participant decision. The participant is at any time free to discontinue treatment without 
prejudice to further treatment. A participant who discontinues treatment is normally 
expected to continue to participate in the study (eg, for safety and survival follow-up) 
unless they specifically withdraw their consent to all further participation in any study 
procedures and assessments (see Section 7.2)

Severe non-compliance with the CSP as judged by the investigator or AstraZeneca.

Pregnancy or intent to become pregnant (see Appendix F and Section 8.4.14).

Initiation of subsequent anticancer therapy.

Initiation of treatment with another investigational agent.

Subjective disease progression (global deterioration of health status) without objective 
evidence of PD according to RECIST 1.1.
Note that discontinuation from study intervention is NOT the same thing as a withdrawal from 
the study.

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
6 6 of 1 6 5
See t he S o A ( Secti o n  1. 3 ) for data t o be c ollecte d at t he ti me of st u d y  int er ve nt i on 
di sc o nti n uati on (i e, t he E n d -of -Treat m e nt Visit) a n d f ollo w - u p a n d f or a n y furt her e val uat i ons 
t hat nee d t o be c o m plete d.
7. 1. 1
F oll o w- u p of P artici p a nts P ost Disc o nti n u ati o n of St u d y I nter ve nti o n
All partici pa nts w h o disc o nt i n ue t he st u d y int er ve ntio n will be f o ll owe d u p f or safet y 
assess me nts 
 after t heir last d o se of st u d y i nter ve nti on. If t he da y  o n w hic h t he 
i n vesti gat or deter mi nes t hat t he patie nt s h o ul d disc o nti n ue st u d y int er ve nt i on is o ver 
 
after t he last d ose of st u d y int er ve nt i on recei ve d b y  t he patie nt, a n a d ditio nal  s af et y fol l ow- u p 
assess me nt is n ot nee de d. A d dit i onal assess me nts t o be perf or me d at t he ti me of t he  
 
S af et y F o ll ow- u p Vi sit are detaile d i n t he S o A (see Secti o n 1. 3 ). For I L D/ p ne u m o nit is, safety 
f oll ow- u p will c o nt i n ue u ntil t he res ol uti on of I L D/ p ne u m o nit is. All A E SIs, re gar dless of 
se verity or seri o us ness, m ust b e f ol l owe d u nt il eit her e ve nt res ol uti on, e n d of st u d y , i ncl u di n g 
a n y p ost -treat me nt f oll o w-u p, tri al ter mi nat i on, wi t h dra wal of c o nse nt, or partici pa nt deat h 
(see Secti o n 8. 4. 1 1 ).
P arti cipa nts w h o ha ve disc o nti n ue d st u d y  int er ve nti o n pri or t o o bjecti ve R E CI S T 1. 1 -defi ne d 
r a diol o gical  pr o gressio n , re gar dless of w het her or n ot t he y ha ve c o m me nce d s u bse q ue nt 
a nt ica ncer t hera p y, will be fol l owe d u p wi t h t u mo ur assess me nts as i n dicate d i n t he S o A (see 
Secti o n  1. 3 ) u ntil R E CI S T 1. 1-defi ne d P D or deat h re gar dless of w het her or n ot t he 
parti ci pa nt starte d a s u bse q ue nt a ntica ncer t hera p y,  u nless t he y ha ve wit h dra w n all c o nse nt t o 
st u d y-relate d assess me nts.
S u bse q ue nt a ntica ncer dr u g treat me nts a d mi nistere d si nce t he e n d o f treat me nt wit h st u d y 
i nter ve nt i on m ust be m o nit ore d a n d rec or de d i n t he e C R F u nt il t he e n d of t he st u d y. Best 
res p o nse a n d t he date of P D o n s u bse q ue nt t hera pies, as assesse d b y local sta n dar d cli nical 
practi ce, will be rec or de d i n t he e C R F. S u bse q ue nt a ntica ncer dr u g treat me nts ma y c o m me nce 
f oll owi n g disc o nt i n uati on of st u d y  int er ve nt i on, i ncl u di n g at P D.
7. 1. 2
F oll o w- u p f or S ur vi v al
P arti cipa nts will be f oll o we d u p f or s ur vi val stat us a n d s u bse q ue nt a ntica ncer t hera p y  as 
i n dicate d i n t he S o A (see Secti o n 1. 3 ) u ntil deat h, wit hdra wal  of c o nse nt, or t he e n d of t he 
st u d y. S ur vi val inf or m at i on ma y be o btai ne d via tele p h o ne c o ntact wit h t he partici pa nt or t he 
parti ci pa nt’s fa mil y, or b y c o ntact wit h t he partici pa nt’s c urre nt p h ysicia n, or l ocal deat h 
r e gistries. A d dit i onal assess me nts i ncl u di n g s u bse q ue nt a nt i-ca ncer t hera p y, are t o be rec or de d 
at t he ti me of s ur vi val f o ll o w-u p a n d are detaile d i n t he S o A. See Secti o n 8. 2. 4 f or a d diti onal 
i nf or mat i on..
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7. 2
P artici p a nt Disc o nti n u ati o n/ Wit h dr a w al Fr o m t he St u d y

A partici pa nt ma y wit h dra w fr o m t he st u d y at a n y time at hi s/ her o w n re q uest or ma y be 
wi t hdra w n at a n y  ti me at t he discretio n of  t he i n vestigat or f or safet y,  be ha vi our al , 
c o mplia nce, or a d mi nistrati ve reas o ns. T his is e x pecte d t o be u nc o m m o n.

A partici pa nt w h o c o nsi ders wit h dra wi n g fr o m t he st u d y must be i nf or me d b y  t he 
i n vesti gat or a b o ut m o difie d f oll ow- u p o pti o ns t o e ns ure t he c ollecti o n o f e n d p o i nts a n d 
safety i nf or mat i on i ncl u di n g ne w A Es a n d f oll ow- u p o n a n y o n g o i n g A Es a n d 
c o nc o mita nt me dicat i ons (e g, tele p h o ne c o ntact at 
 after st u d y 
i nter ve nt i on is disc o nti n ue d, a c o ntact wit h a relati ve or treati n g p h ysicia n, or i nf or mati on 
fr om me dical rec or d s).

At  t he ti me of wit h dra wal fr om t he st u d y, if p ossi ble, a n Earl y St u d y I nter ve nti on 
Di sc o nti n uatio n visi t s h o uld be c o n d ucte d, as s h o w n i n t he S o A (see Secti o n  1. 3 ). See 
S o A f or data t o be c ollecte d at t he ti me of st u d y  wit h dra wal a n d fol l ow- u p a n d f or a n y  
f urt her e val uati ons t hat nee d t o be c o m plete d.

T he parti ci pa nt will disc o nt i n ue t he st u d y int er ve nti o n a n d be wit h dra w n fr o m t he 
st u d y at t hat ti me.

If t he partici pa nt wit h dra ws c o nse nt f or discl os ure of f ut ure i nf or mati on, t he s p o ns or ma y  
retai n a n d c o nti n ue t o use a n y data c ollecte d bef ore s uc h a wit h dra wal of c o nse nt.

If a partici pa nt wit h dra ws fr om t he st u d y, it s h o uld be c o nfir me d if he/s he s till a grees f or 
e xist i n g sa m ples t o be use d i n li ne wit h t he ori gi nal c o nse nt. If he/s he re q uests wit h dra wal 
of  c o nse nt f or use of sa m ples, destr ucti o n of a n y sa m ples ta ke n a n d n ot teste d s h o ul d be 
carrie d o ut i n li ne wit h w hat was state d i n t he i nf or me d c o nse nt a n d l o c al  re g ulati on. T he 
i n vesti gat or m ust d oc u me nt t he decisi on o n use of e xist i n g sa m ples i n t he site st u d y 
rec or ds a n d i nf or m t he st u d y tea m.
7. 3
L oss t o F oll o w -u p
A parti ci pa nt will be c o nsi dere d l ost t o f oll o w -u p if  he or s he re peate dl y fails t o r et ur n f or 
sc he d ule d visits a n d n o c o ntact has bee n esta blis he d b y t he ti me t he st u d y  is c o mplete d (see 
Secti o n  4. 4 ), s uc h t hat t here is i ns ufficie nt i nf or mati o n t o deter mi ne t he partici pa nt’s stat us at 
t hat ti me. 
P arti cipa nts w h o decli ne t o c o n ti n ue partici pati on i n t he st u d y, i ncl u di n g tele p h o ne c o ntact,
s h o uld be d oc u m e nte d as ‘ wit hdra wal of c o nse nt’ rat her t ha n ‘l ost t o f oll o w -u p.’ I n vest i gat ors 
s h o uld d o c u m e nt atte mpts t o re -esta blis h c o ntact wit h missi n g partici pa nts t hr o u g h o ut t he 
st u d y p erio d. If  c o ntact wit h a missi n g partici pa nt is re -esta blis he d, t he partici pa nt s h o uld n ot 
be c o nsi dere d l ost t o f oll o w -u p a n d e val u ati o ns s h o ul d res u me acc or di n g t o t he C S P.
T he f o ll owi n g acti o ns m ust be ta ke n if a partici pa nt fails t o ret ur n t o t he cli nic f or a re q uire d 
st u d y visit:

T he site m ust atte m pt t o c o ntact t he partici pa nt a n d resc he d ule t he misse d visit as s o o n as 
p ossi ble a n d c o u nsel t he partici pa nt o n t he i m p orta nce o f ma i ntai ni n g t he assi g ne d visit 
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schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study.

Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls, texts 
or emails, and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented in the 
participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to have been 
lost to follow-up from the study.

Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant during survival follow-up within legal and ethical boundaries for all 
participants enrolled. Public sources may be searched for vital status information in 
accordance with applicable local laws. If vital status is determined as deceased, this will 
be documented and the participant will not be considered lost to follow-up. Sponsor 
personnel will not be involved in any attempts to collect vital status information.
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix A.
In order to support secondary efficacy endpoints of PFS, and OS analyses, the survival status 
of all participants in the Full Analysis Set should be re-checked; this includes those 
participants who withdrew consent or are classified as ‘lost to follow-up.’

Lost to follow-up: Site personnel should check hospital records and a publicly available 
death registry (if available), as well as checking with the participants’ current physician, 
to obtain a current survival status (the applicable eCRF modules will be updated), in 
accordance with applicable local laws.

In the event that the participant has actively withdrawn consent to the processing of their 
personal data, the survival status of the participant can be obtained by site personnel from 
publicly available death registries (if available) where it is possible to do so under 
applicable local laws to obtain a current survival status.
8
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarised in the SoA (see Section 1.3). Data 
collection following study analysis until the end of the study is described below. 

Clinical Study Protocol waivers or exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 

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record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilised for screening or baseline 
purposes provided the procedures met the CSP-specified criteria and were performed 
within the time frame defined in the SoA.
Instructions for the collection and handling of human biological samples will be provided in 
the study-specific Laboratory Manual. Samples should be stored in a secure storage space 
with adequate measures to protect confidentiality. For further details on handling of human 
biological samples, see Appendix C.
Data Collection Following Study Analysis until the End of the Study
For SAE and AE reporting and laboratory assessment collection after final analysis, see 
Section 8.4.12. After the final DCO and database closure, only SAEs will be reported for the 
purposes of this study (see Section 8.4.12). 
In addition, any AEs of ILD/pneumonitis will be followed up until resolution. For other safety 
reporting collection after final analysis, see Section 8.4.12.
8.1
Administrative and General/Baseline Procedures
Demographic data to be collected includes age at screening, sex, race, and ethnicity. 
Medical history includes substance usage, smoking history, type and frequency of tobacco 
use, e-cigarette use, vaping, and family history of premature cardiovascular disease.
8.2
Efficacy Assessments
8.2.1
Imaging Tumour Assessments 
Tumour assessments will use images from CT (preferred) or MRI, with IV contrast, of the 
chest and abdomen (including the entire liver and both adrenal glands) collected during 
screening/baseline and at regular (follow-up) intervals during study intervention. Pelvic 
imaging is recommended only when primary or metastatic disease in the pelvic region is 
likely. Any other areas of disease involvement should be additionally imaged at 
screening/baseline and regular intervals based on known metastasis sites or by the signs and 
symptoms of individual participants. The imaging modality used for baseline tumour 
assessment, CT/MRI for chest, abdomen and pelvis, MRI for brain, and bone image for bone 
should be kept the same consistently at each subsequent follow-up assessment throughout the 
study if possible. It is important to follow the tumour assessment schedule as closely as 
possible (see Section 1.3) relative to the date of the first dose of study intervention. 
Screening/baseline imaging should be performed no more than 28 days before the date of the 
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pri or t o t he date of t he first d ose of st u d y  int er ve nt i o n. A n e xisti n g sca n will be acce pta ble as 
baseli ne if perf or me d wit hi n 2 8 da ys pri or t o date of e nr o l me nt a n d is c o nsiste nt wit h t he 
re q uir e d mo dalit ies. 
Treat me nt c o nti n ues Q 3 W a n d sca n ni n g/t u m o ur assess me nts will be perf or me d e ver y 6 wee ks 
( ± 7 da ys) fr o m t he date of t he first d ose of st u d y i nter ve nti on u nt il R E CI S T 1. 1 -defi ne d 
r a diol o gical  P D b y in vesti gat or assess me nt, e ve n if t he partici pa nt disc o nt i n ues or dela ys 
st u d y int er ve ntio n or i ni tiates ne w a nt ica ncer t hera p y u nless t he y ha ve wit h dra w n all c o nse nt 
t o st u d y r elate d assess me nts. 
 
 T he i nte nt of t his 
 is t o 
mi ni mise 
. T he sca ns fr om all 
assess me nts of t u m o ur res p o nse, i ncl u di n g t he f o ll o w-u p assess me nt, will be se nt f or I C R 
re vie w. If a n u nsc he d ule d assess me nt is perf or me d (e g, t o i n vesti gate cli nical si g ns/s y m pt o ms 
of  pr o gressio n) a n d t he parti cipa nt has n ot pr o gresse d, e ver y  att e mpt s h o ul d be m a de t o 
perf or m  t he s u bse q ue nt assess me nts at t he ne xt sc he d ule d visit. 
T he R E CI S T 1. 1 assess me nts of baseli ne i ma ges i de nt if y T Ls ( defi ne d as meas ura ble) a n d 
N T Ls. O n -st u d y ima ges are e val uate d f or T Ls a n d N T Ls c h ose n at baseli ne, a n d f or N L s
w he n t he y  a p pear. T his allo ws deter mi nat i on of f o ll ow- u p T L res p o nse, N T L lesi o n res p o nse, 
t he prese nce o f u ne q ui v ocal N Ls, a n d o verall ti me p oi nt res p o nses ( C R, P R, S D, P D, or N E).
W he n t u m o ur assess me nts at a visit are perf or me d o ver m ult i ple da ys, t he date of res p o nse 
( C R, P R, S D, no n -C R/ P D [ partici pa nts wit h N T Ls o nl y], or N E) s h o ul d be rec or de d as t he 
date of t he last ra di o gra p hic e val uat i on i ncl u de d i n t he series f or t hat assess me nt, a n d t he date 
of  pr o gressio n s h o ul d be rec or de d as t he date of t he earliest ra di o gra p hic e val uat i on i ncl u de d 
i n t he series f or t hat assess me nt.
F or all partici pa nts, a 
 m ust be 
perf or m e d 
 
. Partic i pa nts 
 at baseli ne m ust 
 
 a n d m ust 
 
 u ntil ra di ol ogical  pr o gressio n per R E CI S T 1. 1 b y i n vesti gat or assess me nt. 
 
 
. Ot her wise, 
 is re q uire d o nl y if  
 
. W he n 
 is s us pecte d, brai n 
M RI or C T sca n s h o ul d be use d t o deter mi ne  
 per R E CI S T 1. 1. 
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8. 2. 2
Ce ntr al Re a di n g of Sc a ns 
All partici pa nts’ ra di o gra p hic i ma gi n g sca ns , i n clu di n g u nsc he d ule d visit sca ns, will b e 
c ollecte d o n a n o n g oi n g basis a n d se nt t o a n Astra Ze neca-a p p o i nte d i C R O f or q ualit y c o ntr ol, 
st ora ge, a n d f or I C R. Di gital c o pies of all ori gi nal sca ns s h o ul d be st ore d at t he i n vesti gat or 
site as s o urce d oc u me nts. Ele ctr o nic i ma ge tra nsfer fr o m t he site s t o t he iC R O is str o n gl y  
e nc o ura ge d. I C R of i ma ges will be perf or me d at t he discret i on of Astra Ze neca. Res ults of 
t hese i n de pe n de nt re vie ws will n ot be c o m m u nicate d t o i n vesti gat ors, a n d res ults of 
i n vesti gat or t u m o ur assess me nts will n ot be s hare d wit h the ce ntral re vie wers. 
F urt her details of t he I C R will be d oc u me nte d i n a n I n de pe n de nt Re vie w C harter.
8. 2. 3
B o ne Sc a n or S kelet al S ur ve y
 b o ne sca n or s keletal s ur ve y p erfor m e d 
 
, a n d 
. 
B o ne sci nt i gra p h y is t he preferre d m o dality.  If a partici pa nt ha d a c h o li ne P E T/ C T, or 
diff usi o n- w ei g hte d M RI as part of t he r o uti ne cli nical ma na ge me nt perf or me d wit hi n 2 8 da ys 
of  start of st u d y int er ve nt i on, i t m a y be ut ilise d as a scree ni n g sca n t o d oc u me nt b o ne disease. 
H o we ver, if fl u or o -de o x y gl uc ose -P E T/ C T i s use d, a de dicate d hi g h q ualit y str uct ural C T or 
M RI of t he rele va nt part of t he s kelet o n is rec o m me n de d t o e ns ure t hat a n y  c ha n ges re prese nt 
a tr ue b o ne metastasis a n d n ot a n o n -ma li g na nt lesi o n (e g, a n i nfla m mat or y lesio n ).
A d dit i onal o n -st u d y bo ne sca ns or s keletal s ur ve ys ma y  be perf or m e d, if cli nicall y in dicate d.
B o ne l esio ns i de nt ifie d o n a n is ot o pic b o ne sca n at baseli ne a n d c o nfir me d b y C T, M RI, or 
X -ra y s h o uld be rec or de d as N T Ls a n d f o ll owe d b y  t he sa me met h o d ( C T, M RI, or X -ra y), as 
i n dicate d i n t he S o A (see Secti o n 1. 3 ).
8. 2. 4
O ver all S ur vi v al
Assess me nts f or s ur vi val will be c o n d ucte d e ver y  3 mo nt hs ± 1 4 d a y s fol l owi n g o bject i ve P D 
or di sc o nti n uatio n of  st u d y int er ve nt i on u nt il deat h, wit h dra wal of c o nse nt, or t he e n d of t he 
st u d y. S ur vi val inf or m at i on ma y be o btai ne d via tele p h o ne c o ntact wit h t he partici pa nt, 
parti ci pa nt’s fa mil y, b y c o ntact wit h t he partici pa nt’s c urre nt p h ysicia n, or l ocal deat h 
r e gistries, w here a p plica ble acc or di n g t o l ocal la ws, as descri be d i n Sect i on  7. 2 .
8. 3
S afet y Assess me nts
Pl a n ne d ti me p o i nts f or all safety assess me nts are pr o vi de d i n t he S o A (see Secti o n  1. 3 ).
8. 3. 1
P h ysic al E x a mi n ati o ns
A f ull p h ysical e xa mi nati on will be p erf or m e d at scree ni n g/ baseli ne a n d i ncl u de assess me nts 
of  t he f oll owi n g: ge neral  a p peara nce, res pirat or y, c ar dio vasc ular, a b d o me n, s ki n, hea d a n d 
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nec k (i ncl u di n g ears, e yes, n ose, a n d t hr oat), l y m p h n o des, t h y r oid, m usc ul os k el et al  (i ncl u di n g 
s pi ne a n d e xtre mities), ur o ge nital, der mat ol o gical, gastr oi ntesti nal, e n d ocri ne, 
hae mat ol o gic/l y m p hat ic, a n d ne ur ol o gical s yste ms. Tar gete d p h ysical e xa mi nat i ons are t o be 
use d b y t he i n vest i gat or o n t he basis of cli nical o bser vat i ons a n d s y m pt o mat ol o g y .
A tar gete d p h ysical e xa mi nat i on will  incl u de, at a mi ni m u m, assess me nts of t he s ki n, l u n gs, 
car dio vasc ular s yste m , a n d a b d o me n (li ver a n d s plee n).
P h ysical e xa mi nat i on, as well as assess me nt of hei g ht a n d wei g ht, will be perf or me d at 
ti meli nes as s pecifie d i n t he S o A (see Secti o n 1. 3 ). I n vesti gat ors s h o ul d pa y s pecial atte nti o n 
t o cli nical si g ns relate d t o pre vi o us seri o us ill nesses, as ne w or w orse ni n g a b n or malities ma y 
q ualif y  as A Es. See Sectio n  8. 4. 5 f or details.
8. 3. 2
Vit al Si g ns
Vi t al si g ns will be assesse d at ti meli nes as s pecifie d i n t he S o A (see Secti o n  1. 3 ) a n d as 
cli nicall y i n dicate d. If meas ure d o n t he da y of inf usi o n, 
s h o uld be meas ure d  
 
 (see Secti o n 8. 3. 5. 2 ). Partici pa nts s h o ul d re mai n at t he site f or at least  
 
 p ost i nf usi on of e ver y  d ose of Dat o-D X d f or cl ose o bser vati o n f or p ossi ble alle r gic 
reactio ns a n d I R Rs. 
B o d y  t e mperat ure, p ul se rate, res pirat or y r at e, a n d bl o o d press ure will be assesse d.
Bl o o d press ure a n d p ulse meas ure me nts will be assesse d i n t he seate d or
s u pi ne/se mi-rec u m be nt p ositio n wi t h a c o mpletel y  a ut o mate d de vice. Ma n ual tec h ni q ues will 
be use d o nl y  if a n a ut o mate d de vice is n ot a vaila ble. Bl o o d press ure a n d p ulse meas ure me nts 
s h o uld be prece de d b y at least 5 mi n utes of rest f or t he partici pa nt i n a q uiet setti n g wit h o ut 
di stractio ns (e g, tel e visio n  a n d cell p h o nes).
O ne rea di n g of p ulse rate a n d bl o o d press ure will be ta ke n.
Si t u atio ns i n w hic h vital si g ns res ults s h o ul d be re p orte d as A Es are descri be d i n 
Secti o n 8. 4. 5 . 
F or a n y  AEs of  inf usi o n react i ons, t he vital si g ns val ues s h o ul d be e ntere d i nt o t he e C R F.
8. 3. 3
Electr oc ar di o gr a ms
Tri plicate 1 2 -lea d E C Gs will be perf or me d at scree ni n g wit hi n 7 da ys bef ore e nr ol me nt. 
Electr ocar di o gra ms will be perf or me d after t he parti ci pa nt has bee n rest i n g i n a 
s u pi ne/se mi-rec u m be nt p ositio n f or at l east 5 mi n utes ( ± 2 mi n utes) a n d rec or de d, w hile t he 
parti ci pa nt re mai ns i n t hat p osit i on usi n g a n E C G mac hi ne t hat a ut o mat icall y calc ulates t he 
heart rate a n d meas ures P R, R R, Q R S, Q T, a n d Q Tc F i nter vals, as p ossi ble. Refer t o Secti o n  7
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for QTcF withdrawal criteria and any additional QTcF readings that may be necessary. 
Manual calculation of QTcF is acceptable.
All ECGs should be assessed by the investigator as to whether they are clinically significantly 
abnormal. Any clinically significant abnormalities detected require triplicate ECG results. At 
each time point at which triplicate ECG are required, 3 individual ECG tracings should be 
obtained in succession, no more than 2 minutes apart. The full set of triplicates should be 
completed within 5 minutes. Subsequent ECGs will only be taken in triplicate if abnormalities 
were noted at screening. At any visit during which a participant exhibits a heart rate ≤50 bpm 
or other clinical symptoms suggesting a need for an ECG investigation, the ECG will be 
repeated.
Situations in which ECG results should be reported as AEs are described in Section 8.4.5.
8.3.4
Clinical Safety Laboratory Assessments
Blood and urine samples for determination of clinical chemistry, haematology, coagulation,
and urinalysis will be taken at the visits indicated in the SoA (see Section 1.3). 
Additional safety samples may be collected if clinically indicated at the discretion of the 
investigator. The date, time of collection and results (values, units, and reference ranges) will 
be recorded on the appropriate eCRF.
The clinical chemistry, haematology, coagulation, and urinalysis will be performed at a local 
laboratory at or near to the investigator site. Sample tubes and sample sizes may vary 
depending on laboratory method used and routine practice at the site. Every effort should be 
made to obtain and provide the corresponding laboratory reference ranges.
Other safety laboratory tests include assessment for pregnancy (serum at screening or 
serum/urine at other time points), hepatitis B and C serology, and HIV antibody test. Prior 
HIV serology (anti-HIV with or without HIV RNA, as appropriate), hepatitis B serology 
(HBsAg, anti-HBs, and anti-HBc with or without HBV DNA, as appropriate), and hepatitis C 
serology (anti-HCV antibody with or without HCV RNA, as appropriate) testing results can 
be used if performed within 120 days before screening. In this case, there is no need for a 
repeat test during the 28 day screening period. If an HIV infection meets the criteria outlined 
in Section 5.2, monitoring of viral RNA load and CD4+ count is recommended. Participants 
must be tested for HIV if acceptable by local regulations or an IRB/EC.
Pregnancy tests may be performed at the site using a licensed test (urine beta-human chorionic 
gonadotropin pregnancy or serum test per institutional guideline) for all FOCBP. A negative 
serum pregnancy test (test must have a sensitivity of at least 25 mIU/mL) must be documented 
during screening for all FOCBP. If a serum pregnancy test is collected greater than 72 hours 
prior to the first dose of study intervention, perform a repeat pregnancy test (urine or serum 

Clinical Study Protocol - D9266C00001
AstraZeneca
Datopotamab deruxtecan (Dato-DXd, DS-1062a)
CONFIDENTIAL AND PROPRIETARY
74 of 165
per institutional guideline) within 72 hours before the first dose of study intervention. Perform 
repeat pregnancy tests (urine or serum per institutional guideline) within 72 hours before each 
infusion at each cycle, at EoT, and the first follow-up visit. A positive urine pregnancy test 
result must immediately be confirmed using a serum test. If a positive urine pregnancy test 
result is confirmed using a serum test, then the participant should not be treated. 
Laboratory assessments that yield abnormal, clinically significant results should be repeated 
as clinically indicated (preferably within 72 hours) and recorded in the eCRF.
The laboratory variables to be measured are listed in Table 6.
Table 6
Laboratory Safety Variables
Haematology/Haemostasis (whole blood)
Clinical Chemistry (serum or plasma)
Differential white blood cell count (neutrophils, lymphocytes, 
monocytes, eosinophils, basophils)
Albumin
Haematocrit 
Alkaline phosphatase
Haemoglobin
ALT
Platelet count
AST
Red blood cell count
Bilirubin, total
White blood cell count
Calcium, total/ionized
Chloride
Urinalysis
Creatinine (serum)
Glucose
Lactate dehydrogenase
Haemoglobin/Erythrocytes/Blood
Magnesium
Protein/Albumin
Potassium
Protein, total
Coagulation
Sodium
Coagulation variables (aPTT or PTT and prothrombin 
time/INR)
Urea nitrogen/blood urea nitrogen/urea
ALT, alanine aminotransferase; aPTT, activated partial thromboplastin time; AST, aspartate aminotransferase; 
INR, international normalised ratio; PTT, partial thromboplastin time.
The investigator should assess the available results with regard to clinically relevant 
abnormalities in documentation. Situations in which laboratory safety results should be 
reported as AEs are described in Section 8.4.5.
All participants with CTCAE Grade 3 or Grade 4 laboratory values at the time of completion 
or discontinuation from study intervention must be followed and have further tests performed 
until the laboratory values have returned to Grade 1 or Grade 2, unless these values are not 
likely to improve because of the underlying disease.

