A Phase IB/II, 2-stage, Open-label, Multicenter Study to Determine the Efficacy and Safety of Durvalumab (MEDI4736) + Paclitaxel and Durvalumab (MEDI4736) in Combination With Novel Oncology Therapies With or Without Paclitaxel for First-line Metastatic Triple Negative Breast Cancer
Phase: PHASE1
Conditions: Triple Negative Breast Neoplasms
Sponsor: AstraZeneca

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Clinical Study Protocol 
Drug Substance 
Durvalumab (MEDI4736), 
paclitaxel, and novel 
oncology therapies 
Study Code 
D933LC00001 
Version 
11.0 
Date 
07 November 2024 
A Phase IB/II, 2-Stage, Open-label, Multicenter Study to Determine the 
Efficacy and Safety of Durvalumab (MEDI4736) + Paclitaxel and 
Durvalumab (MEDI4736) in Combination With Novel Oncology Therapies 
With or Without Paclitaxel for First-line Metastatic Triple Negative Breast 
Cancer 
Sponsor: AstraZeneca AB, 151 85 Södertälje, Swed n 
Regulatory Agency Identifying Number(s):  
IND number:   
139640 
EudraCT number: 
2018-000764-29 
EU CT Number:  
2024-511646-40-00 
Clinicaltrials.gov identifier: NCT03742102 
Redacted for Public Disclosure

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• 
The risks were updates to durvalumab are as following: abdominal pain, 
cough/productive cough, thyroiditis, dysphonia, dysuria, pruritus, night sweats, 
anaphylaxis, pyrexia, oedema peripheral, upper respiratory tract infections, 
pneumonia, oral candidiasis, dental and oral soft tissue infections, influenza, myalgia, 
cytokine release syndrome, immune thrombocytopenia, encephalitis and immune-
mediated arthritis in Section 2.3.1.1.2 to align with durvalumab IB Edition 20. 
• 
Guidelines for overlapping toxicities of
for patients on 
Arms 7 and 8 regardless of causality assessment for dose modification were updated 
in Section 6.5.2.6. based on Dato-DXd programme standards. 
• 
IRR including anaphylaxis was removed as AESI for Dato-DXd in Section 8.3.14.5 
based on latest Dato-DXd programme standards. 
• 
Ocular Surface Toxicity’ AESI updated to ‘Ocular Surface Events’; and keratitis 
updated as an important identified risk in Section 8.3.14.5 based on the Dato-DXd 
programme standards. 
• 
The guidance for Dato-DXd was updated for AE possibly causally related to Dato-
DXd that have confirmed etiology other than ILD/pneumonitis to follow the 
management guidance outlined in “Other Non-Laboratory Adverse Events” dose 
modification section of Dato-DXd TMGs in Section 8.4.6.6 based on Dato-DXd 
programme standards. 
• 
The IRR management guidance for Dato-DXd previous text was deleted to updated 
to refer to the management guidance outlined in Dato-DXd TMGs in Section 8.4.6.6 
based on latest Dato-DXd programme standards. 
 
The following amendment changes were made due to revisions of the AstraZeneca protocol 
template revisions: 
• 
Addition of EU CT Number on the title page. 
• 
Updated definition of end of study and patient considered to have completed the 
study in Section 4.4 based on new TransCelerate – CSP template. 
• 
Removed the sentence “patients will not be permitted to continue immunotherapy if 
progression occurs after confirmed response to immunotherapy treatment in the TLs” 
in Section 6.1.3. 
• 
Updated reporting requirement following final analysis. “No further data collection is 
required, except for reporting of SAEs and AESIs” was updated to “No further data 
collection is required, except for reporting of SAEs and AEs” in Section 6.6 based on 
latest AstraZeneca SOP. 
• 
Updates were made in Appendix A-1 (Regulatory and ethical considerations) and 
added regulatory reporting requirements for SAEs to include the EU mandatory text 
and the latest CSP template. 
• 
Updates were made in the Appendix A-3 (Informed consent process) based on the 
latest CSP template.  
• 
Retention of records and documents by the Investigator was updated to include 
“Records and documents, including signed ICFs, pertaining to the conduct of this 
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This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
standard procedures. The Clinical Study Protocol 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. 

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TABLE OF CONTENTS 
VERSION HISTORY ............................................................................................................... 2 
TABLE OF CONTENTS .......................................................................................................... 6 
LIST OF TABLES .................................................................................................................. 14 
LIST OF FIGURES ................................................................................................................. 16 
LIST OF APPENDICES ......................................................................................................... 17 
1 
PROTOCOL SUMMARY.................................................................................... 18 
1.1 
Schedule of activities ............................................................................................ 18 
1.2 
Synopsis ................................................................................................................ 61 
1.3 
Schema .................................................................................................................. 71 
2 
INTRODUCTION ................................................................................................ 72 
2.1 
Study rationale ...................................................................................................... 72 
2.2 
Background ........................................................................................................... 72 
2.2.1 
Triple negative breast cancer ................................................................................ 72 
2.2.1.1 
BRCA mutations in TNBC ................................................................................... 74 
2.2.2 
Immunotherapy in breast cancer ........................................................................... 74 
2.2.3 
Immunotherapies .................................................................................................. 75 
2.2.4 
Durvalumab .......................................................................................................... 77 
2.2.5 
Durvalumab in combination with chemotherapy and rationale for novel 
treatment combinations ......................................................................................... 77 
2.2.6 
Capivasertib (AZD5363) ...................................................................................... 82 
2.2.6.1 
Clinical experience of capivasertib ....................................................................... 83 
2.2.7 
Oleclumab ............................................................................................................. 84 
2.2.8 
DS-8201a (trastuzumab deruxtecan) .................................................................... 85 
2.2.9 
Dato-DXd (datopotamab deruxtecan; DS-1062a) ................................................ 86 
2.3 
Benefit/risk assessment ......................................................................................... 88 
2.3.1 
Durvalumab .......................................................................................................... 88 
2.3.1.1 
Potential benefits of durvalumab .......................................................................... 88 
2.3.1.2 
Potential risks of durvalumab ............................................................................... 88 
2.3.2 
Capivasertib (AZD5363) ...................................................................................... 89 
2.3.2.1 
Potential benefits of capivasertib .......................................................................... 89 
2.3.2.2 
Potential risks identified from non-clinical studies of capivasertib...................... 90 
2.3.2.3 
Potential risks of capivasertib from early clinical studies .................................... 91 
2.3.2.4 
Potential risks of capivasertib in combination with paclitaxel ............................. 91 
2.3.3 
Oleclumab (MEDI9447) ....................................................................................... 92 
2.3.3.1 
Potential benefits of oleclumab ............................................................................ 92 
2.3.3.2 
Potential risks of oleclumab.................................................................................. 93 
2.3.3.3 
Potential risks of durvalumab + oleclumab .......................................................... 93 
2.3.4 
DS-8201a (trastuzumab deruxtecan) .................................................................... 94 
2.3.4.1 
Potential benefits of DS-8201a ............................................................................. 94 
2.3.4.2 
Potential risks of DS-8201a .................................................................................. 94 
2.3.4.3 
Potential risks of durvalumab + DS-8201a ........................................................... 96 

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2.3.5 
Dato-DXd (datopotamab deruxtecan; DS-1062a) ................................................ 96 
2.3.5.1 
Potential benefits of Dato-DXd ............................................................................ 96 
2.3.5.2 
Potential risks of Dato-DXd ................................................................................. 97 
2.3.5.3 
Potential risks of durvalumab + Dato-DXd .......................................................... 97 
2.3.6 
Overall benefit/risk ............................................................................................... 98 
3 
OBJECTIVES AND ENDPOINTS ...................................................................... 99 
4 
STUDY DESIGN ............................................................................................... 101 
4.1 
Overall design ..................................................................................................... 101 
4.1.1 
Study conduct mitigation during study disruptions due to cases of civil crisis, 
natural disaster, or public health crisis ............................................................... 102 
4.1.2 
Part 1 study design overview .............................................................................. 103 
4.1.3 
Part 2 study design overview .............................................................................. 104 
4.1.4 
Part 1 safety run-in period and combination dose finding .................................. 104 
4.1.4.1 
Overview............................................................................................................. 104 
4.1.4.2 
Definitions .......................................................................................................... 105 
4.1.4.3 
Safety Review Committee .................................................................................. 107 
4.2 
Scientific rationale for study design ................................................................... 107 
4.2.1 
Rationale for efficacy study endpoints ............................................................... 107 
4.2.2 
Rationale for other study endpoints .................................................................... 109 
4.2.3 
Rationale for treatment duration ......................................................................... 109 
4.2.4 
Rationale for exclusion of male patients from study .......................................... 109 
4.3 
Justification for dose ........................................................................................... 109 
4.3.1 
Durvalumab dose rationale, including rationale for fixed dosing ...................... 109 
4.3.2 
Paclitaxel dose rationale ..................................................................................... 110 
4.3.3 
Capivasertib dose rationale ................................................................................. 110 
4.3.4 
Oleclumab dose rationale ................................................................................... 111 
4.3.5 
DS-8201a (trastuzumab deruxtecan) dose rationale ........................................... 112 
4.3.6 
Dato-DXd (datopotamab deruxtecan; DS-1062a) dose rationale ....................... 112 
4.4 
End of study definition ....................................................................................... 113 
4.5 
Study termination................................................................................................ 113 
4.6 
Site closure.......................................................................................................... 114 
5 
STUDY POPULATION ..................................................................................... 115 
5.1 
Inclusion criteria ................................................................................................. 115 
5.2 
Exclusion criteria ................................................................................................ 117 
5.3 
Lifestyle restrictions ........................................................................................... 123 
5.4 
Screen failures .................................................................................................... 125 
6 
STUDY TREATMENTS ................................................................................... 125 
6.1 
Treatments administered ..................................................................................... 125 
6.1.1 
Investigational products ...................................................................................... 125 
6.1.1.1 
Guidelines applicable to all treatments administered IV .................................... 129 
6.1.1.2 
Durvalumab (MEDI4736) .................................................................................. 129 
6.1.1.3 
Paclitaxel............................................................................................................. 131 

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6.1.1.4 
Capivasertib (AZD5363) .................................................................................... 131 
6.1.1.5 
Oleclumab (MEDI9447) ..................................................................................... 133 
6.1.1.6 
DS-8201a (trastuzumab deruxtecan) .................................................................. 135 
6.1.1.7 
Dato-DXd (datopotamab deruxtecan; DS-1062a) .............................................. 137 
6.1.2 
Dose and treatment regimens.............................................................................. 140 
6.1.2.1 
Durvalumab and paclitaxel combination therapy (Arm 1) ................................. 141 
6.1.2.2 
Durvalumab + paclitaxel + novel treatment combination arms (Arms 2 and 5): 
overview ............................................................................................................. 142 
6.1.2.3 
Durvalumab + paclitaxel + capivasertib combination therapy arm (Arm 2) ...... 143 
6.1.2.4 
Durvalumab + paclitaxel + oleclumab combination therapy arm (Arm 5) ........ 144 
6.1.2.5 
Durvalumab + DS-8201a (trastuzumab deruxtecan) combination therapy arm 
(Arm 6) ............................................................................................................... 144 
6.1.2.6 
Durvalumab + Dato-DXd combination therapy arm (Arms 7 and 8) ................. 145 
6.1.3 
Duration of treatment and criteria for treatment through progression ................ 145 
6.1.4 
Storage ................................................................................................................ 146 
6.2 
Measures to minimize bias: randomization and blinding ................................... 146 
6.2.1 
Patient enrollment and randomization ................................................................ 146 
6.2.1.1 
Enrollment procedures ........................................................................................ 148 
6.2.2 
Procedures for handling incorrectly enrolled or randomized patients ................ 148 
6.2.3 
Methods for assigning treatment groups ............................................................ 149 
6.2.4 
Methods for ensuring blinding ........................................................................... 149 
6.3 
Treatment compliance ........................................................................................ 149 
6.3.1 
Treatment compliance for IV study drugs .......................................................... 150 
6.3.2 
Treatment compliance for capivasertib .............................................................. 150 
6.4 
Concomitant therapy ........................................................................................... 150 
6.4.1 
Other concomitant treatment .............................................................................. 153 
6.4.2 
Ancillary treatment for management of immuno-oncology related toxicities.... 154 
6.5 
Dose modification ............................................................................................... 154 
6.5.1 
Dose modifications at the cohort level during the safety run-in period of Part 1154 
6.5.2 
Individual patient dose modifications during all study parts .............................. 155 
6.5.2.1 
Durvalumab ........................................................................................................ 155 
6.5.2.2 
Paclitaxel............................................................................................................. 155 
6.5.2.3 
Capivasertib ........................................................................................................ 156 
6.5.2.4 
Oleclumab ........................................................................................................... 157 
6.5.2.5 
DS-8201a (trastuzumab deruxtecan) .................................................................. 158 
6.5.2.6 
Dato-DXd (datopotamab deruxtecan; DS-1062a) .............................................. 159 
6.6 
Treatment after the end of the study ................................................................... 162 
7 
DISCONTINUATION OF TREATMENT AND PATIENT WITHDRAWAL 163 
7.1 
Discontinuation of study treatment ..................................................................... 163 
7.1.1 
Procedures for discontinuation of study treatment ............................................. 164 
7.2 
Lost to follow-up ................................................................................................ 165 
7.3 
Withdrawal from the study ................................................................................. 165 
8 
STUDY ASSESSMENTS AND PROCEDURES.............................................. 167 
8.1 
Efficacy assessments .......................................................................................... 167 

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8.1.1 
Survival assessments .......................................................................................... 168 
8.1.2 
Central Reading of Scans.................................................................................... 168 
8.2 
Safety assessments .............................................................................................. 168 
8.2.1 
Clinical safety laboratory assessments ............................................................... 168 
8.2.2 
Physical examinations ........................................................................................ 171 
8.2.3 
Vital signs ........................................................................................................... 172 
8.2.4 
Electrocardiograms ............................................................................................. 173 
8.2.5 
Echocardiograms/multiple gated acquisition scans ............................................ 173 
8.2.6 
Early patient review for safety ............................................................................ 173 
8.2.7 
........................................................................................... 174 
8.2.8 
WHO/ECOG performance status ....................................................................... 174 
8.2.9 
Other safety assessments .................................................................................... 174 
8.2.9.1 
Pneumonitis/ILD investigation ........................................................................... 174 
8.2.9.2 
Safety assessments for durvalumab + DS-8201a (Arm 6) and durvalumab + 
Dato-DXd ( Arms 7 and 8) ................................................................................. 175 
8.2.9.3 
Dental Assessments for Dato-DXd ( Arms 7 and 8) .......................................... 176 
8.3 
Collection of adverse events ............................................................................... 176 
8.3.1 
Method of detecting AEs and SAEs ................................................................... 176 
8.3.2 
Time period and frequency for collecting AE and SAE information ................. 177 
8.3.3 
Follow-up of AEs and SAEs............................................................................... 177 
8.3.4 
Adverse event data collection ............................................................................. 177 
8.3.5 
Causality collection ............................................................................................ 178 
8.3.6 
Adverse events based on signs and symptoms ................................................... 179 
8.3.7 
Adverse events based on examinations and tests ............................................... 179 
8.3.8 
Hy’s law .............................................................................................................. 179 
8.3.9 
Pneumonitis/ILD Cases ...................................................................................... 180 
8.3.10 
Disease under study ............................................................................................ 180 
8.3.11 
Disease progression ............................................................................................ 180 
8.3.12 
New cancers ........................................................................................................ 180 
8.3.13 
Deaths ................................................................................................................. 180 
8.3.14 
Adverse events of special interest....................................................................... 181 
8.3.14.1 
Durvalumab ........................................................................................................ 181 
8.3.14.2 
Capivasertib ........................................................................................................ 182 
8.3.14.3 
Oleclumab ........................................................................................................... 182 
8.3.14.4 
DS-8201a (trastuzumab deruxtecan) .................................................................. 183 
8.3.14.5 
Dato-DXd (datopotamab deruxtecan; DS-1062a) .............................................. 184 
8.4 
Safety reporting and medical management......................................................... 185 
8.4.1 
Reporting of serious adverse events ................................................................... 185 
8.4.2 
Safety Data to be Collected Following the Final Data Cutoff of the Study ....... 186 
8.4.3 
Pregnancy ........................................................................................................... 186 
8.4.3.1 
Maternal exposure .............................................................................................. 186 
8.4.3.2 
Paternal exposure ................................................................................................ 187 
8.4.4 
Overdose ............................................................................................................. 187 
8.4.5 
Medication error, drug abuse, and drug misuse .................................................. 188 
8.4.5.1 
Timelines ............................................................................................................ 188 
8.4.5.2 
Medication error ................................................................................................. 188 
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9.3.2.1 
Adverse events .................................................................................................... 208 
9.3.2.2 
Safety assessments .............................................................................................. 208 
9.3.3 
Calculation or derivation of pharmacokinetic variables (Part 1 only) ................ 209 
9.3.3.1 
Population pharmacokinetics and exposure-response/safety analysis ................ 209 
9.3.3.2 
Pharmacokinetic analysis.................................................................................... 209 
9.3.4 
Immunogenicity analysis (Part 1 only) ............................................................... 210 
9.3.5 
Calculation or derivation of biomarker variables ............................................... 210 
9.3.6 
Calculation or derivation of pharmacogenetic variables .................................... 210 
9.4 
Statistical analyses .............................................................................................. 210 
9.4.1 
Safety analyses.................................................................................................... 211 
9.4.1.1 
Safety analyses for Part 1 ................................................................................... 211 
9.4.1.2 
Safety analyses for Part 2 ................................................................................... 211 
9.4.2 
Efficacy analyses ................................................................................................ 211 
9.4.2.1 
Planned Analyses ................................................................................................ 211 
9.4.2.2 
Exploratory analyses to be conducted if deemed necessary ............................... 213 
9.4.3 
Pharmacokinetic data .......................................................................................... 213 
9.4.4 
Pharmacokinetic/pharmacodynamic relationships ............................................. 214 
9.4.5 
Biomarker data.................................................................................................... 214 
9.4.6 
Methods for multiplicity control ......................................................................... 214 
9.5 
Interim analyses .................................................................................................. 214 
10 
REFERENCES ................................................................................................... 215 
11 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS .......................................................................................... 226 
Appendix A Regulatory, ethical and study oversight considerations ................................. 227 
A-1 
Regulatory and ethical considerations ................................................................ 227 
A-2 
Financial disclosure ............................................................................................ 229 
A-3 
Informed consent process ................................................................................... 229 
A-4 
Data protection.................................................................................................... 230 
A-5 
Committees` structure ......................................................................................... 230 
A-6 
Dissemination of clinical study data ................................................................... 231 
A-7 
Data quality assurance ........................................................................................ 231 
A-8 
Source documents ............................................................................................... 232 
A-9 
Study and Site Closure ....................................................................................... 232 
A-10 
Publication policy ............................................................................................... 233 
Appendix B 
Adverse event definitions and additional safety information ........................ 234 
B-1 
Definition of adverse events ............................................................................... 234 
B-2 
Definitions of serious adverse event ................................................................... 234 
B-3 
Life threatening ................................................................................................... 235 
B-4 
Hospitalization .................................................................................................... 235 
B-5 
Important medical event or medical treatment ................................................... 235 
B-6 
CTCAE grade ..................................................................................................... 236 

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Appendix P 
Changes related to mitigation of study disruptions due to Cases of civil 
crisis, natural disaster, or public health crisis ..................................................... 286 
P-1 
Reconsent of study patients during study interruptions ...................................... 286 
P-2 
Telemedicine visit to replace on-site visit (where applicable) ........................... 286 
P-3 
Data capture during telemedicine or remote visits ............................................. 286 
Appendix Q Ophthalmologic Assessment Form was removed .......................................... 287 
Appendix R 
................................ 288 
Appendix S 
Abbreviations ................................................................................................. 289 
Appendix T 
Protocol Version History ............................................................................... 296 
 
CCI 

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LIST OF TABLES  
Table 1 
Arm 1 (durvalumab + paclitaxel): Schedule of activities for screening 
and treatment periods (applies to Part 1 of the study) ................................. 19 
Table 2 
Arm 2 (durvalumab + paclitaxel + capivasertib): Schedule of activities 
for screening and treatment periods (applies to Parts 1 and 2 of the 
study) ........................................................................................................... 24 
Table 3 
Arm 5 (durvalumab + paclitaxel + oleclumab): Schedule of activities for 
screening and treatment periods (applies to Parts 1 and 2 of the study) ..... 30 
Table 4 
Arm 6 (durvalumab + DS-8201a; T-DXd [trastuzumab deruxtecan]): 
Schedule of activities for screening and treatment periods (applies to 
Parts 1 and 2 of the study) ........................................................................... 35 
Table 5 
Arm 7 (durvalumab + Dato-DXd [datopotamab deruxtecan; DS-1062a]): 
Schedule of activities for screening and treatment periods (applies to 
Parts 1 and 2 of the study) ........................................................................... 43 
Table 6 
Arm 8 (durvalumab + Dato-DXd [datopotamab deruxtecan; DS-1062a]): 
Schedule of activities for screening and treatment periods (applies to 
Parts 1 and 2 of the study) ........................................................................... 51 
Table 7 
Schedule of assessments for patients who have completed/discontinued 
treatment (applies to Parts 1 and 2) ............................................................. 58 
Table 8 
Treatment arms ............................................................................................ 64 
Table 9 
Treatments and treatment duration .............................................................. 67 
Table 10 
Durvalumab and nab-paclitaxel TEAEs of special interest ........................ 78 
Table 11 
Study objectives .......................................................................................... 99 
Table 13 
Study treatments ........................................................................................ 126 
Table 14 
Capivasertib dispensation schedule in safety run-in period ...................... 133 
Table 15 
Treatment arms .......................................................................................... 141 
Table 16 
Prohibited concomitant medications and foods ........................................ 151 
Table 17 
Supportive medications ............................................................................. 153 
Table 18 
Dose level modification in cohorts with dose reduction during the safety 
run-in period .............................................................................................. 155 
Table 19 
Dose level reductions for individual patients receiving capivasertib ........ 156 
Table 20 
Dose modifications for general capivasertib-related toxicities ................. 157 
Table 21 
Dose level modification for individual patients receiving DS-8201a ....... 159 
Table 22 
Dose level modification for individual patients receiving Dato-DXd ...... 161 
Table 23 
Clinical chemistry ..................................................................................... 170 
Table 24 
Hematology ............................................................................................... 170 