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
7 5 of 1 6 5
N ote: I n case a partici pa nt s h o ws a n A S T or A L T ≥ 3 × U L N t o get her wi t h T B L ≥2 × U L N 
pl ease refer t o  A p pe n di x D ‘ Acti ons re q uire d i n cases of i ncreases i n li ver bi oc he mistr y a n d 
e val uat i on of H L,’ f or f urt her i nstr ucti o ns. 
8. 3. 5
Ot her S afet y Assess me nts
8. 3. 5. 1
Ec h oc ar di o gr a m/ M ulti g ate d Ac q uisiti o n Sc a n 
A n E C H O or M U G A sca n t o assess L V E F will be perf or me d at t he visits as s h o w n i n t he S o A 
(see Secti o n 1. 3 ). T he mo dali t y of t he car diac fu n cti o n assess me nts m u st be c o nsiste nt f or a 
gi ve n partici pa nt (ie, if E C H O is use d f or t he scree ni n g assess me nt f or a gi ve n partici pa nt, 
t he n E C H O s h o ul d als o be use d f or s u bse q ue nt sca ns f or t hat partici pa nt). T he partici pa nts 
s h o uld als o be e xa mi ne d usi n g t he sa me mac hi ne a n d o perat or w he ne ver p ossi ble, a n d 
q ua nt itati ve meas ure me nts s h o ul d be ta ke n (ie, acc urate t o 1 % a n d n ot esti mate d t o 5 %). All 
E C H Os/ M U G As will be e val uate d b y  t he i n vestigat or or dele gate d p h ysicia n f or m o nit ori n g 
car dia c fu n cti o n. If  a M U G A sca n is cli nicall y i n dicate d at t he ti me of Dat o -D X d i nf usi o n, i t 
s h o uld be perf or m e d, a n d its res ults s h o uld be e val uate d bef ore i nf usi o n wi t h Dat o-D X d.
If a partici pa nt has ha d a n E C H O or M U G A perf or me d wit hi n 4 wee ks pri or t o 
di sc o nti n uati on of st u d y  int er ve ntio n, t h e disc o nti n uati o n visit E C H O/ M U G A sca n is n ot 
re q uire d u nless cli nicall y in dicate d. If a partici pa nt has a n y  cli nicall y si g nifica nt decrease i n 
L V E F ( greater t ha n 
 p oi nts t o bel o w  
), t here s h o ul d be f oll ow- u p wi t hi n 
4 wee ks u nt il res ol uti on.
Si t u atio ns i n w hic h E C H O or M U G A res ults s h o ul d be re p orte d as A Es are descri be d i n 
Secti o n  8. 4. 5 .
8. 3. 5. 2
P ul m o n ar y Assess me nts
 s h o uld be e val uate d b y  t he i n vestigat or or t he del e gate p h ysicia n at t he 
ti me p oi nts o utli ne d i n t he S o A (see Secti o n 1. 3 ) a n d as cli nicall y i n dicate d.  If 
is 
meas ure d o n t he da y  of inf usi o n , it s h o uld be meas ure d 
 (see t he 
S o A a n d Secti o n  8. 3. 2 ). 
 a n d 
 ma y be 
perf or m e d 
 a n d s h o ul d i ncl u de basic 
s pir o metr y at a mi ni m u m with o pti o nal  a d ditio n al c o mp o ne nts as m e nt i one d i n  Ta ble 7.
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
7 6 of 1 6 5
T a ble 7
S pir o metr y C o m p o ne nt
Re q uire d s pir o metr y c o m p o ne nts
O pti o n al s pir o metr y c o m p o ne nts
F V C ( L)
P E F
F V C % pre dicte d
F E V 1 ( L)
F E V 6
F E V 1 % pre dicte d
T L C
F E V 1/ F V C %
R V
; F E V, f orce d e x pirat or y v ol u me; F E V1, F E V i n 
o ne sec o n d; F E V6, F E V i n 6 sec o n ds; F V C, f orce d vital ca pacit y; P E F, pea k e x pirat or y fl o w; R V, resi d ual 
v ol u me; T L C, t otal l u n g ca pacit y
 will be perf or me d/e nc o ura ge d if feasi ble, 
b ut f or partici pa nts wit h pri or se vere a n d/ or pri or cli nicall y si g nifica nt p ul m o nar y  dis or ders, it 
is a re q uire me nt. I n e ve nt of s us pecte d I L D/ p ne u m o nitis, refer t o Secti o n 8. 3. 5. 3 a d dit i onal 
p ul m o nar y  assess me nts.
Hi g h -res ol uti on C T of t he c hest will be perf or me d/e nc o ura ge d if feasi ble ( ot her wise n o n -
c o ntrast c hest C T is acce pta ble; 1 t o 2 m m slice t hic k ness rec o m me n de d) a n d if 
I L D/ p ne u m onit is is s us pecte d. C hest C T a n d/ or c hest H R C T sca ns will be re vie we d se paratel y 
f or safety f or t he prese nce of I L D/ p ne u m onit is pri or t o a d mi nistrati o n of t he ne xt sc he d ule d 
d ose of Dat o -D X d. 
8. 3. 5. 3
I L D/ P ne u m o nitis I n vesti g ati o n
F or s us pecte d I L D/ p ne u m o nit is (ie, if ne w or w orse ni n g p ul m o n ar y  s y m pt o ms [e g, d ys p n oea, 
c o u g h, or fe ver] or ra di o l ogi cal a b n or malit y s u g gesti ve of I L D/ p ne u m onit is is o bser ve d), 
treat me nt wit h Dat o-D X d s h o ul d be dela ye d, a n d a f ull i n vest i gati on is re q uire d as descri be d 
i n t he Dat o-D X d T M Gs (see t he T M G A n ne x). 
E val uat i ons s h o ul d i ncl u de t he f o ll owi n g:

 
 
 
 
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
7 7 of 1 6 5

T he res ults of t he f ull dia g n ostic w or k u p (i ncl u di n g 
 
, etc) will be ca pt ure d i n t he e C R F. It is str o n gl y rec om me n de d t o 
perf or m  a full  dia g n ostic w or k u p t o e xcl u de alter nati ve ca uses, s uc h as
 
. I n t he 
prese nce of
 
 
T he f o ll owi n g assess me nts s h o ul d be p erfor m e d, if feasi ble, t o e n ha nce t he i n vesti gati o n a n d 
di a g n osis of p ote ntial cases of I L D/ p ne u m o nit is. T he res ults of t he assess me nt will be 
c ollecte d.

Ot her ite ms:
-
W he n I L D/ p ne u m o nit is is s us pecte d d uri n g treat me nt wit h st u d y int er ve ntio n, t he 
 s h o ul d be meas ure d w here p ossi ble:
o
I L D/ p ne u m onit is 
o

A d dit i onal cli nical c he mistr y: 
8. 3. 5. 4
E aster n C o o per ati ve O n c ol o g y Gr o u p Perf or m a nce St at us
T he E C O G perf or ma nce stat us will be assesse d at t he ti mes s pecifie d i n t he S o A base d o n t he 
f oll owi n g:
0
F ull y  acti ve; a ble t o carr y o ut all us ual acti vities with o ut restrict i ons.
1
Restricte d i n stre n u o us acti vit y,  but a m b ulat o r y a n d a ble t o carr y o ut li g ht w or k or w or k 
of  a se de ntar y nat ure (e g, li g ht h o use w or k or office w or k).
2
A m b ulat or y  a n d ca pa ble of self-care, b ut u na ble t o carr y o ut a n y w or k acti vities; u p a n d 
a b o ut more t ha n 5 0 % of wa ki n g h o urs.
3
Ca pa ble of o nl y li mite d se lf- care; c o nfi ne d t o be d or c hair m ore t ha n 5 0 % of wa ki n g 
h o urs.
4
C o m pletel y disa ble d; u na ble t o carr y  o ut a n y self-care a n d t otall y c o nfi ne d t o be d or 
c hair.
5
Dea d.
A n y si g nifica nt c ha n ge fr o m baseli ne or scree ni n g m ust be re p orte d as a n A E.
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
7 8 of 1 6 5
8. 3. 5. 5
O p ht h al m ol o gic Assess me nts
O p ht hal m o l ogic assess me nts i ncl u di n g b ut n ot li mite d t o vis ual ac uit y testi n g, slit la m p 
e xa mi nat i on, i ntra oc ular press ure meas ure me nt, f u n d osc o p y , a n d fl u orescei n stai ni n g will be 
perf or m e d as s pecifie d i n t he S o A (see Secti o n  1. 3 ) a n d as cli nicall y i n dicate d b y a n 
o p ht hal m o l ogist, or if u na vaila ble, a n ot her lice nse d e y e care pr o vider. A s ui ta ble alter nati ve t o 
fl u orescei n stai ni n g of t he c or nea ma y be use d i n e xce pti onal circ u msta nces w here fl u orescei n 
is n ot a vaila ble. A n o p ht hal m o l ogic assess me nt s h o ul d be c o nsi dere d f or a n y  o c ular s y m pt o ms 
i ncl u di n g, b ut n ot li mite d t o, dr y e ye, decrease d or bl urre d visi on, f orei g n -b o d y  se nsati on, 
p h o t o p h o bia, teari n g, pai n, a n d e ye re d ness. All O As ( baseli ne, as cli nicall y  in dicate d, E O T) 
s h o uld be d oc u m e nte d o n w or ks heets i n t he e C R F, a n d c o pies of all c o ns ultati o n re p orts 
s h o uld be file d i n t he s o urce n otes. Please refer t o t he Dat o -D X d Site O p ht hal m ol o gic 
Assess me nt Ma n ual f or f urt her details.
P arti cipa nts w h o are recei vi n g Dat o -D X d s h o ul d be a d vise d t o use artificial tears 
( preser vati ve-free if p ossi ble) 4 ti mes dail y as a pre ve ntati ve meas ure a n d u p t o 8 ti mes dail y 
as cli nicall y nee de d a n d t o a v o i d t he use of c o ntact le nses. T he use of ot her e ye me dicatio ns 
(e g, t o pical c ortic oster oids) f or pr o p h yla xis s h o ul d be at t he discreti o n o f a n o p ht hal m o l ogist, 
or if u na vaila ble, a n ot her lice nse d e ye care pr o vi der.
F urt her rec o m me n dat i ons f or pre ve nti n g a nd treati n g oc ul ar s urface t o xicit y are a vaila ble i n 
t he S o A a n d t he T M Gs (see t he A n ne x d oc u me nt t o t his C S P). A n y si g nifica nt c ha n ge fr o m 
baseli ne m ust be re p orte d as a n A E (see Secti o n 8. 4. 5 ).
8. 3. 5. 6
 will be starte d 
 
 as s pecifie d i n t he S o A. 
 will be pr o vi de d 
 
, 
w hic h will i ncl u de 
. A n 
 will als o be pr o vi de d t o eac h e nr olle d partici pa nt bef ore 
st u d y dr u g i nitiatio n.
P arti cipa nts s h o ul d a d here t o t he f oll o wi n g g ui da nce:

 
 
 
 
is hi g hl y rec o m me n de d.
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
7 9 of 1 6 5
-
N ote: Partici pa nts are all o we d t o 
 
 
 base d o n i nstit uti o nal/l ocal g ui deli nes.

I n t he a bse nce of
 
 is rec om me n de d.

 
 s h o ul d als o be c o nsi dere d.
T he f o ll owi n g al g ori t h m, t o be f ollo w e d f r o m ste ps 1 t o 4, ma y be use d as a g uida nce t o sel ect 
:
1
. If n ot a vaila ble, t he n use→
2
. If n ot a vaila ble, t he n use→
3
. If n ot a vaila ble, t he n use→
4
.
 s h o ul d als o i ncl u de e d ucati n g partici pa nts o n t he i m p orta nce of
 
 
 
As per i n vest i gat or j u d g me nt, a pr ofessi onal
 
F or f urt her i nf or mati o n, refer t o t he Dat o -D X d T M Gs (see t he A n ne x d oc u me nt t o t his C S P).
8. 4
A d verse E ve nts a n d Seri o us A d verse E ve nts
T he pri nci pal i n vest i gat or is res p o nsi ble f or e ns uri n g t hat all staff i n v ol ve d i n t he st u d y are 
fa miliar with t he c o nte nt of t his sect i on.
T he defi nit i ons of a n A E or S A E ca n be f o u n d i n  A p pe n di x B.
A d verse e ve nts will be re p orte d b y  t he partici pa nt ( or, w he n a p pr o priate, b y a care gi ver, 
s urr o gate, or t he partici pa nt’s le gall y a ut h orise d re prese ntati ve). 
T he i n vest i gat or a n d a n y desi g nees are res p o nsi ble f or detecti n g, d oc u me nti n g, rec or di n g, a n d 
re p orti n g e ve nts t hat meet t he defi niti on of a n A E.
8. 4. 1
Ti m e Peri o d a n d Fre q ue nc y f or C ollecti n g A E a n d S A E I nf or m ati o n
A d verse e ve nts a n d S A Es will be c ollecte d fr o m t he ti me of si g nat ure of t he I C F, t hr o u g h o ut 
t he I nter ve nt i on Peri o d a n d ( ot her t ha n I L D/ p ne u m o nit is) i ncl u di n g t he safety f oll ow- u p 
p eri o d ( w hi c h is 2 8 da ys [ + 7 da ys] after t he disc o nti n uati on of all st u d y i nter ve nt i ons). All 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
8 0 of 1 6 5
I L D/ p ne u m onit is e ve nts re gar dless of se verity s h o uld be re p orte d be y o n d t he 
 
safety f oll ow- u p peri o d . All A E SIs, re gar dless of se verit y or s eri o us ness, m ust be f o ll owe d 
u nt il either e ve nt res ol uti o n, e n d of st u d y , i ncl u di n g a n y p ost -treat me nt fol l ow- u p, tri al 
ter mi nati o n, wit h dra wal of c o nse nt, or partici pa nt deat h. If a n e ve nt t hat starts or w orse ns p ost 
t he defi ne d safet y f oll ow- u p peri o d n ote d a b o ve i s c o nsi dere d t o be d ue t o a late o nset t o xicit y 
t o st u d y int er ve nt i on, t he n it s h o uld be re p orte d as a n S A E as a p plica ble. C ollecti o n a n d 
re p orti n g of A Es a n d S A Es after t he fi nal D C O is descri be d i n Secti o n 8. 4. 1 2 . 
Pre -e xist i n g me d ical c o n diti ons t hat ma y ha ve bee n i de ntifie d b y ma n dat or y  scree ni n g 
pr oce d ures (e g, cataract 
, be ni g n c yst o n baseli ne 
i ma gi n g, etc.) s h o ul d be rec or de d as me dical hist or y i n t he e C R F.
If t he i n vesti gator bec o mes a ware of a n S A E wit h a s us pecte d ca usal relat i ons hi p t o t he st u d y  
i nter ve nt i on t hat occ urs after t he e n d of t he cli nical st u d y  in a parti ci pa nt treate d b y hi m or 
her, t he i n vest i gat or s hall, wit h o ut u n d ue dela y, re p ort t he S A E t o t he s p o ns or.
T h e fol l owi n g t yp es of  e ve nts s h o uld be re p orte d b y  t he i n vestig at or i n t he E D C wi t hi n 2 4 
h o urs of a ware ness:

S eri o us a d verse e ve nts (see Secti o n 8. 4. 1 3 )

All p ote ntial 
 cases s h o ul d be re p orte d wit hi n 2 4 h o urs, i ncl u di n g b ot h 
serio us a n d n o n -serio us p ote ntial  
 cases 
 
.

He pati c e ve nts ( b ot h seri o us a n d n o n-serio us) w hic h meet t he P H L criteria defi ne d as a n 
ele vate d A L T or A S T ≥ 3 × U L N a n d a n ele vate d T B L ≥ 2 × U L N re gar dless if it is d ue 
t o disease pr o gressi o n per i n vesti gat or assess me nt, t hat ma y occ ur at differe nt ti me p oi nts 
d uri n g t he st u d y c o n duct , s h o ul d al wa ys be re p orte d t o t he s p o ns or. T hese e ve nts m ust be 
re p orte d i n t he e C R F, wit h t he i n vesti gat or’s assess me nt of seri o us ness, se verity,  
ca usalit y,  a n d a detaile d narrati ve. A  
 is b uilt wit hi n t he e C R F t o c ollect rele va nt 
a d ditio nal  inf or m atio n f or t hese p ote nti al cases. If t he partici pa nt disc o nt i n ues st u d y 
i nter ve nt i on d ue t o li ver e nz y me a b n or malit ies, t he partici pa nt will ha ve a d diti onal 
cli nical a n d la b orat or y e valu ati o ns as descri be d i n  A p pe n di x D i n or der t o deter mi ne t he 
nat ure a n d se verit y of  t he p ote ntial li ver i nj ur y.

(see Secti o n 8. 4. 1 1 ).

(see Secti o n 8. 4. 1 1) . 


O ver d ose (see Secti o n 8. 5 ). 
A d dit i onal rele va nt i nf or mat i on re gar d i n g t he A E SIs, re gar dless of seri o us ness, will be 
c ollecte d t hr o u g h 
 wit hi n t he cli nical st u d y data base (see Secti o n 8. 4. 1 1 ).
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

Clinical Study Protocol - D9266C00001
AstraZeneca
Datopotamab deruxtecan (Dato-DXd, DS-1062a)
CONFIDENTIAL AND PROPRIETARY
81 of 165
8.4.2
Follow-up of AEs and SAEs
Any AEs that are unresolved at the participant’s last AE assessment in the study are followed 
up by the investigator for as long as medically indicated but without further recording in the 
eCRF. AstraZeneca retains the right to request additional information for any participant with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
Adverse Event Variables
The following variables will be collected for each AE:

Adverse event (verbatim)

Date (and time, if applicable) when the AE started and stopped

Initial CTCAE 5.0 grade, plus any changes in CTCAE 5.0 grade

Whether the AE is serious or not (Appendix B)

Investigator causality rating against the study intervention(s) (yes or no)

Action taken with regard to study intervention(s)

Adverse event caused participant’s withdrawal from study (yes or no)

Administration of treatment for the AE

Outcome
In addition, the following variables will be collected for SAEs:

Date AE met criteria for SAE

Date investigator became aware of SAE

Seriousness criteria

Date of hospitalisation

Date of discharge

Probable cause of death

Date of death

Autopsy performed

Causality assessment in relation to study procedure(s)

Causality assessment to other medication
The grading scales found in the CTCAE 5.0 will be utilised for all events with an assigned 
CTCAE 5.0 grading. For those events without assigned CTCAE 5.0 grades, the 
recommendation in the CTCAE 5.0 criteria that converts mild, moderate, and severe events 
into CTCAE 5.0 grades should be used. A copy of the CTCAE 5.0 can be downloaded from 
the Cancer Therapy Evaluation Program website (http://ctep.cancer.gov).

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8.4.3
Causality Collection
The investigator should assess causal relationship between study intervention and each AE, 
and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable possibility 
that the event may have been caused by the study intervention?’
For SAEs, causal relationship should also be assessed for other medication and study 
procedures. Note that for SAEs that could be associated with any study procedure the causal 
relationship is implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B.
8.4.4
Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the participant or reported in response to the open question 
from the study site staff: ‘Have you had any health problems since the previous visit/you were 
last asked?’ or revealed by observation will be collected and recorded in the eCRF. When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms. However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately.
8.4.5
Adverse Events Based on Examinations and Tests
The results from the CSP-mandated laboratory tests, vital signs, physical examinations, ECGs, 
and ECHO/MUGA scans, ECOG performance status, and ophthalmologic assessments will be 
summarised in the CSR. 
Deterioration as compared with baseline in CSP-mandated laboratory values, vital signs, 
ECGs, and ECHO/MUGA scans should therefore only be reported as AEs if they fulfil any of 
the SAE criteria, are the reason for discontinuation of treatment with the study intervention or 
are considered to be clinically relevant as judged by the investigator (which may include, but 
are not limited to, consideration as to whether treatment or non-planned visits were required or 
other action was taken with the study intervention, eg, dose adjustment or study intervention 
delay).
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE, and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting investigator 
uses the clinical, rather than the laboratory term (eg, anaemia versus low haemoglobin value). 
In the absence of clinical signs or symptoms, clinically relevant deteriorations in 
non-mandated parameters should be reported as AE(s).

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Deterioration of a laboratory value that is unequivocally due to PD should not be reported as 
an AE/SAE.
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally 
related to the disease under study.
8.4.6
Hy’s Law
Cases where a participant shows elevations in liver biochemistry may require further 
evaluation and occurrences of AST or ALT ≥ 3 × ULN together with TBL ≥2 × ULN may 
need to be reported as SAEs. Please refer to Appendix D for further instruction on cases of 
increases in liver biochemistry and evaluation of HL.
8.4.7
Disease Progression
Disease progression can be considered as a worsening of a participant’s condition attributable 
to the disease for which the study intervention is being studied. It may be an increase in the 
severity of the disease under study and/or increases in the symptoms of the disease. The 
development of new, or progression of existing, metastasis to the primary cancer under study 
should be considered as PD and not an AE. Events that are unequivocally due to PD should 
not be reported as AEs during the study, with the exception of hepatic events that meet PHL 
criteria as defined in Section 8.4.1.
8.4.8
Disease Under Study
Symptoms of disease under study are those that might be expected to occur as a direct result 
of NSCLC (Cohort 1), TNBC (Cohort 2), or other advanced or metastatic solid tumours in 
future cohorts, or procedures used to diagnose or treat the disease under study. Events that are 
unequivocally due to disease under study should not be reported as an AE during the study 
unless they meet SAE criteria.
8.4.9
New Cancers
The development of a new cancer should be regarded as an AE and will generally meet at 
least one of the serious criteria. New primary cancers are those that are not the primary reason 
for the administration of study intervention and are identified after the participant’s inclusion 
in this study. They do not include metastases of the original cancer.
8.4.10
Deaths
All deaths that occur during the study Intervention Period, or within the CSP-defined 
Post-intervention Follow-up Period after the administration of the last dose of study 
intervention, must be reported as follows:

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
Death clearly resulting from PD should be documented in the eCRF in the Statement of
Death page. It should not be reported as an SAE.

Where death is not due (or not clearly due) to PD under study, the AE causing the death 
must be reported as an SAE within 24 hours. It should also be documented in the 
Statement of Death page in the eCRF. The report should contain a comment regarding the 
co-involvement of PD, if appropriate, and should assign the main and contributory causes 
of death.

Deaths with an unknown cause should always be reported as an SAE and documented in 
the Statement of Death page in the eCRF, but every effort should be made to determine a 
cause of death. A post-mortem may be helpful in the assessment of the cause of death, 
and if performed, a copy of the post-mortem results should be forwarded to AstraZeneca 
Patient Safety or its representative within the usual time frames.
Deaths occurring after the CSP-defined safety follow-up period after the administration of the 
last dose of study intervention should be documented in the Statement of Death page. If the 
death occurred as a result of an event that started after the defined safety follow-up period and 
the event is considered to be due to a late-onset toxicity to study intervention, then it should 
also be reported as an SAE.
8.4.11
Adverse Events of Special Interest
Adverse events of special interest are events of scientific and medical interest specific to the 
further understanding of Dato-DXd safety profile and require close monitoring and rapid 
communication by the investigators to AstraZeneca. An AESI can be serious or non-serious. 
All AESIs will be recorded in the eCRF using a recognised medical term or diagnosis that 
accurately reflects the event. Serious AESIs will be recorded and reported as per Section 
8.4.13. AESIs are detailed in the IB, Section 5.5.1.3.
All AESIs, regardless of severity or seriousness, must be followed until either event 
resolution, end of study, including any post-treatment follow-up, trial termination, withdrawal 
of consent, or participant death.
Concomitant medications administered as treatment for drug-related AESIs should be 
recorded until either event resolution, end of study, trial termination, withdrawal of consent, or 
participant death.
For the Dato-DXd clinical programme, based on the available pre-clinical data, current 
clinical developmental program, review of the cumulative literature, reported toxicities for 
drugs with similar monoclonal antibody and payload of Dato-DXd and biological plausibility, 
the relevant PTs for ILD/pneumonitis, IRR, oral mucositis/stomatitis, mucosal inflammation 
other than oral mucositis/stomatitis, and ocular surface toxicity are considered to be AESIs. 
Refer to the current IB for a summary of preliminary clinical study data.

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
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C O N FI D E N TI A L A N D P R O P RI E T A R Y
8 5 of 1 6 5
I L D/ P ne u m o nitis
I L D is c o nsi dere d 
 base d o n a c o m pre he nsi ve c u m ulati ve re vie w of 
t he a vaila ble safet y data fr o m  t he cli nical de velo p me nt pr o gra m , as well as t he res ults of 
p ote nti al I L D/ p ne u mo ni tis cases re vie we d b y t he i n de pe n de nt I L D A dj u dicat i on C o m mittee, 
a vaila ble data fr o m rece nt e pide mi ol o g y/li terat ure, biol o gi c al pla usi bilit y, a n d safety 
i nf or mat i on fr om dr u gs wi t h a si milar mo n o cl o nal a nt i b o d y a n d/ or pa yl oa d as Dat o-D X d. 
All p ote ntial I L D/ p ne u m o nit is cases s h oul d be re p orte d wit hi n 2 4 h o urs, i ncl u di n g b ot h 
serio us a n d n o n -serio us p ote ntial  I L D/ p ne u mo ni tis cases ( p ote ntial I L D/ p ne u m onit is is 
descri be d i n t he E ve nt A dj u dicat i on Si te Ma n ual). A T Q is b uilt withi n t he e C R F t o c ollect 
r ele va nt a d ditio n al  inf or mat i on f or t hese p ote ntial cases re gar dless of seri o us ness.
All I L D/ p ne u m o nit is e ve nts re gar dless of se verity s h o uld be re p orte d be y o n d t he 2 8 + 7 -
d a y safety f oll ow- u p peri o d.
Rec o m me n dat i ons f or pre ve nti n g a n d treati n g I L D/ p ne u m onit is are a vaila ble i n t he T M G 
A n ne x.
I nterstiti al lu n g disease/ p ne u m o nit is s h o ul d be r ule d o ut if a partici pa nt de vel o ps ra di o gra p hic 
c ha n ges p ote ntiall y c o nsiste nt wit h I L D/ p ne u m o niti s or de velo ps a n ac ute o nset of ne w or 
w orse ni n g p ul m o nar y  or ot her relate d sig ns/s y m pt o m s s uc h as d ys pn oea, c o u g h, or fe ver. If 
t he A E is c o nfir me d t o ha ve a n aeti ol og y  ot her t ha n I L D/ p ne u m onit is, f oll ow t he ma na ge me nt 
g ui da nce o utli ne d i n t he T M G A n ne x.
If t he A E is s us pecte d t o be I L D/ p ne u m o nitis, treat me nt wit h st u d y int er ve nt i on s h o ul d be 
d el a ye d pe n din g f urt her e val uat i ons. E val uat i ons s h o ul d i ncl u de t h ose o utli ne d i n 
Secti o n 8. 3. 5. 3 . If t he A E is c o nfir me d t o be I L D/ p ne u m onit is, f oll ow t he m a na ge me nt 
g ui da nce o utli ne d i n t he T M G A n ne x. All e ve nts of I L D/ p ne u m o nit is, re gar dless of se verity 
or seri o us ness, will be f o ll owe d u nt il res ol uti on i nclu di n g after Dat o D X d - disc o nti n uati o n. A n 
a ut o ps y in cases of Gra de 5 I L D/ p ne u m o nit is is e nc o ura ge d. A n i n depe n de nt I L D 
A d j u dicati on C o m mittee is res p o nsi ble f or re vie wi n g all cases o f p ote nti al I L D/ p ne u mo ni tis 
(see Secti o n 9. 6. 1 ).
I nf usi o n-rel ate d Re acti o n 
I nf usi on- r elate d reactio n is 
 ass ociate d wit h Dat o-D X d treat me nt. A d dit i onal 
data f or t hese ≥ Gra de 3 A Es will be c ollecte d via T Qs of I R R.
Rec o m me n dat i ons f or pre ve nti n g a n d treati n g I R R are a vaila ble i n t he T M G A n ne x.
Or al M uc ositis/ St o m atitis 
Or al  mu c osi tis/st o mat itis A Es are c o nsi dere d as 
 a n d A E SIs ass ociate d wit h 
Dat o D X d treat me nt. M uc osal i nfla m mat i on ot her t ha n oral m uc osit is/st o mat itis is als o a n 
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
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C O N FI D E N TI A L A N D P R O P RI E T A R Y
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i de ntifie d ris k b ut is c o nsi dere d as a se parate A E SI. A d diti onal data f or t hese A Es re gar dless 
of  C T C A E gra di n g will be c ollecte d via T Qs of oral m uc ositis/st o matitis. 
M u c os al I nfl a m m ati o n Ot her t h a n Or al M uc ositis/ St o m atitis
M uc osal  infla m mat i on A Es are c o nsi dere d as 
 ass ociate d wit h Dat o-D X d 
treat me nt a n d as a se parate A E SI fr o m oral m uc ositis/st o matit is. A d diti onal data f or t hese A Es 
re gar dless of C T C A E gra di n g will be c o llecte d via T Qs of m uc osal i nfla m mati on.
Oc ul ar S urf ace T o xicit y
Oc ul ar s urface t o xicit y (e g, dr y e ye, keratitis) is c o nsi dere d a n A E SI ass ociate d wit h 
Dat o -D X d treat me nt. Dr y e ye is c o nsi dere d as 
 a n d keratitis as  
 
 wit hi n t his A E SI. A d ditio n al  data f or t hese A Es re gar dless of C T C A E gra di n g are 
c ollecte d via e C R F T Qs f or oc ular s urface t o xicit y. Rec o m me n dat i ons f or pre ve nti n g a n d 
treati n g oc ular s urface t o xicity are a vaila ble i n t he S o A (see Secti o n  1. 3 ) a n d T M Gs (see t he 
T M G A n ne x), res pecti vel y. 
Pl ease refer t o t he Dat o- D X d Site O p ht hal m o l ogic Assess me nt Ma n ual f or f urt her details.
8. 4. 1 2
S afet y D at a t o be C ollecte d F oll o wi n g t he Fi n al D at a C ut -off of t he 
St u d y
F or parti ci pa nts c o nti n ui n g t o recei ve Dat o- D X d after t he fi nal D C O a n d data base cl os ure, 
A Es a n d S A Es will be c o llecte d, b ut o nl y S A Es will be re p orte d. I n a d diti o n, it is 
rec o m me n de d t hat partici pa nts c o nti n ue t he sc he d ule d site visits a n d i n vesti gat ors m o nit or t he 
parti ci pa nt’s safet y lab orat or y  res ults p erio di call y d uri n g treat me nt wit h Dat o- D X d i n or der t o 
ma na ge A E s, c o nsiste nt wit h t he d ose m o dificati on g ui deli nes f or m a na ge me nt of st u d y 
i nter ve nt i on- r elate d t o xicities (see t he T M G A n ne x). All data after t he fi nal D C O a n d 
data base cl os ure will be rec or de d i n t he partici pa nt n otes b ut, wit h t he e xce pt i on of S A Es, wi ll 
n ot ot her wise be re p orte d f or t he p ur p oses of t his st u d y .
All S A Es t hat occ ur i n partici pa nts still recei vi n g Dat o -D X d ( or wit hi n t he 2 8 + 7 da ys 
f oll owi n g t he last d ose of Dat o -D X d) after t he fi nal D C O m ust be re p orte d as detaile d i n 
Secti o n  8. 4. 1 3 . 
8. 4. 1 3
Re p orti n g of Seri o us A d verse E ve nts
All S A Es ha ve t o be re p orte d, w het her or n ot c o nsi dere d ca usall y relate d t o t he st u d y 
i nter ve nt i on , or t o t he st u d y pr oce d ure(s). All S A Es will be rec or de d i n t he e C R F.
If a n y S A E occ urs i n t he c o urse of t he st u d y, t he n i n vestigat ors or ot her si te pers o n nel i nf or m 
t he a p pr o priate Astra Ze neca re prese ntati ves wit hi n o ne da y , ie, i m me diatel y b ut n o l ater t h a n 
2 4 h o urs of  w he n he or s he bec o mes a ware of it.
C CI
C CI
C CI

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The designated AstraZeneca representative works with the investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
one calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately. Investigators or other site personnel inform AstraZeneca 
representatives of any follow-up information on a previously reported SAE within one 
calendar day, ie, immediately but no later than 24 hours of when he or she becomes aware of 
it.
Once the investigators or other site personnel indicate an AE is serious in the EDC system, an 
automated email alert is sent to the designated AstraZeneca representative.
If the EDC system is not available, then the investigator or other study site staff reports a SAE 
to the appropriate AstraZeneca representative by telephone followed by completion of a paper 
SAE form.
The AstraZeneca representative will advise the investigator/study site staff how to proceed. 
For further guidance on the definition of a SAE, see Appendix B of the CSP.
The reference document for definition of expectedness/listedness is the IB for Dato-DXd.
8.4.14
Pregnancy
All pregnancies and outcomes of pregnancy with conception dates following the first date of 
study intervention, including pregnancy in the partner of male participants, should be reported 
to AstraZeneca.
8.4.14.1
Maternal Exposure
If a participant becomes pregnant during the course of the study, study intervention should be 
discontinued immediately. The sponsor must be notified of any female participant or partner 
of a male participant who becomes pregnant while receiving or within 7 months of 
discontinuing Dato-DXd.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study intervention
under study may have interfered with the effectiveness of a contraceptive medication. 
Congenital anomalies/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth, or congenital anomaly) should be followed up and documented even if the 
participant was discontinued from the study.

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If any pregnancy occurs in the course of the study, then the investigator or other site personnel 
informs the appropriate AstraZeneca representatives within one day, ie, immediately but no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within one 
or 5 calendar days for SAEs (see Section 8.4.13) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP cohort in the eCRF is used to report the pregnancy and the PREGOUT is used 
to report the outcome of the pregnancy.
8.4.14.2
Paternal Exposure 
Non-sterilised male participants who intend to be sexually active with a FOCBP should refrain 
from fathering a child or donating or banking sperm for the duration of the study (from the 
time of screening) and for 4 months after the last dose of Dato-DXd. 
Pregnancy of the participant’s partner is not considered to be an AE. However, the outcome of 
all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth, or congenital anomaly) occurring from the date of the first dose of study intervention 
until 4 months after the last dose of study intervention should be followed up and documented 
in the medical record and provided to the AstraZeneca Patient Safety data entry site. Consent 
from the partner must be obtained before the information is collected and reported to 
AstraZeneca.
Where a report of pregnancy is received, prior to obtaining information about the pregnancy, 
the investigator must obtain the consent of the participant’s partner. The study team should 
adopt the Master Pregnant Partner Form in line with local procedures/requirements and submit 
it to the relevant Regulatory Authority/IRBs/IECs prior to use.
8.4.15
Special Situations of Medication Error, Drug Abuse, or Drug Misuse
8.4.15.1
Timelines
In the event of a medication error, drug abuse, or drug misuse in the course of the study, then 
the investigator or other site personnel informs the appropriate AstraZeneca representatives 
within one day, ie, immediately but no later than 24 hours of when he or she becomes aware 
of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is completed within one (Initial Fatal/Life-threatening or follow-up 
Fatal/Life-threatening) or 5 (other serious initial and follow-up) calendar days if there is an 

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SAE associated with the event of medication error, drug abuse, or drug misuse and within 30 
days for all other events.
8.4.15.2
Medication Error
For the purposes of this clinical study, a medication error is an unintended failure or mistake 
in the treatment process for an AstraZeneca study intervention that either causes harm to the 
participant or has the potential to cause harm to the participant.
The full definition and examples of medication error can be found in Appendix B 4.
8.4.15.3
Drug Abuse
Drug abuse is the persistent or sporadic intentional, non-therapeutic excessive use of study 
intervention for a perceived reward or desired non-therapeutic effect.
The full definition and examples of drug abuse can be found in Appendix B 4.
8.4.15.4
Drug Misuse
Drug misuse is the intentional and inappropriate use of study intervention for medicinal 
purposes outside of the authorised product information, or for unauthorised study 
interventions, outside of the intended use as specified in the CSP and includes deliberate 
administration of a product by the wrong route.
The full definitions and examples of drug misuse can be found in Appendix B 4.
8.5
Overdose
Refer to Section 6.8 for definition and treatment of overdose.

An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE module in the eCRF and on the Overdose eCRF module.

An overdose without associated symptoms is only reported on the Overdose eCRF 
module.
If an overdose on an AstraZeneca study intervention occurs in the course of the study, the 
investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within one 
or 5 calendar days for overdoses associated with an SAE (see Section 8.4.13) and within 30 
days for all other overdoses.

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Dat o p ota ma b der u xteca n ( Dat o - DX d, D S -1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
9 0 of 1 6 5
8. 6
H u m a n  Bi ol o gic al S a m ples
I nstr uctio ns f or t he c ollect i on, ha n dli n g, st ora ge, a n d s hi p pi n g of bi o l ogi cal sa m ples will be 
pr o vi de d i n t he st u d y -s pecific la b orat or y ma n ual. Sa mples s h o ul d be st ore d i n a sec ure st ora ge 
s pace wit h a de q uate meas ures t o pr otect c o nfi de nt iality.  
S a m ples will  be st ore d f or a ma xi m u m of o ne year fr o m t he p u blicati on of t he fi nal C S R i n 
li ne wit h c o nse nt a n d l ocal re q uire me nts, after w hic h t he y will be destr o ye d/re patriate d.

P K sa m ples will be dis p ose d wit hi n si x m o nt hs of Bi oa nal yt ical Re p ort fi nalisat i on.

A D A sa m ples will be dis p ose d wit hi n o ne year of fi nal C S R p u blicat i on. A D A sa m ples 
will o nl y be use d f or A D A assa y f or t his st u d y .

S a m ples c o llecte d i n C hi na will be st ore d a n d dis p ose d of acc or di n g t o l ocal la ws a n d 
re g ulat i ons.
F or f urt her details o n Ha n dli n g of H u ma n Bi o l ogi c al S a m ples, see  A p pe n di x C . 
8. 6. 1
P h ar m ac o ki netics

Bl o o d sa m ples will be c ollecte d f or meas ure me nt of plas ma c o nce ntrati o ns of Dat o-D X d, 
t otal a nti-T R O P 2 a nt i b o d y, a n d D X d as s pecifie d i n t he S o A a n d Ta ble 8. If 
, a d diti onal bl o o d sa m ples f or P K a nal yses ma y be c ollecte d 
if feasi ble.
T a ble 8
P h ar m ac o ki netic S a m pli n g Sc he d ule
C ycles
D a ys
I nte nsi ve S a m pli n g P K C o h ort ( at 
le ast 6 p artici p a nts i n e ac h c o h ort)a
S p arse S a m pli n g P h ar m ac o ki netic 
C o h ort (f or t he rest of t he 
p artici p a nts)
1 
1
Pr e -d ose :
Wit hi n 8
h o urs bef ore i nf usi o n 
P ost -d ose : 

Wit hi n 3 0 mi n utes after e n d of 
i nf usi o n 

5 h o urs ( ± 1 5 mi n utes) after 
i nf usi o n start

7 h o urs ( ± 1 5 mi n utes) after 
i nf usi o n start
Pr e -d ose :
Wit hi n 8
h o urs bef ore i nf usi o n
P ost -d ose : 

Wit hi n 3 0 mi n utes after e n d of 
i nf usi o n

5 h o urs ( ± 1 5 mi n utes) after 
i nf usi o n start
2 
2 4 h o urs ( ± 2 h o urs) after Da y 1 
i nf usi o n start
N o ne
8
7 da ys ( ± 1 da y) after Da y 1 i nf usi o n 
start
N o ne
1 5 
1 4 da ys ( ± 1 da y) after Da y 1 i nf usi o n 
start
N o ne
2
1 ( ± 2)
Pr e -d ose : 
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Cycles
Days
Intensive Sampling PK Cohort (at 
least 6 participants in each cohort)a
Sparse Sampling Pharmacokinetic 
Cohort (for the rest of the 
participants)
Within 8 hours before infusion
4
1 (±3)
Pre-dose: Within 8 hours before infusion
Post-dose: Within one hour after end of infusion
8
1 (±3)
Pre-dose: Within 8 hours before infusion
Post-dose: Within one hour after end of infusion
a
Participation in the intensive sampling PK cohort will be optional.

Plasma samples will be used to analyse the PK of Dato-DXd, total anti-TROP2 antibody, 
and DXd. Samples collected for analyses of Dato-DXd, total anti-TROP2 antibody, and 
DXd plasma concentration may also be used to evaluate safety or efficacy aspects related 
to concerns arising during or after the study.

Plasma concentrations of the 3 analytes (Dato-DXd, total anti-TROP2 antibody, and 
DXd) will be summarised for all evaluable participants in the PK analysis population 
using descriptive statistics at time points indicated in the SoA and Table 8.

Non-compartment PK parameters that can be derived with sparse PK sampling may be 
reported as data allow. The non-compartment PK parameters to be obtained and reported 
in the intensive PK cohort may include, but are not limited to the Cmax, the trough 
observed concentration, Tmax, AUC, t½, and CL, if the data allow. Details on the analysis 
of PK assessments will be provided in the SAP.

Population PK and E-R analyses will be performed to characterise the relationships 
among dose, exposure, and the efficacy and safety endpoints, if applicable. The results of 
the popPK and E-R analyses will be reported separately from the CSR.
8.6.1.1
Determination of Drug Concentration
Samples for determination of drug concentration in plasma will be assayed by bioanalytical 
test sites operated by or on behalf of AstraZeneca, using an appropriately validated 
bioanalytical method. Full details of the analytical method used will be described in a separate 
Bioanalytical Report.
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation, if performed, will be reported in a 
separate Bioanalytical Report.
8.6.2
Immunogenicity Assessments
Blood samples for determination of ADA in plasma will be collected per the SoA and assayed 
by bioanalytical test sites operated by or on behalf of AstraZeneca, using an appropriately 
validated bioanalytical method. Full details of the methods used will be described in a separate 
report.

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
9 2 of 1 6 5
A nt i-dr u g a nt i b od y  sa m ples ma y als o be f urt her teste d f or c haracterisati on of t he A D A 
res p o nse. Ne utralisi n g A D A ma y be deter mi ne d w he n A D A is p ositi ve. 
T he effect of i m m u n o ge nicit y o n P K, efficac y, a n d safet y will be e val uate d, if t he data all o w.
8. 6. 3
P h ar m ac o d y n a mics
P har ma c o d y na mic para meters are n ot e val uate d i n t his st u d y.
8. 7
H u m a n  Bi ol o gic al S a m ple Bi o m ar kers
8. 7. 1
C ollecti o n of M a n d at or y S a m ples f or Bi o m ar ker A n al ysis
P arti cipa nt c o nse nt t o t he st u d y  incl u des partici pat i o n i n t he ma n dat or y bi omar ker assess me nt 
c o mp o ne nts of t he st u d y. Ma n dat or y c ollecti on of t u m o ur ti ss ue f or bio m ar ker researc h is 
re q uire d as part of t he st u d y, o nce lo c al  re g ulat or y a p pr o val is o btai ne d. 
S a m ples f or bi o m ar ker assess me nt are re q uire d a n d will be c o llecte d fr om all e nr olle d 
parti ci pa nts i n t his stu d y  as s pecifie d i n t he S o A base d o n l ocal re g ulat or y a p pr o val.
T u m o ur s a m ples c ollecte d f or T R O P 2 testi n g fr o m partici pa nts i n C hi na will be destr o y e d or 
re patriate d wit hi n 
 of t he fi nal C S R p u blicati o n. H u ma n Ge netic Res o urces a p pr o val 
will be f o ll ow e d f or C hi na sa m ple c ollect i on a n d usa ge.
T u m o ur s a m ples o btai ne d fr o m  t he pri mar y t u mo ur or fr o m  a metastatic site (e xcl u di n g b o ne) 
bef ore e nr o l me nt are ma n dat or y for all  e nr olle d partici pa nts i n t his st u d y base d o n lo c al  
re g ulat or y a p pr o val. A fres h t u mo ur sa m ple c ollecte d d uri n g scree ni n g is preferre d, if 
cli nicall y feasi ble i n t he f or m of a n F F P E tiss ue. F or t he F F P E tiss ues, a mi ni m u m o f 5 sli des 
of  fres hl y pre pare d, u nstai ne d, 4- t o 5-micr o n sect i o ns are re q uire d. If s uc h a de n o v o 
c ollect i on is not f easi ble, a n arc hi val t u m o ur sa m ple c ollecte d as cl ose t o scree ni n g as p ossi ble 
m ust be pr o vi de d, i n t he f or m of a mi ni m u m o f 5 sli des of fres hl y  pre pare d, u nstai ne d, 4- t o 5-
micr o n sect i ons fr om t he arc hi val F F P E t u m o ur sa m ple. As u nc o ntr olle d o xi dat i on pr ocesses 
affect t u m o ur secti o ns, t u m o ur tiss ue bl o c ks are preferre d. 
T u m o ur lesi o n s use d f or fres h bi o psies s h o ul d n ot be t he sa me lesi ons use d as R E CI S T 1. 1 
T Ls, u nless t here are n o ot her lesi o ns s ui ta ble f or bio ps y a n d i n t his i nsta nce o nl y  c ore nee dle 
( n ot e xcisi onal/i ncisi o nal) bi o ps y is all o we d. C ollecti o n of t u m o ur cells fr o m fl ui d s uc h as 
ascites or ple ural eff usi o n is n ot per mitte d. T he t u m o ur sa m ple m ust n ot be ta ke n fr om a 
pre vi o usl y irra diate d lesi o n.  
S a m ples will  be teste d f or T R O P 2 pr otein meas ure d b y i m m u n o hist oc he mistr y , t o e val uate 
t heir ass ociat i on wi t h t he o bser ve d cli nical res p o nses t o Dat o-D X d (i ncl u di n g b ut n ot li mite d 
t o O R R, P F S, a n d O S, as well as ke y safety e n d p o i nts).
C CI