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Table 25 
Coagulation ............................................................................................... 171 
Table 27 
Summary of outcome variables and analysis populations ........................ 204 
Table 28 
Pre-planned statistical and sensitivity analyses to be conducted .............. 212 
Table 29 
Summary of imaging modalities for tumor assessment ............................ 252 
Table 30 
RECIST 1.1 evaluation of target lesions ................................................... 260 
Table 31 
RECIST 1.1 evaluation of non-target lesions ........................................... 261 
Table 32 
RECIST 1.1 overall visit response ............................................................ 262 
Table 33 
CYP3A4-interacting medication that should be avoided or used with 
caution ....................................................................................................... 268 
Table 34 
CYP3A4, CYP2D6, or CYP2C9 substrates that should be avoided or 
used with caution ....................................................................................... 269 
Table 35 
MATE1 and/or OCT2 transporter substrates that should be used with 
caution ....................................................................................................... 271 
Table 36 
Toxicity management guidelines for DS-8201a ....................................... 273 
 

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LIST OF FIGURES  
Figure 1 
Study design ................................................................................................ 71 
Figure 2 
Overall survival and progression free survival in patients treated with 
sacituzumab govitecan versus treatment of physician’s choice in patients 
with previously treated metastatic triple-negative breast cancer in the 
ASCENT study (NCT02574455) ................................................................ 81 
Figure 3 
Dosing schedule for durvalumab + paclitaxel combination therapy ......... 142 
Figure 4 
Dosing schedule for durvalumab + paclitaxel + capivasertib combination 
therapy ....................................................................................................... 143 
Figure 5 
Dosing schedule for durvalumab + paclitaxel + oleclumab combination 
therapy ....................................................................................................... 144 
Figure 6 
Dosing schedule for durvalumab + DS-8201a (trastuzumab deruxtecan) 
combination therapy .................................................................................. 144 
Figure 7 
Dosing schedule for durvalumab + Dato-DXd (datopotamab deruxtecan; 
DS-1062a) combination therapy ............................................................... 145 
Figure 8 
Dato-DXd Dose Delay Guidelines ............................................................ 160 
 
 

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LIST OF APPENDICES  
Appendix A 
Regulatory, ethical and study oversight considerations ............................ 227 
Appendix B 
Adverse event definitions and additional safety information ................... 234 
Appendix C 
Handling of human biological samples ..................................................... 240 
Appendix D 
Genetics ..................................................................................................... 243 
Appendix E 
Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s law .............................................................................. 247 
Appendix F 
Guidelines for evaluation of objective tumor response using RECIST 1.1 
Criteria (Response Evaluation Criteria in Solid Tumors) ......................... 252 
Appendix G 
International Airline Transportation Association (IATA) 6.2 guidance 
document ................................................................................................... 264 
Appendix H 
National Institute of Allergy and Infectious Disease and Food Allergy 
and Anaphylaxis Network guidance for anaphylaxis diagnosis ............... 265 
Appendix I 
Guidance for management of specific adverse events in studies of 
capivasertib was removed to an Annex ..................................................... 266 
Appendix J 
Guidance for management of specific adverse events in studies of 
selumetinib was removed .......................................................................... 267 
Appendix K 
Guidance regarding potential interactions of capivasertib with 
concomitant medications ........................................................................... 268 
Appendix L 
Guidance for management of specific adverse events in studies of DS-
8201a (trastuzumab deruxtecan) ............................................................... 272 
Appendix M 
Guidance for management of specific adverse events of Dato-DXd 
(datopotamab deruxtecan) was removed to an Annex .............................. 281 
Appendix N 
Durvalumab weight-based dose calculation .............................................. 282 
Appendix O 
Instructions Related to COVID-19 (For Arms 6, 7, and 8 Only) .............. 283 
Appendix P 
Changes related to mitigation of study disruptions due to Cases of civil 
crisis, natural disaster, or public health crisis ........................................... 286 
Appendix Q 
Ophthalmologic Assessment Form was removed ..................................... 287 
Appendix R 
........................... 288 
Appendix S 
Abbreviations ............................................................................................ 289 
Appendix T 
Protocol Version History ........................................................................... 296 
 
CCI 

Clinical Study Protocol - 11 
AstraZeneca 
Durvalumab (MEDI4736), paclitaxel, and novel oncology therapies 
CONFIDENTIAL AND PROPRIETARY 
18 (322) 
1 
PROTOCOL SUMMARY  
1.1 
Schedule of activities  
The procedures for the screening and treatment periods of this study are presented in Table 1 
through Table 6. The procedures for the follow-up period are presented in Table 7. The study 
is designed using a 2-stage approach (see Section 4.1). Study activities apply to both study 
parts, unless otherwise noted. 
A pre-screen ICF is to be signed by patients in Arm 8 who do not have a prior determination 
of positive PD-L1 status, to permit determination of PD-L1 expression status by local testing 
prior to the 28-day screening window. At the time of signing the pre-screen ICF, Investigators 
should ensure that there is a reasonable possibility that the patient would be a candidate for 
this study based on available information. When a pre-screen ICF is signed, the main ICF 
should not be signed until PD-L1 positive expression status has been established. 
Whenever vital signs and blood draws are scheduled for the same nominal time, the 
assessments should occur in the following order: vital signs and then blood draws. The timing 
of the vital signs assessments should be such that it allows the blood draw (eg, 
pharmacokinetic
sample) to occur at the timepoints indicated in the schedules of 
activities (SoAs). Whenever electrocardiograms (ECGs), vital signs, and blood draws are 
scheduled for the same nominal time, the assessments should occur in the following order: 
ECG, vital signs, and then blood draws. The timing of the first 2 assessments should be such 
that it allows the blood draw (eg, PK blood sample) to occur at the timepoints indicated in the 
SoAs. 
For all arms, patients may delay durvalumab dosing under certain circumstances. 
• 
Dosing may be delayed per the dosing modification and toxicity management 
guidelines due to either an immune or a non-immune-related adverse event (AE). 
• 
If dosing must be delayed for reasons other than treatment-related toxicity, dosing 
will resume as soon as feasible. 
• 
Dosing intervals of subsequent durvalumab cycles may be shortened as clinically 
feasible in order to gradually align treatment cycles with the schedule of tumor 
efficacy assessments (Response Evaluation Criteria in Solid Tumors, version 1.1 
[RECIST 1.1]). Based on the half-life of durvalumab, subsequent time between 
consecutive doses cannot be less than
days for Arms
and cannot be 
less than
days for Arms
(see the current Investigator’s Brochure for 
durvalumab). 
Information on dose modification (including dose reductions, as applicable) for all 
investigational products (IPs) is provided in Section 6.5. 
Following the final DCO date by study arm, patients will be managed per standard of care 
(SoC) assessments at Investigator discretion.  
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Clinical Study Protocol - 11 
AstraZeneca 
Durvalumab (MEDI4736), paclitaxel, and novel oncology therapies 
CONFIDENTIAL AND PROPRIETARY 
22 (322) 
 
Screening 
C1 
C2 
C3 
C4 
C5 to PD 
Final visit 
For 
details, see 
Section 
Week 
-4 to -1 
0 
2 
Visits are driven by the treatment dosing schedule: q4w ±3 
days, unless dosing needs to be held for toxicity reasons. 
EOT visit 
Day 
-28 to -1 
1a 
15 
q28days ±3 days, unless dosing needs to be held for toxicity 
reasons 
EOT visit 
Efficacy evaluations 
Tumor assessments (CT or MRI) 
(RECIST 1.1)y 
X 
On-study tumor assessments occur q8w ±1 week for the first 48 weeks (relative to the date of treatment 
assignment for Part 1) and then q12w ±1 week thereafter until RECIST 1.1-defined radiological progression 
or until the patient has been taken off-study (end of study, death, or patient withdrawal of consent). The on-
study schedule of q8w ±1 week for the first 48 weeks and then q12w ±1 week thereafter until progression 
MUST be followed regardless of any delays in dosing. For clinically stable patients receiving study 
treatment after RECIST 1.1-defined PD, tumor assessments MUST continue for the duration of study 
treatment. 
8.1, 
Appendix F 
a 
Every effort should be made to minimize the time between treatment assignment (Part 1) and starting treatment (ie, within 3 days thereafter). 
b 
Written informed consent and any locally required privacy act document authorization must be obtained prior to performing any protocol-specific procedures, including 
screening/baseline evaluations. All patients will be required to provide consent to supply a sample of their tumor (archived [≤3 months old] or recently acquired biopsy) for 
entry into this study. This consent is included in the main patient ICF. Informed consent of study procedures and tumor biopsy sample may be obtained prior to the 28-day 
screening window, if necessary. The collection of additional biopsies upon progression is strongly encouraged. If laboratory or imaging procedures were performed for 
alternate reasons prior to signing consent, these can be used for screening purposes with consent of the patient. However, all screening laboratory and imaging results must 
have been obtained within 28 days of treatment assignment (Part 1). 
c 
Body weight is recorded at each visit along with vital signs. Height will be measured at screening only. Blood pressure and pulse should be performed before, during and 
after the first infusion; subsequent assessments should be performed before each infusion. 
d 
ECGs will be performed in triplicate at screening only and in triplicate thereafter, only if any clinically significant abnormalities are detected. 
e 
Individual sites are required to indicate in the unscheduled visit eCRF if an ECG or a urinalysis was performed during study treatment. 
f 
A MUGA scan or ECHO to assess LVEF will be conducted at screening and then only if clinically indicated thereafter. The modality of the cardiac function assessments 
must be consistent within patient (ie, if ECHO is used for the screening assessment, then ECHO should also be used for subsequent scans if required). The patients should 
also be examined using the same machine and operator whenever possible. 
g 
Serum or plasma clinical chemistry (including LFT monitoring), hematology, and coagulation assessments may be performed more frequently if clinically indicated. At 
screening, serum chemistry will include fasting plasma glucose. Subsequent measurements of glucose can be either fasting or non-fasting plasma glucose measurement.  
h 
If screening clinical chemistry, hematology, and coagulation assessments are performed within 3 days prior to D1 (first infusion day), they do not need to be repeated at D1. 
i 
Complete blood count with differential must be checked each week when paclitaxel is administered, either 1 day prior to or on the day that paclitaxel is administered. 
j 
Free T3 or free T4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system. 
k 
If TSH is measured within 14 days prior to D1 (first infusion day), it does not need to be repeated at D1. 
l 
The site will specify the type of test used and will provide appropriate laboratory reference range. The preferred method is urine dipstick. 
m 
For women of childbearing potential only. A urine or serum pregnancy test is acceptable. Women of childbearing potential are required to have a serum pregnancy test 
within 7 days prior to the first dose of study drug and then a urine or serum pregnancy test every cycle (q4w). Pregnancy test may occur on D1, but results must be available 
and reviewed by the treating physician or Investigator prior to commencing an infusion. 
n 
Durvalumab PK assessments will occur only in Part 1 of the study. PK sampling from C1 through C4 will be pre-dose (may not exceed 6 hours prior to start of infusion) and 
post-infusion (within 1 hour after the end of infusion and before paclitaxel administration). 

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Clinical Study Protocol - 11 
AstraZeneca 
Durvalumab (MEDI4736), paclitaxel, and novel oncology therapies 
CONFIDENTIAL AND PROPRIETARY 
29 (322) 
 
<<Arm 3 (durvalumab + paclitaxel + selumetinib) was removed with Protocol Version 3>> 
<<Arm 4 (durvalumab + paclitaxel + danvatirsen) was removed with Protocol Version 4>>

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Clinical Study Protocol - 11 
AstraZeneca 
Durvalumab (MEDI4736), paclitaxel, and novel oncology therapies 
CONFIDENTIAL AND PROPRIETARY 
40 (322) 
 
Screening 
C1 
C2 
C3 
C4 
C5  
C6 to 
PD 
Final 
visit 
For details, 
see Section 
Week 
-4 to -1 
0 
1 
2 
3 
4 
5 
Visits are driven by the treatment dosing 
schedule: q3w, unless dosing needs to be 
held for toxicity reasons. 
EOT 
visit 
 
Cycle Day 
-28 to -1 
1a 
8 
15 
1 
8 
15 
q21 days, unless dosing needs to be held 
for toxicity reasons 
Window (days) 
 
0a 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±7 
 
Efficacy evaluations 
Tumor assessments (CT 
or MRI) (RECIST 1.1)dd 
X 
On-study tumor assessments occur q6w ±1 week for the first 48 weeks (relative to the date of treatment assignment) 
and then q12w ±1 week thereafter until RECIST 1.1-defined radiological progression or until the patient has been 
taken off-study (end of study, death, or patient withdrawal of consent). The on-study schedule of q6w ±1 week for 
the first 48 weeks and then q12w ±1 week thereafter until progression MUST be followed regardless of any delays in 
dosing. For clinically stable patients receiving study treatment after RECIST 1.1-defined PD, tumor assessments 
MUST continue for the duration of study treatment. 
8.1, 
Appendix F 
a 
Every effort should be made to minimize the time between treatment assignment and starting treatment (within 3 days thereafter). 
b 
Written informed consent and any locally required privacy act document authorization must be obtained prior to performing any protocol-specific procedures, including 
screening/baseline evaluations. All patients will be required to provide consent to supply a sample of their tumor (archived [≤3 months old] or recently acquired biopsy) for 
entry into this study. This consent is included in the main patient ICF. Informed consent of study procedures and tumor biopsy sample may be obtained prior to the 28-day 
screening window, if necessary. The collection of additional biopsies upon progression is strongly encouraged. If laboratory or imaging procedures were performed for 
alternate reasons prior to signing consent, these can be used for screening purposes with consent of the patient. However, all screening laboratory and imaging results must 
have been obtained within 28 days of treatment assignment. 
c 
Body weight is recorded at each visit along with vital signs. Height will be measured at screening only. Blood pressure and pulse should be performed before, during and 
after the first infusion; subsequent assessments should be performed before each infusion. 
d 
ECGs will be performed at screening, prior to administration of IMP at C1D1, and every fourth cycle (once) thereafter (eg, C5, C9, C13). Triplicate ECGs will be performed 
at screening. Subsequent ECGs will be performed in triplicate only if abnormalities are noted. When done in triplicate, ECGs will be taken in close succession, while in a 
supine/semi-recumbent position. If 12-lead ECG is abnormal, follow institutional guidelines. 
e 
Individual sites are required to indicate in the unscheduled visit eCRF if an ECG or a urinalysis was performed during study treatment. 
f 
A MUGA scan or ECHO to assess LVEF will be conducted at screening and before treatment on D1 of C5 and then every 4 cycles (±7 days) (eg, Cycle 5, 9, 13…). The 
modality of the cardiac function assessments must be consistent within patient (ie, if ECHO is used for the screening assessment, then ECHO should also be used for 
subsequent scans if required). The patients should also be examined using the same machine and operator whenever possible. 
g 
should be obtained within
days prior to Cycle 1 Day 1
hould be obtained before and after each infusion.
should be evaluated by PI or the delegate 
physician prior to the administration of IP at each visit. 
h 
PFT as a minimum should include spirometry. Minimum requirement of: FVC (L), FVC% predicted, FEV1 (L), FEV1% predicted, FEV1/FVC%. Optional components to 
include PEF, FEV6, TLC, DLCO. DLCO will be performed (when feasible), but for patients with prior severe and/or clinically significant pulmonary disorders, DLCO is a 
requirement. 
i 
Ophthalmologic assessments including visual acuity testing, slit lamp examination, and fundoscopy will be performed at screening and EOT and as clinically indicated. 
CCI 
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CCI 
CCI 

Clinical Study Protocol - 11 
AstraZeneca 
Durvalumab (MEDI4736), paclitaxel, and novel oncology therapies 
CONFIDENTIAL AND PROPRIETARY 
42 (322) 
scans (scheduled and unscheduled) must be stored at the investigative site as source documents. For clinically stable patients receiving study treatment after RECIST 1.1-
defined PD, a follow-up scan is collected no earlier than 4 weeks after and no later than the next regularly scheduled imaging visit after the prior RECIST 1.1-defined PD, 
and this scan is evaluated using the criteria for evaluation of scans collected after a RECIST 1.1-defined PD outlined in Appendix F. If an unscheduled assessment was 
performed and the patient has not progressed, every attempt should be made to perform the subsequent assessments at their next regularly scheduled visit. See Section 6.1.3, 
Section 8.1, and Appendix F for additional details relevant to tumor assessments. 
Note: All assessments on treatment days are to be performed prior to infusion, unless otherwise indicated. 
ADA  Anti-drug antibodies; AE  Adverse event; C  Cycle; CT  Computed tomography;
 D  Day; DLCO Diffusion capacity of the 
lungs for carbon monoxide; 
 DS-8201a  Trastuzumab deruxtecan; ECG  Electrocardiogram; ECHO  Echocardiogram; ECOG  Eastern 
Cooperative Oncology Group; eCRF  Electronic case report form; EOT  End of treatment; FEV  Forced expiratory volume; FFPE  Formalin-fixed and paraffin-embedded; 
FVC  Forced vital capacity; HbA1c  Glycosylated hemoglobin; HIV  Human immunodeficiency virus; HRCT  High-resolution computed tomography; ICF  Informed 
consent form; IV  Intravenous; IMP  Investigational medicinal product; LFT  Liver function test; LVEF  Left ventricular ejection fraction; MRI  Magnetic resonance 
imaging; MUGA  Multiple gated acquisition; PD  Progression of disease; PEF  Peak expiratory flow; PFT  Pulmonary function test; PK  Pharmacokinetic; q3w  Every 
3 weeks; q12w  Every 12 weeks; RECIST  Response Evaluation Criteria In Solid Tumors;
 SAE  Serious adverse event; T3  Triiodothyronine;
T4  Thyroxine; T-DXd  Trastuzumab deruxtecan;  TLC  Total lung capacity; TSH  Thyroid-stimulating hormone; WHO  World Health Organization. 
CCI 
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Clinical Study Protocol - 11 
AstraZeneca 
Durvalumab (MEDI4736), paclitaxel, and novel oncology therapies 
CONFIDENTIAL AND PROPRIETARY 
60 (322) 
ADA  Anti-drug antibodies; AE  Adverse event; CT  Computed tomography; Dato-DXd  Datopotamab deruxtecan; DS-8201a  Trastuzumab deruxtecan; 
ECHO  Echocardiogram; ECOG  Eastern Cooperative Oncology Group; eCRF  Electronic case report form; IP  Investigational product; LVEF  Left ventricular ejection 
fraction; MRI  Magnetic resonance imaging; MUGA  Multiple gated acquisition; PD  Progression of disease; PK  Pharmacokinetics; q8w  Every 8 weeks; q12w  Every 
12 weeks; RECIST  Response Evaluation Criteria in Solid Tumors; SAE  Serious adverse event; T3  Triiodothyronine; T4  Thyroxine; TSH  Thyroid-stimulating hormone; 
TNBC  Triple negative breast cancer; WHO  World Health Organization. 

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Objectives and endpoints - Part 2a 
Primary objective: 
Endpoint/variable: 
To assess the efficacy of durvalumab + novel 
oncology therapies with or without paclitaxel in 
terms of ORR 
Endpoint based on Investigator assessment according to 
RECIST 1.1: 
• 
ORR: The percentage of evaluable patients with an 
Investigator-assessed visit response of CR or PR. Part 1 
and Part 2 data will be pooled for efficacy analysis. 
Secondary objectives: 
Endpoint/variable: 
To further assess the efficacy of durvalumab + 
novel oncology therapies with or without 
paclitaxel in terms of PFS, DoR, OS, and PFS6b 
Endpoints based on Investigator assessment according to 
RECIST 1.1: 
• 
PFS: Time from date of first dose until the date of 
objective radiological disease progression using 
RECIST 1.1 or death (by any cause in the absence of 
progression) 
• 
DoR: Time from date of first detection of objective 
response until the date of objective radiological disease 
progression according to RECIST 1.1 
• 
PFS6: PFS at 6 months following date of first dose  
• 
OS: Time from date of first dose until the date of death 
by any cause  
To assess the safety and tolerability profile of 
durvalumab + novel oncology therapies with or 
without paclitaxel 
AEs, exposure, physical examinations, laboratory findings, 
ophthalmologic assessments (Arms 7 and 8 only), and vital 
signs 
 
Exploratory objective: 
Endpoint/variable: 
To collect blood and tissue samples to evaluate 
molecular/biological responses and/or identify 
candidate markers that may correlate with the 
likelihood of clinical benefit 
Blood
 including but not limited to the 
following, and their association with treatment benefit: 
• 
etected by H&E  
• 
etected by IHC 
• 
• 
a 
All mentioned endpoints for Part 2 will be analyzed in the dataset of Part 1 plus Part 2 patients in each 
cohort and additionally may be analyzed for each part separately. 
b 
Progression-free survival at 6 months following date of first dose (PFS6) is equivalent to the proportion 
of patients alive and progression free at 6 months following date of first dose (APF6). 
ADA  Anti-drug antibodies; AE  Adverse event; CR  Complete response
 Dato-DXd  Datopotamab deruxtecan; DoR  Duration of response; H&E  Hematoxylin and 
eosin stain; IHC  Immunohistochemistry;
ORR  Objective response rate; 
OS  Overall survival; PFS  Progression-free survival; PK  Pharmacokinetics; PR  Partial response; 
RECIST 1.1  Response Evaluation Criteria in Solid Tumors, version 1.1;
 
 
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Overall design: 
This is a Phase IB/II, 2-stage, open-label, multicenter study to determine the efficacy and 
safety of durvalumab in combination with novel oncology therapies (ie, capivasertib, 
oleclumab, DS-8201a [trastuzumab deruxtecan], and Dato-DXd [datopotamab deruxtecan]) 
with or without paclitaxel and durvalumab + paclitaxel as first-line treatment in patients with 
metastatic (Stage IV) TNBC. The study is designed to concurrently evaluate potential novel 
treatment combinations with clinical promise using a 2-stage approach. The study will use a 
design to evaluate which cohorts may proceed to expansion.  
The treatment arms are defined in Table 8. Part 1 is a Phase IB study of safety, initial efficacy, 
and PK/ADA. Part 2 will expand patient enrollment in a particular arm if an adequate efficacy 
signal is observed for that arm in Part 1. The treatment regimens evaluated in Part 2 will 
depend on the evaluation of safety and efficacy outcomes in Part 1.  
Table 8 
Treatment arms  
Study part 
Arm 
Study treatment 
1 
1 
durvalumab + paclitaxel 
1 
2 
durvalumab + paclitaxel + capivasertib  
1 
3 
Removed (Protocol Version 3) 
1 
4 
Removed (Protocol Version 4)  
1 
5 
durvalumab + paclitaxel + oleclumab 
1 
6 
durvalumab + DS-8201a (trastuzumab deruxtecan) 
1 
7 
durvalumab + Dato-DXd (datopotamab deruxtecan)  
1 
8 
durvalumab + Dato-DXd (datopotamab deruxtecan) a 
2 
 
Treatment arms that meet pre-defined endpoints from Part 1 may be 
expanded in Part 2b 
a 
Patients with PD-L1 positive status. 
b 
Refer to Section 4.1.3 (Part 2 study design overview). 
 