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
9 3 of 1 6 5
F or f urt her details o n Ha n dli n g of H u ma n Bi o l ogi c al S a mples , i ncl u di n g st ora ge, re-use, a n d 
destr ucti o n, refer t o A p pe n di x  B 4 a n d t he La b orat or y Ma n ual.
8. 7. 2
C ollecti o n of O pti o n al Bi o m ar ker S a m ples
O pti o nal  bio m ar ker sa m ples will n ot be c ollecte d i n C hi na. 
8. 8
O pti o n al Ge n o mics I niti ati ve S a m ple
N ot a p plica ble
8. 9
He alt h Ec o n o mics
N ot a p plica ble
8. 1 0
St u d y P artici p a nt Fee d b ac k Q uesti o n n aire
N ot a p plica ble
9
S T A TI S TI C A L C O N SI D E R A TI O N S
Stati stical a nal yses will be perfor me d b y Astra Ze neca or its re prese ntati ves. 
A c o m pre he nsi ve S A P will be pre pare d pri or t o e nr ol me nt of t he first partici pa nt i n t he st u d y.
9. 1
St atistic al H y p ot heses
T he pri mar y  e n d p oi nt of t he st u d y is c o nfir me d O R R b y I C R, defi ne d as t he pr o p orti o n of 
p artici pa nts i n eac h c o h ort wit h c o nfir me d C R or c o nfir me d P R, as assesse d b y  I C R base d o n 
R E CI S T 1. 1.
I n vie w of t he o pe n-lab el , si n gle-ar m, m ultiple -c o h ort st u d y d esig n, n o f or m al statistical 
h y p ot hesis will be teste d a n d, u nless ot her wise s pecifie d, st u d y data will be prese nte d usi n g 
descri pt i ve statistics. H o we ver, c o nfir me d O R R b y I C R per R E CI S T 1. 1 is c o nsi dere d a n 
earl y si g nal for cli nical be nefi t.
9. 2
S a m ple Size Deter mi n ati o n
S a m ple size j ustific ati o n f or C o h ort 1 – N S C L C
A p pr o xi matel y  4 0 eli gi ble N S C L C partici pa nts will  be e nr olle d t o ha ve preli mi nar y efficac y 
a n d safet y data f or Dat o -D X d. If t he o bser ve d O R R b y I C R is
 t he 9 5 % t w o-si de d 
CI base d o n 4 0 partici pa nts is 
 If t he o bser ve d O R R is 
 t he t w o-
side d 9 5 % CI i s 
 If t he o bser ve d O R R is 
 t he t w o-si de d 9 5 % CI 
is 
T he sa m ple size will als o pr o vi de reas o na ble ut ility f or safety a nal yses. 
Wit h a sa m ple size of 4 0 partici pa nts, t he pr o ba bilit y  of o bser vi n g o ne or m ore i nsta nces of  a 
C CI
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Da t o p ota ma b der u xteca n ( Dat o- D X d, D S-1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
9 4 of 1 6 5
s pecific A E wit h a tr ue i nci de nce rate of 1 %, 2 %, a n d 5 % is 3 3. 1 %, 5 5. 4 %, a n d 8 7. 1 %, 
res pecti vel y.
F or 
 of t he 4 0 eli gi ble N S C L C partici pa nts wi t ho ut m eas ura ble disease at 
baseli ne b y I C R, t he i nf or mat i on bel o w s h o ws t he o bser ve d O R R ( 9 5 % CI) base d o n t he R E S 
wi t h
 partici pa nts wit h o ut m eas ura ble disease at baseli ne as assesse d b y  I C R. 
N u m ber of p artici p a nts i n R E S
N u m ber of 
o bser ve d 
res p o n ders
O bser ve d O R R ( 9 5 % CI)
 of parti ci pa nts wi t ho ut 
meas ura ble disease at baseli ne as 
assesse d b y I C R)
 
S a m ple size j ustific ati o n f or C o h ort 2 – T N B C
A p pr o xi matel y  7 8 eli gi ble T N B C partici pa nts will be e nr olle d t o ha ve preli mi nar y efficac y 
a n d safet y data f or Dat o -D X d. Se ve nt y- ei g ht partici pa nts will
 
 
 T he sa m ple size will als o pr o vi de 
reas o na ble utility f or safety a nal yses. Wit h a sa m ple size o f 7 8 partici pa nts, t he pr o ba bilit y of  
o bser vi n g o ne or m ore i nsta nces of a s pecific A E wit h a tr ue i nci de nce rate of 1 %, 2 %, or 5 % 
is 5 4. 3 %, 7 9. 3 %, 9 8. 2 %, res pecti vel y. 
F or 
 of t he 7 8 eli gi ble T N B C partici pa nts wi t ho ut m eas ura ble disease at baseli ne 
as assesse d b y I C R, t he i nf or mati o n bel o w s h o ws t he o bser ve d O R R 
 
 base d o n t he R E S wit h 
 partici pa nts wi t ho ut m eas ura ble 
di sease at baseli ne b y I C R. 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
9 5 of 1 6 5
N u m ber of p artici p a nts i n R E S
O bser ve d 
O R R
% ( n/ N)
 
 of pa rtici pa nts wi t ho ut 
meas ura ble disease at baseli ne b y I C R)
 of parti ci pa nts wi t ho ut 
meas ura ble disease at baseli ne b y I C R)
9. 3
P o p ul ati o ns f or A n al yses
T he p o p ulat i ons f or a nal ysis o f eac h c o h ort are defi ne d i n  Ta ble 9 . Eac h c o h ort will be treate d 
as a se parate st u d y for a nal ysis.
T a ble 9
P o p ul ati o ns f or A n al ysis
P o p ul ati o n/ A n al ysis Set
Descri pti o n
E nr olle d
All partici pa nts w h o pr o vi de i nf or me d c o nse nt a n d t he partici pa nts are c o nfir me d 
as eli gi ble irres pecti ve of w het her t he y recei ve d t he st u d y treat me nt.
F A S
E nr olle d partici pa nts w h o ha ve recei ve d at least o ne d ose of treat me nt.
Partici pa nts w h o were e nr olle d b ut di d n ot s u bse q ue ntl y recei ve st u d y 
i nter ve nti on are n ot i ncl u de d i n t he a nal ysis.
R E S
E nr olle d partici pa nts w h o recei ve d at least o ne d ose of st u d y i nter ve nti o n a n d ha d 
meas ura ble disease at baseli ne b y I C R.
P K a nal ysis set
E nr olle d partici pa nts w h o ha ve recei ve d at least o ne d ose of treat me nt a n d ha d 
meas ura ble ser u m c o nce ntrati o ns of Dat o -D X d.
A D A e val ua ble set
Partici pa nts i n t he F A S wit h a n o n -missi n g baseli ne Dat o -D X d A D A res ult a n d at 
least one p ost -baseli ne Dat o -D X d A D A res ult.
A D A, a nti -dr u g a nti b o d y; F A S, f ull a nal ysis set; I C F, i nf or me d c o nse nt f or m; I C R, i n de pe n de nt ce ntral re vie w; 
P K, p har mac o ki netic; R E S, res p o nse e val ua ble set.
9. 4
St atistic al A n al yses
T he S A P will be fi nalise d pri or t o e nr ol me nt of t he first partici pa nt i n t he st u d y , a n d it will 
i ncl u de a m ore tec h nical a n d detaile d descri pti on of t he statist ical a nal yses descri be d i n t his 
secti on. T his sect i on is a s u m mar y of t he pla n ne d statistical a nal yses of t he m ost i m p orta nt 
e n d p o i nts, i ncl u di n g pri mar y a n d sec o n dar y e nd p oi nts. T he statist ical a nal ysis will be 
perf or m e d se paratel y f or eac h c o h ort. 
9. 4. 1
Ge ner al C o nsi der ati o ns
T he D C O f or t he pri mar y a nal ysis o f O R R b y I C R will occ ur a p pr o xi matel y 6 m o nt hs after 
t he last partici pa nt has i nit iate d st u d y int er ve ntio n f or t hat c o h ort. D urati o n of res p o nse, D C R, 
C CI
C CI
C CI
C CI
C CI

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BOR, TTR, PFS, OS, and available safety, immunogenicity, and PK data will also be 
summarised at this time. 
The DCO for the full final analysis of ORR by ICR will occur approximately 12 months after 
the last participant has initiated study intervention for that cohort. The full final analysis will 
report the analyses of all primary and secondary endpoints, including updated ORR and DoR, 
DCR, BOR, TTR, PFS, OS, PK, immunogenicity, and safety. 
The below general principles will be followed: 

Descriptive statistics will be used for all variables, as appropriate. Continuous variables 
will be summarised by the number of observations, mean, standard deviation, median, 
upper and lower quartiles minimum, and maximum. For log-transformed data, it is more 
appropriate to present geometric mean, coefficient of variation, median, minimum and 
maximum. Categorical variables will be summarised by frequency counts and percentages 
for each category.

Unless otherwise stated, percentages will be calculated out of the population total.

In general, for efficacy, the last observed measurement prior to the start of study 
intervention will be considered the baseline measurement. For RECIST 1.1 tumour 
assessments, baseline must be no more than 28 days before the date of the first dose of 
study intervention. If a baseline radiological tumour assessment is performed more than 
28 days before the first dose of study intervention, then it will be reported as a protocol 
deviation, but the scan will still be included as baseline. For safety endpoints, the last 
observation before the first dose of study intervention will be considered the baseline 
measurement unless otherwise specified.  Depending on the extent of any impact, 
summaries of data relating civil crisis, natural disaster, or public health crisis may be 
generated if appropriate. More details will be provided in the SAP.
Table 10 provides a summary of endpoints and corresponding analysis populations.
Table 10
Summary of Outcome Variables and Analysis Populations
Outcome Variable
Population(s)
Primary Efficacy Variable
Confirmed ORR by ICR per RECIST 1.1
Primary analysis: RES
Supplementary analyses: 
FAS
Secondary Efficacy Variables
• Confirmed ORR by investigator assessment per RECIST 1.1
• DoR, DCR, BOR, and TTR by ICR and by investigator assessment per RECIST 1.1 
Primary analysis: RES
Supplementary analyses: 
FAS
• PFS by ICR and by investigator assessment per RECIST 1.1
• OS
Primary analysis: FAS

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Outcome Variable
Population(s)
Baseline and Other Variables
• Demography, baseline, and disease characteristics
• Important deviations
• Medical/surgical history
• Previous and subsequent anticancer therapy
• Concomitant medications/procedures
Primary analysis: FAS
Pharmacokinetics
• Pharmacokinetics data
PK analysis set
Immunogenicity
• Anti-drug antibodies
ADA Evaluable Set
Safety
• Exposure to study intervention
• Safety data
FAS
a
DoR analysis will be based on the subset of participants in the RES who achieved confirmed response.
ADA, anti-drug antibody; AEs, adverse events BOR, best overall response; DCR, disease control rate; DoR, 
duration of response; FAS, full analysis set; ICR, independent central review; ORR, objective response rate; 
OS, overall survival; PFS, progression-free survival; PK, pharmacokinetic; RECIST 1.1, Response Evaluation 
Criteria in Solid Tumours Version 1.1; RES, response evaluable set.
9.4.2
Efficacy
9.4.2.1
Primary Endpoint
9.4.2.1.1
Calculation or Derivation of Tumour Response Variables
9.4.2.1.1.1 Investigator RECIST 1.1-based assessments 
All RECIST 1.1 assessments, whether scheduled or unscheduled, will be included in the 
calculations regardless of whether a participant discontinues study intervention or receives 
another anticancer therapy. 
At each visit, participants will be programmatically assigned a RECIST 1.1 visit response of 
CR, PR, SD, PD, or NE depending on the status of their disease compared with baseline and 
previous assessments. Baseline will be assessed within 28 days prior to enrolment. The 
tumour response endpoints (ORR, DoR, DCR, BOR, TTR, and PFS) will then be derived 
from the scan dates and overall visit responses.
9.4.2.1.1.2 Independent Central Review
An ICR of radiological scans will be performed on all participants to confirm the robustness 
of the investigator-assessed ORR, DoR, DCR, BOR, TTR, and PFS endpoints. 
All images will be collected centrally. The imaging scans will be reviewed by 2 independent 
radiologists using RECIST 1.1 and will be adjudicated, if required. For each participant, the 
ICR will define the overall visit response data (CR, PR, SD, PD, or NE) and the relevant scan 

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dates for each time point (ie, for visits where response or progression is/is not identified). If a 
participant has had a tumour assessment that cannot be evaluated, then the participant will be 
assigned a visit response of NE (unless there is evidence of progression, in which case the 
response will be assigned as PD). Endpoints ORR, DoR, DCR, BOR, TTR, and PFS will then 
be derived from the scan dates and overall visit responses. 
Further details of the ICR will be documented in an Independent Review Charter.
9.4.2.1.1.3 Primary Endpoint: Confirmed ORR by ICR
The primary endpoint of the study is confirmed ORR by ICR according to RECIST 1.1. 
Confirmed ORR (per RECIST 1.1 by ICR) is defined as the percentage of participants in each 
cohort with a confirmed response of CR or PR. Data obtained up until progression or the last 
evaluable assessment with the absence of progression will be included in the assessment of 
ORR. Participants who discontinue study intervention without progression, receive a 
subsequent anticancer therapy, and then respond will not be included as responders in the 
calculation of ORR (note that for this analysis palliative radiotherapy is not considered a 
subsequent anti-cancer therapy). 
A confirmed response of CR or PR means that a response of CR or PR is recorded at one visit 
and confirmed by repeat imaging not less than 4 weeks after the response was first observed, 
with no evidence of progression between the initial and CR/PR confirmation visits.
ORR is based on the ICR data and using all scans regardless of whether they were scheduled 
or not.
Analyses of Primary Endpoint
The primary analysis of the primary endpoint will be based on the RES population. The ORR 
will be estimated with 2-sided 95% exact CI using the Clopper-Pearson method. Summaries 
will be produced presenting the number and percentage of participants with a confirmed 
tumour response. 
Supplementary Analysis
Supplementary analysis of the primary endpoint will be performed in the FAS using the same 
methods as described above.
Sensitivity Analysis
Details of any sensitivity analyses to be conducted for the primary endpoint will be described 
in the SAP, as appropriate.
Subgroup Analysis
Details of any subgroup analyses to be conducted for the primary endpoint will be specified in 
the SAP, as appropriate.

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9.4.2.2
Secondary Endpoint(s)
9.4.2.2.1
Confirmed Objective Response Rate by Investigator Assessment
The secondary efficacy endpoint of confirmed ORR is defined as the proportion of 
participants who have a confirmed CR or PR, as determined by the investigator at local site 
per RECIST 1.1.
Analysis Methods
Investigator-assessed ORR will be estimated using the same methods as those specified for 
ORR by ICR for the RES (see Section 9.4.2.1.1.3). Supplementary analysis will be performed 
using the FAS. 
9.4.2.2.2
Duration of Response
Duration of Response by ICR
For participants who achieve a confirmed CR/PR per RECIST 1.1 by ICR, DoR is defined as 
the time from the date of first documented response (which is subsequently confirmed) until 
the date of documented progression (using RECIST 1.1 by ICR) or death in the absence of 
PD. The time of the initial response will be defined as the latest of the dates contributing 
towards the first documented response of CR or PR that is subsequently confirmed. The end 
of response should coincide with the date of progression or death from any cause used for the 
PFS endpoint. If a participant does not progress following a response, then their DoR will be 
the PFS censoring time (ie, DoR = date of PFS event or censoring – date of first response + 1).
Duration of Response by Investigator Assessment
For participants who achieve a confirmed CR/PR per RECIST 1.1 by investigator assessment, 
DoR is defined as the time from the date of first documented response (which is subsequently 
confirmed) until the date of documented progression (using RECIST 1.1 by investigator 
assessment) or death in the absence of PD.
Data will be handled as described above for DoR by ICR.
Analysis Methods
The DoR will be analysed in the subset of participants in the RES who achieved confirmed 
response. Supplementary analysis will be performed using the FAS.
The survival distribution for DoR will be estimated by the Kaplan-Meier method, and the 
results will be presented graphically. The estimate of median DoR and corresponding 95% CI 
using the Brookmeyer-Crowley method with log-log transformation will be reported.

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9.4.2.2.3
Disease Control Rate
Disease Control Rate by ICR
The DCR by ICR at the time of each DCO is defined as the percentage of participants who 
have a confirmed CR/PR or SD for at least 5 weeks (ie, 6 weeks – 1 week to allow for an early 
assessment within the assessment window) after the date of the first dose of study intervention 
(without subsequent anticancer therapy) per RECIST 1.1 by ICR.
Disease Control Rate by Investigator Assessment
The DCR by investigator assessment at the time of each DCO is defined as the percentage of 
participants who have a confirmed CR/PR or SD for at least 5 weeks (ie, 6 weeks – 1 week to 
allow for an early assessment within the assessment window) after the date of the first dose of 
study intervention (without subsequent anticancer therapy) per RECIST 1.1 by investigator 
assessment.
Analysis Methods
The DCR will be summarised descriptively with the number and percentage of participants 
with a confirmed CR/PR or SD for at least 5 weeks in the RES. Supplementary analysis will 
be performed using the FAS. 
9.4.2.2.4
Best Overall Response
Confirmed Best Overall Response by ICR
The BOR is a participant’s best response during their participation in the study, but prior to 
starting any subsequent anticancer therapy, up until RECIST 1.1-defined progression by ICR 
or the last evaluable assessment in the absence of RECIST 1.1-defined progression by ICR.
Categorisation of BOR will be based on RECIST 1.1 by ICR using the following response 
categories: (confirmed) CR, (confirmed) PR, SD, PD, and NE; unconfirmed CR/PR will be 
included in SD.
Confirmed Best Overall Response by Investigator Assessment
The BOR is calculated based on the overall visit responses per RECIST 1.1 using investigator 
assessments. The BOR is a participant’s best response during their participation in the study, 
but prior to starting any subsequent anticancer therapy, up until RECIST 1.1 defined 
progression or the last evaluable assessment in the absence of RECIST 1.1 defined 
progression.
Categorisation of BOR will be based on RECIST 1.1 by investigator assessment using the 
following response categories: (confirmed) CR, (confirmed) PR, SD, PD, and NE; 
unconfirmed CR/PR will be included in SD.

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For guidance on the evaluation of tumour response per RECIST 1.1, see Appendix E.
The BOR will be determined programmatically based on RECIST 1.1 using all investigator 
assessments up until the first progression event per RECIST 1.1 as determined by the 
investigator. For participants whose first progression event is death, BOR will be calculated 
based on all evaluable RECIST 1.1 assessments prior to death.
For participants who die with no evaluable RECIST 1.1 assessments, if death occurs ≤ 91 days 
(ie, 2 × [6 weeks] + 1 week) after the date of the first dose of study intervention, then BOR 
will be assigned to the PD category. For participants who die with no evaluable RECIST 1.1 
assessments, if the death occurs > 91 days (ie, 2 × [6 weeks] + 1 week) after the date of the 
first dose of study intervention, BOR will be assigned to the NE category.
Analysis Methods
Confirmed BOR will be summarised descriptively by n (%) for each category (confirmed CR, 
confirmed PR, SD, PD, and NE) in the RES. Supplementary analysis will be performed using 
the FAS.
9.4.2.2.5
Time to Response
Time to Response by ICR
The TTR is defined as the time from the date of the first dose of study intervention until the 
date of first documented objective response, which is subsequently confirmed per RECIST 1.1 
as assessed by ICR. The analysis will include participants who have a confirmed response. 
Data obtained from the date of the first dose of study intervention up until progression, or the 
last evaluable assessment in the absence of progression, will be included in the assessment of
TTR. Participants who go off treatment without a response or progression, receive a 
subsequent therapy, and then respond will not be included. 
Time to Response by Investigator Assessment
The TTR is defined as the time from the date of the first dose of study intervention until the 
date of first documented objective response, which is subsequently confirmed per RECIST 1.1 
as assessed by the investigator. Data will be handled as described above for TTR by ICR.
Analysis Methods
The TTR will be summarised descriptively among participants in the RES who have a 
confirmed response. Supplementary analysis will be performed using the FAS.

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9.4.2.2.6
Progression-Free Survival
Progression-free Survival by ICR
The PFS will be defined as the time from the date of the first dose of study intervention until 
the date of objective PD per RECIST 1.1 as assessed by ICR or death (by any cause in the 
absence of progression) (ie, date of event or censoring – date of the first dose of study 
intervention + 1). The analysis will include all participants regardless of whether the 
participant withdraws from study intervention, receives another anti-cancer therapy or 
clinically progresses prior to RECIST 1.1 progression. Participants who have not progressed 
or died at the time of analysis will be censored at the time of the latest date of assessment from 
their last evaluable RECIST 1.1 assessment. However, if the participant progresses or dies 
after 2 or more consecutive missed visits, the participant will be censored at the time of the 
latest evaluable RECIST 1.1 assessment prior to the 2 missed visits. (Note: NE visit is not 
considered as missed visit).
If the participant has no evaluable tumour assessment visits or does not have baseline data, 
they will be censored at Day 1, unless they die within 2 tumour assessment visits of baseline 
(< 91 days [2 × 6 weeks] + 1 week allowing for a late assessment within the visit window). 
Progression-free Survival by Investigator Assessment
The PFS by investigator assessment is defined as the time from the date of the first dose of 
study intervention until the date of PD per RECIST 1.1 as assessed by the investigator or 
death (by any cause in the absence of progression) (ie, date of event or censoring – date of the 
first dose of study intervention + 1). 
Data will be handled as described above for PFS by ICR.
Analysis Methods
The survival distribution for PFS will be estimated by the Kaplan-Meier method, and the 
results presented graphically. The estimate of median PFS and corresponding 95% CI using 
the Brookmeyer-Crowley method with log-log transformation will be reported. Summaries of 
the number and percentage of participants experiencing a PFS event and the type of event 
(RECIST 1.1 or death) will be provided along with median PFS for each treatment. The 
proportion of participants alive and progression-free at 3-monthly intervals from the date of 
the first dose of study intervention will be estimated. The analysis will be performed using the 
FAS.
9.4.2.2.7
Overall Survival
The OS is defined as the time from the date of the first dose of study intervention until death 
due to any cause. The analysis will include all participants, regardless of whether the 
participant withdraws from study intervention or receives another anti-cancer therapy. Any 

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
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Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 0 3 of 1 6 5
parti ci pa nt n ot k n o w n t o ha ve die d at t he ti me of a nal ysis will be ce ns ore d base d o n t he last 
rec or de d date o n w hic h t he partici pa nt was k n o w n t o be ali ve. 
N ote: S ur vi val calls will be ma de at a n i ncrease d fre q ue nc y lea di n g u p t o a n d after t he D C O
date f or t he a nal ysis (t hese c o ntacts will be ma de u nt il t he date of data base l oc k). If 
parti ci pa nts are c o nfir me d t o be ali ve or if t he deat h date is after t he D C O date, t he n t hese 
parti ci pa nts will be ce ns ore d at t he dat e of D C O .
A n al ysis Met h o ds
T he s ur vi val distri b ut i on f or O S will be esti mate d b y t he Ka pla n-Meier m et h o d, a n d t he 
res ults prese nte d gra p hicall y. S u m maries of t he n u m ber a n d perce nta ge of partici pa nts 
e x perie nci n g a n O S e ve nt will be pr o vi de d al o n g wit h m e dia n O S a n d c orres p o n di n g 9 5 % CI 
usi n g t he Br o o k me yer -Cr o wl e y met h o d wit h lo g -l o g tra nsf or mati on . T he pr o p ortio n of  
parti ci pa nts ali ve at 3-m o nt hl y i nter vals fr o m t he date of t he first d ose of st u d y  int er ve nt i on 
will be esti mate d. T he a nal ysis will be per f or me d usi n g t he F A S.
9. 4. 2. 3
Terti ar y/ E x pl or at or y E n d p oi nt(s)
Refer t o t he S A P f or details o n t he a nal yses of tertiar y /e x plor at or y  e n d p oi nts.
9. 4. 3
S afet y
S af et y a nal yses will be perf or me d usi n g t he F A S. Safet y data will be prese nte d usi n g 
descri pt i ve statistics u nless ot h er wise s pecifie d. S u m mar y st atistics f or c o nti n u o us varia bles 
will i ncl u de n u m ber of partici pa nts, mea n, sta n dar d de viat i on, mi ni m u m, me dia n, a n d 
ma xi m u m. Fre q ue nc y  ta bles a n d s hift ta bles will i ncl u de n u m ber a n d perce nta ge of 
parti ci pa nts i n t he res pecti ve cate g or y. U nless ot her wise state d, perce nta ges will be calc ulate d 
o ut of t he p o p ulat i on t otal.
B aseli ne
I n ge neral, t he baseli ne val ue f or statistical a nal ysis is t he last n o n-missi n g val ue pri or t o 
a d mi nistrati o n of t he first d ose of st u d y int er ve nt i on. Details are descri be d i n t he S A P.
A d verse E ve nts
T he A Es will be c o de d usi n g t he m ost rece nt versi o n of Me d D R A t hat will be release d f or 
e xec uti o n at Astra Ze neca a n d C T C A E 5. 0.
Treat me nt -e mer ge nt A d verse E ve nts: T he f o ll owi n g e ve nts are c o nsi dere d T E A Es: 

A d verse e ve nts wit h a n o nset date o n or after t he first d ose of st u d y  int er ve nt i on a n d 
wi t hi n  
 after t he last d ose of st u d y int er ve nti o n or u p t o t he da y  prior t o t he 
start of s u bse q ue nt t hera p y, w hic he ver c o mes first.
C CI