The primary objective of Part 1 will be safety. The safety and tolerability of each combination 
will be assessed. Additionally, an efficacy analysis for futility (based on ORR) will be 
assessed using a
design to determine enrollment for Part 2. Part 1 of the study 
will enroll the first 20 patients to the durvalumab + paclitaxel arm and monitor for toxicity; 
additional patients may be enrolled in order to have 20 evaluable patients. Patient assignment 
to one of the novel treatment combination arms that is open for enrollment will start after 
completion of recruitment to the durvalumab + paclitaxel arm. Each subsequent cohort will 
undergo a safety run-in period, except for Arm 8, given that the durvalumab + Dato-DXd 
combination was already evaluated in Arm 7 and found to be tolerable with no DLTs. In the 
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safety run-ins, 6 patients are planned to be enrolled to initially inform the safety profile and 
determine the combination dose; more or fewer patients may be enrolled, depending on how 
many patients are evaluable for dose-limiting toxicities (DLTs) and how many patients have 
DLTs. The novel treatment combination cohorts meeting the safety evaluation criteria (ie, no 
more than 1 of 6 DLT-evaluable patients experience DLTs during the first treatment cycle) 
will be expanded to 30 patients. Additional cohorts may be opened at prespecified lower dose 
levels if the initial doses are not tolerated. Any decision to introduce additional cohorts in 
order to investigate an alternative dosing regimen will be at the discretion of AstraZeneca 
after discussion with the Safety Review Committee (SRC). Efficacy assessments based on 
ORR (as determined by the Investigator according to RECIST 1.1) will be made when each 
cohort has completed enrollment and all patients have either had the opportunity to complete 
at least 2 on-treatment response evaluations or have discontinued treatment. 
The primary objective of Part 2 will be efficacy, with a primary endpoint of ORR. Efficacy of 
the durvalumab + novel oncology therapy combinations with or without paclitaxel will be 
evaluated. A given treatment arm from Part 1 will be analyzed before an arm with the same 
treatment may be expanded into Part 2, and no patients from Part 1 may enroll in Part 2. 
Within each study part, there will be no crossover between treatment arms. Initiation of Part 2 
will be considered if the safety profile and ORR observed in at least 1 of the novel treatment 
combination arms in Part 1 of the study meet a threshold criterion for ORR. Any impact on 
paclitaxel exposure (delays and discontinuations) observed during Part 1 will be considered in 
the decision.  
In both study parts, the imaging schedule will be as follows: response evaluation will be 
performed using computed tomography (CT) or magnetic resonance imaging (MRI) at 
screening (as baseline), with follow-up imaging every 8 weeks ±1 week (for Arms 1 through 5 
[ie, arms with 4-week cycles]) or every 6 weeks ±1 week (for Arms 6, 7, and 8 [ie, arm with 
3-week cycles]) for 48 weeks and every 12 weeks ±1 week thereafter until RECIST 
1.1-defined radiological progression or until the patient has been taken off study (end of study, 
death, or patient withdrawal of consent). 
All tumor assessments should be reported on the electronic case report form until enrollment 
is complete and all patients have had the opportunity to complete at least 2 on-treatment 
response evaluations; AstraZeneca will inform sites once this milestone has been reached. 
After data cutoff (DCO) for any treatment arm in Part 1 for ORR, patients must continue to 
follow the schedules of activities, and all safety assessments will be collected per Section 1.1. 
Following the final DCO date by study arm, participants will be managed per SoC 
assessments at Investigator discretion.  

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Study period: 
In both study parts, patients will receive treatment until any discontinuation criteria are met 
(see Section 7.1), including clinical progression or radiological progression (refer to 
Appendix F) and Investigator determination that the patient is no longer benefiting from 
treatment with IP. 
Number of patients: 
This study will enroll approximately 57 response-evaluable patients (ie, patients eligible to be 
included in the Response Evaluable Analysis Set) per arm (ie, 30 patients in Part 1 and 
27 patients in Part 2 per treatment arm, with the exception of Arm 1; Arm 1 will enroll 
20 patients in Part 1 and will not be included in Part 2). The study is sized to allow the use of a 
design within each treatment arm, with the exception of Arm 1. 
Part 1: At least 20 patients will be enrolled in the durvalumab + paclitaxel arm and at least 
30 patients in each of the other novel treatment combination arms, for a total of approximately 
170 patients (durvalumab + paclitaxel arm and 4 novel treatment combination arms). 
Additional patients may be enrolled in order to have at least 20 or 30 evaluable patients per 
durvalumab + paclitaxel arm or novel treatment combination arm, respectively. 
Part 2: Approximately 27 patients will be assigned to each treatment arm, for an anticipated 
total of 57 response-evaluable patients (ie, patients eligible to be included in the Response 
Evaluable Analysis Set) per arm (ie, 30 patients in Part 1 and 27 patients in Part 2 per 
treatment arm, with the exception of Arm 1, which will enroll 20 patients in Part 1 and will 
not be included in Part 2). Arm expansion from 30 patients in Part 1 to an additional 27 
patients from Part 2 will be determined based on a futility analysis utilizing a
design, and Sponsor decision. 
Target patient population: 
Patients with locally assessed and locally confirmed advanced/unresectable or metastatic 
TNBC, as defined by the most recent American Society of Clinical Oncology/College of 
American Pathologists guidelines, who are ≥18 years of age with Stage IV breast 
adenocarcinoma, had no prior systemic treatment for metastatic disease, have a tumor 
evaluable by RECIST 1.1, and are immunotherapy naïve will be eligible for this study. 
Patients must provide a tumor sample (archived or per routine clinical care) for determination 
of PD-L1 expression; however, the results of this assessment will not be used for 
inclusion/exclusion or stratification purposes. For enrollment into Arm 6 (durvalumab + DS-
8201a), patients must provide documentation of locally determined advanced/unresectable or 
metastatic TNBC with HER2-low tumor expression (IHC 2+/ISH–, IHC 1+/ISH–, or 
IHC 1+/ISH untested). (Note: ISH may be determined by either fluorescence in situ 
hybridization [FISH] or dual in situ hybridization [DISH]). For enrollment into Arm 8 
(durvalumab + Dato-DXd), patients must provide documentation of locally determined 
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advanced/unresectable or metastatic TNBC that is PD-L1 positive as determined by a 
pre-existing test or by local testing during pre-screening.  
Treatments and treatment duration: 
Durvalumab will be administered according to 28-day cycles (Arms 1 through 5) or 21-day 
cycle (Arms 6, 7, and 8). The dosage and mode of administration for durvalumab, paclitaxel, 
and each novel oncology therapy to be evaluated in a novel treatment combination arm are 
summarized in Table 9. 
Please note that if a patient’s weight falls to ≤30 kg after initiation of study treatment, then the 
patient should receive weight-based dosing equivalent to 20 mg/kg (Arms 1 through 5 only) of 
durvalumab every 4 weeks [q4w] after consultation between the Investigator and the Study 
Clinical Lead, until the weight improves to >30 kg, at which point the patient should start 
receiving the fixed dosing of durvalumab 1500 mg every cycle. Arms 6, 7, and 8 would not 
require weight-based dosing because the weight restriction is due to endotoxin limits per dose 
and is not applicable for doses <1500 mg. 
Table 9 
Treatments and treatment duration  
Target Compound 
Dose 
Route Schedule 
PD-L1 
Durvalumab (MEDI4736) 1500 mg (Arms 1 through 
5) 
1120 mg (Arms 6, 7, and 8) 
IV 
q4w (Arms 1 through 5) 
q3w (Arms 6, 7 and 8) 
NA 
Paclitaxel 
90 mg/m2 (Arms 1 and 5) 
80 mg/m2 (Arm 2)a 
IV 
4-week cycles: 3 weeks once weekly 
(D1, D8, and D15) and 1 week off 
AKT 
Capivasertib (AZD5363) 400 mg 
oral 
bid in a 4-week cycle; 3 weeks on 
(D2, D3, D4, and D5) and 1 week 
offb 
CD73 
Oleclumab (MEDI9447) 
3000 mg 
IV 
q2w for the first 2 cycles (D1 and 
D15 of C1 and C2); q4w starting at 
C3 (D1) 
HER2 
DS-8201a (trastuzumab 
deruxtecan) 
5.4 mg/kg 
IV 
q3w 
TROP2 
Dato-DXd  
(datopotamab deruxtecan) 
6.0 mg/kg 
IV 
q3w 
a 
For patients on Arm 2 who were treated prior to Protocol Version 4, dosing may continue unchanged 
(ie, if the patient was treated at starting dose 90 mg/m2 without dose modifications, they may continue at this 
dose, as clinically indicated). 
b 
Capivasertib should not be taken during any week that the paclitaxel infusion is not administered – 
either due to a scheduled off-drug-week or an unscheduled omission or delay. 
AKT protein kinase B; bid  Twice daily; C  Cycle; CD  Cluster of differentiation; D  Day; 
IV  Intravenous; NA  Not applicable; PD-L1  Programmed cell death ligand 1; q1w  Every 1 week; q2w  Every 
2 weeks; q3w  Every 3 weeks; q4w  Every 4 weeks. 

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Duration of treatment 
Unless specific treatment discontinuation criteria are met, all patients will continue therapy 
until clinical progression or radiological progression (defined in Appendix F). 
Progression during treatment 
Patients who are clinically stable at an initial RECIST 1.1-defined progression of disease (PD) 
to receive
at the
with
who
at the 
can 
receive
and
should
for the duration of
Follow-up of patients post discontinuation of study drug 
Patients who have discontinued treatment due to toxicity, symptomatic deterioration, or 
clinical progression during treatment or who have commenced subsequent anticancer therapy 
will be followed up with tumor assessments until RECIST 1.1-defined PD plus an additional 
optional follow-up scan or until death (whichever comes first) and followed for survival. 
These patients are not eligible for re-treatment at any time.  
Survival 
All patients assigned or randomized to treatment should be followed for survival. 
Safety Review Committee 
A SRC will review the initial safety profile for each of the novel treatment combination arms 
in Part 1 after 6 DLT-evaluable patients have completed the first treatment cycle or had a DLT 
during the first treatment cycle for each treatment arm and will review safety and tolerability 
data on an ongoing basis. In Arm 8, a review of the initial safety profile will not be 
undertaken, given that Arm 8 does not have a safety run-in; however, the SRC review safety 
and tolerability data in Arm 8 on an ongoing basis. Additional details on the use of the SRC 
during the Part 1 safety run-in period are provided in Section 4.1.4.3. 
An SRC will continue to be used throughout Part 1 and in Part 2 of the study, as appropriate. 
Sample size 
Part 1 of this study enrolled 20 patients in Arm 1 (now closed to enrollment) and will enroll 
30 patients in all other treatment arms. Part 2 will enroll a further 27 patients in each treatment 
arm that meets the
noted below. 
The primary objective for Part 1 is safety; 20 patients in the durvalumab + paclitaxel arm and 
30 patients per novel treatment combination arm are considered appropriate to characterize the 
AE profile of each combination. Twenty patients in the durvalumab + paclitaxel arm (Arm 1) 
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Safety 
The Safety Analysis Set will be used to summarize all safety data according to the treatment 
received. Data from all cycles of treatment will be combined in the presentation of safety data. 
The AEs (both in terms of Medical Dictionary for Regulatory Activities [MedDRA] preferred 
terms and Common Terminology Criteria for Adverse Event [CTCAE] grade) will be listed 
individually by patient. The number of patients experiencing each AE will be summarized by 
treatment arm and CTCAE grade. Other safety data will be assessed in terms of clinical 
chemistry, hematology, and vital signs and summarized using appropriate summary statistics 
by treatment arm. 
Efficacy 
Efficacy will be assessed in terms of ORR, PFS, DoR, OS, and PFS6 following assignment of 
study treatment based on patients pooled from Part 1 and Part 2 in treatment arms 2 to 8 
(Arm 1 will not be included in Part 2). A secondary objective in Part 1 and the primary 
objective of Part 2 is to assess the efficacy of durvalumab + novel oncology therapies with or 
without paclitaxel, and durvalumab + paclitaxel in terms of confirmed ORR as determined by 
the Investigator according to RECIST 1.1. The number and percentage of patients who 
achieve confirmed response (CR or PR) as determined by the Investigator according to 
RECIST 1.1 in each treatment arm will be summarized, and the 95% Clopper-Pearson CIs 
will be calculated. To meet additional secondary efficacy objectives, PFS, DoR, OS, and PFS6 
will be summarized by treatment arm and Kaplan-Meier plots will be presented for PFS, DoR, 
and OS. The FAS will be used to summarize efficacy data according to the assigned treatment. 
Efficacy data will also be explored in terms of PD-L1 status based on the FAS. 
Pharmacokinetics and antidrug antibodies 
PK and antidrug antibodies (ADAs) will be summarized using the PK Analysis Set and 
ADA-evaluable set, respectively. The details of the PK and ADA analysis will be provided in 
the Statistical Analysis Plan. 

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1.3 
Schema  
The general study design is summarized in Figure 1.  
Figure 1 
Study design  
 
 
a 
In patients with PD-L1 positive status. 
b 
In Part 1, the novel treatment combination arms will include a safety run-in period with a planned 
enrollment of 6 patients. Fewer than 6 patients may be enrolled if 2 patients have DLTs before 6 patients 
are enrolled; more than 6 patients may be enrolled in order to have 6 DLT-evaluable patients. No safety 
run-in will occur in Arm 8 given that the durvalumab + Dato-DXd combination was found to be tolerable 
with no DLTs in Arm 7. 
c 
See Section 9.1 for additional details. 
1L  First-line; DLT  Dose-limiting toxicity; DoR  Duration of response; Durva  Durvalumab; ECOG  Eastern 
Cooperative Oncology Group; ORR  Objective response rate; OS  Overall survival; Pac  Paclitaxel; Dato-
DXd  Datopotamab deruxtecan; DS-8201a  Trastuzumab deruxtecan; PFS  Progression-free survival; 
PFS6  Progression-free survival 6 months following  date of first dose; PS  Performance status; 
RECIST  Response Evaluation Criteria in Solid Tumors; TNBC  Triple negative breast cancer. 
 
 

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2 
INTRODUCTION  
2.1 
Study rationale  
This is a Phase IB/II, 2-stage, open-label, multicenter study to determine the efficacy and 
safety of durvalumab in combination with novel oncology therapies with or without paclitaxel 
and durvalumab with paclitaxel for the treatment of first-line metastatic triple negative breast 
cancer (TNBC). Clinical studies to date have revealed a substantial proportion of patients with 
TNBC who do not derive benefit from the combination of taxanes and immune checkpoint 
inhibitors (programmed cell death 1 [PD-1])/programmed cell death ligand 1 [PD-L1]), 
despite the encouraging responses of these therapies in a limited patient population. 
Modalities with promise for breast cancer (BC) and therapies with available clinical safety and 
combination data with durvalumab will be prioritized for study towards developing a novel 
treatment combination. 
2.2 
Background  
A detailed description of the chemistry, pharmacology, efficacy, and safety of durvalumab and 
each novel oncology therapy is provided in the respective Investigator’s Brochure for each 
molecule. 
2.2.1 
Triple negative breast cancer  
Globally, BC is the most diagnosed cancer among women (GLOBOCAN 2012), the second 
most common cancer overall, and the fifth leading cause of cancer deaths. BC is the leading 
cause of cancer death among European women, responsible for an estimated 91585 deaths in 
2012 (GLOBOCAN 2012) and is projected to kill 40610 women in the United States (US) in 
2017 (Desantis et al 2017, Noone et al 2017). Despite significant improvements in early 
detection and treatment, most women who develop metastatic disease will eventually succumb 
to the disease. 
BC subtypes are based on the tumor expression of the estrogen receptor (ER), progesterone 
receptor (PgR), and human epidermal growth factor receptor 2 (HER2). Hormone 
receptor-positive tumors (ER+, PgR+) are treated with agents that interrupt hormonal 
pathways, and HER2+ tumors are treated with agents that down-regulate HER2 activity. 
However, no targeted therapies currently exist for TNBC, the subtype of BC characterized by 
a lack of tumor expression of ER, PgR, or HER2. 
TNBC accounts for 15% to 20% of newly diagnosed BC (Hudis and Gianni 2011). Among all 
early-stage (Stages I to III) BC subtypes, TNBC has the highest probability of relapse and 
portends the poorest OS. Metastatic (Stage IV) TNBC has an aggressive clinical course and 
shorter PFS and OS than early-stage TNBC. Affected patients are managed by serial 
administration of single-agent chemotherapeutics, generally with adverse events (AEs) that 

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impact quality of life and poor clinical outcomes. TNBC patients have a poor prognosis and 
limited treatment options and thus present an unmet medical need. 
The current standard of care (SoC) for early-stage TNBC is a taxane-based regimen, with 
further addition of an anthracycline in the neoadjuvant setting. The standard clinical practice 
for early-stage TNBC following completion of definitive local and systemic chemotherapy 
treatment is observation. Cytotoxic chemotherapy is the main systemic therapy for patients 
presenting with advanced TNBC. Platinum salts, taxanes, and antibody drug conjugates with 
topoisomerase I inhibitors have been evaluated in patients with metastatic TNBC, with the 
following results for monotherapies and combination therapies: 
• 
In Study TBCR009, patients received cisplatin or carboplatin as first-line or 
second-line therapy. The objective response rate (ORR) was 25.6% overall (32.6% 
with cisplatin and 18.7% with carboplatin), with a median PFS of 2.9 months and an 
OS of 11 months (Isakoff et al 2015). 
• 
In the TNT study, patients with metastatic or locally advanced TNBC were treated 
with either carboplatin or docetaxel in the first-line setting. Response rates of 31.4% 
for carboplatin and 35.6% for docetaxel were not significantly different. Patients 
bearing breast cancer susceptibility gene (BRCA) 1/2 germline mutations responded 
better to carboplatin than to docetaxel, with an ORR of 68.0% versus 33.3%, 
respectively (Ganpenrieder et al 2017). 
• 
CBCSG006, a randomized Phase III study, explored cisplatin + gemcitabine 
compared with paclitaxel + gemcitabine as first-line therapy for metastatic TNBC 
(Hu et al 2015). With 120 patients per group, the ORR and median PFS were 64% 
and 7.7 months in the cisplatin + gemcitabine group and 49% and 6.5 months in the 
paclitaxel + gemcitabine group. Of note, the OS results for both combination cohorts 
were similar (19.37 months for cisplatin + gemcitabine and 18.07 months for 
paclitaxel + gemcitabine). 
• 
In Study DS8201-A-J101, a Phase I study enrolling patients with HER2 
low-expressing breast tumors (HER2 IHC1-2+), patients were treated with DS-8201a 
(trastuzumab deruxtecan) monotherapy. Overall response rates of 37% (20/54) were 
reported in extensively pretreated patients, including a subset of TNBC patients 
(DS-8201 Investigator’s Brochure Version 6). Evaluation of patients with HER2 
low-expressing breast tumors in this study is ongoing. The response rates of DS-
8201a, which delivers a topoisomerase I inhibitor to the tumor, were comparable to 
overall response rates with docetaxel in earlier lines of therapy (Ganpenrieder et al 
2017). 
• 
In the ASCENT study, a randomized Phase III study in patients with previously 
treated metastatic TNBC, the trophoblast cell surface protein 2 (TROP2) antibody-
drug conjugate (ADC), sacituzumab govitecan, was compared with treatment of 
physician’s choice. Of the 529 patients enrolled, median PFS for sacituzumab 
govitecan was 5.6 months versus 1.7 months for SoC chemotherapy (hazard ratio 
0.41; P<0.0001), median OS was 12.1 months for sacituzumab govitecan versus 6.7 
months for SoC chemotherapy (hazard ratio 0.48; P<0.0001) and overall response 

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rate was 35% versus 5% (Bardia et al 2020).DS1062-A-J101 is an ongoing Phase 1, 
2-part, multicenter, nonrandomized, open-label, multiple dose, first-in-human study 
of Dato-DXd. The TNBC cohort enrolled 24 patients (22 patients on 6.0 mg/kg and 
2 patients on 8.0 mg/kg) who were heavily pretreated (21 patients with ≥ 2 prior lines 
of therapy). A total of 6 patients (25%) discontinued the study due to disease 
progression. No patients discontinued the study due to an AE. Dose reductions due to 
AEs occurred in 6 patients (25%) and were mostly due to stomatitis (3 patients 
[13%]) and mucosal inflammation (2 patients [8%]). Most patients (67%) 
experienced mild to moderate AEs that were nonhematologic. There were no cases of 
Grade 3 diarrhoea or neutropenia and no cases of adjudicated drug-related interstitial 
lung disease (ILD). Antitumor response as measured by ORR from a blinded 
independent central review (BICR) was 43% and the disease control rate (DCR) was 
95% (Bardia 2021). 
• 
Overall, serial monotherapy of chemotherapeutics is the primary SoC, with 
promising ORR and PFS; however, OS still remains poor. 
 
2.2.1.1 
BRCA mutations in TNBC  
Germline BRCA1/2 mutation is a known risk factor for breast cancer, with current National 
Comprehensive Cancer Network (NCCN) guidelines recommending screening for all women 
diagnosed with TNBC who are younger than 60 years old (NCCN Guidelines). BRCA1 and 
BRCA2 defective tumors are intrinsically sensitive to poly (ADP-ribose) polymerase 
inhibitors. The OlympiaD trial evaluated patients with a BRCA1/2 mutation and randomized 
previously treated patients with breast cancer who received either olaparib or standard of care. 
The patients who received olaparib had an improved PFS of 7.0 months compared to 4.2 
months (HR 0.58) (Robson et al 2017). It is currently unknown whether BRCA1/2 mutations 
are predictive of benefit with the current proposed treatment regimens. 
2.2.2 
Immunotherapy in breast cancer  
Given the broad success of immune checkpoint inhibitors in providing durable clinical 
response in multiple cancer types (see Section 2.2.3), the utility of PD-1/PD-L1 blockade in 
BC is under active investigation. Although checkpoint inhibitors have been successfully 
approved in melanoma, non-small cell lung cancer (NSCLC), and bladder cancer, to date, 
none have been approved in BC at the time of writing this protocol. In clinical studies, the 
ability to modulate the immune system in BC has been demonstrated with antibodies that 
target PD-1 (pembrolizumab) and PD-L1(durvalumab, atezolizumab, and avelumab). 
In JAVELIN, 168 patients (BC subtypes: 42.9% ER+/PgR+, 34.5% TNBC, 15.5% HER2+, 
and 7.1% unknown) received avelumab monotherapy and had an ORR of 4.8% (Heery et al 
2017). Although responses were seen in all BC subtypes, they appeared to be higher in TNBC 
(8.6%) or in patients with high PD-L1 expression (defined by ≥10% PD-L1[+] immune cells). 
In 9 PD-L1(+) and 39 PD-L1(-) TNBC patients (48 patients total), the ORRs were 44.4% and 
2.6%, respectively. In an atezolizumab study, PD-L1 status was prospectively assessed 

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(positive criteria: >5% PD-L1-staining immune cells), and ORR was 13% in PD-L1(+) and 
5% in PD-L1(-) patients, of 112 evaluable TNBC patients in total; the ORR was much higher 
(26%) for patients receiving first-line treatment (Emens et al 2015). In KEYNOTE-012 and 
KEYNOTE-086, patients with TNBC were treated with pembrolizumab, and PD-L1 
expression was assessed (positive criteria: >1% of tumor or immune cells stained for antibody 
22C3) (Nanda et al 2016). In KEYNOTE-012, an ORR of 18.5% was observed in 27 PD-
L1(+) patients. KEYNOTE-086 included both salvage therapy and first-line cohorts for 
metastatic PD-L1(+) TNBC and reported ORRs of 4.8% and 23.1%, respectively. Although 
encouraging responses to immunotherapies have been seen in patients with high PD-L1 tumor 
expression (PD-L1[+] patients), particularly as a first-line treatment, this population represents 
only a subset of TNBC patients who could thus derive clinical benefit. 
Several studies have evaluated the addition of immunotherapy to standard chemotherapy, with 
the goal of stimulating or “priming” the immune system. As was observed in the 
immunotherapy-alone studies, there was a trend toward higher response rates (ORR of 46%) 
in patients treated first line. The IMPassion 130 study evaluated 902 patients with untreated 
metastatic TNBC. Patients were randomly assigned to atezolizumab or placebo in 
combination with nab-paclitaxel to assess PFS and OS. The changes in PFS data were 
significant in both the intention-to-treat (ITT) analysis group (the median PFS was 7.2 months 
with atezolizumab plus nab-paclitaxel compared to 5.5 months with placebo plus nab-
paclitaxel [p=0.002]) and the PD-L1-positive tumor analysis subgroup (the median PFS was 
7.5 months with atezolizumab plus nab-paclitaxel compared to 5.0 months with placebo plus 
nab-paclitaxel [p<0.001]) (Schmid et al 2018b). The IMPassion 131 study, in which paclitaxel 
is evaluated instead of nab-paclitaxel, is ongoing at the time of this protocol amendment. 
Pembrolizumab and eribulin combinations were explored in 95 previously treated metastatic 
TNBC patients of any PD-L1 status; the ORR for patients who had seen 2 or 3 prior lines of 
therapy or were treatment naïve was 27.3% and 41.2%, respectively, and did not appear to be 
dependent on PD-L1 status (Tolaney et al 2016). These promising results are being followed 
up in KEYNOTE-355, an ongoing Phase III study of first-line pembrolizumab with 
chemotherapy in metastatic TNBC. 
2.2.3 
Immunotherapies  
It is increasingly understood that cancers are recognized by the immune system and that, 
under some circumstances, the immune system may control or even eliminate tumors 
(Dunn et al 2004).  
PD-L1 is part of a complex system of receptors and ligands that are involved in controlling T 
cell activation. The PD-1 receptor (cluster of differentiation [CD]279) is expressed on the 
surface of activated T cells (Keir et al 2008). It has 2 known ligands: PD-L1 (B7-H1; CD274) 
and programmed cell death ligand-2 (PD-L2; B7-DC; CD273) (Okazaki and Honjo 2007). 
PD-1 and PD-L1/PD-L2 belong to a family of immune checkpoint proteins that act as 

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coinhibitory factors, which can halt or limit the development of T cell response. When PD-L1 
binds to PD-1, an inhibitory signal is transmitted into the T cell, which reduces cytokine 
production and suppresses T cell proliferation. Tumor cells exploit this immune checkpoint 
pathway as a mechanism to evade detection and inhibit immune response. 
PD-L1 is constitutively expressed by B-cells, dendritic cells, and macrophages (Qin et al 
2016). Importantly, PD-L1 is commonly over-expressed on tumor cells or on non-transformed 
cells in the tumor microenvironment (Pardoll 2012). PD-L1 expressed on the tumor cells 
binds to PD-1 receptors on the activated T cells, leading to the inhibition of cytotoxic T cells. 
These deactivated T cells remain inhibited in the tumor microenvironment. The PD-1/PD-L1 
pathway represents an adaptive immune resistance mechanism that is exerted by tumor cells in 
response to endogenous antitumor activity. 
The inhibitory mechanism described above is co-opted by tumors that express PD-L1 as a way 
of evading immune detection and elimination. The binding of an anti-PD-L1 agent to the 
PD-L1 receptor inhibits the interaction of PD-L1 with the PD-1 and CD80 receptors expressed 
on immune cells. This activity overcomes PD-L1-mediated inhibition of antitumor immunity. 
While functional blockade of PD-L1 results in T cell reactivation, this mechanism of action 
(MOA) is different from direct agonism of a stimulatory receptor such as CD28. 
PD-L1 is expressed in a broad range of cancers. Based on these findings, an anti-PD-L1 
antibody could be used therapeutically to enhance antitumor immune responses in patients 
with cancer. Results of pre-clinical and clinical studies of monoclonal antibodies (mAbs) 
targeting the PD-L1/PD-1 pathway have shown evidence of clinical activity and a manageable 
safety profile, supporting the hypothesis that an anti-PD-L1 antibody could be used to 
therapeutically enhance antitumor immune response in cancer patients (Brahmer et al 2012, 
Hirano et al 2005, Iwai et al 2002, Okudaira et al 2009, Topalian et al 2012, Zhang et al 2008) 
with responses that tend to be more pronounced in patients with tumors that express PD-L1 
(Powles et al 2014, Rizvi et al 2015, Segal et al 2015). In addition, high mutational burden 
(eg, in bladder carcinoma; Alexandrov et al 2013) may contribute to the responses seen with 
immune therapy. 
Clinical data has now been added to a wealth of pre-clinical data showing that blockade of 
negative regulatory signals to T cells such as PD-L1 has promising clinical activity. 
Nivolumab and pembrolizumab, 2 anti-PD-1 agents, and atezolizumab and durvalumab (see 
Section 2.2.4), 2 anti-PD-L1 agents, have been granted approvals by agencies for the 
treatment of a number of malignancies, including metastatic melanoma, squamous and non-
squamous cell NSCLC, squamous cell carcinoma of the head and neck and urothelial 
carcinoma. In addition, there are data from agents in the anti-PD-1/PD-L1 class showing 
clinical activity in a wide range of tumor types. 

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2.2.4 
Durvalumab  
Durvalumab is a human mAb of the immunoglobulin G (IgG) 1 kappa subclass that blocks the 
interaction of PD-L1 (but not PD-L2) with PD-1 on T cells and CD80 (B7.1) on immune cells. 
It is being developed by AstraZeneca/MedImmune for use in the treatment of cancer. 
(MedImmune is a wholly owned subsidiary of AstraZeneca; AstraZeneca/MedImmune will be 
referred to as AstraZeneca throughout this document.). The proposed MOA for durvalumab is 
interference in the interaction of PD-L1 with PD-1 and CD80 (B7.1). The blockade of 
PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of immune responses, 
including those that may result in tumor elimination. In vitro studies demonstrate that 
durvalumab antagonizes the inhibitory effect of PD-L1 on primary human T cells, resulting in 
restored interferon-gamma (IFN-γ)-induced proliferation (Stewart et al 2015). In vivo studies 
have shown that durvalumab inhibits tumor growth in xenograft models via a T cell-dependent 
mechanism (Stewart et al 2015). Based on these data, durvalumab is expected to stimulate the 
patient’s antitumor immune response by binding to PD-L1 and shifting the balance toward an 
antitumor response. Durvalumab has been engineered to reduce antibody-dependent cellular 
cytotoxicity and complement-dependent cytotoxicity.  
To date, durvalumab has been given to an estimated 14260 patients as part of ongoing studies 
either as monotherapy or in combination with other anticancer agents. Details on the safety 
profile of durvalumab are summarized in Section 8.3.14. Refer to the current durvalumab 
Investigator’s Brochure for a complete summary of pre-clinical and clinical information, 
including safety, efficacy, and pharmacokinetics (PK). 
2.2.5 
Durvalumab in combination with chemotherapy and rationale for 
novel treatment combinations  
There is a strong rationale for adding PD-1/PD-L1 blockade to chemotherapy. In fact, there 
are several reports describing the prognostic value of immune signature and tumor-infiltrating 
lymphocytes (TILs) for outcome to chemotherapy, including the following: 
• 
Large retrospective analysis of patient samples demonstrating that patients with 
increased TILs have a robust correlation with increased response to chemotherapy 
(Savas et al 2016). 
• 
Paclitaxel monotherapy when given to patients with BC increases the percentage of 
TILs, promoting a more immunogenic environment (Demaria et al 2001). 
• 
Chemotherapy is thought to synergize with PD-1/PD-L1 blockade by making the 
tumor “immunogenic” through initiating cell death, promoting phagocytosis of tumor 
cells, and ultimately leading to reactivation of immune-mediated tumor surveillance.  
• 
RNA sequencing analysis of breast tumors demonstrated a strong link between 
expression of immune markers and the percentage of TIL embedded in the lesion. 
BC cases with the highest TIL percentage were generally TNBC. In addition, 

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large-scale gene expression analysis demonstrated strong associations between 
immunomodulatory genes and outcome to chemotherapy (Savas et al 2016). 
 
As discussed in Section 2.2.2, a substantial proportion of patients do not derive benefit from 
the combination of chemotherapy and PD-1/PD-L1 inhibition; therefore, developing a novel 
treatment combination with other immunotherapies or targeted therapies is of particular 
interest. 
Durvalumab has previously been combined with taxane therapy and was found to be well 
tolerated in an ongoing study (Study NCT02250326). Seventy-eight patients with recurrent 
metastatic NSCLC were treated with nab-paclitaxel and durvalumab. The median number of 
treatment cycles was 7.0 (range: 1 to 14 cycles), with a median treatment duration of 
24.4 weeks (range: 1.4 to 41.1 weeks). Treatment-emergent adverse events (TEAEs) of 
special interest for durvalumab + nab-paclitaxel are summarized in Table 10. Overall, the 
treatment combination was well tolerated. 
Table 10 
Durvalumab and nab-paclitaxel TEAEs of special interest  
TEAE of special interest, n (%) 
Durvalumab + nab-paclitaxel (N = 78) 
 
All Grades 
Grades 3 and 4 
Non-hematologic 
 
 
Peripheral sensory neuropathy 
19 (24.4) 
3 (3.8) 
Dyspnea 
16 (20.5) 
4 (5.1) 
Hematologic 
 
 
Neutropenia 
13 (16.7) 
5 (6.4) 
Febrile neutropenia 
0 
0 
Anemia 
22 (28.2) 
3 (3.8) 
TEAE  Treatment-emergent adverse event. 
 
The combination of topoisomerase I inhibition and PD-L1 blockade has been shown to result 
in an additive antitumor response in pre-clinical models. In the FM3A murine breast tumor 
model, there was an increase in the proliferation and number of tumor-infiltrating 
CD8+ T cells in response to combination therapy with the topoisomerase I inhibitor, 
irinotecan, and the anti-PD-L1 antibody. Irinotecan alone was also found to decrease the 
number of regulatory T cells in lymph nodes and tumors, augment major histocompatibility 
complex (MHC) class 1 expression on tumor cells, and also increase PD-L1 expression on 
tumor cells and tumor-infiltrating immune cells (Iwai et al 2018). 

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In pre-clinical studies, DS-8201a has been combined with an anti-programmed cell death 
antibody (PD-1) to determine whether there is synergy with topoisomerase I inhibition and 
immunotherapy. The combination of DS-8201a and the anti-PD-1 antibody was more 
effective than either monotherapy in a syngeneic mouse model, using the murine colon cancer 
cell lines CT26.WT that stably expresses human HER2 (DS-8201a Investigator’s Brochure). 
In addition, the combination of DS-8201a and an anti-PD-1 antibody is currently being tested 
in breast cancer patients (Study DS-8201-A-U105; NCT03523572 [completed]; DS8201-A-
U106; NCT04042701). 
Overexpression of TROP2 is associated with more aggressive disease, poorer OS, and worse 
disease-free survival in patients with solid tumors (Goldenberg et al 2018). In breast cancer, 
increased TROP2 mRNA is a strong predictor of lymph node involvement, distant metastasis, 
and poor OS (Lin et al 2013, Zhao et al 2018). Overexpression of TROP2 is observed across 
all breast cancer subtypes, including TNBC where 80% of patients show TROP2 
overexpression (Son et al 2018, Huang et al 2005). In direct assessment of TROP2 activity, 
overexpression of TROP2 mRNA and protein stimulated cell growth with tumor progression 
that was abrogated with a TROP2 knockdown (Trerotola et al 2013). Additionally, in 
evaluation of 702 consecutive breast cancer cases, membrane localization of TROP-2 had an 
unfavorable prognostic factor for OS (HR 1.63; p  =  0.04) (Ambrogi et al 2014). 
It is expected that Dato-DXd will demonstrate efficacy in cancers that have high expression of 
TROP2. In vitro studies indicate that Dato-DXd exhibits TROP2 expression-dependent 
inhibition of cell growth through induction of DNA damage and apoptosis, and in vivo studies 
in human cancer-bearing mouse models have shown administration of Dato-DXd results in 
stronger antitumor activity in TROP-2 high tumors compared to TROP2-low or negative 
tumors. In the TROP2 positive pancreatic CFPAC-1 xenograft mouse mode, Dato-DXd 
induced dose dependent tumor growth inhibition and tumor regression (Okajima et al 2018). 
The biodistribution and antitumor activity of the ADC are expected to depend on the 
expression level of the target antigen in tumor tissue. 
The combination of TROP2 and PD-L1 inhibition has been explored with a bi-specific 
TROP2/PD-L1 chimeric antigen receptor (CAR)-T cell. In in vitro studies, the bi-specific 
TROP2/PD-L1 CAR-T cells showed specific cytotoxicity against TROP2- and PD-L1-
positive expressing gastric cancer cells, which was higher than that of mono-specific CAR-T 
cells, and also produced IFN-γ and interleukin (IL)-2 in response to the overexpression of 
TROP2 and PD-L1 in gastric cancer cells. The bi-specific TROP2/PD-L1 CAR-T cells 
significantly reduced the tumor growth of a xenograft model bearing human gastric tumors 
(Zhao et al 2019). These studies together indicate that treatment of TROP2 expressing cells 
with Dato-DXd may result in DNA damage and apoptosis of target cells, and the combination 
with durvalumab may lead to additive responses driven by enhanced T cell activation through 
reduction of regulatory T cells, augmented MHC class-1 antigen presentation, and inhibition 

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of PD-L1 signaling. In addition to directly targeting TROP-2 expressing cells, the 
hydrolysable linker of Dato-DXd also enables the topoisomerase I inhibitor, DXd, to be 
released into the tumor microenvironment. Thus adjacent tumor cells may also be killed by 
DXd released extracellularly via a bystander effect (Kalinsky et al 2020, Ogitani et al 2016). 
This has been demonstrated in NSCLC patients where responses to Dato-DXd were seen 
irrespective of TROP2 expression (Lisberg et al 2020). 
The potential for TROP2 ADCs in the treatment of breast cancer has been demonstrated with 
the April 2020 FDA accelerated approval of sacituzumab govitecan (TRODELVY; IMMU-
132; Immunomedics, Inc.) for patients with metastatic TNBC who have received at least 2 
prior therapies. This ADC is a conjugate of a humanized TROP2 monoclonal antibody linked 
with SN-38, the active metabolite of irinotecan, enabling the selective delivery of SN-38 to 
TROP2 expressing tumors (Bardia et al 2017). Pre-clinical studies have shown sacituzumab 
govitecan mediated antitumor responses in different tumor types with varying levels of 
TROP2 expression, including a squamous cell lung carcinoma tumor line having low TROP2 
surface expression and a TNBC tumor cell line, HCC1806, with moderate TROP2 levels 
(Goldenberg et al 2015., Cardillo et al 2015, Cardillo et al 2020). These studies support the 
hypothesis that high surface TROP2 expression may be predictive of a positive clinical 
outcome for sacituzumab govitecan. In mice bearing the high TROP2 expressing MDA-MB-
468 TNBC tumor model, this ADC could induce significant tumor regression compared to 
saline or an irinotecan control and mediate the activation of the intrinsic apoptotic pathway 
(Goldenberg et al 2015.). In IMMU-132-01 (NCT01631552), a Phase 1/2 single arm study of 
sacituzumab govitecan monotherapy in patients with epithelial cancers, 108 patients with 
metastatic TNBC, who had received at least 2 prior treatments for metastatic disease, were 
treated with 10 mg/kg sacituzumab govitecan. The most common adverse events (AEs) were 
nausea, diarrhea, fatigue, and myelosuppression, and discontinuation rates due to AEs were 
low (2.8%). The overall response rate was 33.3% (36/108) and the median duration of 
response (DoR) was 7.7 months (Bardia et al 2019). Among patients with TROP2 assessment 
(n=48), there was a trend toward higher PFS in patients with moderate to strong TROP2 
expression (88%) versus those with weak TROP2 expression or no staining (12%) (Bardia et 
al 2017). Furthermore, in the ASCENT study, a randomized Phase 3 study of sacituzumab 
govitecan versus treatment of physician’s choice in patients with previously treated metastatic 
TNBC, sacituzumab govitecan demonstrated significant PFS and OS improvement over SoC 
chemotherapy. Of the 529 patients enrolled, median PFS for sacituzumab govitecan was 
5.6 months versus 1.7 months for SoC chemotherapy (hazard ratio 0.41; P<0.0001), median 
OS was 12.1 months for sacituzumab govitecan versus 6.7 months for SoC chemotherapy 
(hazard ratio 0.48; P<0.0001) and overall response rate was 35% versus 5% (see Figure 2). In 
the safety population (n=224), key treatment-related grade ≥3 AEs with sacituzumab 
govitecan versus SoC chemotherapy were neutropenia (51% versus 33%), diarrhea (10.5% 
versus <1%), anemia (8% versus 5%), and febrile neutropenia (6% versus 2%). No grade >3 
neuropathy or ILD, and no treatment-related deaths were reported (Bardia et al 2020). 