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C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 0 4 of 1 6 5

W o rse ni n g of pre-e xist i n g e ve nts o n or after t he first d ose of st u d y i nter ve nti on a n d 
wi t hi n  
 after t he last d ose of st u d y int er ve nti o n or u p t o t he da y  prior t o t he 
start of s u bse q ue nt t hera p y, w hic he ver c o mes first. 
O nl y T E A Es will be prese nte d.
T he T E A Es will be prese nte d b y S yste m Or ga n Class a n d/ or P T c o veri n g n u m ber a n d 
perce nta ge of partici pa nts re p orti n g at least o ne e ve nt a n d n u m ber of e ve nts w here 
a p pr o priate. 
A n o ver vie w of T E A Es will be pr o vi de d as f o ll ows: t he n u m ber a n d perce nta ge of 
parti ci pa nts wit h a n y T E A E, T E A Es wit h t he o utc o me of deat h, seri o us T E A Es, a n d T E A Es 
lea di n g t o disc o nti n uati o n of st u d y int er ve ntio n, as well  as T E A Es lea di n g t o st u d y 
i nter ve nt i on d ose i nterr u pti o ns, a n d A Es lea di n g t o st u d y i nter ve nt i on d ose re d ucti o n.
Se parate T E A E ta bles will be pr o vi de d ta ki n g i nt o c o nsi derati o n t he relat i ons hi p t o st u d y  
i nter ve nt i on as assesse d b y t he i n vesti gat or, t he C T C A E 5. 0 gra de, seri o us ness, deat h, a n d 
e ve nts lea di n g t o disc o nt i n uati o n of st u d y int er ve ntio n, as well as ot her acti o n ta ke n relate d t o 
st u d y int er ve ntio n, A E SIs, a n d ot her si g nifica nt T E A Es (if a p plica ble).
A n a d dit i on al  ta ble will be prese nte d f or t he n u m ber a n d perce nta ge of partici pa nts wit h m ost 
c o m m o n T E A Es. M ost c o m m o n T E A Es will be defi ne d i n t he S A P.
All A Es will be liste d i ncl u di n g, b ut n ot li mite d t o, ver bati m ter m, P T, S yste m Or ga n Class, 
C T C A E 5. 0 gra de, relat i ons hi p t o st u d y  dr u g, start a n d e n d dates, a n d o utc o me. N o n-T E A Es 
will be fla g ge d i n t he list i n g.
Vit al Si g ns
F or eac h sc he d ule d p o st-baseli ne visit, descri pt i ve statistics f or all vit al si g n para meters will 
be prese nte d f or o bser ve d val ues a n d c ha n ge fr o m baseli ne.
Details o f vit al si g n a nal yses will be pr o vi de d i n t he S A P. 
Electr oc ar di o gr a ms
F or eac h sc he d ule d p ost- baseli ne visit, descri pt i ve statistics f or all E C G para meters will be 
prese nte d f or o bser ve d val ues a n d c ha n ge fr o m baseli ne. T he Q Tc F will be deri ve d d uri n g 
creatio n of  t he re p ortin g data base usi n g re p orte d E C G val ues ( R R a n d Q T) usi n g t he 
f oll owi n g f or m ula, w here R R is i n sec o n ds:
Q Tc F = 
  √ Details o f E C G a nal yses will be pr o vi de d i n t he S A P.
C CI

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Laboratory Parameters
For each scheduled post-baseline visit, descriptive statistics for all clinical chemistry and 
haematology parameters will be presented for observed values and change from baseline. 
Elevation in liver parameters for assessment of Hy’s Law will be performed and reported 
appropriately if potential cases are identified during the course of the study. 
Corrected calcium will be derived during creation of the reporting database using the 
following formula:
Corrected calcium (mmol/L) = total calcium (mmol/L) + ([40 – albumin (g/L)] × 0.02)
A shift table for urinalysis will be presented with baseline assessment against the maximum 
on study intervention category. 
Supportive laboratory listings will cover observed values and changes from baseline for each 
individual participant as well as abnormalities.
Details of laboratory analyses will be provided in the SAP.
Other Safety Analyses
All other safety endpoints, eg, physical examination findings, including WHO/ECOG 
performance status, ECHO/MUGA, and ophthalmologic findings, will be listed.
Appropriate summaries of all safety data will be produced as defined in the SAP.
Further details can be found in the SAP.
9.4.4
Other Analyses
9.4.4.1
Pharmacokinetics
Plasma concentrations of the 3 analytes (Dato-DXd, total anti-TROP2 antibody and DXd) will 
be summarised for all evaluable participants in the PK analysis population using descriptive 
statistics at time points indicated in the SoA by cohort.
Non-compartment PK parameters that can be derived with sparse PK sampling, such as peak 
and trough concentrations, may be reported as data allow. If full PK samples are collected in a 
subset of participants, the non-compartment PK parameters to be obtained and reported in the 
full PK cohort may include, but are not limited to the Cmax, the trough observed concentration, 
Tmax, AUC, t1/2 and CL, if the data allow. Details on the analysis of PK assessments will be 
provided in the SAP. Population PK and E-R analyses will be performed to characterise the 
relationships of dose, exposure, efficacy and safety endpoints, if applicable. The results of the 
population PK and E-R analyses will be reported separately from the CSR.

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
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Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2a)
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9. 4. 4. 3
O pti o n al E x pl or at or y Ge netic S a m ple
N ot a p plica ble
9. 4. 4. 4
I m m u n o ge nicit y D at a 
I mm u n o ge nicit y res ults will be liste d b y p artici pa nt, a n d a s u m mar y will be pr o vide d b y  t he 
n u m ber a n d perce nta ge of parti ci pa nts w h o de vel o p detecta ble a nt i-Dat o -D X d a nti b o dies. T he 
i m m u n o ge nicity titr e a n d ne utralisi n g A D A data will be liste d f or sa m ples c o nfir me d p ositi ve 
f or t he prese nce of a nti Dat o D X d a nti b o dies. 
T he effect of i m m u n o ge nicit y as well as t he effect of its ne utralisi n g pr o perties o n P K, 
p har mac o d y na mics, efficac y , a n d safety will be e val uate d, if t he data all o w. 
9. 4. 4. 5
C O VI D -1 9 I m p act 
De pe n di n g o n t he e xte nt of a n y i m pact, s u m maries of data relat i n g t o partici pa nts dia g n ose d 
wi t h C O VI D-1 9, a n d i m pact of C O VI D -1 9 o n st u d y c o n d uct (i n partic ular misse d visits, 
d el a ye d or disc o nti n ue d st u d y int er ve ntio n, a n d ot her pr ot oc ol de viati o ns) ma y be ge nerate d if 
a p pr o priate. F urt her detail will be pr o vi de d i n t he S A P.
9. 5
I nteri m A n al yses 
A n i nteri m a nal ysis is n ot pla n ne d i n t his st u d y.
9. 6
D at a M o nit ori n g C o m mittee 
T he safet y of  all Astra Ze neca cli nical st u dies is cl osel y mo ni t ore d o n a n o n g oi n g basis b y 
Astra Ze neca re prese ntati ves i n c o ns ultat i on wi t h P atie nt Safet y.  Iss ues i de ntifie d will be 
a d dressed; f or i nsta nce, t hi s c o uld i n v o l ve a me n d me nts t o t he C S P a n d letters t o i n vesti gat ors. 
A n I n de pe n de nt Data M o nit ori n g C o m mit t e e is n ot c o nsidere d necessar y  for t hi s o pe n-la bel, 
si n gle-ar m st u d y.
9. 6. 1
I L D A dj u dic ati o n C o m mittee
 
T o e ns ure a de q uate a n d rele va nt 
 
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 0 7 of 1 6 5
s yste mat ic a d diti on al  data c ollecti on will be c o n d ucte d 
 
 
 
 
 
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS

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Appendix A
Regulatory, Ethical, and Study Oversight Considerations
A 1
Regulatory and Ethical Considerations

This study will be conducted in accordance with the CSP and with the following:
-
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines
-
Applicable ICH GCP Guidelines
-
Applicable laws and regulations

The CSP, CSP amendments, ICF, IB, and other relevant documents (eg, advertisements) 
must be submitted to an IRB/IEC by the investigator and reviewed and approved by the 
IRB/IEC before the study is initiated.

Any amendments to the CSP will require IRB/IEC and applicable Regulatory Authority 
approval before implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants.

AstraZeneca will be responsible for obtaining the required authorisations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
CRO but the accountability remains with AstraZeneca.

The investigator will be responsible for providing oversight of the conduct of the study at 
the site and adherence to requirements of 21 CFR 312.120, ICH guidelines, the IRB/IEC, 
European Regulation 536/2014 for clinical studies (if applicable), European Medical 
Device Regulation 2017/745 for clinical device research (if applicable), and all other 
applicable local regulations.
Regulatory Reporting Requirements for Serious Adverse Events

Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and investigators.

For all studies except those utilising medical devices investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the IB and will notify the IRB/IEC, if appropriate according to 
local requirements.

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Regulatory Reporting Requirements for Serious Breaches

Prompt notification by the investigator to AstraZeneca of any (potential) serious breach of 
the protocol or regulations is essential so that legal and ethical obligations are met.
-
A ‘serious breach’ means a breach likely to affect to a significant degree the safety 
and rights of a participant or the reliability and robustness of the data generated in the 
clinical study.

If any (potential) serious breach occurs in the course of the study, investigators or other 
site personnel will inform the appropriate AstraZeneca representatives immediately after 
they become aware of it.

In certain regions/countries, AstraZeneca has a legal responsibility to notify both the local 
regulatory authority and other regulatory agencies about such breaches.
-
AstraZeneca will comply with country-specific regulatory requirements relating to 
serious breach reporting to the regulatory authority, IRB/IEC, and investigators. If 
European Union Clinical Trials Regulation 536/2014 applies, AstraZeneca is 
required to enter details of serious breaches into the European Medicines Agency 
Clinical Trials Information System. It is important to note that redacted versions of 
serious breach reports will be available to the public via the Clinical Trials 
Information System.

The investigator should have a process in place to ensure that:
-
The site staff or service providers delegated by the investigator/institution are able to 
identify the occurrence of a (potential) serious breach.
-
A (potential) serious breach is promptly reported to AstraZeneca or delegated party, 
through the contacts (e-mail address or telephone number) provided by AstraZeneca.
A 2
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for one year after completion of the study.
A 3
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorised representative and answer all questions regarding 
the study.

Participants must be informed that their participation is voluntary and they are free to 
refuse to participate and may withdraw their consent at any time and for any reason 
during the study. Participants or their legally authorised representative will be required to 
sign a statement of informed consent that meets the requirements of 21 Code of Federal 

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Regulations 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act requirements, where applicable, and the IRB/IEC or study centre.

The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorised person obtaining the informed consent must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorised representative.
The ICF will contain a separate section that addresses and documents the collection and use of 
any mandatory and/or optional human biological samples. The investigator or authorised 
designee will explain to each participant the objectives of the analysis to be done on the 
samples and any potential future use. Participants will be told that they are free to refuse to 
participate in any optional samples or the future use and may withdraw their consent at any 
time and for any reason during the retention period. 
Participants who are rescreened are required to sign a new ICF.
A 4
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information that would make the participant identifiable will not be 
transferred.

The participant must be informed that his/her personal study-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure and use 
of their data must also be explained to the participant in the informed consent.

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorised personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities.

The participant must be informed that data will be collected only for the business needs. 
We will only collect and use the minimum amount of personal data to support our 
business activities and will not make personal data available to anyone (including internal 
staff) who is not authorised or does not have a business need to know the information. 

The participant must be informed that in some cases their data may be pseudonymised. 
The General Data Protection Regulation defines pseudonymisation as the processing of 
personal data in such a way that the personal data can no longer be attributed to a specific 
individual without the use of additional information, provided that such additional 
information is kept separately and protected by technical and organisational measures to 

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ensure that the personal data are not attributed to an identified or identifiable natural 
person.
Unless previously specified, the biomarker data will have unknown clinical significance and 
AstraZeneca will not provide biomarker assessment results to participants, their family 
members, any insurance company, any employer, a clinical study investigator, a general 
physician, or any other third party, unless required to do so by law. However, AstraZeneca 
may share data and biosamples with research partners, for example Daiichi Sankyo.
The participant’s samples will not be used for any purpose other than those described in the 
study CSP. 
A 5
Committees Structure
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
AstraZeneca representatives in consultation with Patient Safety. Issues identified will be 
addressed; for instance, this could involve amendments to the CSP and letters to investigators.
A 6
Dissemination of Clinical Study Data
A description of this clinical study will be available on http://astrazenecaclinicaltrials.com and
http://www.clinicaltrials.gov, as will the summary of the study results when they are available. 
The clinical study and/or summary of study results may also be available on other websites 
according to the regulations of the countries in which the study is conducted.Data Quality 
Assurance

All participant data relating to the study will be recorded on the CRF unless transmitted to 
the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the eCRF.

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory authority inspections and provide direct access to source data documents.

Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities, and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring Plan.

AstraZeneca or designee is responsible for medical oversight throughout the conduct of 
the study, which includes clinical reviews of study data in accordance with the currently 
approved protocol. Monitoring details describing clinical reviews of study data from a 
medical perspective are included in more detail in the Monitoring Plan.

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
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.

The sponsor assumes accountability for actions delegated to other individuals (eg, CROs).

Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorised site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved CSP and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.

Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for a minimum of 25 years after study archiving or as 
required by local regulations, according to the AstraZeneca GRAD Schedule. No records 
may be destroyed during the retention period without the written approval of 
AstraZeneca. No records may be transferred to another location or party without written 
notification to AstraZeneca.
A 8
Source Documents

Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site.

Data reported on the eCRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.

Definition of what constitutes source data can be found in the source data agreement 
form. All information in original records and certified copies of original records of 
clinical findings, observations, or other activities in a clinical study necessary for the 
reconstruction and evaluation of the study are defined as source documents. Source data 
are contained in source documents (original records or certified copies). 
A 9
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first site opening is considered the first act of recruitment and will be the study start date.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.

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Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the CSP, the requirements of the IRB/IEC or 
local health authorities, the sponsor’s procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
Participants from terminated sites will have the opportunity to be transferred to another site to 
continue the study.
A 10
Publication Policy

The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments.

The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicentre studies only in their entirety and not as individual site data. In 
this case, a co-ordinating investigator will be designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.

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Appendix B
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
B 1
Definition of Adverse Events
An AE is the development of any untoward medical occurrence (other than progression of the 
malignancy under evaluation) in a participant or clinical study participant administered a 
study intervention, which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavourable and unintended sign (eg, an abnormal laboratory 
finding), symptom (for example nausea, chest pain), or disease temporally associated with the 
use of a medicinal product, whether or not considered related to the study intervention. 
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study intervention has been administered.
B 2
Definitions of Serious Adverse Event
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, follow-up) 
that fulfils one or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-participant hospitalisation or prolongation of existing hospitalisation

Results in persistent or significant disability or incapacity

Is a congenital anomaly or birth defect

Is an important medical event that may jeopardise the participant or may require medical 
treatment to prevent one of the outcomes listed above
AEs for malignant tumours reported during a study should generally be assessed as serious 
AEs. If no other seriousness criteria apply, the ‘Important Medical Event’ criterion should be 
used. In certain situations, however, medical judgment on an individual event basis should be 
applied to clarify that the malignant tumour event should be assessed and reported as a 
non-serious AE. For example, if the tumour is included as medical history and progression 
occurs during the study, but the progression does not change treatment and/or prognosis of the 
malignant tumour, the AE may not fulfil the attributes for being assessed as serious, although 
reporting of the progression of the malignant tumour as an AE is valid and should occur. Also, 
some types of malignant tumours, which do not spread remotely after a routine treatment that 
does not require hospitalisation, may be assessed as non-serious; examples in adults include 
Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy.

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The above instruction applies only when the malignant tumour event in question is a new 
malignant tumour (ie, it is not the tumour for which entry into the study is a criterion and that 
is being treated by the study intervention under study and is not the development of new or 
progression of existing metastasis to the tumour under study). Malignant tumours that—as 
part of normal, if rare, progression—undergo transformation (eg, Richter’s transformation of 
B-cell chronic lymphocytic leukaemia into diffuse large B cell lymphoma) should not be 
considered a new malignant tumour.
Life-threatening
‘Life-threatening’ means that the participant was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
participant’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form, it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalisation
Outpatient treatment in an emergency room is not in itself an SAE, although the reasons for it 
may be (eg, bronchospasm, laryngeal oedema). Hospital admissions and/or surgical operations 
planned before or during a study are not considered AEs if the illness or disease existed before 
the participant was enrolled in the study, provided that it did not deteriorate in an unexpected 
way during the study.
Important Medical Event or Medical Treatment
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life-threatening or result in 
death, hospitalisation, disability, or incapacity but may jeopardise the participant or may 
require medical treatment to prevent one or more outcomes listed in the definition of serious. 
These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgment must be used.

Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation

Development of drug dependency or drug abuse

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Intensity Rating Scale:
The grading scales found in the revised CTCAE 5.0 will be utilised for all events with an 
assigned CTCAE 5.0 grading. For those events without assigned CTCAE 5.0 grades, the 
recommendation in the CTCAE 5.0 criteria that converts mild, moderate and severe events 
into CTCAE 5.0 grades should be used. A copy of the CTCAE 5.0 can be downloaded from 
the Cancer Therapy Evaluation Program website (http://ctep.cancer.gov). The applicable 
version of CTCAE should be described clearly.
B 3
A Guide to Interpreting the Causality Question
When making an assessment of causality, consider the following factors when deciding if 
there is a ‘reasonable possibility’ that an AE may have been caused by the drug:

Time course. Exposure to suspect drug. Has the participant actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug?

Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?

De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug?

No alternative cause. The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, or other host or environmental factors.

Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? AstraZeneca would not normally recommend or support a 
rechallenge.

Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered, such as the following:

Is this a recognised feature of overdose of the drug?

Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.

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The causality assessment is performed based on the available data including enough 
information to make an informed judgment. With no available facts or arguments to suggest a 
causal relationship, the event(s) will be assessed as ‘not related.’
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.
B 4
Medication Error, Drug Abuse, or Drug Misuse
For the purposes of this clinical study, a medication error is an unintended failure or mistake 
in the treatment process for an AstraZeneca study intervention that either causes harm to the 
participant or has the potential to cause harm to the participant.
A medication error is not lack of efficacy of the drug, but rather a human- or process-related 
failure while the drug is in control of the study site staff or participant.
Medication error includes situations where an error: 

occurred.

was identified and intercepted before the participant received the drug.

did not occur, but circumstances were recognised that could have led to an error.
Examples of events to be reported in clinical studies as medication errors are as follows:

Drug name confusion.

Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the participant.

Drug not administered as indicated, for example, wrong route, dose (error greater than ± 
10%), or wrong site of administration.

Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a 
solid tablet.

Drug not stored as instructed eg, kept in the fridge when it should be at room temperature. 

Wrong participant received the medication (excluding IRT/RTSM errors).

Wrong drug administered to participant (excluding IRT/RTSM errors).
Examples of events that do not require reporting as medication errors in clinical studies are as 
follows:

Errors related to or resulting from IRT/RTSM - including those that lead to one of the 
above listed events that would otherwise have been a medication error. 

Participant accidentally missed drug dose(s) eg, forgot to take medication.

Accidental overdose (will be captured as an overdose).

Participant failed to return unused medication or empty packaging.

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Medication errors are not regarded as AEs, but AEs may occur as a consequence of the 
medication error.
Drug Abuse
For the purpose of this study, drug abuse is defined as the persistent or sporadic intentional, 
non-therapeutic excessive use of study intervention for a perceived reward or desired non-
therapeutic effect. 
Any events of drug abuse, with or without associated AEs, are to be captured and forwarded 
to the DES using the Drug Abuse Report Form. This form should be used both if the drug 
abuse happened in a study participant or if the drug abuse regards a person not enrolled in the 
study (such as a relative of the study participant). 
Examples of drug abuse include but are not limited to: 

The study intervention is used by a person not enrolled in the study with the intent of 
getting a perceived reward.

The study intervention in the form of a tablet is crushed and injected or snorted with the 
intent of getting high.
Drug Misuse 
Drug misuse is the intentional and inappropriate use of the study intervention for medicinal 
purposes outside of the authorised product information, or for unauthorised study 
interventions, outside the intended use as specified in the CSP and includes deliberate 
administration of a product by the wrong route. 
Events of drug misuse, with or without associated AEs, are to be captured and forwarded to 
the DES using the Drug Misuse Report Form. This form should be used both if the drug 
misuse happened in a study participant or if the drug misuse regards a person not enrolled in 
the study (such as a relative of the study participant). 
Examples of drug misuse include but are not limited to: 

The study intervention is used with the intention to cause an effect in another person.

The study intervention is sold to other people for recreational purposes.

The study intervention is used with the connotation to cause an effect or facilitate assault 
in another person.

The study intervention is deliberately administered by the wrong route.

The study intervention is split in half because it is easier to swallow, when it is stated in 
the protocol that it should be swallowed whole.

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
Only half the dose of study intervention is taken because the participant feels that he/she 
is feeling better when not taking the whole dose.

Someone who is not enrolled in the study takes the study intervention.

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Appendix C
Handling of Human Biological Samples
C 1
Chain of Custody
A full chain of custody is maintained for all samples throughout their lifecycle.
The investigator at each centre keeps full traceability of collected biological samples from the 
participants while in storage at the centre until shipment or disposal (where appropriate) and 
records relevant processing information related to the samples whilst at site.
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps record of receipt of arrival and onward 
shipment or disposal.
AstraZeneca or delegated representatives will keep oversight of the entire lifecycle through 
internal procedures, monitoring of study sites, auditing or process checks, and contractual 
requirements of external laboratory providers.
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks or other 
sample archive facilities and will be tracked by the appropriate AstraZeneca Team during for 
the remainder of the sample lifecycle. 
If required, AstraZeneca will ensure that remaining biological samples are returned to the site 
according to local regulations or at the end of the retention period, whichever is the sooner.
C 2
Withdrawal of Informed Consent for Donated Biological Samples 
If a participant withdraws consent specifically to the subsequent use of donated biological 
samples, the samples will be disposed of/destroyed/repatriated, and the action documented. If 
samples are already analysed, AstraZeneca is not obliged to destroy the results of this 
research. The participant will be presented with the option to opt out of the subsequent use of 
the donated samples during the withdrawal process. If the participant decides to opt out, then 
the donated samples will be disposed of. If the participant withdraws consent without opting 
out for the subsequent use of the donated samples, then the samples will be used as per CSP.
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes outlined in the informed consent.
The investigator:

Ensures participant’s withdrawal of informed consent to the use of donated samples is 
highlighted immediately to AstraZeneca or delegate.

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
Ensures that relevant human biological samples from that participant, if stored at the 
study site, are immediately identified, disposed of as appropriate, and the action 
documented.

Ensures that the participant and AstraZeneca are informed about the sample disposal.
AstraZeneca ensures the organisation(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and that the action is documented and study site notified.
C 3
International Air Transport Association Guidance Document 
(62nd Edition)
Labelling and Shipment of Biohazard Samples
The IATA (https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx ) classifies 
infectious substances into 3 categories: Category A, Category B or Exempt
Category A infectious substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.
Category A pathogens are, for example, Ebola or Lassa fever virus. Infectious substances 
meeting these criteria which cause disease in humans or both in humans and animals must be 
assigned to UN 2814. Infectious substances which cause disease only in animals must be 
assigned to UN 2900.
Category B infectious substances are infectious substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are, for example, Hepatitis A, C, D, and E 
viruses. They are assigned the following UN number and proper shipping name:

UN 3373 – Biological Substance, Category B
They are to be packed in accordance with UN3373 and IATA 650.
Exempt: Substances that do not contain infectious substances or substances that are unlikely 
to cause disease in humans or animals are not subject to these regulations unless they meet the 
criteria for inclusion in another class.

Clinical study samples will fall into Category B or exempt under IATA regulations.

Clinical study samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging. 
(https://www.iata.org/whatwedo/cargo/dgr/Documents/DGR-60-EN-PI650.pdf).

Biological samples transported in dry-ice require additional dangerous goods 
specification for the dry-ice content.

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Appendix D
Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law
D 1
Introduction
This appendix describes the process to be followed in order to identify and appropriately 
report PHL cases and HL cases. It is not intended to be a comprehensive guide to the 
management of elevated liver biochemistries. 
In studies where laboratory data are not routinely collected, the investigator should be vigilant 
for cases of PHL cases from ad hoc laboratory tests or AEs. Additional safety samples for 
example, liver chemistry tests to determine PHL cases, may be collected if clinically indicated 
at the discretion of the investigator.
Specific guidance on managing liver abnormalities can be found in the TMG Annex.
During the course of the study the investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a participant meets PHL 
criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated TBL from 
a local laboratory. 
The investigator will also review AE data (for example, for AEs that may indicate elevations 
in liver biochemistry) for possible PHL events.
The investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether HL criteria are met. HL 
criteria are met if there is no alternative explanation for the elevations in liver biochemistry 
other than DILI caused by the study intervention. 
The investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting SAEs and AEs according to the outcome of the review and assessment in line with 
standard safety reporting processes.
D 2
Definitions
PHL
Aspartate aminotransferase or ALT ≥ 3 × ULN together with TBL ≥2 × ULN at any point 
during the study following the start of study intervention irrespective of an increase in alkaline 
phosphatase.

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HL
AST or ALT ≥ 3 × ULN together with TBL ≥2 × ULN, where no other reason, other than 
the study intervention, can be found to explain the combination of increases, eg, elevated 
alkaline phosphatase indicating cholestasis, viral hepatitis, or another drug. 
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.
D 3
Identification of Potential Hy’s Law Cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any participant who meets any of the following identification criteria in 
isolation or in combination:

ALT ≥ 3 × ULN

AST ≥ 3 × ULN

TBL ≥2 × ULN
Local laboratories being used
The investigator will, without delay, review each new laboratory report and, if the 
identification criteria are met, will:

Notify the AstraZeneca representative.

Determine whether the participant meets PHL criteria (see Section D 2 Definitions within 
this Appendix for definition) by reviewing laboratory reports from all previous visits.

Promptly enter the laboratory data into the laboratory eCRF.
D 4
Follow-up
D 4.1
Potential Hy’s Law Criteria Not Met
If the participant does not meet PHL criteria the investigator will:

Inform the AstraZeneca representative that the participant has not met PHL criteria. 

Perform follow-up on subsequent laboratory results according to the guidance provided in 
the CSP.
D 4.2
Potential Hy’s Law Criteria Met
If the participant does meet PHL criteria the investigator will:

Determine whether PHL criteria were met at any study visit prior to starting study 
intervention (See Section D 6).

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
Notify the AstraZeneca representative who will then inform the study team. 

Within one day of PHL criteria being met, the investigator will report the case as an SAE 
of PHL; serious criterion ‘Important medical event’ and causality assessment ‘yes/related’ 
according to the CSP process for SAE reporting.

For participants that met PHL criteria prior to starting study intervention, the investigator 
is not required to submit a PHL SAE unless there is a significant change# in the 
participant’s condition. 

The study clinical lead contacts the investigator, to provide guidance, discuss and agree 
an approach for the study participants’ follow-up (including any further laboratory 
testing) and the continuous review of data.

Subsequent to this contact, the investigator will:
-
Monitor the participant until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated. Completes follow-up SAE Form as required.
-
Investigate the aetiology of the event and perform diagnostic investigations as 
discussed with the study clinical lead. 
-
Complete the 3 Liver eCRF Modules as information becomes available. 
#A ‘significant’ change in the participant’s condition refers to a clinically relevant change in 
any of the individual liver biochemistry parameters (ALT, AST, or TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the investigator, this 
may be in consultation with the study clinical lead if there is any uncertainty.
D 5
Review and Assessment of Potential Hy’s Law Cases
The instructions in this section should be followed for all cases where PHL criteria are met.
As soon as possible after the biochemistry abnormality was initially detected, the study 
clinical lead contacts the investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
study intervention, to ensure timely analysis and reporting to health authorities within 
15 calendar days from date PHL criteria was met. The AstraZeneca Global Clinical Lead or 
equivalent and Global Safety Physician will also be involved in this review together with 
other subject matter experts as appropriate. 
According to the outcome of the review and assessment, the investigator will follow the 
instructions below.
Where there is an agreed alternative explanation for the ALT or AST and TBL elevations, 
a determination of whether the alternative explanation is an AE will be made and 
subsequently whether the AE meets the criteria for an SAE:

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
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF.

If the alternative explanation is an AE/SAE, update the previously submitted PHL SAE 
and AE eCRFs accordingly with the new information (reassessing event term; causality 
and seriousness criteria) following the AstraZeneca standard processes.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the study intervention:

Send updated SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes. 
-
The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply.
-
As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If there is an unavoidable delay of over 15 calendar days in obtaining the information 
necessary to assess whether or not the case meets the criteria for HL, then it is assumed that 
there is no alternative explanation until such time as an informed decision can be made:

Provides any further update to the previously submitted SAE of PHL, (report term now 
‘Hy’s Law case’) ensuring causality assessment is related to study intervention and 
seriousness criterion is medically important, according to CSP process for SAE reporting.

Continue follow-up and review according to the agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are still met. Update the previously submitted PHL SAE report 
following CSP process for SAE reporting, according to the outcome of the review and 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined.
D 6
Actions Required When Potential Hy’s Law Criteria are Met 
Before and After Starting Study Intervention 
This section is applicable to participants with liver metastases who meet PHL criteria on study 
intervention, having previously met PHL criteria at a study visit prior to starting study 
intervention.
At the first on-study intervention occurrence of PHL criteria being met the investigator will 
determine if there has been a significant change in the participant’s condition compared with 
the last visit where the PHL criteria were met.

If there is no significant change, no action is required.

If there is a significant change, notify the AstraZeneca representative, who will inform the 
study team, then follow the subsequent process described in Section D 4.2.

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D 7
Actions Required for Repeat Episodes of Potential Hy’s Law
This section is applicable when a participant meets PHL criteria on study intervention and has 
already met PHL criteria at a previous on study intervention visit.
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence. 
The investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question:
Was the alternative cause for the previous occurrence of PHL criteria being met found to be 
the disease under study, eg, chronic or progressing malignant disease, severe infection or liver 
disease or did the participant meet PHL criteria prior to starting study intervention and at their 
first on-study intervention visit as described in Section D 6 of this Appendix?
If No: Follow the process described in Section D 4.2 for reporting PHL as an SAE.
If Yes: Determine if there has been a significant change in the participant’s condition
compared with when PHL criteria were previously met.

If there is no significant change no action is required.

If there is a significant change follow the process described in Section D 4.2 for reporting 
PHL as an SAE.
D 8
Laboratory Tests
The Hy’s Law related laboratory tests will be performed at local laboratories in this study.
The list below represents the standard, comprehensive list of follow-up tests that are 
recommended but not mandatory to further evaluate increases in liver biochemistry and 
Hy’s Law. This list may be modified according to clinical judgment. Any test result must be 
recorded.

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Hy’s Law lab tests
Additional standard chemistry and coagulation 
tests
GGT
LDH
Prothrombin time
INR
Viral hepatitis
IgM anti-HAV 
IgM and IgG anti-HBc
HBsAg
HBV DNAa
IgM and IgG anti-HCV
HCV RNAa
IgM anti-HEV
HEV RNA
Other viral infections
IgM & IgG anti-CMV
IgM & IgG anti-HSV
IgM & IgG anti-EBV
Autoimmune hepatitis
Antinuclear antibody
Anti-liver/kidney microsomal antibody
Anti-smooth muscle antibody
Metabolic diseases
Alpha-1-antitrypsin
Ceruloplasmin
Iron
Ferritin
Transferrin saturation
CMV, cytomegalovirus; DNA, deoxyribonucleic acid; EBV, Epstein-Barr virus; GGT, gamma glutamyl transferase; HAV, 
hepatitis A virus; HBc, hepatitis B core antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis 
C virus; HEV, hepatitis E virus; HSV, herpes simplex virus; IgG, immunoglobulin G; IgM, immunoglobulin M; INR, 
international normalised ratio; LDH, lactate dehydrogenase; RNA, ribonucleic acid.
a
HCV RNA and HBV DNA are only tested when anti-HCV IgG/anti-HBc IgM or IgG is positive or inconclusive.

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Appendix E
Guidelines for Evaluation of Objective Tumour Response 
Using RECIST 1.1 Criteria (Response Evaluation Criteria in 
Solid Tumours)
E 1
Introduction
This appendix details the implementation of RECIST 1.1 guidelines (Eisenhauer et al 2009). 
Investigator assessments will use the RECIST 1.1 guidelines described in this appendix.
E 2
Imaging modalities and acquisition specifications for RECIST 1.1
A summary of the imaging modalities that can be used for tumour assessment of TLs, NTLs 
and NLs is provided in Table E11.
Table E11
Summary of Imaging Modalities for Tumour Assessment
Target Lesions 
Non-Target Lesions
New Lesions
CT
MRI
CT
MRI
Plain X-ray
Chest X-ray
CT
MRI
Plain X-ray
Chest X-ray
Bone scan (Scintigraphy)
18F-fluoro-deoxyglucose-PET/CT
CT, computed tomography; PET/CT, positron emission tomography/CT; MRI, magnetic resonance imaging.
E 2.1
Computed Tomography and Magnetic Resonance Imaging 
Computed tomography with IV contrast is the preferred imaging modality (although MRI with 
IV contrast is acceptable if CT is contraindicated) to generate reproducible anatomical images 
for tumour assessments (ie, for measurement of TLs, assessment of NTLs, and identification 
of NLs). It is essential that the same correct imaging modality, image acquisition parameters 
(eg, anatomic coverage, imaging sequences, etc), imaging facility, tumour assessor (eg, 
radiologist), and method of tumour assessment (eg, RECIST 1.1) are used consistently for 
each participant throughout the study. The use of the same scanner for serial scans is 
recommended, if possible. It is important to follow the image collection/tumour assessment 
schedule as closely as possible (refer to the SoA), and this on-study imaging schedule MUST 
be followed regardless of any delays in dosing or missed imaging visits. If an unscheduled 
assessment is performed (eg, to investigate clinical signs/symptoms of progression) and the 
participant has not progressed, every attempt should be made to perform the subsequent scan 
acquisitions at the next scheduled imaging visit.
Due to its inherent rapid acquisition (seconds), CT is the imaging modality of choice. Body 
scans should be performed with breath-hold scanning techniques, if possible. Therefore, CT of 
the chest is recommended over MRI due to significant motion artefacts (eg, heart, major blood 

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vessels, breathing) associated with MRI. MRI has excellent contrast and spatial and temporal 
resolutions; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. The modality used at follow-up should be the same as 
was used at baseline, and the lesions should be measured/assessed on the same pulse 
sequence. In general, local oncology diagnostic imaging parameters are applied for scan 
acquisition. It is beyond the scope of this appendix to prescribe specific MRI pulse sequence 
parameters for all scanners, body parts, and diseases.
The most critical CT and MRI image acquisition parameters for optimal tumour evaluation are 
anatomic coverage, contrast administration, slice thickness, and reconstruction interval.
a. Anatomic coverage: Optimal anatomic coverage for most solid tumours is the chest, 
abdomen and pelvis. Coverage should encompass all areas of known predilection for 
metastases in the disease under evaluation and should additionally investigate areas that may 
be involved based on signs and symptoms of individual participants. Because a lesion later 
identified in a body part not scanned at baseline would be considered as a NL representing 
PD, careful consideration should be given to the extent of imaging coverage at baseline and at 
subsequent follow-up time points. This will enable better consistency not only of tumour 
measurements but also identification of new disease.
Required anatomical regions to be imaged for assessment of tumour burden (TLs and/or 
NTLs) at baseline and follow-up visits vary according to the study, and these time points are 
specified in the SoA. Examples include the following:

Intravenous contrast-enhanced CT of chest-abdomen (including the entire liver and both 
adrenal glands) (-pelvis).

Non-contrast CT of chest and IV contrast-enhanced abdomen (including the entire liver 
and both adrenal glands) (-pelvis).

Intravenous contrast-enhanced CT or MRI of the head and neck.

Intravenous contrast-enhanced MRI (preferred) or CT of the brain.
For chest-abdomen (-pelvis) imaging, the following are scanning options in decreasing order 
of preference, with additional options (2 to 4) for consideration when participants have 
sensitivity to IV contrast or have compromised renal function:
1
Chest-abdomen (-pelvis) CT with IV CT contrast (most preferred).
2
Chest CT without IV-contrast + abdomen (-pelvis) MRI with IV MRI contrast, if CT IV 
contrast (iodine based) is medically contraindicated at any time during the study.
3
Chest-abdomen (-pelvis) CT without IV contrast, if both IV CT and MRI contrast are 
medically contraindicated or the participant has compromised renal function.

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4
Chest-abdomen (-pelvis) MRI with IV MRI contrast, if CT cannot be performed at any 
time during the study.
b. Intravenous contrast administration: Optimal visualisation and measurement of 
metastases in solid tumours require consistent administration (dose and rate) of IV contrast as 
well as timing of scanning. An adequate volume of a suitable contrast agent should be given 
so that the tumour lesions are demonstrated to best effect and a consistent method is used on 
subsequent examinations for any given participant. Oral contrast is recommended to help 
visualise and differentiate structures in the abdomen and pelvis.
c. Slice thickness and reconstruction interval: It is recommended that CT or MRI scans be 
acquired/reconstructed as contiguous (no gap) slices with ≤ 5 mm thickness throughout the 
entire anatomic region of interest for optimal lesion measurements. Exceptionally, particular 
institutions may perform medically acceptable scans at slice thicknesses > 5 mm. If this 
occurs, the minimum size of measurable lesions at baseline should be twice the slice thickness 
of the baseline scans.
For CT scans, all window settings should be included in the assessment, particularly in the 
thorax where lung and soft tissue windows should be considered. When measuring lesions, the 
TL should be measured on the same window setting for repeated examinations throughout the 
study.
E 2.2
Chest X-ray
Chest X-ray assessment will not be used for the assessment of TLs. Chest X-ray can, however, 
be used to assess NTLs and to identify the presence of NLs. However, there is preference that 
a higher resolution modality, such as CT, be used to confirm the presence of NLs.
E 2.3
Plain X-ray 
Plain X-ray may be used as a method of assessment for bone NTLs and to identify the 
presence of new bone lesions.
E 2.4
Isotopic bone scan 
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI, or 
X-ray at baseline should be recorded as NTLs and followed by the same method per baseline 
assessment (CT, MRI, or X-ray).
Isotopic bone scans may be used as a method of assessment to identify the presence of new 
bone lesions at follow-up visits. NLs may be recorded in case positive hot-spots appear on a 
bone scan that were not present on a previous bone scan; however, a newly observed 
equivocal hot-spot on a bone scan that cannot be verified with correlative imaging (CT, MRI, 

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or X-ray) of the same anatomical region shall not be the only trigger for a PD assessment at 
that time point.
E 2.5
18F-Fluoro-deoxyglucose-PET/CT
18F-fluoro-deoxyglucose PET/CT scans may be used as a method for identifying new 
extrahepatic lesions (but not intrahepatic lesions) for RECIST 1.1 assessments according to 
the following algorithm: NLs will be recorded where there is positive 18F-fluoro-deoxyglucose 
uptake1 not present at baseline or prior 18F-fluoro-deoxyglucose-PET scan or in a location 
corresponding to a NL on a companion CT/MRI collected close in time to the 18F-fluoro-
deoxyglucose-PET scan. The PET portion of the PET/CT introduces additional data that may 
bias an investigator if it is not routinely or serially performed. Therefore, if there is no 
baseline or prior 18F-fluoro-deoxyglucose-PET scan available for comparison, and no 
evidence of NLs on companion CT/MRI scans, then follow-up CT/MRI assessments should 
continue as per the regular imaging schedule to verify the unequivocal presence of NLs.
At present, low-dose or attenuation correction CT portions of a combined 
18F-fluoro-deoxyglucose-PET/CT scan are of limited use in anatomically based efficacy 
assessments, and it is therefore suggested that they should not substitute for dedicated 
diagnostic contrast-enhanced CT scans for tumour measurements by RECIST 1.1. In 
exceptional situations, if a site can document that the CT performed, as part of a PET/CT 
examination, is of identical diagnostic quality (with IV contrast) to a dedicated diagnostic CT 
scan, then the CT portion of the PET/CT can be used for RECIST 1.1 tumour assessments. 
Caution that this is not recommended because the PET portion of the CT introduces additional 
(PET) data that may bias an investigator if it is not routinely or serially performed.
E 2.6
Ultrasound 
Ultrasound examination will not be used for RECIST 1.1 assessment of tumours as it is not a 
reproducible acquisition method (operator dependent), is subjective in interpretation, and may 
not provide an accurate assessment of the true tumour size. Tumours identified by ultrasound 
will need to be assessed by correlative CT or MRI anatomical scan.
E 2.7
Other tumour assessments
E 2.7.1Clinical examination 
Clinical examination of skin/surface lesions (by visual inspection or manual palpation) will 
not be used for RECIST 1.1 assessments. Tumours identified by clinical examination will 
need to be assessed by correlative CT or MRI anatomical scans.
                                               
1
A positive 18F-fluoro-deoxyglucose-PET scan lesion should be reported only when an uptake (eg, standard uptake 
value) greater than twice that of the surrounding tissue or liver is observed.

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E 2.7.2Endoscopy and laparoscopy 
Endoscopy and laparoscopy will not be used for tumour assessments as they are not validated 
in the context of tumour assessment.
E 2.7.3Histology and cytology
Histology or tumour markers on tumour biopsy samples will not be used as part of the tumour 
response assessment as per RECIST 1.1.
Results of cytological examination for the neoplastic origin of any effusion (eg, ascites, 
pericardial effusion, and pleural effusion) that appears or worsens during the study will not be 
used as part of the tumour response assessment as per RECIST 1.1.
Furthermore, an overall assessment of CR (all other disease disappears/reverts to normal) 
would be changed to PR if an effusion remains present radiologically.
E 3
Measurability of tumour lesions at baseline
E 3.1
RECIST 1.1 measurable lesions at baseline
A tumour lesion that can be accurately measured at baseline as ≥ 10 mm in the longest 
diameter for non-nodal lesions or ≥ 15 mm in short axis2 diameter for lymph node lesions with 
IV contrast-enhanced CT or MRI and that is suitable for accurate repeated measurements. 
Please see additional RECIST 1.1 guidance below on measurability of intrahepatic 
hepatocellular carcinoma lesions and porta hepatis lymph nodes.
E 3.2
Non-measurable lesions at baseline

Truly non-measurable lesions include the following:
-
Bone lesions (see exception below for soft tissue component)
-
Leptomeningeal disease
-
Ascites, pleural effusion, or pericardial effusion
-
Inflammatory breast disease
-
Lymphangitic involvement of skin or lung

All other lesions, including small lesions (longest diameter < 10 mm or pathological 
lymph nodes with ≥ 10 mm to < 15 mm short axis diameter at baseline)3

Previously irradiated lesions4
                                               
2
The short axis is defined as the longest in-plane axis perpendicular to the long axis.
3
Lymph nodes with < 10 mm short axis diameter are considered non-pathological and should not be recorded or 
followed as NTLs.
4
Localised post-radiation changes that affect lesion size may occur. Therefore, lesions that have been previously 
irradiated are typically considered non-measurable and as NTL at baseline and followed up as part of the NTL 
assessment.

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
Brain metastasis
E 3.3
Special considerations regarding lesion measurability at baseline

Bone lesions:
-
Bone scan, PET scan, or plain X-ray alone 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, can be considered measurable if the soft tissue component meets the 
definition of measurability.
-
Blastic lesions are considered non-measurable.

Cystic lesions thought to represent cystic metastases can be considered measurable 
lesions if they meet the criteria for measurability from a radiological point of view, but if 
non-cystic lesions are present in the same participant, these should be selected over cystic 
lesions as TLs.
E 3.4
RECIST 1.1 TL selection at baseline
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including 
lymph nodes collectively considered as a single organ), representative of all lesions involved 
should be identified as TLs at baseline. TLs should be selected on the basis of their size 
(longest diameter for non-nodal lesions or short axis diameter for nodal lesions), 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 that can be measured reproducibly 
should be selected.
Lymph nodes, in any location (local/regional and distant), are collectively considered as a 
single organ, with a maximum of 2 lymph nodes as TLs. A bilateral organ (eg, adrenal 
glands), a segmented organ (eg, liver), or a multilobed organ (eg, lung) is each considered as a 
single organ.
The site and location of each TL should be documented, as well as the longest axis diameter 
for non-nodal lesions (or short axis diameter for lymph nodes). All measurements should be 
recorded in millimetres. At baseline, the sum of the diameters for all TLs will be calculated 
and reported as the baseline sum of diameters. At follow-up visits, the sum of diameters for all 
TLs will be calculated and reported as the follow-up sum of diameters.

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E 3.4.1Special cases for TL assessment at baseline

For TLs measurable in 2 or 3 dimensions, always report the longest diameter. For 
pathological lymph nodes measurable in 2 or 3 dimensions, always report the short axis 
diameter.

When lymph nodes are coalesced and no longer separable in a conglomerate mass, the 
vector of the longest diameter should be used to determine the perpendicular vector for 
the maximal short axis diameter of the coalesced mass. Non-nodal lesions that coalesce 
should similarly be assessed by the longest axis diameter.

Tumour lesions selected for newly acquired screening biopsy should not be selected as 
TLs, unless imaging occurred at least approximately 2 weeks after biopsy, allowing time 
for healing.

If the CT/MRI slice thickness used is > 5 mm, the minimum size of measurable disease at 
baseline should be twice the slice thickness of the baseline scan.

If a lesion has completely disappeared, the diameter should be recorded as 0 mm. If a 
lesion appears in the same location on a subsequent scan, it will be recorded as a NL.
E 3.5
RECIST 1.1 NTL selection at baseline
All other lesions, including non-measurable lesions and surplus measurable lesions, not 
recorded as TLs should be identified as NTLs at baseline. Measurements of these lesions are 
not required, but the presence or absence of each should be noted throughout follow-up.
E 4
Evaluation of tumour response and progression
E 4.1
RECIST 1.1 TL assessment at follow-up
This section defines the criteria used to determine objective tumour visit response for 
RECIST 1.1-defined TLs (Table E12). These TLs will be the most reproducible lesions, not 
necessarily the largest lesions so as to prevent influence by imaging modality, technique, or 
biological functions. The imaging modality, location, and scan date of each TL identified 
previously at baseline should be documented at follow-up visits with the long axis diameter 
for non-nodal lesions or short axis diameter for lymph node lesions. All measurements should 
be recorded in millimetres. The sum of the diameters for all TLs at each follow-up visit will 
be compared with the baseline sum of diameters (for response or SD) or to the smallest prior 
(nadir) sum of diameters (for progression).
Special cases for TL assessment at follow-up:

If a lesion has completely disappeared, the diameter should be recorded as 0 mm. If a 
lesion appears in the same location on a subsequent scan, it will be recorded as an NL.

If a TL splits into 2 or more parts, the sum of the diameters of those parts should be 
recorded.

If 2 or more TLs merge, then the sum of the diameters of the combined lesion should be 
recorded for one of the lesions and 0 mm recorded for the other lesion(s). If the merged 

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TLs are non-nodal lesions, record the long axis diameter of the merged lesion. If 
pathologic lymph nodes coalesce and are no longer individually separable within a 
conglomerate mass, the vector of the longest diameter of the coalesced mass should be 
used to determine the perpendicular vector for the maximal short axis diameter.

If a TL is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned. If an accurate measure can be given, this should be 
recorded, even if it is below 5 mm.

If a TL cannot be measured accurately due to it being too large, provide an estimate of the 
size of the lesion. The choice of ‘Too large to measure’ in the CRF will trigger an overall 
visit response of PD.