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Sacituzumab govitecan is also being investigated in combination with the anti-PD-1 antibody, 
pembrolizumab, in patients with PD-L1-negative metastatic TNBC (NCT04468061). 
Figure 2 
Overall survival and progression free survival in patients treated with 
sacituzumab govitecan versus treatment of physician’s choice in 
patients with previously treated metastatic triple-negative breast cancer 
in the ASCENT study (NCT02574455)  
 

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In this Phase IB/II study, novel oncology therapies designed for immune modulation by 
different mechanisms are being tested in combination with durvalumab (PD-L1 blocker) with 
and without paclitaxel (chemotherapy). Modalities with promise for BC and therapies with 
available clinical safety and combination data with durvalumab will be prioritized for study. 
Background on the novel oncology therapies is provided in Section 2.2.6 through 
Section 2.2.9. 
2.2.6 
Capivasertib (AZD5363)  
Capivasertib (previously known as AZD5363) is a potent, selective inhibitor of the kinase 
activity of the serine/threonine-specific protein kinase AKT (protein kinase B [PKB]) (Davies 
et al 2012). Capivasertib is being developed as a potential treatment for solid and 
hematological malignancies. 
AKT is a node of multiple signaling pathways promoting tumorigenesis, inhibiting apoptosis, 
impacting on the cell cycle, and promoting invasion and migration. All 3 AKT isoforms are 
activated in different tumor types, including breast, prostate, ovarian, pancreatic, and gastric 
cancers, and this activation is often associated with resistance to established cancer therapies 
as well as advanced disease and/or poor prognosis (Altomare et al 2005). AKT activation in 
tumors is largely due to input from other signaling pathways upstream of AKT (eg, mutation 
of oncogenes such as Ras or Bcr-abl, mutation of receptor tyrosine kinases such as epidermal 
growth factor receptor, amplification of HER2, loss of phosphatase and tensin homolog 
[PTEN] function, or mutations of phosphoinositide-3-kinase [PI3K]).  
The PI3K/AKT signaling pathway is often activated in TNBC through activating mutations in 
PIK3CA or AKT1 and/or inactivating alterations in PTEN (Cancer Genome Atlas Network 
2012, Curtis et al 2012, Shah et al 2012). Deficient expression of PTEN is a common finding 
in TNBC and has been associated with a higher degree of AKT pathway activation (LoRusso 
2016, Millis et al 2015). The prevalence of TNBC patients with tumors harboring 
PIK3CA/AKT1/PTEN alterations is reported to be in the range of 23% to 41% (Ciriello et al 
2015, Curtis et al 2012, Kim et al 2017, Pereira et al 2016, Wilson et al 2019). 
Inhibitors of AKT are anticipated to have efficacy when combined with cytotoxic 
chemotherapies or when combined with targeted or antihormonal agents. Capivasertib inhibits 
all 3 AKT isoforms (AKT1, AKT2, and AKT3) and therefore has the potential to provide 
clinical benefit over a range of therapeutic indications. A significant relationship has been 
found in pre-clinical studies between the presence of a PI3K, catalytic, alpha polypeptide 
(PIK3CA) mutation or PTEN mutations and sensitivity to monotherapy with capivasertib in a 
panel of 182 cancer cell lines (p=0.0059; t-test). Capivasertib inhibits the growth of several 
human breast cancer xenograft models, including the TNBC xenograft model HCC1187 and 
the HER2+, PIK3CA mutant xenograft models BT474 and HCC1954. Combination studies in 

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breast cancer xenograft models, including the TNBC xenograft model HCC1187, demonstrate 
significantly increased efficacy when capivasertib and docetaxel are combined, compared to 
treatment with taxane or capivasertib alone. The HCC1187 xenograft model does not carry 
mutations of PIK3CA, AKT1 or PTEN, confirming that activity in combination studies is not 
restricted to models with intrinsic, aberrant PI3K pathway activation (Davies et al 2012). 
2.2.6.1 
Clinical experience of capivasertib  
As of the final data cut-off (DCO) date of 04 October 2017, approximately 456 patients have 
been exposed to capivasertib in AstraZeneca-sponsored studies, including 297 patients treated 
with capivasertib monotherapy, 92 patients treated with capivasertib in combination dosing 
with paclitaxel, and 67 patients treated with capivasertib in combination dosing with 
fulvestrant. Of the 5 studies in the clinical development program, 2 are ongoing 
(Studies D3610C00001 and D3610C00002), 2 were completed (Studies D3610C00004 and 
D3610C00007), and 1 (Study D3610C00003) was terminated early following an unscheduled 
interim analysis indicating that capivasertib was unlikely to generate a positive efficacy signal 
in this setting.  
In addition, 18 Investigator-sponsored studies of capivasertib are planned or ongoing. 
Tumor response data available from 2 Phase I studies—D3610C00001 (Parts A and B) 
(Western population) and D3610C00004 (Japan)—showed that 3 of the 131 patients had 
Response Evaluation Criteria in Solid Tumors (RECIST) partial responses (PRs): 1 patient 
whose tumor was positive for PIK3CA mutation and 2 patients with tumors that tested 
positive for AKT1 mutation. These Phase I studies recruited patients from advanced cancer 
populations who had been heavily pre-treated and showed resistance to a number of prior 
therapies. The expansion parts of Study D3610C00001 (Parts C and D) recruited an advanced 
cancer population selected for patients with proven PIK3CA (Part C) or AKT1 (Part D) 
mutations. In patients with ER+ BC, 1 patient had a confirmed RECIST response of PR in 
Part C (PIK3CA mutation). In patients with gynecological cancer, 2 patients with PIK3CA-
mutant cancer had a confirmed RECIST response of PR. In patients with AKT1 E17K-mutant 
tumors (n=52) and a median of 5 lines of prior therapy, the median PFS was 5.5 months (95% 
CI: 2.9 to 6.9 months) in patients with ER+ BC, 6.6 months (95% CI: 1.5 to 8.3 months) in 
patients with gynecologic cancer, and 4.2 months (95% CI: 2.1 to 12.8 months) in patients 
with other solid tumors (Banerji et al 2017). 
Of note, while the addition of capivasertib to first-line weekly paclitaxel in 
ER+HER- advanced BC (Study D3610C00002 [BEECH]) did not improve PFS in the overall 
or the PIK3CA-mutation positive population (Turner et al 2017), recently reported data on the 
externally sponsored randomized, double-blind, placebo-controlled, Phase II study PAKT 
showed that the same combination was highly effective in metastatic TNBC patients as first-
line therapy, substantially improving PFS and OS in the overall population. The benefits were 

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more pronounced in patients with PIK3CA/AKT1/PTEN-altered tumors detected by next-
generation sequencing (NGS) (Schmid et al 2018a). Capivasertib in combination with 
paclitaxel was well tolerated overall and had a manageable safety profile, with no marked 
impact on the tolerability and dose intensity of paclitaxel. In response to the positive results 
from the PAKT study, a Phase III study (CAPItello-290, NCT03997123) is being conducted 
with the aim to provide confirmatory evidence of the efficacy and safety of capivasertib in 
combination with paclitaxel versus placebo + paclitaxel as first-line treatment for patients with 
locally advanced (not amenable to resection with curative intent) or metastatic TNBC. 
Details on the safety and risk profile of capivasertib alone and in combination therapy are 
provided in Sections 2.3.2.2, 2.3.2.3, and 2.3.2.4. Further details regarding capivasertib are 
provided in the capivasertib Investigator’s Brochure. 
2.2.7 
Oleclumab  
Oleclumab (MEDI9447) is a human mAb of the IgG1 lambda (λ) subtype that selectively 
binds to and inhibits the ectonucleotidase activity of CD73. The triple mutation, 
L234F/L235E/P331S (according to the European Union [EU] numbering convention), is 
encoded in the heavy chain constant region to significantly reduce IgG effector function. 
Oleclumab inhibits the catalysis of adenosine monophosphate (AMP) to adenosine and 
organic phosphate by CD73. Extracellular adenosine is believed to mediate the 
immunosuppressive effects of both MDSCs and regulatory T cells, among others (Antonioli et 
al 2013). The enzymatic blockade of CD73 caused by binding of oleclumab to CD73 may 
therefore lead to increased antitumor immunity. 
CD73 inhibition has been studied in several in vivo models. In mouse tumor models, targeting 
cancer cell CD73 using RNA interference inhibited tumor growth by direct inhibition of tumor 
cell migration and metastasis (Zhi et al 2007) and by freeing antitumor T cells from the 
suppressive effects of extracellular adenosine, restoring efficacy of adoptive T cell therapy 
(Jin et al 2010). In a variety of mouse tumor models, CD73 antagonist antibodies may rescue 
endogenous antitumor responses, especially in tumor types with high levels of expression of 
CD73, such as TNBC (Stagg et al 2010). Ablation of CD73 in gene-targeted mice resulted in 
the suppression of growth of colon cancer, lymphoma, mammary tumors, and melanoma 
(Stagg et al 2011). Furthermore, in murine models of mammary carcinoma and melanoma, 
dual inhibition of CD73 and the adenosine A2A receptor resulted in reduced tumor growth, 
increased immune infiltrates, and improvement in OS as compared to either placebo or each 
treatment as monotherapy (Young et al 2016), suggesting that dual inhibition of the 
adenosinergic pathway may be an effective therapeutic approach. 
In 122 samples from patients with TNBC, high CD73 protein expression was inversely related 
to patient disease-free survival and OS (Buisseret et al 2017). Notably, CD73 gene expression 
is significantly associated with a worse prognosis in TNBC patients but not in patients with 

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luminal or HER2+ BC (Loi et al 2013). It is postulated that in TNBC, CD73 overexpression 
may confer chemoresistance to doxorubicin, or other anthracycline therapies, by suppressing 
adaptive antitumor immune responses via activation of A2A adenosine receptors. In pre-
clinical models, targeted blockade of CD73 in TNBC reversed the effect and enhanced 
doxorubicin-mediated antitumor immune responses, significantly prolonging survival (Loi et 
al 2013). Chemotherapy, including paclitaxel, has also been reported to induce the 
transcription of PD-L1 and CD73 in TNBC (Samanta et al 2018), creating an environment that 
is highly susceptible to a paclitaxel, durvalumab, and oleclumab combination. 
Details on the potential benefits of oleclumab based on clinical experience are provided in 
Section 2.3.3.1. 
Details on the safety and risk profile of oleclumab alone and in combination therapy are 
provided in Sections 2.3.3.2 and 2.3.3.3. 
2.2.8 
DS-8201a (trastuzumab deruxtecan)  
DS-8201a (T-DXd) is an ADC that targets HER2. The molecule consists of an antibody 
component (MAAL-9001), which is a humanized immunoglobulin G1 (IgG1) monoclonal 
antibody with reference to the amino acid sequence of trastuzumab. The antibody is 
covalently conjugated via a maleimide tetrapeptide linker to the drug component, an exatecan 
derivative that is a topoisomerase I inhibitor (DXd). This ADC has a high drug-to-antibody 
ratio (DAR) (7-8:1) with homogenous conjugation with DXd. DS-8201a is cleaved by 
lysosomal enzymes and releases DXd in the cytoplasm after it binds to HER2 receptor and 
gets internalized in tumor cells. DS-8201a is expected to inhibit tumor growth on the basis of 
the following reasons: it exhibits antibody dependent cellular cytotoxicity similar to those of 
trastuzumab when it binds to HER2; the DXd that is released from DS-8201a after the 
internalization induces apoptosis by inhibiting topoisomerase I. 
As of 08 June 2019, 1036 patients received at least 1 dose of DS-8201a. In the ongoing 
DS8201-A-J101 study, the overall efficacy results in patients with HER2-positive breast 
cancer at 5.4 mg/kg or 6.4 mg/kg demonstrated a confirmed ORR of 52.5%. In patients with 
HER2-low expressing tumors (HER2 IHC1+ or 2+), the overall response rates of 37% (20/54) 
were reported in extensively pretreated patients. A subset of the patients with HER2 low 
tumors in the study were diagnosed with TNBC. The overall efficacy results in patients with 
other cancers demonstrated a confirmed ORR of 29.5%. 
Details on the safety and risk profile of DS-8201a alone and in combination therapy are 
provided in Sections 2.3.3.2 and 2.3.3.3. Further details regarding DS-8201a are provided in 
the DS-8201a Investigator’s Brochure. 

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2.2.9 
Dato-DXd (datopotamab deruxtecan; DS-1062a)  
Dato-DXd is an ADC that targets tumor-associated calcium signal transducer 2, TROP2, a 
transmembrane protein that is highly expressed in various epithelial tumors including 
esophageal squamous cell carcinoma, breast cancer, and non-small cell lung cancer. The 
molecule consists of a recombinant humanized anti-TROP2 IgG1 monoclonal antibody, 
MAAP-9001a, which is covalently conjugated to a drug linker, MAAA-1162a, via thioether 
bonds. Upon binding to TROP2, Dato-DXd is internalized, and after enzymatic processing, 
the topoisomerase I inhibitor, DXd, is released, leading to inhibition of tumor growth and 
apoptosis of target cells. In non-clinical toxicology studies, lung toxicity, corneal toxicity, skin 
toxicity, intestinal toxicity, lymphatic/hematopoietic system toxicity, reproductive and 
accessory organ toxicities, hepatic toxicity, renal toxicity, and joint cartilage toxicity were 
found in association with the administration of Dato-DXd. As with any therapeutic antibodies, 
there is a possibility of infusion-related reactions and immune responses causing allergic or 
anaphylactic reactions to Dato-DXd. 
DS1062-A-J101 is an ongoing Phase I first-in-human study evaluating escalating doses of 
Dato-DXd in advanced solid tumors, including TNBC. Clinical data are available evaluating 
escalating doses of DS 1062a (0.27 to 10.0 mg/kg) in unselected patients with advanced 
NSCLC or TNBC who have relapsed or are refractory to standard of care therapy (Lisberg et 
al 2020). 
The Phase 1 study had a dose escalation phase and a dose expansion phase. A total of 
208 patients were enrolled as of the Investigator’s Brochure DCO, 04 September 2020. The 
median duration of treatment was 2.76 months (range: 0.7 to 20.0 months). The patients 
treated include pathologically documented unresectable advanced NSCLC or TNBC who have 
been refractory to or relapsed on standard treatment. In the escalation phase, dose-limiting 
toxicities occurred in 3 subjects: 2 subjects at 10 mg/kg (1 with Grade 3 stomatitis and 1 with 
Grade 3 mucosal inflammation) and 1 subject at 6.0 mg/kg (Grade 3 maculo-papular rash). 
The maximum tolerated dose was determined at 8.0 mg/kg during the expansion phase.  
As of the DCO, 189 patients were evaluable for a response assessment (defined as having at 
least 1 dose of Dato-DXd and at least 1 pre- and post-baseline tumor assessment or 
discontinued treatment). The ORR by BICR was 15.4% (6 PRs in 39 patients) in the 6.0 
mg/kg dose group and 23.8% (19 PRs in 80 patients) in the 8.0 mg/kg dose group. The DCR 
was 66.7% (6 PRs and 18 stable disease [SDs] in 39 patients) in the 6.0 mg/kg dose group and 
80.0% (19 PRs and 43 SDs in 80 patients) in the 8.0 mg/kg dose group. Duration of response 
was not sufficiently mature as of the DCO, but preliminary results supported the durability of 
the response with median DoR by BICR of 5.5 months at 8.0 mg/kg and not yet reached at 4.0 
and 6.0 mg/kg. 

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As of the DCO, TEAEs were reported in 95.7% of 208 patients; TEAEs ≥ Grade 3 were 
reported in 42.8 % and serious TEAEs occurred in 34.1% of patients. The most frequent (≥ 
20% of patients) TEAEs regardless of causality were nausea (46.6%), stomatitis (38.9%), 
fatigue (34.1%), alopecia (33.7%), decreased appetite (24.5%), vomiting (23.1%), and 
constipation (20.7%). A serious adverse event (SAE) of infusion-related reaction (IRR) 
occurred in 3 patients (1 on 4 mg/kg, 1 on 6 mg/kg, and 1 on 8 mg/kg) and 1 patient with a 
history of allergy had an SAE of anaphylaxis (4 mg/kg). Apart from 2 patients with a Grade 3 
IRR (1 on 4 mg/kg and 1 on 6 mg/kg), IRR cases were mild or moderate, and manageable by 
close observation and dose modification. 
Twenty patients (9.6%) had a TEAE associated with discontinuation of study drug. 
Twenty-eight patients (13.5%) and 35 patients (16.8%) had TEAEs that were associated with 
dose interruption or dose reduction, respectively. There were 14 patients (6.7%) with an ILD 
event that was independently adjudicated as treatment related, including 12 patients (14.6%) 
on 8.0 mg/kg, 1 patient (2.2%) on 6.0 mg/kg, and 1 patient (2.0%) on 4.0 mg/kg. National 
Cancer Institute - Common Terminology Criteria for Adverse Events (NCI CTCAE) grades 
for these 14 events were as follows: three Grade 1, six Grade 2, two Grade 3, and three Grade 
5 events. The patients with an adjudicated drug related Grade 5 ILD were on 8.0 mg/kg. 
Interstitial lung disease/pneumonitis is considered an important identified risk for Dato-DXd. 
Established treatment guidelines are in place to manage toxicities associated with Dato-DXd.  
At the DCO, 46 patients were dosed at 6.0 mg/kg, the planned dose level for Dato-DXd to be 
combined with durvalumab in BEGONIA. The median duration of treatment was 2.07 months 
(range: 0.7 to 19.7 months) at the 6.0 mg/kg dose. At the 6.0 mg/kg dose, dose interruptions, 
reductions, and discontinuations due to AEs occurred in 9 (19.6%), 4 (8.7%), and 4 (8.7%) 
patients, respectively. Of the 39 response-evaluable patients at the 6.0 mg/kg dose level 
(defined as having at least 1 dose of Dato-DXd and at least 1 post-baseline tumor assessment 
or discontinued treatment), 6 (15.4%) patients had a confirmed PR, and 2 of these patients 
discontinued due to PD. Forty-two (91.3%) patients at the 6.0 mg/kg dose experienced a 
TEAE, with 7 (15.2%) patients having treatment-related TEAEs ≥ Grade 3 and with 4 (8.7%) 
patients having serious treatment-related TEAEs. There was 1 (2.2%) patient with an ILD 
event that was independently adjudicated as treatment related. This ILD event was Grade 2 
according to NCI CTCAE. There was 1 patient with a Grade 5 TEAE in this dose cohort, 
which was not related to study drug. Overall, Dato-DXd was noted to have an acceptable and 
manageable safety profile.  
An oral presentation at the European Society for Medical Oncology, Breast Cancer Congress 
2021 presented results on the TNBC cohort in Dato-Dxd DS1062-A-J101 ongoing Phase 1 
study through 08 January 2021. The Dato-DXd TNBC Cohort enrolled 24 patients (22 
patients on 6.0 mg/kg and 2 patients on 8.0 mg/kg) who were heavily pretreated (21 patients 
with ≥ 2 prior lines of therapy). A total of 6 patients (25%) discontinued the study due to 

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disease progression. No patients discontinued the study due to an AE. Dose reductions due to 
AEs occurred in 6 patients (25%) and were mostly due to stomatitis (3 patients [13%] and 
mucosal inflammation (2 patients [8%]). Most patients (67%) experienced mild to moderate 
AEs that were nonhematologic. There were no cases of Grade 3 diarrhoea or neutropenia and 
no cases of adjudicated drug-related ILD. Antitumor response as measured by ORR from a 
BICR was 43% and the DCR was 95% (Bardia 2021). 
Details on the safety and risk profile of Dato-DXd alone and in combination therapy are 
provided in Sections 2.3.5.2 and 2.3.5.3. Further details regarding Dato-DXd are provided in 
the Dato-DXd Investigator’s Brochure. 
2.3 
Benefit/risk assessment  
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of durvalumab and each novel oncology therapy may be found in the respective 
Investigator’s Brochure for each molecule. 
2.3.1 
Durvalumab  
2.3.1.1 
Potential benefits of durvalumab  
The majority of the safety and efficacy data currently available for durvalumab (MEDI4736) 
are based on the first-in-human, single-agent study (Study 1108) in patients with advanced 
solid tumors. Overall, as of 07 May 2015, 456 of 694 patients treated with durvalumab 
10 mg/kg every 2 weeks (q2w) were evaluable for response. Evaluable patients were defined 
as having ≥24 weeks of follow-up, measurable disease at baseline, and ≥1 follow-up scan or 
discontinued because of PDs or death without any follow-up scan. In PD-L1 unselected 
patients, the ORR in TNBC was <10%, with a DCR of 4.2% at 24 weeks. A Phase I/II study 
of durvalumab in combination with olaparib (a poly-adenosine-diphosphate-ribose polymerase 
inhibitor) is ongoing in patients with advanced solid tumors, including TNBC. 
2.3.1.2 
Potential risks of durvalumab  
2.3.1.2.1 OVERALL IMMUNOTHERAPY RISKS  
Monoclonal antibodies directed against immune checkpoint proteins, such as PD-L1 as well as 
those directed against PD-1 or cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), aim 
to boost endogenous immune responses directed against tumor cells. By stimulating the 
immune system, however, there is the potential for adverse effects on normal tissues. 
Most adverse drug reactions seen with the immune checkpoint inhibitor class of agents are 
thought to be due to the effects of inflammatory cells on specific tissues. These risks are 
generally events with a potential inflammatory or immune-mediated mechanism and may 
require more frequent monitoring and/or unique interventions such as immunosuppressants 
and/or endocrine therapy. These immune-mediated effects can occur in nearly any organ 

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system and are most commonly seen as gastrointestinal AEs such as colitis and diarrhea, 
pneumonitis/ILD, hepatic AEs such as liver enzyme elevations, skin events such as rash and 
dermatitis, and endocrinopathies including hypothyroidism and hyperthyroidism.  
2.3.1.2.2 DURVALUMAB RISKS  
Risks with durvalumab include, but are not limited to, diarrhea/colitis, abdominal pain, 
cough/productive cough, pneumonitis/ILD, endocrinopathies (ie, events of 
hypophysitis/hypopituitarism, adrenal insufficiency, hyper- and hypo-thyroidism, thyroiditis, 
type I diabetes mellitus [which may present with diabetic ketoacidosis] and diabetes 
insipidus), dysphonia, hepatitis/increases in transaminases (ALT and AST increase), 
nephritis/increases in creatinine, dysuria, rash/dermatitis, pruritus, night sweats, IRRs, 
hypersensitivity reactions and anaphylaxis, pancreatitis, serious infections, pyrexia, oedema 
peripheral, upper respiratory tract infections, pneumonia, oral candidiasis, dental and oral soft 
tissue infections, influenza, myalgia, cytokine release syndrome, and other rare or less 
frequent inflammatory events including neuromuscular toxicities (eg, Guillain-Barré 
syndrome, myasthenia gravis, myocarditis, myositis/polymyositis, immune thrombocytopenia, 
and encephalitis), pericarditis, sarcoidosis, uveitis, and other events involving the eye (eg, 
keratitis and optic neuritis), skin (eg, scleroderma, vitiligo and pemphigoid), rheumatological 
events (polymyalgia rheumatic and immune-mediated arthritis), vasculitis, non-infectious 
meningitis, non-infectious encephalitis, and psoriasis.  
For information on all identified and potential risks with durvalumab, please always refer to 
the current version of the durvalumab Investigator’s Brochure. 
In monotherapy clinical studies, AEs at an incidence of >20% include events such as fatigue, 
cough, decreased appetite, dyspnea and nausea. Approximately 10% of patients discontinued 
the drug due to an AE. Please see the current version of the Investigator’s Brochure for a 
detailed summary of the monotherapy data including AEs, SAEs, and CTC Grade 3 to 5 
events reported across the durvalumab program. 
The majority of treatment-related AEs were manageable with dose delays, symptomatic 
treatment, and, in the case of events suspected to have an immune basis, the use of established 
treatment guidelines for immune-mediated toxicity (see Section 8.4.6.1). 
A detailed summary of durvalumab monotherapy AE data can be found in the current version 
of the durvalumab Investigator’s Brochure. 
2.3.2 
Capivasertib (AZD5363)  
2.3.2.1 
Potential benefits of capivasertib  
The PI3K/AKT/PTEN pathway is frequently deregulated in TNBC and drives tumor growth 
and cell survival. PI3K pathway activation is frequently associated with resistance to 