When a TL has had any intervention (eg, definitive radiotherapy, embolisation, surgery, 
transarterial chemo-embolisation, etc) during the study, the size of the TL should still be 
provided where possible and the intervention recorded in the RECIST 1.1 CRF for the 
current imaging visit and all subsequent visits. If a TL has been completely removed 
(surgery) or disappears, the longest diameter should be recorded as 0 mm.
Table E12
RECIST 1.1 Evaluation of Target Lesions
CR
Disappearance of all TLs since baseline. Any pathological lymph nodes 
selected as TLs must have a reduction in short axis diameter to < 10 mm.
PR
At least a 30% decrease in the sum of the diameters of TL, taking as reference 
the baseline sum of diameters.
SD
Neither sufficient decrease in the sum of diameters to qualify for PR nor 
sufficient increase to qualify for PD.
PD
At least a 20% increase in the sum of diameters of TLs, taking as reference the 
smallest previous sum of diameters (nadir). This includes the baseline sum if 
that is the smallest on study. In addition to the relative increase of 20%, the 
sum must demonstrate an absolute increase of at least 5 mm from nadir.
NE
Only relevant if any of the TLs at follow-up were not assessed or NE (eg, 
missing anatomy) or had a lesion intervention at this visit. Note: If the sum of 
diameters meets the PD criteria, PD overrides NE as a TL response.
Not applicable
Only relevant if no TLs present at baseline.
CR, complete response; NE, not evaluable; PD, progression of disease; PR, partial response; SD, stable disease; TL, target 
lesion.
E 4.2
RECIST 1.1 NTL assessment at follow-up
All other lesions (or sites of disease) not recorded as TLs should be identified as NTLs at 
baseline (Table E13). Measurements are not required for these lesions, but their status should 
be followed at subsequent visits. At each visit, an overall assessment of the NTL response 
should be recorded by the investigator.
To achieve ‘unequivocal progression’ on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of SD or PR in TLs, 
the overall tumour burden has increased sufficiently to merit unequivocal progression by 

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NTLs. A modest ‘increase’ in the size of one or more NTLs is usually not sufficient to qualify 
for unequivocal progression status. The designation of overall progression solely on the basis 
of change in non-target disease in the face of SD or PD of target disease will therefore be 
extremely rare.
Table E13
RECIST 1.1 Evaluation of Non-Target Lesions
CR
Disappearance of all NTLs since baseline. All lymph nodes must be 
non-pathological in size (< 10 mm short axis).
Non-CR/non-PD
Persistence of one or more NTLs.
PD
Unequivocal progression of existing NTLs. Unequivocal progression may be due 
to an important progression in one lesion only or in several lesions. In all cases, 
the progression MUST be clinically significant for the physician to consider 
changing (or stopping) therapy.
NE
Only relevant when one or some of the NTLs were not assessed and, in the 
investigator’s opinion, they are not able to provide an evaluable overall NTL 
assessment at this visit.
Note: For participants without TLs at baseline, this is relevant if any of the NTLs 
were not assessed at this visit and the progression criteria have not been met.
Not applicable
Only relevant if no NTLs present at baseline.
CR, complete response; NE, not evaluable; NTL, non-target lesion; PD, progression of disease; TL, target lesion.
E 4.3
RECIST 1.1 NL identification at follow-up
Details, including the imaging modality, the date of scan, and the location of any NLs will 
also be recorded in the CRF. The presence of one or more NLs is assessed as progression. The 
finding of a NL should be unequivocal, ie, not attributable to differences in scanning 
technique, change in imaging modality, or findings thought to represent something other than 
tumour. If a NL is equivocal, for example because of its small size, the treatment and tumour 
assessments should be continued until the previously (pre-existing) NL has been assessed as 
unequivocal at a follow-up visit, and then the progression date should be declared using the 
date of the initial scan when the NL first appeared.
A lesion identified at a follow-up assessment in an anatomical location that was not scanned at 
baseline is considered an NL and will indicate PD.
E 4.4
RECIST 1.1 evaluation of overall visit response at follow-up
Derivation of overall visit response as a result of the combined assessment of TLs, NTLs, and 
NLs uses the algorithm shown in Table E14.
Table E14
RECIST 1.1 Overall Visit Response
Target Lesions
Non-Target Lesions
New Lesions
Overall Visit Response
CR
CR
No
CR

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Target Lesions
Non-Target Lesions
New Lesions
Overall Visit Response
CR
NA
No
CR
CR
Non-CR/Non-PD 
No
PR
CR
NE
No 
PR
PR
Non-PD or NE or NA
No
PR
SD 
Non-PD or NE or NA
No
SD
NE
Non-PD or NE or NA
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Note: An overall assessment of CR (all other disease disappears/reverts to normal) would be changed to PR if ascites remains 
present radiologically.
CR, complete response; NA, not applicable (only relevant if there were NTLs at baseline), NE, not evaluable; NTL, non-
target lesion; PD, progression of disease; PR, partial response; SD, stable disease; TL, target lesion.
The following overall visit responses are possible depending on the extent of tumour disease 
at baseline:

For participants with TLs (at baseline): CR, PR, SD, PD, or NE.
E 5
References
Eisenhauer et al 2009
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 
2009;45(2):228-47.

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 3 9 of 1 6 5
A p pe n di x F
C o ntr ace pti o n Re q uire me nts
C o ntrace pti o n re q uire me nts f or t his st u d y  are as f ollo ws.
F 1
Fe m ale P artici p a nts
Fe males n ot of c hil d beari n g p ote ntial are defi ne d as t h ose w h o are eit her per m a ne nt l y 
sterilise d (ie, h ysterect o m y , bilateral o o p h orect o m y, or bilateral sal pi n gect o m y ) or w h o are 
p ost -me n o pa usal.
Fe males will be c o nsi dere d p ost -me n o pa usal if t he y ha ve bee n a me n orr h oeic f or 1 2 m o nt hs 
pri or t o pl a n ne d e nr o l me nt wit h o ut a n alter nat i ve me dical ca use. T he f oll o wi n g a ge-s pecific 
re q uire me nts a p pl y:

Fe males < 5 0 y e ars old are c o nsi dere d p ost -me n o pa usal if t he y ha ve bee n a me n orr h oeic 
f or 1 2 mo nt hs or m or e pri or t o t he first d ose of st u d y  int er ve nt i on f oll owi n g ce ssati on of 
e x o ge n o us h or m o nal treat me nt a n d f o llicle-sti m ulati n g h or m o ne le vels i n t he 
p ost -me n o pa usal ra n ge.

Fe males ≥5 0 y ears old are c o nsi dere d p ost -me n o pa usal if t he y ha ve bee n a me n orr h oeic 
f or 1 2 mo nt hs or m or e f ol l owi n g cessat i on of e x o ge n o us h or m o n al tr e at me nt, or ha d 
r a diat i on- i n d uce d me n o pa use wit h last me nses > 1 year a g o, or ha d 
c he m ot hera p y-i n d uce d me n o pa use wit h last me nses > 1 ye ar a g o.

I n q uesti ona ble cases, a bl o o d sa m ple wit h si m ulta ne o us f o llicle-sti m ulati n g h or m o ne 
> 4 0 mI U/ m L a n d oestra di ol  < 4 0 p g/ m L ( < 1 4 7 p m o l/ L) is c o nfir mat or y.
Fe males of c hil d -beari n g p ote ntial w h o are n ot t otall y se x uall y a bst i ne nt (ie, refrai ni n g fr om 
heter ose x ual i nterc o urse d uri n g t he e nt ire perio d of  ris k ass ociate d wit h st u d y int er ve ntio ns) 
a n d i nte n d t o be se x uall y acti ve wit h a n o n-sterilise d male part ner m ust use at least o ne hi g hl y 
effect i ve met h o d of c o ntrace pti o n fr o m e nr o l me nt t hr o u g h o ut t he st u d y a n d f or  
 
 after t he last d ose of Dat o-D X d (Ta ble F 1 5 ). A hig hl y effect i ve met h o d of 
c o ntrace pti o n is defi ne d as o ne t hat has a fail ure rate of < 1 % per y ear w he n use d c o nsiste nt l y 
a n d c orrectl y. Cessat i on of c o ntrace pti o n after t his ti me s h o uld be disc usse d wit h a 
res p o nsi ble p h ysicia n.
Fe males o n H R T a n d w h ose me n o pa usal stat us is i n d o u bt will be re q uire d t o use o ne of t he 
c o ntrace pti o n met h o ds o utli ne d f or F O C B P if t he y wis h t o c o nti n ue t heir H R T d uri n g t he 
st u d y. Ot her wise, t he y must d isc o nti n ue H R T t o all o w c o nfir mat i on of p ost -me n o pa usal stat us 
pri or t o st u d y  e nr ol me nt. For m ost f or ms of H R T, at least 2 t o 4 wee ks will ela pse bet wee n t he 
cessat i on of t hera p y  a n d t he blo o d dra w; t hi s i nter val de pe n ds o n t he t ype a n d d osa ge of H R T. 
F o llo wi n g c o nfi r mat i on of t heir p ost -me n o pa usal stat us, t he y  ca n res u me use of H R T d uri n g 
t he st u d y wit ho ut use of a c o ntrace pti ve met h o d.
C CI

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 4 0 of 1 6 5
N o n -sterilise d male part ners of a w o ma n of c hil d beari n g p ote ntial m ust use a male c o n d o m 
pl us s per mici de (c o n d o m al o ne i n c o u ntries w here s per mici des are n ot a p pr o ve d)  fr o m t he 
ti me of scree ni n g of t heir fe male part ner, t hr o u g h o ut t heir partici pati on i n t he st u d y, a n d f or  
 after t heir fe male part ner’s last d ose of Dat o-D X d i n a d dit i on t o t he fe male 
parti ci pa nt usi n g a hi g hl y effecti ve c o ntrace pti ve met h o d. Cessati o n of birt h c o ntr ol after t his 
p oi nt s h o ul d be disc usse d wit h a res p o nsi ble p h ysicia n. Peri o dic a bst i ne nce (cale n dar, 
s y m pt ot her mal, p ost-o v ul at i on met h o ds), decl arati o n of a bst i ne nce f or t he d uratio n of  
e x p os ure t o I M P, wit h dra wal (c oit us i nterr u pt us), s per mici des o nl y, a n d lactati o nal 
a me n orr h oea met h o d are n ot acce pta ble met h o ds of c o ntrace pti o n. Fe male c o n d o m a n d male 
c o n d o m s h o uld n ot be use d t o get her. T otal se x ual a bsti ne nce is a n acce pta ble me t ho d 
pr o vi de d i t is t he us ual lifestyle of t he partici pa nt ( defi ne d as refrai ni n g fr o m heter ose x ual 
i nterc o urse d uri n g t he e nt ire perio d of  ris k ass ociate d wit h t he st u d y treat me nts). T he 
relia bility of se x ual a bst i ne nce nee ds t o be e val uate d i n relati on t o t he d urati o n of t he cli nical 
trial. Fe male partici pa nts must n ot d o nate, or retrie ve f or t heir o w n use, o va, a n d s h o ul d 
refrai n fr om breastfee di n g fr o m t he ti me of scree ni n g a n d t hr o u g h o ut t he I nter ve nt i on Peri o d, 
a n d f or 
 after t he last d ose of st u d y i nter ve nt i on. Preser vat i on of o va s h o ul d 
be c o nsi dere d pri or t o e nr ol me nt i n t his st u d y .
F 2
M ale P artici p a nts Wit h a Fe m ale P art ner of C hil d be ari n g 
P ote nti al
N o n -sterilise d male partici pa nts (i ncl u di n g males sterilise d b y a met h o d ot her t ha n bilateral 
orc hi dect o m y , e g, vasect o m y) w h o i nte n d t o be se x uall y acti ve wit h a fe male part ner of 
c hil d beari n g p ote ntial m ust be usi n g a n acce pta ble met h o d of c o ntrace pti o n s uc h as male 
c o n d o m plus s per mici de (c o n d o m  alo ne i n c o u ntries w here s per mici des are n ot a p pr o ve d) 
fr om t he ti me of scree ni n g t hr o u g h o ut t he t otal d urati o n of t he st u d y  a n d t he dr u g was h o ut 
p eri o d (
 after t he last d ose of st u d y int er ve nt i on), i n a d dit i on t o t he fe male 
part ner usi n g a hi g hl y effecti ve c o ntrace pti ve met h o d, t o pre ve nt pre g na nc y i n a part ner. 
N ot e n ga gi n g i n se x ual act i vity f or t he d uratio n of  t he st u d y a n d dr u g was h o ut peri o d is a n 
acce pta ble practice. T he relia bilit y of se x ual a bsti ne nce nee ds t o be e val uate d i n relat i on t o t he 
d urati o n of  t he cli nical trial a n d t he preferre d a n d us ual lifest yle of t he partici pa nt. Peri o dic 
a bsti ne nce (e g, cale n dar, o v ulati o n s y m pt ot her mal, p ost -o v ulati o n met h o ds), decl arat i on of 
a bsti ne nce f or t he d urati o n of e x p os ure t o st u d y  int er ve nt i on, a n d wit h dra wal (c o itus 
i nterr u pt us), s per mici des o nl y, a n d lactati o nal a me n orr h oea met h o d are n ot acce pta ble 
met h o ds of c o ntrace pti o n. Fe male c o n d o m a n d male c o n d o m s h o uld n ot be use d t o get her.
Male parti ci pa nts s h o uld r ef rai n fr o m s per m d o nati o n or ba n ki n g f or t he d urati o n of t he st u d y 
(fr o m t he ti me of scree ni n g) a n d f or 4 m o nt hs after t he last d ose of Dat o-D X d. Preser vati o n of 
s per m s h o uld be c o nsi dere d pri or t o e nr ol me nt i n t his st u d y .
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 4 1 of 1 6 5
Vasect o mise d males are c o nsi dere d fert ile if t here was n o me dical assess me nt of t he s ur gical 
s uccess an d s h o ul d st ill use a male c o n d om pl us s per mici de as i n dicate d a b o ve d uri n g t he 
cli nical st u d y.
E ve n if t he fe male part ner is pre g na nt, male partici pa nts s h o ul d st ill use a c o n d o m pl us 
s per mici de ( w here a p pr o ve d), as i n dicate d a b o ve d uri n g t he cli nical st ud y , if t here is a 
c o ncer n a b o ut da ma gi n g t he de vel o pi n g f oet us fr o m dr u g i n ejac ulate.
Fe male part ners ( of c hil d beari n g p ote ntial) of male partici pa nts m ust als o use a hi g hl y  
effect i ve met h o d of c o ntrace pti o n fr o m t he ti me of scree ni n g of t heir male part ner, t hr o u g h o ut 
t heir p artici pat i on i n t he st u d y, a n d f or 
after t heir male part ner’s last d ose of 
Dat o -D X d (Ta ble F 1 5 ).
F 3
Hi g hl y Eff ecti ve Met h o ds of C o ntr ace pti o n
Hi g hl y  effecti ve met h o ds of c o ntrace pti o n, defi ne d as o ne t hat res ults i n a l o w fail ure rate 
(ie, less t ha n 1 % per year) w he n use d c o nsiste ntl y a n d c orrectl y, are descri be d i n  Ta ble F 1 5 .
N ote t hat s o m e c o ntrace pti o n met h o ds are n ot c o nsi dere d hi g hl y effecti ve (e g, male or fe male 
c o n d o m wit h or wit ho ut s per mici d e; f e male ca p, dia p hra g m, or s p o n ge wit h or wit h o ut 
s per mici de; n o n -c o p per c o ntai ni n g i ntra uteri ne de vice; pr o gest o ge n -o nl y  or al h or mo nal  
c o ntrace pti ve pills w here i n hi bit i on o f o v ul at i on is n ot t he pri mar y m o de of acti on [e xcl u di n g 
Cerazette/ des o gestrel, w hic h is c o nsi dere d hi g hl y effect i ve]; a n d tri p hasic c o m bi ne d oral 
c o ntrace pti ve pills).
T a ble F 1 5
Hi g hl y Effecti ve Met h o ds of C o ntr ace pti o n ( < 1 % F ail ure R ate)
N o n -H or m o n al Met h o ds
H or m o n al Met h o ds
•
T otal se x ual a bsti ne nce (e val uate i n relati o n t o 
t he d uratio n of t he cli nical st u d y a n d t he 
preferre d a n d us ual lifest yle c h oice of t he 
partici pa nt)
•
Vasect o mise d se x ual part ner ( wit h partici pa nt 
ass ura nce t hat part ner recei ve d p ost -vasect o m y 
c o nfir mati on of az o os per mia)
•
Bilateral t u bal occl usi o n
•
I ntra uteri ne de vice ( pr o vi de d c oils are 
c o p per -ba n de d)
•
I njecti o n: Me dr o x y pr o gester o ne i njecti o n 
(e g, De p o -Pr o vera ® )a
•
Le v o n or gestrel -releasi n g i ntra uteri ne s yste m 
(e g, Mire na® )a
•
Pr o gester o ne T i ntra uteri ne de vice
•
I m pla nts: Et o n o gestrel-releasi n g i m pla nts 
(e g, I m pla n o n® or  N or pla nt® )
•
I ntra va gi nal de vices: 
Et hi n ylestra di ol/et o n o gestrel -releasi n g 
i ntra va gi nal de vices (e g, N u va Ri n g® ) 
•
C o m bi ne d pill: N or mal a n d l o w d ose c o m bi ne d 
or al c o ntrace pti ve pill
•
Patc h: N o rel gestr o mi n/et hi n ylestra di ol-releasi n g 
tra ns der mal s yste m (e g, Ort h o E vra ® )
•
Mi ni pill: Pr o gester o ne base d oral c o ntrace pti ve 
pill usi n g des o gestrel: Cerazette ® is c urre ntl y t he 
o nl y  hi g hl y effecti ve pr o gester o ne-base d pill
a
H or m o nal met h o ds n ot pr o ne t o dr u g -dr u g i nteracti o ns.
C CI

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 4 2 of 1 6 5
A p pe n di x G
C o nc o mit a nt Me dic ati o ns
G 1
G u i d a nce Re g ar di n g P otenti al I nter acti o ns Wit h C o nc o mit a nt 
Me dic ati o ns
T he use of a n y  nat ur al/ her bal pr o d ucts or ot her ‘f ol k re me dies’ s h o ul d be disc o ura ge d, b ut use 
of  t hese pr o d ucts, as well as use of all vita mi ns, n utriti o nal s u p ple me nts, a n d all ot her 
c o nc o mita nt me dicat i ons m ust be rec or de d i n t he e C R F.
P arti cipa nts s h o ul d be cl os el y  mo ni t ore d w he n Dat o-D X d is c o nc o mita nt l y use d with dr u gs 
t hat i n hi bit C Y P 3 A, O A T P 1 B 1, O A T P 1 B 3, M A T E 2 -K, P -g p, B C R P, a n d M R P 1. F or a list of 
i n hi bit or dr u gs, refer t o t he F D A Ta ble of S u bstrates, I n hi bit ors a n d I n d ucers or l ocall y 
a vaila ble s o urces.
G 2
Restricte d, Pr o hi bite d, a n d Per mitte d C o nc o mit a nt 
Me dic ati o ns/ T her a pies
Restricte d, pr o hi bite d, a n d per mitte d c o nc o mita nt me dicat i ons/t hera pies are descri be d i n 
T a ble G 1 6 , Ta ble G 1 7 , a n d Ta ble G 1 8 . Refer als o t o t he d ose m o dificat i on g ui deli nes f or 
ma na ge me nt of st u d y  int er ve ntio n -relate d t o xicities i n t he T M G A n ne x. Partici pa nts m ust be 
i nstr ucte d n ot t o ta ke a n y me dicat i ons, i ncl u di n g o ver -t he- c o u nter pr o d ucts, wit h o ut first 
c o ns ult i n g with t he i n vest i gat or.
F or a list of i n hi bit or dr u gs, refer t o t he U S F o o d a n d Dr u g A d mi nistrati o n Ta ble of 
S u bstrates, I n hi bit ors a n d I n d ucers ( U S F D A 2 0 2 1 ) or locall y a vaila ble s o urces.
T a ble G 1 6
Restricte d Me dic ati o ns/ T her a pies
Me dic ati o n/cl ass of dr u g/t her a p y
Us a ge (i ncl u di n g li mits f or d ur ati o n per mitte d a n d 
s peci al sit u ati o ns i n w hic h it is all o we d)
T o bacc o pr o d ucts, e -ci garettes, a n d va pi n g
Use of t o bacc o pr o d ucts, e -ci garettes, a n d va pi n g is 
str on gl y  disc o ura ge d b ut n ot pr o hi bite d. 
A n y  pri or or c urre nt use of t hese pr o d ucts m ust be 
rec or de d i n t he e C R F.
H or m o nal t hera p y
F or n o n -ca ncer -relate d c o n diti o ns (e g, i ns uli n f or 
dia betes a n d H R T) o nl y.
C ortic oster oi ds
As cli nicall y i n dicate d, e g, f or s pecific a d verse dr u g 
reacti o ns (refer t o T M Gs d oc u me nt) a n d/ or ac ute, 
s ym pt o matic treat me nt (see m ore detaile d g ui da nce i n
Ta ble G 1 8 ).
Per mitte d f or o pti mal s y m pt o m c o ntr ol or pai n 
ma na ge me nt.  
 Dat o -D X d t hera p y f or t he
d urati o n of 
 a n d restart at least  wee ks 
after c o m pleti o n of 
. C urati ve 
ra di ot hera p y is 
.
C CI
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 4 3 of 1 6 5
Me dic ati o n/cl ass of dr u g/t her a p y
Us a ge (i ncl u di n g li mits f or d ur ati o n per mitte d a n d 
s peci al sit u ati o ns i n w hic h it is all o we d)
A nti- res or pti ve/ b o ne t hera p y (e g, bis p h os p h o nates, 
R A N K L i n hi bit ors)
F or treat me nt of b o ne metastases a n d oste o p or osis.
Dat o -D X d, dat o p ota ma b der u xteca n; e C R F, electr o nic case re p ort f or m; H R T, h or m o ne re place me nt t hera p y; 
R A N K L, rece pt or acti vat or of n uclear fact or ka p pa B li ga n d; T M G, t o xicit y ma na ge me nt g ui deli nes.
T a ble G 1 7
Pr o hi bite d Me dic ati o ns/ T her a pies
Pr o hi bite d me dic ati o n/cl ass of dr u g/t her a p y
Us a ge
A n y  c o nc urre nt a ntica ncer t hera p y (i ncl u di n g 
c he m ot hera p y, bi ol o gic, tar gete d a ge nts, 
i m m u n ot hera p y, a nti b o d y, reti n oi d, or a nti-ca ncer 
h or m o nal treat me nt) ot her t ha n t h ose u n der 
i n vesti gati o n i n t his st u d y (i ncl u di n g c urati ve 
ra di ot hera p y a n d ra di ot hera p y t o t he t h ora x)
M ust n ot be gi ve n c o nc o mita ntl y w hile t he partici pa nt 
is o n st u d y i nter ve nti o n. C o nc urre nt use of h or m o nes 
f or n on- ca ncer -relate d c o n diti o ns (e g, i ns uli n f or 
dia betes a n d H R T) is acce pta ble.
C hl or o q ui ne a n d h y dr o x yc hl or o q ui ne
C o nc o mita nt treat me nt wit h c hl or o q ui ne or 
h y dr o x y c hl or o q ui ne is n ot all o we d w hile t he 
partici pa nt is o n Dat o -D X d. If treat me nt wit h 
c hl or o q ui ne or h y dr o x yc hl or o q ui ne treat me nt is 
a bs ol utel y re q uire d, st u d y i nter ve nti o n m ust be 
dela ye d. If c hl or o q ui ne or h y dr o x yc hl or o q ui ne is 
a d mi nistere d, t he n a was h o ut peri o d of 
 
is re q uire d bef ore restarti n g Dat o-D X d .
C CI

Clinical Study Protocol - D9266C00001
AstraZeneca
Datopotamab deruxtecan (Dato-DXd, DS-1062a)
CONFIDENTIAL AND PROPRIETARY
144 of 165
Prohibited medication/class of drug/therapy
Usage
Concomitant use of chronic systemic (IV or oral)
corticosteroids or other immunosuppressive 
medications except for managing AEs
Dato-DXd cannot be administered when the 
participant is taking immunosuppressive medications, 
including corticosteroids with the exception of:
•
short-term courses (<2 weeks)
•
low to moderate dose 
•
long-term, alternate-day treatment with short-
acting preparations; maintenance physiologic 
doses (replacement therapy)
•
administered topically (skin or eyes), by aerosol, 
or by intra-articular, bursal, or tendon injection
Treatment with corticosteroids to prevent or treat 
hypersensitivity reactions to radiographic contrast 
agents is allowed. 
A temporary period of steroid treatment will be 
allowed for different indications after discussion with 
the sponsor study physician (eg, COPD, radiation, 
nausea, etc). 
Use of immunosuppressive medications for the 
management of study intervention-related AEs or in 
participants with contrast allergies is acceptable. For 
the treatment of specific adverse drug reactions (refer 
to the TMGs in the TMG Annex).
Immunosuppressive medications also include drugs 
like methotrexate, azathioprine, and tumour necrosis 
factor-alpha blockers.
Other investigational therapeutic agents
Must not be given concomitantly while the participant 
is on study intervention.
Herbal and natural remedies that may interfere with 
interpretation of study results
Must not be given concomitantly unless agreed by the 
sponsor.
AE, adverse event; COVID-19, coronavirus 2019-nCoV; Dato-DXd, datopotamab deruxtecan; HRT, hormone 
replacement therapy; IV, intravenous; TMGs, toxicity management guidelines.
Table G18
Supportive Medications/Therapies
Supportive medication/class of drug/therapy
Usage
Pre-medications for prevention of IRR or as 
supportive treatment of Dato-DXd-induced AEs for 
Dato-DXd
Antihistamines and acetaminophen with or without 
glucocorticoids must be taken as pre-medication prior 
to any dose of Dato DXd and may be used as 
supportive treatment of Dato-DXd-induced AEs..

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
Dat o p ota ma b der u xteca n ( Dat o - D X d, D S-1 0 6 2a)
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 4 5 of 1 6 5
S u p p orti ve me dic ati o n/cl ass of dr u g/t her a p y
Us a ge
 a ge nts f or Dat o-D X d
Base d o n t he c urre ntl y a vaila ble cli nical safet y data, it 
is hi g hl y rec o m me n de d t hat partici pa nts recei ve 
 a ge nts pri or t o i nf usi o n of 
Dat o -D X d a n d o n s u bse q ue nt da ys as nee de d. 
 s uc h as 
 a n d  
 
 s h o ul d be c o nsi dere d a n d 
a d mi nistere d i n acc or da nce wit h t he prescri bi n g 
i nf or mati o n or i nstit uti o nal g ui deli nes. 
 
 ca n be use d, if nee de d..
 
a ge nts
 f or m ulati o ns are per mitte d 
t o pre ve nt a n d ma na ge certai n A Es (see 
Secti o n 8. 3. 5. 6 ).
C o nc o mita nt me dicati o ns or pr o p h ylactic or 
s u p p orti ve treat me nts (e g, aceta mi n o p he n or 
di p he n h y dra mi ne) dee me d necessar y t o pr o vi de 
a de q uate A E ma na ge me nt, e xce pt f or t h ose 
me dicati o ns i de ntifie d as “ pr o hi bite d,” as liste d 
a b o ve
As per T M Gs, i n vesti gat or’s discreti o n a n d 
i nstit uti o nal g ui deli nes. T o be a d mi nistere d as 
prescri be d b y t he i n vesti gat or e xce pt f or t h ose 
me dicati o ns i de ntifie d as “ pr o hi bite d,” as liste d i n
Ta ble G 1 7 .
Best s u p p orti ve care (i ncl u di n g a nti bi otics, 
n utriti o nal s u p p o rt, c orrecti o n of meta b olic 
dis or ders, o pti mal s y m pt o m c o ntr ol, a n d pai n 
ma na ge me nt 
 
 e xce pt f or t h ose me dicati o ns i de ntifie d as 
“ pr o hi bite d,” as liste d a b o ve
S h o ul d be use d, w he n necessar y, f or all partici pa nts 
e xce pt f or t h ose me dicati o ns i de ntifie d as 
“ pr o hi bite d,” as liste d i n Ta ble G 1 7 .
Dietar y  s u p ple me nts, me dicati o ns n ot prescri be d b y 
t he i n vesti gat or, a n d alter nati ve/c o m ple me ntar y 
treat me nts
C o nc o mita nt use is disc o ura ge d b ut n ot pr o hi bite d.
Partici pa nts wit h br o nc h o p ul m o nar y dis or ders w h o 
re q uire i nter mitte nt use of br o nc h o dilat ors (e g, 
al b uter ol)
Per mitte d.
I n hale d ster oi ds, i ntra-artic ular ster oi d i njecti o ns, 
a n d ot her t o pical ster oi d f or m ulati o ns
Per mitte d.
F o o ds or me dicati o ns t hat are m o derate i n d ucers or 
i n hi bit ors of C Y P 3 A 4/ 5
Per mitte d.
Re q uire d f or ma na ge me nt of ot her me dical 
c o n diti ons
As re q uire d e xce pt f or t h ose i de ntifie d as ‘ pr o hi bite d,’ 
as liste d i n Ta ble G 1 7 .
5- H T 3, 5- h y dr o x ytr y pta mi ne 3; A E, a d verse e ve nt; C Y P, c yt oc hr o me P 4 5 0; Dat o -D X d, dat o p ota ma b 
der u xteca n; N K 1, ne ur o ki ni n -1; I R R, i nf usi o n -relate d reacti o n; R A N K L, rece pt or acti vat or of n uclear fact or 
ka p pa B li ga n d; S A E, seri o us a d verse e ve nt; T M Gs, t o xicit y ma na ge me nt g ui deli nes.
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

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Appendix H
Changes Related to Mitigation of Study Disruptions Due to 
Cases of Civil Crisis, Natural Disaster, or Public Health 
Crisis
Note: Changes below should be implemented only during study disruptions due to any of or a 
combination of civil crisis, natural disaster, or public health crisis (eg, during quarantines and 
resulting site closures, regional travel restrictions, and considerations if site personnel or study 
participants become infected with COVID-19 or similar pandemic infection) during which 
participants may not wish to or may be unable to visit the study site for study visits. These 
changes should only be implemented if allowable by local/regional guidelines and following 
notification from the sponsor and instructions on how to perform these procedures will be 
provided at the time of implementation.
Please note that during civil crisis, natural disaster, or public health crisis, some study 
assessments and procedures may not be conducted due to international or local policies or 
guidelines, hospital or clinic restrictions and other measures implemented to ensure the 
participant’s safety. If in doubt, please contact the AstraZeneca Study Physician.
H 1
Reconsent of Study Participants During Study Interruptions
During study interruptions, it may not be possible for the participants to complete study visits 
and assessments on site and alternative means for carrying out the visits and assessments may 
be necessary, eg, remote visits. Reconsent should be obtained for the alternative means of 
carrying out visits and assessments and should be obtained prior to performing the procedures 
described in Sections H 2 to H 5. Local and regional regulations and/or guidelines regarding 
reconsent of study participants should be checked and followed. Reconsent may be verbal if 
allowed by local and regional guidelines (note: in the case of verbal reconsent, the ICF should 
be signed at the participant’s next contact with the study site). Visiting the study sites for the 
sole purpose of obtaining reconsent should be avoided. 
H 2
Rescreening of Participants to Reconfirm Study Eligibility
Additional rescreening for screen failure due to study disruption can be performed in 
previously screened participants. The investigator should confirm this with the designated 
study physician.
In addition, during study disruption there may be a delay between confirming eligibility of a 
participant and either enrolment into the study or commencing of dosing with study 
intervention. If this delay is outside the screening window specified in Section 1.3, the 
participant will need to be rescreened to reconfirm eligibility before commencing study 
procedures. This will provide another opportunity to re-screen a participant in addition to that 
detailed in Section 5.4. The procedures detailed in Section 1.3 must be undertaken to confirm 
eligibility using the same enrolment number as for the participant.

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H 3
Home or Remote Visit to Replace On-site Visit (Where 
Applicable)
A qualified HCP from the study site or TPV service will visit the participants home or other 
remote location as per local standard operating procedures as applicable. Supplies will be 
provided for a safe and efficient visit. The qualified HCP will be expected to collect 
information per the CSP. 
H 4
Telemedicine Visit to Replace On-site Visit (Where Applicable)
In this appendix, the term telemedicine visit refers to remote contact with the participants
using telecommunications technology, including phone calls, virtual or video visits, and 
mobile health devices.
During a civil crisis, natural disaster, or public health crisis, on-site visits may be replaced by 
a telemedicine visit if allowed by local/regional guidelines. Having a telemedicine contact 
with the participants will allow adverse events, concomitant medication, and other information 
to be reported and documented. 
H 5
Data Capture During Telemedicine or Home or Remote Visits
Data collected during telemedicine or home/remote visits will be captured by the qualified 
HCP from the study site or TPV service.

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Appendix I
Abbreviations
Abbreviation or Special 
Term
Explanation
ADA
anti-drug antibody
ADC
antibody-drug conjugate
AE
adverse event
AESI
adverse event of special interest
AGA
actionable genomic alteration
AIDS
acquired immunodeficiency syndrome
ALK
anaplastic lymphoma kinase
ALT
alanine aminotransferase
AST 
aspartate aminotransferase
AUC
area under the curve
AUC0-17d
area under the curve from 0 to 17 days
AUCtau
area under the plasma concentration-time curve during the dosing interval
BCRP
breast cancer resistance protein
BOR
best overall response
BRAF/RAF
B-Raf proto-oncogene/Raf proto-oncogene
BRCA
breast cancer gene
CD
cluster of differentiation
CI
confidence interval
CL
total body clearance
Cmax
maximum observed concentration
CONSORT
Consolidated Standards of Reporting Trials
COPD
chronic obstructive pulmonary disease
COVID-19
coronavirus 2019-nCoV
CR
complete response
CRF
case report form
CrCL
creatinine clearance
CRO
Contract Research Organisation
CSCO
Chinese Society of Clinical Oncology
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CT
computed tomography
CTCAE 5.0
National Cancer Institute Common Terminology Criteria for Adverse Events 
version 5.0
CYP
cytochrome P450

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Abbreviation or Special 
Term
Explanation
Dato-DXd
datopotamab deruxtecan
DCO
data cut-off
DCR
disease control rate
DDI
drug-drug interaction
DES
AstraZeneca Patient Safety data entry site
DFI
disease-free interval
DILI
drug-induced liver injury
DNA
deoxyribonucleic acid 
DoR
duration of response
DXd
MAAA-1181a; released drug in datopotamab deruxtecan
E-R
exposure-response
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)
ECG
electrocardiogram
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EGFR
epidermal growth factor receptor
EoT
end of treatment
FAS
full analysis set
FDA
Food and Drug Administration
FFPE
formalin fixed and paraffin embedded
FOCBP
female of childbearing potential
GCP
Good Clinical Practice
GEJ
gastroesophageal junction
HBc
hepatitis B core antigen
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCP
health care professional
HCV
hepatitis C virus
HER2
human epidermal growth factor receptor 2
HGR
human genomic resources
HIV
human immunodeficiency virus
HL
Hy’s Law

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Abbreviation or Special 
Term
Explanation
HRCT
high-resolution CT
HRT
hormone replacement therapy
IATA
International Airline Transportation Association
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
ICR
independent central review
iCRO
imaging CRO
IEC
Independent Ethics Committee
ILD
interstitial lung disease
IMP
investigational medicinal product
IRB
Institutional Review Board
IRR
infusion-related reaction
IRT
Interactive Response Technology
ITT
intent to treat
IV
intravenous
LVEF
left ventricular ejection fraction
MATE2-K
multidrug and toxin extrusion 2-K
MedDRA
Medical Dictionary for Regulatory Activities
METex14
MET proto-oncogene exon 14
MRI
magnetic resonance imaging
MRP1
multidrug resistance protein 1
MUGA
multigated acquisition
NAbs
neutralising antibodies
NCCN
National Comprehensive Cancer Network
NE
not evaluable
NF
nuclear factor
NIMP
non-investigational medicinal product
NL
new lesion
NSCLC
non-small-cell lung cancer
NTL
non-target lesion
NTRK
Neurotrophic tyrosine receptor kinase
OAT/OATP
organic anion transporter/organic anion transporter polypeptide
OCP
oral care plan
ORR
objective response rate

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
dat o p ota ma b der u xteca n
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 5 1 of 1 6 5
A b bre vi ati o n or S peci al 
Ter m
E x pl a n ati o n
O S
o verall s ur vi val
P- g p
P- gl yc o pr otei n
P A R P
P ol y ( A D P-ri b ose) p ol ymerase
P C R
p ol y merase c hai n reacti o n
P D
pr o gressi o n of disease
P D - 1
pr o gra m me d cell deat h pr otei n 1
P D -L 1
pr o gra m me d deat h -li ga n d 1
P E T
p ositr o n e missi o n t o m o gra p h y
P F S
pr o gressi o n -free s ur vi val
P H L
P ote ntial H y’s La w
P K
P har mac o ki netic(s)
P o p P K
p o p ulati o n p har mac o ki netic
P R
partial res p o nse
P T
Preferre d Ter m
Q 3 W
e ver y 3 wee ks
Q Tc F
Q T i nter val c orrecte d b y Fri dericia’s f or m ula
R A N K L
rece pt or acti vat or of n uclear fact or ka p pa B li ga n d
R E CI S T 1. 1
Res p o nse E val uati o n Criteria i n S oli d T u m o urs , Versi o n 1. 1
R E S
Res p o nse E val ua ble Set
R E T
rearra n ge d d uri n g tra nsfecti o n
R N A
ri b o n ucleic aci d
R O S 1
R O S pr ot o -o nc o ge ne 1
R T S M
Ra n d o misati o n a n d Trial S u p pl y Ma na ge me nt
S C L C
s mall-cell l u n g ca ncer
S A E
seri o us a d verse e ve nt 
S A P
Statistical A nal ysis Pla n
S A R S -C o V - 2
se vere ac ute res pirat or y s y n dr o me c or o na vir us 2
S D
sta ble disease
S M Q
sta n dar dise d Me d D R A q uer y
S o A
Sc he d ule of Acti vities
S o C
sta n dar d of care
t1/ 2 
half -life
T A
t hera pe utic area
T B L
t otal bilir u bi n
C CI
C CI

Cli nical St u d y Pr ot oc ol - D 9 2 6 6 C 0 0 0 0 1
Astra Ze neca
dat o p ota ma b der u xteca n
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 5 2 of 1 6 5
A b bre vi ati o n or S peci al 
Ter m
E x pl a n ati o n
T E A E
treat me nt-e mer ge nt a d verse e ve nt
T L
tar get lesi o n
T ma x
ti me t o Cma x
T M G
t o xicit y ma na ge me nt g ui deli ne
T N B C
tri ple-ne gati ve br east ca ncer
T P V
t hir d part y ve n d or
T R O P 2
tr o p h o blast cell s urface pr otei n 2
T T R
ti me t o res p o nse
U L N
u p per li mit of n or mal
U S
U n ite d States 
W H O
W orl d Healt h Or ga nisati o n
w/ v
wei g ht/ v ol u me
C CI
C CI

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Appendix J
Protocol Amendment History
The Protocol Amendment Summary of Changes table for the current amendment is located 
directly before the Table of Contents.
Amendment 2 (Version 3.0; 31 March 2022)
The overall rationale for this amendment is to accomplish the following: 

Expand the inclusion criteria for the NSCLC cohort  to include participants with AGAs

Clarify that the tumour sample collection for TROP2 testing will align with local HGR 
regulations

Clarify the process for Hy’s law testing in China

Align the protocol with the new Product Safety Requirements (PSR V7.0) and the 
Oncology Late Phase Master Clinical Study Protocol (Template V2.0).

Adjust the analysis plan so the primary analysis is based on the RES population, which 
has received at least one dose of study intervention and has measurable disease at baseline 
by ICR
Section # and Name
Description of Change
Brief Rationale
Substantial/Non-
substantial
1.1. Synopsis; 1.2. Schema; 
2.1. Study Rationale; 4.1. 
Study Overview; 5. Study 
Population
Changed the description 
of the NSCLC 
population to include 
those with and without 
AGAs and clarified that 
approximately 
6 participants with 
AGAs will be enrolled. 
Expand the eligible 
study population
Substantial
2.2.2. Non-small-cell Lung 
Cancer
Added a description of 
the typical treatment for 
NSCLC with AGAs
2.3.2. Benefit and Risk 
Assessment
Clarified the AGA status 
of participants in prior 
studies and added 
efficacy and safety data 
for Dato-DXd in 
NSCLC with AGAs.
5.1. Inclusion Criteria
Added inclusion criteria 
specific for NSCLC 
participants with AGAs 
and clarified the criteria 
for participants without 
AGAs
1.1. Synopsis; 7.3. Loss to 
Follow-up; 9.3. Population 
s for Analysis; 9.4.1. 
1) Changed the primary 
efficacy analysis to be 
based on the RES 
1,2) Improve the 
accuracy of the 
primary analysis by 
Substantial

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General Considerations; 
9.4.2.1.1.3. Primary 
Endpoint: Confirmed ORR 
by ICR; 9.4.2.2.1. 
Confirmed Objective 
Response Rate by 
Investigator Assessment; 
9.4.2.2.2. Duration of 
Response; 9.4.2.2.3. 
Disease Control Rate; 
9.4.2.2.5. Time to 
Response; 9.4.2.2.6. 
Progression-free Survival; 
9.4.2.2.7. Overall Survival; 
9.4.3. Safety
population and the 
supplementary analysis 
to be based on the FAS 
population. 
2) Changed the 
secondary efficacy 
analysis of ORR, DCR, 
BOR, DoR, and TTR to 
be based on the RES 
population and PFS and 
OS to be based on the 
FAS population.
3) Clarified that the FAS 
population, along with 
the RES population, will 
include only participants 
who received at least 
one dose of study 
intervention.
4) Removed all mention 
of the Safety Analysis 
Set and clarified that 
safety analysis will be 
based on the FAS.
including only 
those with 
measurable disease 
at baseline as 
determined by ICR 
3) Adjust the 
analysis to include 
only participants 
receiving at least 
one dose of study 
treatment (to align 
with the ITT 
principles for 
single-arm studies 
in the Center for 
Drug Evaluation of 
China statistical 
guidance for 
oncology clinical 
trials).
1.1. Synopsis; 9.4.1. 
General Considerations
Added additional 
analysis at the 6-month 
time point (BOR, TTR, 
OS)
Expand the data 
analysis conducted 
at 6 months
Substantial
1.2. Schema; 1.3. Schedule 
of Activities; 5.1. Inclusion 
Criteria; 5.4. Screen 
Failures; 6.3.1. Participant 
Enrolment; 8.6.1. 
Collection of Mandatory 
Samples for Biomarker 
Analysis
Modified the 
instructions for the 
tumour sample to clarify 
that it will be collected 
for enrolled participants 
only and will be based 
on local approval.
Increase the 
flexibility to enrol 
participants without 
tumour samples in 
case of a delay or 
rejection in the 
HGR submission.
Substantial
1.3. Schedule of Activities
Updated the instructions 
for oral care and the 
footnotes. Added notes 
to clarify procedures. 
Align with PSR 
V7.0 and Template 
V2.0
Substantial
2.2.1. Dato-DXd; 2.3.1. 
Risk Assessment; 4.3 
Justification for Dose; 5.1. 
Inclusion Criteria; 5.2. 
Exclusion Criteria; 5.3.1. 
Meals and Dietary 
Restrictions; 6.3.1. 
Made various updates to 
the text to align with 
Template V2.0.

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Participant Enrolment;  
7.1.1. Follow-up of 
Participants Post 
Discontinuation of Study 
Intervention; 7.1.2. Follow-
up for Survival; 8.1.1. 
Imaging Tumour 
Assessments; 8.1.3. Bone 
Scan or Skeletal Survey; 
8.1.4. Overall Survival; 
8.2.3. Electrocardiograms; 
8.2.4. Clinical Safety 
Laboratory Assessments; 
8.2.5.1. 
Echocardiogram/Multigated 
Acquisition Scan; 8.2.5.3. 
ILD/Pneumonitis 
Investigation; 8.3.1. Time 
Period and Frequency for 
Collecting AE and SAE 
Information; 8.3.2. Follow-
up of AEs and SAEs; 8.3.5. 
Adverse Events Based on 
Examinations and Tests; 
8.3.11. Adverse Events of 
Special Interest; 8.3.15. 
Special Situations of 
Medication Error, Drug 
Abuse, or Drug Misuse; 
Appendix B Adverse 
Events: Definitions and 
Procedures for Recording, 
Evaluating, Follow-up and 
Reporting; Appendix G 
Concomitant Medications; 
Appendix I Instructions 
Related to COVID-19
6.2.2. Preparation of Dato-
DXd; 6.2.2.1. 
Administration of Dato-
DXd 
Updated the time 
allowed for a prepared 
dose of Dato-DXd to 
match the handling 
instructions
6.2.2.1. Administration of 
Dato-DXd; 8.2.5.7. Oral 
Care Plan
Moved the description 
of the oral care plan to 
Section 8.2.5.7 Oral 
Care Plan

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6.6. Dose Modification; 
6.6.1. Management of 
Toxicities
Added a summary of 
management strategies 
and removed the 
specific instructions 
previously in 
subheadings.
8.2.5.5. IRR Including 
Anaphylaxis; 8.2.5.6. 
Ophthalmologic 
Assessments; 8.2.5.7. Oral 
Care Plan; 8.2.5.8. Nausea 
and Vomiting
Added sections about 
assessment of IRR, oral 
care, and nausea and 
vomiting and updated 
the description for 
ophthalmologic 
assessments
Appendix K
Added an appendix with 
the Ophthalmologic 
Assessment Form
5.1 Inclusion Criteria
Changed the criteria for 
the TNBC cohort to 
clarify that if a 
chemotherapy drug is 
changed within 28 days 
of use to another drug, 
the first drug is not 
counted as a prior 
chemotherapy regimen.
Ensure that 
participants have 
received at least 2 
prior chemotherapy 
regimens.
Substantial
8.1.3. Bone Scan or 
Skeletal Survey
Removed the sentence 
about measurable or 
evaluable lesions for 
consistency with the 
inclusion criteria
Correct an 
inconsistency
Non-substantial
8.2.4. Clinical Safety 
Laboratory Assessments
Adjusted the wording to 
align with Section 1.3 
Schedule of 
Assessments
Increase clarity
Non-substantial
8.3.14.2 Paternal Exposure
Changed the duration of 
follow-up for partner’s 
pregnancies from 7 to 4 
months.
Increase 
consistency with 
other sections of the 
CSP
Non-Substantial
9.2. Sample Size 
Determination
Expanded the sample 
size justifications
Increase clarity
Non-substantial
Appendix D. Actions
Required in Cases of 
Increases in Liver 
Biochemistry and 
Evaluation of Hy’s Law
Modified the text to 
clarify that Hy’s Law 
laboratory tests will be 
performed by local 
laboratories and 
adjusted the list of tests
Align with the 
process for Hy’s 
Law testing in 
China
Non-substantial

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Appendix E. Guidelines for 
Evaluation of Objective 
Tumour Response Using 
RECIST 1.1 Criteria 
(Response Evaluation 
Criteria in Solid Tumours)
Removed guidance 
about previously 
irradiated lesions
Improve 
consistency with 
the inclusion 
criteria
Non-substantial
Throughout
Minor editorial and 
document formatting 
revisions
Minor and therefore 
have not been 
summarised
Non-substantial
AE, adverse event; AESI, adverse event of special interest; AGA, actionable genomic alteration; BOR, best 
overall response; Dato-DXd, Datopotamab deruxtecan; FAS, full analysis set; HGR, human genetic resources; 
HIV, human immunodeficiency virus; ICR, independent central review; ILD, interstitial lung disease; NSCLC, 
non-small-cell lung cancer; ORR, objective response rate; OS, overall survival; PSR, product safety 
requirements; RES, response evaluable set; SAE, serious adverse event; SOA, Schedule of Activities; TNBC, 
triple negative breast cancer; TTR, time-to-response
Version 2.0, 17 November 2021
Section 1.3 – Schedule of Activities
Added oral care ptotocol in SoA and clarified daily oral care protocol throughout the study.
For footnote s to Table 1, clarified that artificial tears should be used daily.
For footnote k to Table 1, clarified that flash frozen tissue is not acceptable and remove the 
requirement.
Section 2.3.1 – Risk Assessment
Combined elevations of aminotransferases and bilirubin is removed from AESI list, and 
mucosal inflammation other than oral mucositis/stomatitis is added as AESI.
Section 5.1 – Inclusion Criteria
Clarified that for Cohort 2 if a chemotherapy drug is changed within 28 days of use to 
another drug in the same class (eg, antimetabolite to antimetabolite) for any reason other 
than PD, the first drug is not counted as a prior chemotherapy regimen.
Section 5.2 – Exclusion Criteria
Updated the requirement on washout period of prior anti-cancer therapies to include 
chemotherapy.
Section 6.6.1.3 – Ocular Assessment

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Added clarification that section 6.6.1.3 links to section 8.2.5.5 for ocular assessment.
Section 8.1.1 – Imaging Tumour Assessments
Specified that any other areas of disease involvement should be imaged at regular intervals 
in addition to screening/baseline.
Removed mandatory pelvis scan at regular intervals and following PD assessment for 
participants without pelvis involvement at baseline in Cohort 1 and Cohort 2 to reduce 
unnecessary scan.
Section 8.2.2 – Vital Signs
Updated that blood pressure and pulse measurements will be assessed in the seated or 
supine/semi-recumbent position. 
Section 8.2.4 – Clinical Safety Laboratory Assessments
Updated the list of acceptable values for calcium and urea nitrogen to accommodate sites 
only able to provide ionized calcium and urea.
Section 8.2.5.5 – Ophthalmologic Assessments
Added the updated safety information for use of artificial tears and other eye medications.
Section 8.3.1 – Time Period and Frequency for Collection AE and SAE Information
Updated that Grade ≥ 1 oral mucositis/stomatitis, all mucosal inflammation other than oral 
mucositis/stomatitis events regardless of CTCAE grade and Grade ≥ 1 ocular surface 
toxicities should be reported within 24hours of investigator becoming aware.
Section 8.3.11 – Adverse Events of Special Interest
Combined elevations of aminotransferases and bilirubin is removed from AESI list, and 
mucosal inflammation other than oral mucositis/stomatitis is added as AESI.
Section 8.6.1 – Collection of Mandatory Samples for Biomarker Analysis
Removed the requirement of flash frozen tissues for biomarker analysis.
Appendix E – Guidelines for Evaluation of Objective Tumour
Updated the table for algorithm of overall visit response to align with RECIST 1.1.

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Appendix G – Concomitant Medications 
Add clarification that mouthwash for stomatitis prophylaxis/treatment is allowed for 
ChronicTable G17.
Throughout
Minor revisions in protocol wording and document format to further clarify.
Version 1.0, 20 October 2021
Initial creation 

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SI G N A T U R E P A G E
T his is a re prese nt ati o n of a n electr o nic rec or d t h at w as si g ne d
electr o nic ally a n d t his p a ge is t he m a nifest ati o n of t he electr o nic si g n at ure
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D 9 2 6 6 C 0 0 0 0 1 Cli nical St u d y Pr ot oc ol Versi o n 4
D oc u me nt I D:
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