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chemotherapy, and multiple lines of pre-clinical investigation have demonstrated that the 
addition of AKT- or PI3K-pathway inhibitors can significantly increase the activity of 
chemotherapy and overcome resistance. 
Capivasertib is a potent inhibitor of AKT1, AKT2, and AKT3 (half-maximal inhibitory 
concentration [IC50] <10 nM). Non-clinical in vitro and in vivo assays have demonstrated the 
inhibition of phosphorylation of the AKT substrates GSK3β and PRAS40 and of tumor 
growth in xenograft models. Furthermore, pre-clinical studies have demonstrated strong 
synergistic antitumor activity when capivasertib and taxane chemotherapy are used in 
combination. 
In the randomized, placebo-controlled Phase II study (PAKT) of 140 patients with newly 
diagnosed metastatic TNBC, the median OS was 19.1 months in patients treated with 
capivasertib in combination with paclitaxel compared to 12.6 months for placebo with 
paclitaxel ([HR: 0.61; 95% CI: 0.37 to 0.99; 1-sided p=0.02; 2-sided p=0.04). The median 
PFS was 5.9 months for active treatment compared to 4.2 months for placebo (HR: 0.74; 
95% CI: 0.50 to 1.08), with a greater effect observed in a biomarker-selected population 
(patients with tumors harboring PIK3CA/AKT1/PTEN mutations by NGS). 
2.3.2.2 
Potential risks identified from non-clinical studies of capivasertib  
This section is based on non-clinical toxicology and safety pharmacology studies with 
capivasertib. The toxicological profile of capivasertib has been evaluated in rats and dogs in 
studies of up to 9 months in duration. The key risks identified from non-clinical assessments 
to date are considered to be effects on glucose homeostasis and insulin signaling, cardiac 
function, and renal function. Other tissues affected in non-clinical studies have included the 
reproductive organs, liver, hypothalamic-pituitary axis, and hematopoietic system. In addition, 
genotoxicity and phototoxicity have been assessed. 
Glucose homeostasis and insulin signaling: Marked increases in blood insulin and glucose 
levels were noted following dosing in the dog and rat studies. Levels of insulin and glucose 
had generally returned to normal 24 hours post-dose. AKT is known to be involved in the 
regulation of glucose metabolism (Chang et al 2004); therefore, these changes are likely to be 
related to the primary pharmacology of capivasertib. 
Cardiac function: Capivasertib inhibits the hERG channel, with an IC50 of 73.0 µmol/L, via 
an underlying mechanism that may be due to increases in plasma glucose and insulin levels 
(Marfella et al 2001, van Noord et al 2010). Data from the isolated rabbit heart model suggest 
that capivasertib may be classified as low risk in terms of triggering the QT-associated 
arrhythmia of torsade de pointes. Increases in cardiac contractility have been observed in 
some non-clinical models; the mechanism underlying these observations is unknown. 
Decreases in blood pressure (BP) have also been noted, consistent with the vaso-relaxant 
activity of capivasertib identified in a rat aorta study and the increase in coronary flow seen in 

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the isolated rat and rabbit heart studies. It is possible that the vasoactive effects of capivasertib 
occur via the inhibition of ROCK1, which is known to play an important role in the regulation 
of vascular tone (Altomare et al 2005). 
Renal function: Polyuria, glucosuria, proteinuria, increased water consumption, and 
decreased tubular epithelial cell size have been observed non-clinically, but there was no 
associated histopathology in the kidney. These effects are consistent with the pharmacological 
activity of AKT in terms of a role in proximal tubular glucose and phosphate transport 
(Kempe et al 2010). 
Reproductive toxicity: Studies in rats and dogs showed degenerative changes in the testes 
and epididymides in males, as well as decreased prostate weights. Findings in the female 
reproductive organs (uterus and ovaries) were noted in the rat 1-month toxicity study but were 
limited to a reversible reduction in organ weight, with no histopathological findings. 
Capivasertib had an adverse effect on embryonic survival as well as early postnatal growth 
when administered to pregnant and lactating rats. Exposure to capivasertib was confirmed in 
suckling pups, which may indicate the potential for excretion of capivasertib in milk. 
Additional information is provided in the current version of the Investigator’s Brochure for 
capivasertib. 
2.3.2.3 
Potential risks of capivasertib from early clinical studies  
As of the DCO date of 04 October 2017, 5 clinical studies sponsored by AstraZeneca using 
capivasertib have been initiated. A total of 297 patients have been treated with capivasertib 
monotherapy, 92 patients with capivasertib in combination dosing with paclitaxel, and 
67 patients with capivasertib in combination dosing with fulvestrant (see also Section 2.2.6.1). 
Expected adverse events of special interest (AESIs) for capivasertib are diarrhea, 
hyperglycemia, rash, stomatitis, infection/lower respiratory tract infection, and QT 
prolongation. Most cases can be managed by treatment with other drugs (eg, topical steroids, 
anti-diarrheal drugs) and/or by dose adjustment of capivasertib, per AE toxicity management 
guidelines provided in Section 8.4.6.3. Additionally, the AE of fatigue is commonly reported 
for capivasertib, affecting >30% of patients in the pooled monotherapy intermittent group, 
irrespective of causality. 
Further information on specific AESIs can be found in Section 6.5.2 of the capivasertib 
Investigator’s Brochure. 
2.3.2.4 
Potential risks of capivasertib in combination with paclitaxel  
Capivasertib was administered in combination with weekly paclitaxel in 2 Phase II, 
randomized, placebo-controlled studies. The AE profile was consistent with the individual AE 
profiles of each drug, with no additional observations in relation to safety and tolerability. 

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In the externally sponsored Phase II study, PAKT, of capivasertib in combination with 
paclitaxel compared to placebo with paclitaxel in women with metastatic TNBC, the most 
common Grade ≥3 AEs, were diarrhea (13.2% of capivasertib-treated patients versus 1.4% of 
placebo-treated patients), infection (4.4% versus 1.4%), and neutropenia (2.9% versus 2.9%). 
In the AstraZeneca-sponsored Phase II study, BEECH, of capivasertib in combination with 
paclitaxel compared to placebo with paclitaxel in women with metastatic ER+HER- BC, the 
most common Grade ≥3 AEs, irrespective of causality, were diarrhea (24.1% of 
capivasertib-treated patients versus 1.8% of placebo-treated patients), hyperglycemia (13% 
versus 0), maculo-papular rash (9.3% versus 0), peripheral neuropathy (5.6% versus 1.8), 
alanine aminotransferase (ALT) increased (3.7% versus 3.6%), and stomatitis (3.7% versus 0). 
In both PAKT and BEECH studies, capivasertib in combination with paclitaxel was well 
tolerated overall and had a manageable safety profile, with no marked impact on the 
tolerability and dose intensity of paclitaxel. 
The study design aims to minimize potential risks of the novel treatment combination. Careful 
blood glucose monitoring to evaluate for hyperglycemia will be done throughout the study. 
Toxicity management guidelines are shown in Section 8.4.6.3, and further guidance for 
Investigators is available in the capivasertib Investigator’s Brochure. Secondary prophylaxis 
and loperamide can be used to reduce the risk of capivasertib-induced diarrhea. There is 
overlap between the toxicity profiles for capivasertib and durvalumab (see Section 2.3.1.2), 
notably with diarrhea and rash, which are to be managed with loperamide for prevention and 
the toxicity management guidelines as noted in Section 8.4.6.3. 
2.3.3 
Oleclumab (MEDI9447)  
A detailed summary of oleclumab (MEDI9447) monotherapy and combination data can be 
found in the current version of the oleclumab Investigator’s Brochure. 
2.3.3.1 
Potential benefits of oleclumab  
Oleclumab (MEDI9447) is a human IgG1λ mAb that selectively binds to and inhibits the 
ectonucleotidase activity of CD73. Oleclumab inhibits the catalysis of AMP to adenosine and 
organic phosphate by CD73. The enzymatic blockade of CD73 caused by the binding of 
oleclumab to CD73 may lead to increased antitumor immunity. 
Preliminary data from Study D6070C00001 demonstrate that treatment with oleclumab is well 
tolerated and leads to a reduction in CD73 expression both in the tumor and on circulating 
immune cells. In addition, oleclumab has been demonstrated to inhibit CD73 enzymatic 
activity in patient biopsies after treatment. 
The overall ORR (confirmed and unconfirmed) in the oleclumab 40 mg/kg + durvalumab 
10 mg/kg dose expansion phase was 7.1% (95% CI: 1.5%, 19.5%). The ORR (confirmed and 
unconfirmed) in the CRC and pancreatic cancer cohorts was 4.8% (95% CI: 0.1%, 23.8%) and 

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10.0% (95% CI: 1.2%, 31.7%), respectively. The overall DCR in the dose expansion phase 
was 16.7% (95% CI: 7.0%, 31.4%). The DCR in the CRC and pancreatic cancer cohorts was 
14.3% (95% CI: 3.0%, 36.3%) and 20.0% (95% CI: 5.7%, 43.7%), respectively. 
2.3.3.2 
Potential risks of oleclumab  
In Study D6070C00001, 42 patients enrolled to receive oleclumab monotherapy, and 74 
patients received oleclumab + durvalumab combination therapy. In the monotherapy cohort, 
39 (92.9%) patients experienced ≥1 TEAE, and 23 (54.8%) patients experienced a 
treatment-related TEAE. The most frequently reported TEAEs (in ≥20% of the total patients) 
were fatigue (38.1%) and anemia, abdominal pain, and dyspnea (21.4% each). There were no 
clinically meaningful trends in the incidence of TEAEs across dose groups. The most 
frequently reported treatment-related TEAEs (≥5% of the total patients) were fatigue (16.7%) 
and nausea and anemia (9.5% each). In the monotherapy group, 15 (35.7%) patients 
experienced treatment-emergent serious adverse events (TESAEs). The only SAE reported by 
more than 1 patient was ascites, reported by 3 (7.1%) patients. None of the SAEs were 
treatment related. In oleclumab + durvalumab cohort, 33 (44.6%) patients experienced at least 
1 TESAE, and 4 (5.4%) patients experienced treatment-related SAEs. The most frequently 
reported TESAEs (>2 patients) were abdominal pain and ascites (4.1% each). The 
treatment-related TESAEs of anemia, thrombocytopenia, and abdominal pain were reported 
by 1 patient (1.4%) each. The treatment-related SAE of hepatitis was reported by 2 (2.7%) 
patients. 
Three (7.1%) patients discontinued study treatment due to AE in the oleclumab monotherapy 
dose-escalation phase. Two patients in the oleclumab 10 mg/kg treatment group experienced 
SAEs (a Grade 3 event of ascites and a Grade 4 event of metastases to central nervous system 
[CNS]) that led to discontinuation, and 1 patient in the oleclumab 20 mg/kg group experienced 
Grade 4 pulmonary embolism that led to discontinuation. None of these events were treatment 
related. 
2.3.3.3 
Potential risks of durvalumab + oleclumab  
Among the 74 patients treated with oleclumab + durvalumab combination therapy, 68 (91.9%) 
experienced at least 1 TEAE. Thirty-five (47.3%) patients experienced at least 
1 treatment-related TEAE. The most frequently reported TEAEs (in ≥15% of the total 
patients) were fatigue (25.7%) and abdominal pain, constipation, and vomiting (16.2% each). 
There were no clinically meaningful patterns in the incidence of AEs across all combination 
therapy dose groups. The most frequently reported treatment-related TEAEs (in ≥5% of the 
total patients) were fatigue (13.5%); aspartate aminotransferase (AST) increased, diarrhea, and 
pyrexia (8.1% each); alkaline phosphatase (ALP) increased (6.8%); and ALT increased, 
decreased appetite, and vomiting (5.4% each). Eight (10.8%) patients experienced TEAEs 
leading to discontinuation of treatment with oleclumab and durvalumab combination therapy. 
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discontinuation (1 patient experienced treatment-related nausea and vomiting, 1 patient 
experienced treatment-related AST increased and blood bilirubin increased, and 1 patient 
experienced treatment-related hepatitis). 
2.3.4 
DS-8201a (trastuzumab deruxtecan)  
2.3.4.1 
Potential benefits of DS-8201a  
DS-8201a is under development for the treatment of HER2-expressing cancers and 
HER2-mutant tumors. Based on the preliminary clinical observations in the Phase I study 
(Study DS8201-A-J101), DS-8201a demonstrates antitumor activity in HER2-expressing 
cancers, including HER2-positive and HER2-low breast cancer (see Section 2.2.8). 
2.3.4.2 
Potential risks of DS-8201a  
As of 08 June 2021, 3462 patients have been treated with at least one dose of DS-8201a either 
alone or in combination. Based on data from clinical trials, toxicities considered to be 
associated with administration of DS-8201a include the important identified risks of 
ILD/pneumonitis and neutropenia (including febrile neutropenia). Other identified risks for 
DS-8201a are IRRs, hematological toxicity (thrombocytopenia, anemia, leukopenia, and 
lymphopenia), pulmonary/respiratory AEs (cough, dyspnea, and upper respiratory tract 
infection, epistaxis), gastrointestinal AEs (abdominal pain, constipation, decreased appetite, 
diarrhea, dyspepsia, nausea, stomatitis, and vomiting), hepatic adverse events (hepatic 
function abnormality, ALT increased, AST increased, ALP increased, and blood bilirubin 
increased), skin adverse events (alopecia, rash, and pruritis), pneumonia, hypokalemia, 
dizziness, fatigue, headache, peripheral edema, pyrexia, dry eye, and dehydration. 
Based on the available non-clinical data, review of the cumulative literature, and reported 
toxicities for the same class of agents, the important potential risks for DS-8201a are left 
ventricular ejection fraction (LVEF) decrease and embryo-fetal toxicity. Keratitis is 
considered a potential risk for DS-8201a.  
ILD/pneumonitis and LVEF decrease are considered to be AESIs. 
HER2-targeted agents  
Several agents that target HER2 and prevent its activation or heterodimerization have been 
developed and marketed for the treatment of HER2-positive cancers. These include the 
monoclonal antibodies trastuzumab (Herceptin®) and pertuzumab (Perjeta®), the antibody-
drug conjugate T-DM1 (Kadcyla®), and HER1- and 2-associated tyrosine kinase inhibitor, 
lapatinib (Tykerb®), and neratinib (Nerlynx®). The safety profile of these HER2-targeted 
agents has been well described. The main safety risks identified in patients receiving HER2-
targeted products are described below; these could potentially be expected to occur in patients 
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• 
Cardiotoxicity: Patients treated with trastuzumab are at increased risk for 
developing congestive heart failure (New York Heart Association [NYHA] class II to 
IV) or asymptomatic cardiac dysfunction, including LVEF decrease. Cardiac 
dysfunction, mainly asymptomatic LVEF decrease, has also been observed with 
pertuzumab in combination with trastuzumab. Similarly, cardiac dysfunction has 
been observed in patients receiving T-DM1, at a lower incidence than in patients 
receiving trastuzumab. Most cases have been asymptomatic decreases in LVEF. 
Cardiac dysfunction with lapatinib has occurred mainly in patients receiving the 
combination of trastuzumab and lapatinib and has consisted of predominantly 
asymptomatic LVEF decrease. 
• 
Pulmonary toxicity: Cases of pulmonary toxicity, including ILD and pneumonitis, 
have been observed in patients receiving trastuzumab, T-DM1, and lapatinib. 
Occasionally, these cases have been severe in nature and have resulted in fatal 
outcomes. Risk factors associated with ILD/pneumonitis include prior or concomitant 
therapy with other antineoplastic therapies known to be associated with it such as 
taxanes, gemcitabine, vinorelbine, and radiation therapy. 
• 
Hypersensitivity/infusion-related reactions: The administration of therapeutic 
proteins is associated with a risk of hypersensitivity and/or infusion reactions. 
Hypersensitivity/IRRs have been reported with trastuzumab, pertuzumab and 
T-DM1. These can range from mild reactions to severe anaphylactic shock with fatal 
outcome, as has been the case for trastuzumab. 
• 
Hepatic toxicity: Cases of hepatic toxicity have occurred with T-DM1, lapatinib, and 
trastuzumab. In patients receiving T-DM1, hepatic toxicity has manifested mainly as 
transient asymptomatic liver transaminase elevations, although serious cases of drug-
induced liver failure and nodular regenerative hyperplasia have also been reported. 
Lapatinib has also been associated with serious cases of drug-induced liver injury. 
• 
Hematological toxicity: Hematological toxicity has been observed with all HER2-
targeted therapies. Neutropenia, febrile neutropenia, leukopenia, and anemia have 
occurred commonly with trastuzumab, pertuzumab, and T-DM1. Thrombocytopenia, 
including Grade 3 and 4, is a common occurrence in T-DM1-treated patients. 
Although rare, serious hemorrhagic events have been reported in the setting of 
thrombocytopenia. Lower rates of thrombocytopenia have also occurred with 
trastuzumab and pertuzumab when used, in combination with chemotherapy. 
 
Topoisomerase I inhibitors 
DXd is a derivative of exatecan (DX-8951f), a topoisomerase I inhibitor. Other products of 
the same class include irinotecan and topotecan. Exatecan is a campothecin derivative, which 
has previously been developed by the former Daiichi Pharmaceuticals Co., Ltd. as an 
anticancer therapy. 
• 
The main risks associated with the use of topoisomerase I inhibitors include 
hematological toxicities and gastrointestinal toxicities. Hematological toxicities, 
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pancytopenia, are commonly observed. An increased risk of infections, including 
neutropenic colitis and neutropenic sepsis, has been reported with these agents.  
• 
Diarrhea and delayed onset diarrhea, which can be severe and lead to dehydration, 
have been associated with topoisomerase I inhibitors. Other significant risks include 
ILD/pneumonitis, liver impairment, immune system disorders, and alopecia. Acute 
cholinergic syndrome, manifesting as diarrhea and other cholinergic symptoms, has 
been reported with irinotecan. 
• 
The safety profile of exatecan is broadly similar to the safety profile of other 
topoisomerase I inhibitors, with hematological toxicities and gastrointestinal 
toxicities being the most significant groups of events. 
 
Given the data available on the efficacy and safety of DS-8201a, the overall benefit/risk is 
positive. 
2.3.4.3 
Potential risks of durvalumab + DS-8201a  
At this time, there are limited safety data regarding the combination of durvalumab and DS-
8201a. Given the differing mechanisms of action of durvalumab and DS-8201a, the potential 
for potentiation of toxicities is thought to be limited. Some known overlapping toxicities, for 
example,
 may on theoretical grounds be 
potentiated in the combination arm and particular attention should be paid to these. 
The study design aims to minimize potential risks of the novel treatment combination. Careful 
monitoring of pulmonary function to evaluate for ILD/pneumonitis will be done throughout 
the study. Monitoring toxicity management guidelines are shown in Section 8.4.6.5 and 
Appendix L, with further guidance for Investigators available in the DS-8201 Investigator’s 
Brochure.  
Monoclonal antibodies are not metabolized through classical hepatic enzyme pathways; 
therefore, no PK interaction is anticipated within this study. 
2.3.5 
Dato-DXd (datopotamab deruxtecan; DS-1062a)  
2.3.5.1 
Potential benefits of Dato-DXd  
Data from the ongoing DS1062-A-J101 Phase I study show efficacy across dose groups with 
tumor responses observed at starting doses of 4.0-, 6.0-, and 8.0-mg/kg and an acceptable and 
manageable toxicity profile across doses of Dato-DXd. As of the DCO date of 
04 September 2020, Dato-DXd has demonstrated response rates across these 3 dose cohorts 
with confirmed and durable responses in a study population that includes a significant 
proportion of subjects who were heavily pretreated.  
The proof of concept of targeting TROP2 has been delivered by the TROP2 ADC 
(sacituzumab govitecan), which demonstrates a favorable benefit/risk assessment in patients 
with metastatic TNBC that have received 2 or more lines of therapy (Section 2.2.9). 
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2.3.5.2 
Potential risks of Dato-DXd  
Based on the cumulative review of the safety data, the following are the AESIs to be 
monitored in Dato-DXd studies. ILD/pneumonitis and keratitis are considered important 
identified risks associated with administration of Dato-DXd. Other identified risks for 
Dato-DXd are fatigue (including asthenia, lethargy, and malaise), anemia, dry mouth, 
stomatitis/oral mucositis (including oropharyngeal pain, mouth ulcerations, odynophagia, oral 
pain, glossitis, pharyngeal inflammation, and aphthous ulcer), diarrhoea, constipation, nausea, 
decreased appetite, alopecia, vomiting, dry eye, lacrimation increased, conjunctivitis 
(including conjunctival disorder, conjunctival hyperaemia, and conjunctival irritation), 
photophobia, blepharitis, meibomian gland dysfunction, vision blurred, and visual 
impairment/visual acuity reduced, IRR, rash (including rash maculopapular, rash pruritic, and 
erythematous rash), skin hyperpigmentation (including pigmentation disorder and skin 
discolouration), pruritus, dry skin/xerosis, and madarosis. Embryo-fetal toxicity is considered 
an important potential risk. Mucosal inflammation other than oral mucositis/stomatitis is 
considered a potential risk for Dato-DXd. Dato-DXd has not been studied in participants with 
renal or hepatic impairment. 
The identified/potential risks have been generally manageable through dose modification and 
routine clinical practice. As with any therapeutic antibodies, there is a possibility of IRRs and 
immune responses causing allergic or anaphylactic reactions of Dato-DXd. 
In the Dato-DXd clinical program, inclusion/exclusion criteria and monitoring/management 
guidelines are currently built into the study protocols to mitigate all identified and potential 
risks of Dato-DXd, including the important identified risk of ILD/pneumonitis. 
Potential ILD cases are monitored closely for signs/symptoms of ILD and reviewed
established for the DS-8201a and Dato-DXd 
program. The study protocols include detailed dose modification and supportive care 
guidelines for the proactive management of ILD. In the ongoing DS1062-A-J101 Phase I 
study, the majority of the drug-induced ILD occurred at 8.0 mg/kg. 
Ongoing review of emerging Phase 1 study data has allowed a closer evaluation of benefit: 
risk by dose. Based on the most recent review of safety and efficacy data, Dato-DXd at the 
6.0 mg/kg dose has a more favorable benefit: risk profile compared with that of the 8.0 mg/kg 
and 4.0 mg/kg doses, respectively. Subject to continual review of emerging data, current 
evaluation of benefit: risk supports the selection of 6.0 mg/kg as the optimal dose for further 
development of Dato-DXd in patients with advanced/unresectable or metastatic TNBC. 
2.3.5.3 
Potential risks of durvalumab + Dato-DXd  
At this time, there are no reported safety data regarding the combination of durvalumab and 
Dato-DXd. A Phase IB/II study in advanced or metastatic NSCLC (U104, NCT04612751) 
evaluating durvalumab with Dato-DXd is currently ongoing and will evaluate safety and 
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3 
OBJECTIVES AND ENDPOINTS  
Any exploratory analysis within the study related to tumor size may be reported with the 
primary analysis Clinical Study Report (CSR); all other exploratory analyses may be reported 
separately. Table 11 outlines the objectives of the study. 
Table 11 
Study objectives  
Objectives and endpoints - Part 1 
Primary objective: 
Endpoint/variable: 
To assess the safety and tolerability profile of 
durvalumab + novel oncology therapies with or 
without paclitaxel and durvalumab + paclitaxel 
AEs, exposure, physical examinations, laboratory findings, 
ophthalmologic assessments (Arms 7 and 8 only), and vital 
signs 
Secondary objectives: 
Endpoint/variable: 
To assess the efficacy of durvalumab + novel 
oncology therapies with or without paclitaxel and 
durvalumab + paclitaxel in terms of ORR, PFS, 
DoR, and OS  
Endpoints based on Investigator assessment of RECIST 
1.1: 
• 
ORR: The percentage of evaluable patients with a 
confirmed Investigator-assessed visit response of CR or 
PR  
• 
PFS: Time from date of first dose until the date of 
objective radiological disease progression using 
RECIST 1.1 or death (by any cause in the absence of 
progression) 
• 
DoR: Time from date of first detection of objective 
response (which is subsequently confirmed) until the 
date of objective radiological disease progression 
• 
OS: Time from date of first dose until the date of death 
by any cause 
To assess the PK of durvalumab and novel 
oncology therapies (ie, oleclumab, DS-8201a, and 
Dato-DXd) in all treatment arms 
Serum concentration of durvalumab and serum or plasma 
concentration of novel oncology therapies 
To investigate the immunogenicity of durvalumab 
and applicable novel oncology therapies 
(ie, oleclumab, DS-8201a, and Dato-DXd) in all 
applicable treatment arms 
Presence of ADAs for durvalumab and applicable novel 
oncology therapies 
Exploratory objectives: 
Endpoint/variable: 
To collect blood and tissue samples to evaluate 
molecular/biological responses and/or identify 
candidate markers that may correlate with the 
likelihood of clinical benefit 
Blood
 including but not limited to 
the following, and their association with treatment benefit: 
• 
etected by H&E 
• 
detected by IHC 
• 
• 
To further assess the efficacy of durvalumab + 
novel oncology therapies with or without 
paclitaxel and durvalumab + paclitaxel in terms of 
change in tumor size 
Change in tumor size 
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Objectives and endpoints - Part 2a  
Primary objective: 
Endpoint/variable: 
To assess the efficacy of durvalumab + novel 
oncology therapies with or without paclitaxel in 
terms of ORR 
Endpoint based on Investigator assessment of RECIST 1.1: 
• 
ORR: The percentage of evaluable patients with an 
Investigator-assessed visit response of CR or PR. Part 1 
and Part 2 data will be pooled for efficacy analysis. 
Secondary objectives: 
Endpoint/variable: 
To further assess the efficacy of durvalumab + 
novel oncology therapies with or without 
paclitaxel in terms of PFS, DoR, OS, and PFS6b 
Endpoints based on Investigator assessment of RECIST 
1.1: 
• 
PFS: Time from date of first dose until the date of 
objective radiological disease progression using 
RECIST 1.1 or death (by any cause in the absence of 
progression) 
• 
DoR: Time from date of first detection of objective 
response until the date of objective radiological disease 
progression according to RECIST 1.1 
• 
PFS6: PFS at 6 months following date of first dose 
• 
OS: Time from date of first dose until the date of death 
by any cause 
To assess the safety and tolerability profile of 
durvalumab + novel oncology therapies with or 
without paclitaxel  
AEs, exposure, physical examinations, laboratory findings, 
ophthalmologic assessments (Arms 7 and 8 only), and vital 
signs 
Exploratory objective: 
Endpoint/variable: 
To collect blood and tissue samples to evaluate 
molecular/biological responses and/or identify 
candidate markers that may correlate with the 
likelihood of clinical benefit 
Blood
 including but not limited to 
the following, and their association with treatment benefit: 
• 
detected by H&E 
• 
detected by IHC 
• 
• 
a 
All mentioned endpoints for Part 2 will be analyzed in the data set of Part 1 plus Part 2 patients in each 
cohort and additionally may be analyzed for each part separately. 
b 
Progression-free survival at 6 months following date of first dose (PFS6) is equivalent to the proportion of 
patients alive and progression free at 6 months following date of first dose (APF6). 
ADA  Anti-drug antibody; AE  Adverse event; CR  Complete response
 Dato-DXd  Datopotamab deruxtecan; DoR  Duration of response; H&E  Hematoxylin and 
eosin stain; IHC  Immunohistochemistry;
ORR  Objective response rate; 
OS  Overall survival; PFS  Progression-free survival; PK  Pharmacokinetics; PR  Partial response; RECIST 
1.1  Response Evaluation Criteria in Solid Tumors version 1.1;
 
 
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4 
STUDY DESIGN  
4.1 
Overall design  
This is a Phase IB/II, 2-stage, open-label, multicenter study to determine the efficacy and 
safety of durvalumab + novel oncology therapies (ie, capivasertib, oleclumab, DS-8201a 
[trastuzumab deruxtecan], and Dato-DXd [datopotamab deruxtecan]) with or without 
paclitaxel and durvalumab + paclitaxel alone as first-line treatment in patients with metastatic 
(Stage IV) TNBC. The efficacy and safety of durvalumab + Dato-DXd in patients with PD-L1 
positive TNBC will also be evaluated in Arm 8 in order to further assess safety and efficacy in 
patients with PD-L1 positive tumors. The study is designed to concurrently evaluate potential 
novel treatment combinations with clinical promise using a 2-stage approach. The study will 
use a
test to evaluate which cohorts may proceed to expansion. 
For an overview of the study design, refer to Section 1.3 (see Figure 1). Details on treatments 
given during the study are also presented (see Section 6.1). In Part 1 (Phase IB; safety, initial 
efficacy, and PK/ADA), at least 20 patients will be enrolled into the durvalumab + paclitaxel 
arm and at least 30 patients in each of the novel treatment combination arms; additional 
patients may be enrolled in order to have at least 20 or 30 evaluable patients per arm, as 
appropriate. The safety of durvalumab + paclitaxel has been previously defined 
(see Section 2.2.5). For novel treatment combinations, the novel oncology therapies will be 
dosed in combination with durvalumab with or without paclitaxel using a rolling 6-patient 
design to evaluate for toxicity, where doses for novel oncology therapies will be based on 
RP2Ds defined in previous combination studies (where available). A total of at least 20 
patients will be enrolled in the durvalumab + paclitaxel arm and at least 30 patients in the 
novel treatment combination arms during Part 1. 
The enrollment criteria and screening phase procedures are the same for both study parts. 
After obtaining informed consent, core biopsy tumor samples from the patient will be 
confirmed for TNBC status by a local laboratory (details are provided in Section 5.1). Patients 
who fulfill all of the inclusion criteria and none of the exclusion criteria will be included in the 
study. In Arm 8, a pre-screening phase will also be conducted to identify patients with a 
PD-L1 positive status in patients whose PD-L1 expression status has not been determined 
prior to entry in the study.  
In both study parts, patients will receive treatment until any discontinuation criteria are met 
(see Section 7.1), including clinical progression or radiological progression (refer to 
Appendix F) and Investigator determination that the patient is no longer benefiting from 
treatment with IP. 
In both study parts, the imaging schedule will be as follows: response evaluation will be 
performed using computed tomography (CT) or magnetic resonance imaging (MRI) at 
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• 
Obtaining consent/reconsent for the mitigation procedures  
• 
Telemedicine visit: Remote contact with the patients using telecommunications 
technology, including phone calls, virtual or video visits, and mobile health devices. 
 
For further details on study conduct during a civil crisis, natural disaster, or public health 
crisis, refer to Appendix P. 
4.1.2 
Part 1 study design overview  
The primary objective of Part 1 will be safety. The safety and tolerability of each treatment 
arm will be assessed. Additionally, an efficacy analysis for futility (based on ORR) will be 
assessed using a
design to determine enrollment for Part 2. Part 1 of the study 
will enroll the first 20 patients to the durvalumab + paclitaxel arm (Arm 1) and monitor for 
toxicity; additional patients may be enrolled in order to have 20 evaluable patients. 
Completion of recruitment to the durvalumab + paclitaxel arm will trigger randomized patient 
assignment (see Section 6.2.1.1) to each novel treatment combination arm that is open for 
enrollment. For enrollment onto Arm 6 (durvalumab + DS-8201a), patients must provide 
pathologically-confirmed documentation of advanced/unresectable or metastatic breast cancer 
with HER2 low expression (as defined in Section 5.1). Patients with no HER2 tumor 
expression will be eligible for assignment to any open treatment arm other than Arm 6. For 
enrollment into Arm 8, patients must provide pathologically-confirmed documentation of 
advanced/unresectable or metastatic TNBC with PD-L1 positive status, as determined by a 
pre-existing test or by local testing during pre-screening. 
Each subsequent cohort, apart from Arm 8, will undergo a run-in period, in which 6 patients 
are planned to be enrolled to initially inform the safety profile and determine the RP2D; more 
or fewer patients may be enrolled depending on how many patients are evaluable for 
dose-limiting toxicities (DLTs) and how many patients have DLTs. Additional details on the 
safety run-in period are provided in Section 4.1.4. Briefly, a Safety Review Committee (SRC) 
will evaluate the safety, tolerability, and available PK of each novel treatment combination 
arm in Part 1 and may confirm the RP2D or recommend dose modification based on the first 
6 DLT-evaluable patients who have completed the first treatment cycle or had a DLT during 
the first treatment cycle for each treatment arm. A combination dose will be considered not 
tolerable if 2 or more of up to 6 DLT-evaluable patients experience a DLT at the combination 
dose level. 
The novel treatment combination arms meeting the safety evaluation criteria (ie, no more than 
1 of 6 DLT-evaluable patients experience DLTs during the first treatment cycle at a given 
dose level) will be expanded to at least 30 patients (enrollment sufficient to have 30 evaluable 
patients). 
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Efficacy will be evaluated as a secondary objective. Assessments based on confirmed ORR 
(as determined by the Investigator according to RECIST 1.1) will be made when each cohort 
has completed enrollment and all patients have either had the opportunity to complete at least 
2 on-treatment response evaluations or have discontinued treatment. Each cohort is 
independent, and any signal observed in 1 arm will not have an impact on other arms. 
4.1.3 
Part 2 study design overview  
Part 2 is stage 2 of the
design. The assessment ORR on the first 30 subjects 
recruited in Part 1 (Section 9.1) is applied, and if it is decided to continue recruitment, an 
additional 27 subjects will be recruited at stage 2, for a total of 57 subjects. 
The primary objective of Part 2 will be efficacy, with a primary endpoint of ORR. Efficacy of 
the novel treatment combination arms will be assessed. 
4.1.4 
Part 1 safety run-in period and combination dose finding  
4.1.4.1 
Overview  
Each novel treatment combination arm will undergo a run-in period, in which 6 patients are 
planned to be enrolled to initially inform the safety profile and determine the RP2D. Safety 
run-in will not occur in Arm 8 as the treatment combination was already evaluated in Arm 7 
and found to be tolerable with no DLTs reported. Fewer than 6 patients may be enrolled if 
2 patients have DLTs before 6 patients are enrolled; more than 6 patients may be enrolled in 
order to have 6 DLT-evaluable patients. If patients in the safety run-in phase tolerate a given 
novel treatment combination, the corresponding novel treatment combination arm will directly 
enter into the expansion phase and enroll a total of at least 30 patients (enrollment sufficient to 
have at least 30 evaluable patients per treatment arm). 
An SRC will review the emerging data from the study and will continue to monitor safety data 
on an ongoing basis. The SRC will evaluate the safety, tolerability, and available PK of each 
combination to either confirm the RP2D or to recommend dose modification (Table 18). 
Six DLT-evaluable patients are required to determine the combination recommended dose for 
further clinical evaluation. Patients participating in the safety-run in period who are not 
evaluable for DLTs may be replaced. In the event that recruitment is paused for Arms 2 
through 7 concurrently while they undergo their DLT review period, patients in screening will 
have the opportunity to be assigned to Arm 1 to avoid delay in receiving treatment. 
A combination dose will be considered not tolerable if
6 DLT-evaluable 
patients experience a DLT at the combination dose level. No further patients will be enrolled 
at that dose level; however, any patient who did not experience a DLT will continue at the 
initial assigned dose level until the criteria for dose reduction or treatment discontinuation are 
met. In the event that the initial dose level is not tolerated, a new cohort with up to 6 new 
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DLT-evaluable patients will be opened at a lower dose level (see Table 18); this process may 
be repeated until the lowest dose level is reached. In the event that the lowest dose is not 
tolerated, no additional patients will be enrolled to evaluate that novel treatment combination.  
If no more than
DLT-evaluable patients experience DLTs
 
the SRC will determine an RP2D for the novel treatment combination arm. Once the RP2D is 
identified, additional patients will be enrolled so that a total of at least 30 patients are enrolled 
at the RP2D. Additional patients may be enrolled to have 30 evaluable patients. 
Once a given patient is assigned a dose level, that patient will not be switched to another dose 
level during the safety run-in period, unless the dose is reduced for toxicity (see dose 
reduction and toxicity management guidelines in Sections 6.5.1 and 8.4.6, respectively) in that 
individual (ie, a patient may not participate in more than 1 cohort). 
For Arm 2 (durvalumab + paclitaxel + capivasertib), a new group of 6 DLT-evaluable patients 
will be reviewed following the adjustments specified in protocol amendment 4, in particular 
the decrease in paclitaxel dose (see Section 4.3.2). If this regimen is tolerated, additional 
patients will be enrolled for a total of at least 30 patients across Arm 2. 
No new dose level cohorts will be opened once the RP2D is determined. A total of 30 patients 
will be treated with the RP2D of the novel treatment combination arm, including the 
6 DLT-evaluable patients who were enrolled in the safety run-in phase. Patients who are 
enrolled after the DLT period will be considered evaluable for safety and efficacy if they have 
received at least 1 dose of any IP in the novel treatment combination arms. As such, patients 
who received at least 1 dose of any IP during the initial RP2D determination, but who were 
not DLT evaluable and did not count toward the 6 required patients for RP2D evaluation, will 
be counted as part of the 30 patient safety and efficacy cohort (ie, as part of the at least 
30 evaluable patients). 
4.1.4.2 
Definitions  
4.1.4.2.1 
DLT-EVALUABLE PATIENT  
For making decisions on the dose, an evaluable patient for the assessment of DLTs in the 
safety run-in period (“DLT-evaluable” patient) is defined as a patient who has received the 
full prescribed dose of durvalumab and who has received:  
• 
Arms 2 through 5:
of the prescribed number of doses of paclitaxel and of the 
novel oncology therapy during Cycle 1 (Weeks 0 through 3), and either has 
completed the first 28-day cycle or has a DLT during the first 28-day cycle. 
• 
Arms 6 and 7: must have received the prescribed dose of DS-8201a or Dato-DXd 
therapy, respectively, during Cycle 1 (Weeks 0 through 2), and either has completed 
the first 21-day cycle or has a DLT during the first 21-day cycle. 
 
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addition, PK parameters may be used in determining the RP2D along with safety and efficacy. 
Changes in paclitaxel dosing, including dose delays, reductions, and discontinuations, will be 
considered in the evaluation of safety of the durvalumab + paclitaxel and other novel 
treatment combinations. 
Efficacy is not a primary objective of Part 1. Secondary and exploratory efficacy assessments 
in Part 1 will be based on Investigator assessment according to RECIST 1.1 guidelines. The 
endpoints for assessment of antitumor activity are those routinely included in oncology studies 
and will include ORR, PFS, and DoR (based on RECIST 1.1), as well as OS. ORR will be the 
key secondary endpoint used in Part 1, as it will afford the earliest understanding of which 
combinations have potential for a robust antitumor response. Additional recruitment of 
subjects into Part 2 will be considered based on the ORR assessments specified in Section 9.1. 
Safety of the combination will be continually evaluated throughout enrollment of the trial and 
will be factored in to determine whether a combination moves into Part 2 of this study.  
The primary aim of Part 2 of this study is to determine the efficacy of durvalumab + novel 
oncology therapies in terms of Investigator-assessed ORR in TNBC patients. 
Parts 1 and 2 combined are sized to detect evidence of improved efficacy. Conventionally, 
ORR, PFS, and OS are used as validated measures of clinical benefit. ORR does not 
incorporate survival measures as in OS and PFS; however, it has historically been widely used 
in early phase trials. Simon describes Phase II trials intended to “determine whether [a 
therapy] has sufficient biologic activity… to warrant more extensive development,” and these 
are precisely the aims of this study. OS is generally regarded as the most reliable cancer 
endpoint and is preferred for studies that can be conducted to adequately assess survival. PFS 
may serve as a surrogate endpoint for OS when differences between treatment arms are of 
sufficient magnitude and clinical importance (FDA Guidance 2011, Pazdur 2008). ORR 
improvement in study patients may result in PFS benefits. A PFS secondary endpoint affords 
an earlier understanding of treatment effect than OS. Furthermore, PFS, unlike OS, will not be 
confounded by a crossover effect of subsequent treatments, hence the need to include PFS and 
OS as secondary endpoints. 
The secondary endpoints in Parts 1 and 2, duration of response (DoR), PFS at 6 months 
following date of first dose (PFS6), and OS will be examined to further evaluate the antitumor 
effect of durvalumab + novel oncology therapies with or without paclitaxel versus durvalumab 
+ paclitaxel combination therapy. 
In Part 2, antitumor activity will be based on RECIST 1.1 guidelines. 
Changes in paclitaxel dosing, including dose delays, reductions, and discontinuations, will be 
considered in the evaluation of safety of the durvalumab + paclitaxel arm and durvalumab + 
novel oncology therapies with or without paclitaxel. 

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4.2.2 
Rationale for other study endpoints  
Biological samples will be used to explore potential biomarkers in tumor, plasma, and/or 
serum, which may influence or may be associated with the progression of cancer (and 
associated clinical characteristics) and/or response. 
In Part 1 only, blood samples will be taken to allow for research into the PK of durvalumab 
and the novel oncology therapies and immunogenicity of durvalumab and the novel oncology 
therapies. Arms 7 and 8 (Dato-DXd) will also include plasma PK samples for Part 2 of the 
study.  
4.2.3 
Rationale for treatment duration  
Treatment in this study will continue until any discontinuation criteria are met (see 
Section 7.1), including clinical progression or radiological progression (refer to Appendix F) 
and Investigator determination that the patient is no longer benefiting from treatment with IP. 
4.2.4 
Rationale for exclusion of male patients from study  
Male breast cancer is rare and biologically heterogeneous. These rare patients will be 
excluded from this study, as safety results may be difficult to interpret. 
4.3 
Justification for dose  
For information on dose modifications for each study treatment, see Section 6.5. 
4.3.1 
Durvalumab dose rationale, including rationale for fixed dosing  
Based on available PK and safety data for weight-based doses of 10 mg/kg q2w and 20 mg/kg 
q4w and simulated PK data for a fixed dose of 1500 mg q4w, the fixed-dosing regimen was 
predicted to provide comparable exposure to the body weight-based dosing regimens. 
Durvalumab has a flat exposure-response (efficacy and safety) relationship. Based on all the 
observed and simulated data, a fixed-dosing regimen of 1500 mg q4w was predicted to 
provide similar efficacy and safety profiles as the body weight-based dosing regimens. 
Therefore, a fixed-dosing regimen of 1500 mg q4w was selected for Arms 1 through 5 in this 
study. In Arms 6 (durvalumab + DS-8201a) 7 and 8 (durvalumab + Dato-DXd), a fixed dose 
of 1120 mg durvalumab q3w is included in the current study. This dose is used in multiple 
studies across the durvalumab clinical program and is equivalent to the dose intensity being 
used in all other study arms. A dose of 1120 mg rather than 1125 mg is being used for 
practical reasons (ie, due to the vial sizes available).  
For additional details on the pre-clinical and clinical data that informed durvalumab dose 
selection, see the durvalumab Investigator’s Brochure. 
For information on dose modifications for durvalumab (dose delays only), see Section 6.5.2. 

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4.3.2 
Paclitaxel dose rationale  
In a meta-analysis of randomized, controlled studies in advanced breast cancer (5 studies, 
1471 patients), weekly administration of paclitaxel was compared to administration of every 
3 weeks. The analysis concluded that there was an improvement in OS with weekly paclitaxel 
(pooled HR, 0.78; 95% CI: 0.67 to 0.89; p=0.001). Additionally, the incidence of neutropenia, 
neutropenic fever, peripheral neuropathy, and other SAEs was significantly lower with weekly 
paclitaxel compared to paclitaxel every 3 weeks (Mauri et al 2010). Based on this meta-
analysis, paclitaxel in a 4-week cycle (3 weeks once weekly and 1 week off) was chosen. 
Paclitaxel will be administered at an SoC dose level of 90 mg/m2 in 4-week cycles as follows: 
3 weeks once weekly (Days 1, 8, and 15) and 1 week off.  
For Arm 2 (durvalumab + paclitaxel + capivasertib), the standard dose of weekly paclitaxel 
(for 3 weeks of 4-weekly cycles) has been amended (in Version 4 of the protocol) to 80 mg/m2 
to align with the capivasertib Phase III trial CAPItello-290 (NCT 03997123) (a Phase III 
randomized study assessing the efficacy and safety of capivasertib and paclitaxel versus 
placebo and paclitaxel as first-line treatment for patients with histologically confirmed, locally 
advanced (inoperable) or metastatic TNBC), which was initiated when the current study was 
already ongoing. The choice of such paclitaxel dose in the global CAPItello-290 study was 
determined based on the fact that, while both 80 mg/m2 and 90 mg/m2 doses are commonly 
used in clinical trials and both are considered as standard doses for paclitaxel in metastatic 
TNBC worldwide, 80 mg/m2 is more frequently used in clinical practice (NCCN Guidelines 
V3.2019) (especially in Asian countries); with the intent to minimize toxicity and the 
discontinuation rate for AEs with no expected detriment on efficacy, this is considered 
particularly relevant in the context of a triplet combination with durvalumab + capivasertib + 
paclitaxel. 
For information on dose modifications for paclitaxel, see Section 6.5.2.2. 
4.3.3 
Capivasertib dose rationale  
Capivasertib will be administered orally at a dose of 400 mg bid on an intermittent weekly 
dosing schedule in 4 week cycles as follows: administered on Days 2 through 5 of Weeks 0, 1, 
and 2 (ie, 4 days on and 3 days off each week) followed by 1 week off treatment. 
This dose regimen was selected as the combination dose with weekly paclitaxel for further 
evaluation based on the BEECH study, which evaluated 2 intermittent weekly dosing 
schedules (2 days on/5 days off treatment and 4 days on/3 days off treatment) of capivasertib 
taken bid at ascending doses 3 weeks on and 1 week off in combination with weekly 
paclitaxel 90 mg/m2 (Days 1, 8, and 15 of a 28-day cycle). Although this Phase IIB 
combination regimen failed to demonstrate efficacy in ER+ BC patients (BEECH Part B), 
clinical efficacy was proven in TNBC (PAKT study, which showed a significantly longer PFS 

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and OS with capivasertib + paclitaxel versus with paclitaxel alone). Moreover, based on these 
2 randomized Phase II studies, capivasertib appeared to be well tolerated overall, with no 
marked impact on the tolerability and dose intensity of paclitaxel. 
For additional details on the pre-clinical and clinical data on capivasertib dose selection, see 
the capivasertib Investigator’s Brochure. 
For information on dose modifications for capivasertib, see Section 6.5.2.3. 
4.3.4 
Oleclumab dose rationale  
The oleclumab initial dose of 3000 mg q2w for the first 2 cycles, followed thereafter by q4w 
dosing starting at Cycle 3, was selected based on the available clinical safety, tolerability, 
efficacy, PK, and pharmacodynamic data from the Phase I Study D6070C00001 
(NCT02503774) and from population PK modeling and simulation analysis results. In 
Study D6070C00001, doses of
 and
mg/kg q2w were evaluated both as oleclumab 
monotherapy and in combination with durvalumab
mg/kg q2w. Oleclumab was well 
tolerated, and there were no observed DLTs either as monotherapy or in combination with 
durvalumab at any dose level. The oleclumab
mg/kg q2w dose was identified for 
evaluation with durvalumab
mg/kg q2w in the dose expansion phase of Study 
D6070C00001. 
Population PK analysis with data from 97 patients in Study D6070C00001 indicated only a 
moderate impact of body weight on the PK of oleclumab (coefficient of
on clearance and 
volume of distribution); however, the change expected in PK parameters due to body weight 
was not significant at approximately
Therapy arms (monotherapy/combination) or 
disease type (CRC or pancreatic adenocarcinoma) did not impact the PK parameters 
significantly. To determine the impact of body weight-based dosing of
mg/kg q2w or fixed 
dosing of 3000 mg q2w on oleclumab PK exposure, simulations were conducted
and predicted steady-state 
concentrations (5th, median, and 95th percentiles) were compared. Simulation results 
demonstrated that a body weight-based dose of
mg/kg and a fixed dose of 3000 mg yield 
similar steady-state PK concentrations with similar overall between-patient variability. 
Additionally, the highest concentrations predicted following a fixed dose of 3000 mg q2w 
were lower than the well-tolerated highest exposure observed at
mg/kg q2w dosing of 
approximately
μg/mL. The predicted similarity of exposure following either dosing 
regimen is consistent with literature, showing that an exponent of the covariate model for 
body weight approximately 0.5 is expected to yield similar median PK profiles and population 
variability (Wang et al 2009). However, due to the ease of use and reduced potential dosing 
errors, a fixed-dosing approach is preferable. Based on analyses of safety, PK, and preliminary 
efficacy in Study D6070C00001, an RP2D of 3000 mg 
mg/kg) oleclumab was selected. 
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For additional details on the pre-clinical and clinical data on oleclumab dose selection, see the 
oleclumab Investigator’s Brochure. 
For information on dose modifications for oleclumab, see Section 6.5.2.4. 
4.3.5 
DS-8201a (trastuzumab deruxtecan) dose rationale  
Based on all available information to date, a DS-8201a dose of 5.4 mg/kg q3w has been 
chosen for this study. Doses of 5.4 mg/kg and 6.4 mg/kg DS-8201a monotherapy have been 
tested in clinical studies; both showed efficacy in different tumor types and neither reached 
the MTD. A numerically higher incidence of ILD/pneumonitis was observed with 6.4 mg/kg 
compared to 5.4 mg/kg in breast cancer study populations. DS-8201a is currently being 
evaluated in two Phase I studies in combination with an anti-PD1 antibody (Study DS-8201-
A-U105; NCT03523572 [completed]; DS8201-A-U106; NCT04042701). The recommended 
Phase II dose of 5.4 mg/kg for breast cancer will be evaluated with durvalumab. 
For additional details on the non-clinical and clinical data on DS-8201a dose selection, see the 
DS-8201a Investigator’s Brochure. 
For information on dose modifications for DS-8201a, see Section 6.5.2.5. 
4.3.6 
Dato-DXd (datopotamab deruxtecan; DS-1062a) dose rationale  
In the Phase 1 study (DS1062-A-J101), both 4.0- and 6.0-mg/kg doses were well tolerated and 
showed strong efficacy results in the NSCLC and TNBC cohorts, with a generally comparable 
exposure - safety relationship: 
• 
Positive exposure-response relationships were identified between Dato-DXd 
exposure and efficacy endpoints (ORR and PFS). 
• 
The preliminary exposure-ORR relationship in TNBC appears to be similar to that in 
NSCLC.  
 
The 6 mg/kg dose was therefore selected for the treatment of TNBC participants in this study. 
Efficacy and safety results from the 6.0 mg/kg dose are presented in Section 2.2.9. These data 
indicate a manageable safety profile at the 6.0 mg/kg dose, and further study in breast cancer 
warranted.  
For information on dose modifications for Dato-DXd, see Section 6.5.2.6. 

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4.4 
End of study definition  
For the purpose of Clinical Trial Transparency the definition of the end of the study differs 
under FDA and EU regulatory requirements: 
• 
European Union requirements define study completion as the last visit of the last 
subject for any protocol related activity. 
• 
Food and Drug Administration requirements defines 2 completion dates: 
− 
Primary Completion Date – the date that the final participant is examined or 
receives an intervention for the purposes of final collection of data for the 
primary outcome measure, whether the clinical study concluded according to the 
pre-specified protocol or was terminated. In the case of clinical studies with 
more than one primary outcome measure with different completion dates, this 
term refers to the date on which data collection is completed for all of the 
primary outcomes. 
− 
Study Completion Date – is defined as the date the final participant is examined 
or receives an intervention for purposes of final collection of data for the primary 
and secondary outcome measures and AEs (for example, last participant’s last 
visit), whether the clinical study concludes according to the pre-specified 
protocol or is terminated. 
 
The end of study is defined as the date of the last scheduled procedure shown in the schedule 
of activities for the last patient in the study. 
A patient is considered to have completed the study if they have completed all phases of the 
study including the last scheduled procedure shown in the SoA (including follow up for OS). 
Patients may be withdrawn from the study if the study itself is stopped. The study may be 
stopped if, in the judgment of AstraZeneca, study patients are placed at undue risk because of 
clinically significant findings. 
4.5 
Study termination  
The study may be stopped if, in the judgement of AstraZeneca, study patients are placed at 
undue risk because of the following clinically significant findings: 
• 
Meet individual stopping criteria or are otherwise considered significant 
• 
Assessed as causally related to study treatment 
• 
Not considered to be consistent with continuation of the study 
 

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As this study is testing novel investigational products, emerging information from this study 
or another study that impacts the safety or the benefit/risk profile may lead to the permanent 
closure of any of the study arms. 
Regardless of the reason for termination, all data available for the patient at the time of 
discontinuation of follow-up must be recorded in the electronic case report form (eCRF). 
All reasons for discontinuation of treatment must be documented. 
See Appendix A-6 for guidelines for the dissemination of study results. 
4.6 
Site closure  
The Sponsor or designee reserves the right to close the study site 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 monitoring visit has been performed. 
The Investigator may initiate study site closure at any time, provided that there is reasonable 
cause and that sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include, but 
are not limited to, the following: 
• 
Failure of the Investigator to comply with the protocol, the requirements of the 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) or local 
health authorities, the Sponsor’s procedures, or Good Clinical Practice guidelines 
• 
Inadequate recruitment of participants by the Investigator 
• 
Discontinuation of further study intervention development 
 

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5 
STUDY POPULATION  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted. 
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study in order to be assigned/randomized to a study intervention. Under no circumstances can 
there be exceptions to this rule. Patients who do not meet the entry requirements are screen 
failures; refer to Section 5.4. 
For procedures for withdrawal of incorrectly enrolled patients see Section 6.2.2. 
5.1 
Inclusion criteria  
Informed consent 
1 
Capable of giving signed informed consent, which includes compliance with the 
requirements and restrictions listed in the ICF and in this protocol. 
2 
Provision of signed and dated, written ICF prior to any mandatory study-specific 
procedures, sampling, and analyses 
3 
Prior to collection of the sample for genetic analysis, which is an optional assessment, 
provision of
and analysis in the appropriate section of the 
signed and dated written informed consent 
The ICF process is described in Appendix A-3. 
Age 
4 
Age ≥18 years at the time of screening 
Type of patient and disease characteristics 
5 
Locally confirmed advanced/unresectable or metastatic TNBC, determined from the most 
recent tumor sample taken for diagnostic purposes (accompanied by an associated 
pathology report), defined as the following. (The local testing facility must be acceptable 
for Investigator determination of patient eligibility.) 
− 
Negative for ER with <1% of tumor cells positive for ER on IHC or IHC score 
(Allred) of ≤2, 
− 
Negative for PR with <1% of tumor cells positive for PR on IHC or IHC score 
(Allred) of ≤2 or PR unknown, and 
− 
Negative for HER2 with 0, or 1+ intensity on IHC, or 2+ intensity on IHC and 
no evidence of amplification on in situ hybridization as per the American Society 
of Clinical Oncology-College of American Pathologists HER2 guideline 
(Hammond et al 2010, Wolff et al 2018) 
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5.3 
Lifestyle restrictions  
The following restrictions apply while the patient is receiving IP and for the specified times 
before and after: 
1. 
Female patient of child-bearing potential 
Female patients of childbearing potential who are not abstinent and intend to be sexually 
active with a non-sterilized male partner must use at least 1 highly effective method of 
contraception (Table 12) from the time of screening throughout the total duration of the drug 
treatment and the drug washout period 
after the last dose of durvalumab,
after the last dose of capivasertib, oleclumab, or paclitaxel;
after the last dose of DS-
8201a or Dato-DXd). Non-sterilized male partners of a female patient of childbearing 
potential must use a male condom plus spermicide throughout this period. Cessation of birth 
control after this point should be discussed with a responsible physician. Periodic abstinence, 
the rhythm method, and the withdrawal method are not acceptable methods of contraception. 
Female patients should refrain from breastfeeding throughout this period. Women must not 
donate, or retrieve for their own use, ova from the time of screening and throughout the study 
treatment period, and for at least
months after the final administration of durvalumab, 
capivasertib, oleclumab, or paclitaxel and at least
months after the final administration of 
DS-8201a or Dato-DXd.  
Note: Females of childbearing potential are defined as those who are not surgically sterile 
(ie, bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or 
post-menopausal.  
Women will be considered post-menopausal if they have been amenorrheic for 12 months 
without an alternative medical cause. The following age-specific requirements apply:  
• 
Women <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle-stimulating hormone 
levels in the post-menopausal range for the institution. 
• 
Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments, had radiation-induced menopause with last menses >1 year ago, or had 
chemotherapy-induced menopause with last menses >1 year ago. 
• 
Women who are surgically sterile (ie, bilateral salpingectomy, bilateral 
oophorectomy, or complete hysterectomy) are eligible.  
 
Highly effective methods of contraception, defined as one that results in a low failure rate 
(ie, less than 1% per year) when used consistently and correctly are described in Table 12. 
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Note that some contraception methods are not considered highly effective (eg, male or female 
condom with or without spermicide; female cap, diaphragm, or sponge with or without 
spermicide; non-copper containing intrauterine device; progestogen-only oral hormonal 
contraceptive pills where inhibition of ovulation is not the primary mode of action [excluding 
Cerazette/desogestrel which is considered highly effective]; and triphasic combined oral 
contraceptive pills). 
All patients should also follow the local prescribing information relating to contraception, the 
time limits for such precautions, and any additional restrictions for paclitaxel. 
Table 12 
Highly effective methods of contraception (<1% failure rate)  
Non-hormonal methods 
Hormonal methods 
• 
Total sexual abstinence (evaluate in relation to 
the duration of the clinical study and the 
preferred and usual lifestyle choice of the 
participant) 
• 
Vasectomized sexual partner (with participant 
assurance that partner received post-vasectomy 
confirmation of azoospermia) 
• 
Bilateral tubal occlusion 
• 
Intrauterine device (provided coils are 
copper-banded) 
• 
Injection: Medroxyprogesterone injection 
(eg, Depo-Provera®) a 
• 
Levonorgestrel-releasing intrauterine system 
(eg, Mirena®) a 
• 
Implants: Etonogestrel-releasing implants 
(eg, Implanon® or Nexplanon®) 
• 
Intravaginal devices: 
Ethinylestradiol/etonogestrel-releasing 
intravaginal devices (eg, NuvaRing®)  
• 
Combined pill: Normal and low dose combined 
oral contraceptive pill 
• 
Patch: Norelgestromin/ethinylestradiol-releasing 
transdermal system (eg, Xulane®, Ortho Evra®) 
• 
Mini pill: Progesterone-based oral contraceptive 
pill using desogestrel: Cerazette® is currently the 
only highly effective progesterone-based pill 
a 
Hormonal methods not prone to drug-drug interactions. 
 
2. 
All patients: Patients should not donate blood or blood components while 
participating in this study and through
after the last dose of durvalumab, 
capivasertib, oleclumab, DS-8201a, Dato-DXd, or paclitaxel or until alternate 
anticancer therapy is started.  
3. 
Restrictions relating to concomitant medications and food are described in 
Section 6.4. 
4. 
During study intervention and for
after the last dose of study intervention, 
participants should be advised to avoid prolonged exposure to the sun, wear 
protective clothing including a hat, and seek shade from the sun as much as 
possible; in addition, SPF30+ sunscreen should be used. Exposure to other sources 
of ultraviolet light including sun beds and tanning booths, etc, should be avoided. 
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5. 
Patients enrolled in Arms 6 (durvalumab + DS-8201a) and 7 and 8 (durvalumab + 
Dato-DXd): use of tobacco products and e-cigarettes and vaping is strongly 
discouraged but not prohibited.  
 
5.4 
Screen failures  
Screen failures are patients who do not fulfill the eligibility criteria for the study, and therefore 
must not be assigned treatment or randomized. These patients should have the reason for study 
withdrawal recorded as “eligibility criteria not fulfilled” (ie, patient does not meet the required 
inclusion/exclusion criteria). This reason for study withdrawal is only valid for screen failures 
(ie, not randomized patients). Patients may be rescreened a single time, but they may not be 
re-allocated to treatment.  
A minimal set of screen failure information is required to ensure transparent reporting of 
screen failure patients to meet the Consolidated Standards of Reporting Trials publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any SAEs, including 
patients who are identified in the pre-screening phase as not eligible. 
6 
STUDY TREATMENTS  
Study treatment is defined as any IP(s) (including marketed product comparator and placebo) 
or medical device(s) intended to be administered to a study participant according to the study 
protocol. Study treatment in this study refers to durvalumab, paclitaxel, and any of the novel 
oncology therapies. In arms with an IP that is given IV (ie, oleclumab, DS-8201a, or 
Dato-DXd), the IP should be administered first, followed by durvalumab, and then paclitaxel 
(Arms 1 through 5 only).  
6.1 
Treatments administered  
6.1.1 
Investigational products  
Table 13 summarizes all study IPs. Additional details are provided on the administration of all 
IV-administered IP in Section 6.1.1.1 and on each individual IP in Section 6.1.1.2 through 
Section 6.1.1.6. The treatment regimens are described in Section 6.1.2, with the individual 
treatment arms for Parts 1 and 2 of the study summarized in Table 15. 
 

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Table 13 
Study treatments  
 
Study treatment 
name 
Dosage formulation 
Dosing instructions 
Route of 
administration 
Packaging and labeling 
Provider 
Durvalumab 
(MEDI4736) 
Target: PD-L1 
500 mg vial solution for 
infusion after dilution, 
50 mg/mL 
Arms 1 to 5: 
1500 mg q4w  
 
Arms 6, 7, and 8: 
1120 mg q3w 
IV 
Study treatment will be 
provided in 500 mg vials. Each 
500 mg vial will be labeled in 
accordance with GMP Annex 
13 and per country regulatory 
requirement.a 
MedImmune 
Paclitaxel 
Variable 
Arms 1 and 5: 
90 mg/m2 
Arm 2b: 
80 mg/m2 
 
4-week cycles: 3 weeks 
once weekly (D1, D8, and 
D15) and 1 week off 
IV 
Variable 
Sourced 
locally by sitec 
Capivasertibd,e 
(AZD5363) 
Target: AKT 
200 mg film-coated 
tablets (160 mg 
film-coated tablets for 
dose reduction) 
400 mg bid 4 days on (D2, 
D3, D4, and D5) and 3 
days off 
4-week cycles: 3 weeks 
on (intermittent; see 
above) and 1 week off 
Oral 
Study treatment will be 
provided in bottles of 60 tablets 
for the 200 mg and 160 mg 
tablets. Each bottle will be 
labeled in accordance with 
GMP Annex 13 and per 
country regulatory 
requirement. 
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for Dato-DXd (datopotamab deruxtecan) will show “DS-1062a”or “Dato-DXd” depending on the agreed product name used in the respective approved 
study master label document. All naming conventions for these compounds are correct during this transitional period. 
e 
Capivasertib should not be taken during any week that the paclitaxel infusion is not administered, either due to a scheduled off-drug-week or an 
unscheduled omission or delay. 
bid  Twice daily; C  Cycle; CD  Cluster of differentiation; D  Day; GMP  Good Manufacturing Practice; IV  Intravenous; MEK  Mitogen-activated protein 
kinase/extracellular signal-regulated kinase; PD-L1  Programmed cell death ligand 1; q1w  Every 1 week; q2w  Every 2 weeks; q3w  Every 3 weeks; q4w  Every 
4 weeks; STAT3  Signal transducer and activator of transcription 3. 
 

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Preparation and administration of durvalumab (MEDI4736) doses for IV infusion 
The dose of durvalumab (MEDI4736) for administration must be prepared by the Investigator 
or site’s designated IP manager using an aseptic technique. The total time from needle 
puncture of the durvalumab (MEDI4736) vial to the start of administration must not exceed:  
• 
24 hours at 2°C to 8°C (36°F to 46°F) 
• 
4 hours at room temperature 
• 
If the final product is stored at both refrigerated and ambient temperatures, the total 
time must not exceed 24 hours. 
 
A dose of 1500 mg (for patients >30 kg in weight) for Arms 1 through 5 every 4 weeks or a 
dose of 1120 mg for Arms 6, 7, and 8 every 3 weeks, will be administered using an IV bag 
containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab (MEDI4736) 
concentration ranging from 1 to 15 mg/mL, and delivered through an IV administration set 
with a 0.2 or 0.22 μm filter. Add 30 mL (ie, 1500 mg) or 22.4 mL (ie, 1120 mg) of 
durvalumab (MEDI4736) to the IV bag. The IV bag size should be selected such that the final 
concentration is within 1 to 15 mg/mL. The bag should be mixed by gently inverting to ensure 
homogeneity of the dose in the bag. 
If a patient’s weight falls to ≤30 kg after initiation of study treatment, weight-based dosing at 
20 mg/kg (Arms 1 through 5 only) will be administered using an IV bag size selected such 
that the final durvalumab concentration is within 1 to 15 mg/mL. Arms 6, 7, and 8 would not 
require weight-based dosing because the weight restriction is due to endotoxin limits per dose 
and is not applicable for doses <1500 mg. 
The use of elastomeric pumps and use of a pneumatic tube for transport of either a vial or a 
final prepared product have not been studied and therefore should be avoided. 
The standard infusion time is 1 hour ± 10 minutes; however, if there are interruptions, the total 
allowed time must not exceed 8 hours with the infusion bag maintained at room temperature, 
otherwise a new dose must be prepared from new vials. 
Do not co-administer other drugs through the same infusion line. 
The IV line will be flushed according to local practices to ensure that the full dose is 
administered. Infusion time does not include the final flush time. 
If either preparation time or infusion time exceeds the time limits, a new dose must be 
prepared from new vials. Durvalumab (MEDI4736) does not contain preservatives, and any 
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For detailed dose preparation, refer to the Handling Instructions document provided by 
AstraZeneca. 
6.1.1.3 
Paclitaxel  
The SoC agent, paclitaxel, will either be locally sourced or be centrally supplied by 
AstraZeneca and will be administered according to prescribing information or treatment 
guidance in general use by the investigating site. Under certain circumstances when local 
sourcing is not feasible, AstraZeneca will centrally supply the drug, which will be labeled 
with text translated in the local language in accordance with regulatory guidelines.  
Administration of paclitaxel 
A dose of 90 mg/m2 will be administered IV over 1 hour for Arms 1 and 5 and a dose of 
80 mg/m2 will be administered IV over 1 hour for Arm 2. For patients on Arm 2 who were 
treated prior to Protocol Version 4, dosing may continue unchanged (ie, if the patient was 
treated at a starting dose of 90 mg/m2 without dose modifications, they may continue at this 
dose, as clinically indicated). 
Premedications will be administered 30 to 60 minutes prior to therapy and may include an 
antihistamine (such as diphenhydramine 50 mg administered IV) and an H2 blocker (such as 
ranitidine 50 mg IV or cimetidine 300 mg IV). Corticosteroids (such as dexamethasone 20 
mg) will be administered orally 12 and 6 hours or IV 30 to 60 minutes before paclitaxel. If no 
hypersensitivity reactions occur after the first paclitaxel dose, corticosteroid dose reductions 
are permitted at the Investigator’s discretion. 
6.1.1.4 
Capivasertib (AZD5363)  
Capivasertib (AZD5363) will be supplied by AstraZeneca and labeled and distributed to sites 
by Fisher Clinical Services. Capivasertib will be supplied in bottles of 60 tablets at strengths 
of 200 mg and 160 mg (for dose reductions). Additional information about the IP may be 
found in the capivasertib Investigator’s Brochure. 
Capivasertib tablets should be stored at room temperature, in their original packaging until 
use. 
Administration of capivasertib 
Capivasertib will be administered orally at a dose of 400 mg bid on an intermittent weekly 
dosing schedule in 4-week cycles as follows: administered on Days 2 through 5 of Weeks 0, 1, 
and 2 (ie, 4 days on and 3 days off each week), followed by 1 week off treatment. 
For Cycle 1, prednisone 10 mg (or equivalent) should be taken on Days 2 through 5 of 
Week 0. 

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When possible, all doses of capivasertib should be taken at approximately the same time each 
day (and 12 hours apart in the same day) and in a fasted state (water to drink only) from at 
least 2 hours prior to the dose to at least 1 hour post-dose. If vomiting occurs, a replacement 
dose should not be taken, and the patient should take their allotted dose at the next scheduled 
time. 
Should a patient miss a scheduled dose, the patient will be allowed to take the dose up to a 
maximum of 2 hours after the scheduled dose time. If more than 2 hours after the scheduled 
dose time have passed, the missed dose should not be taken, and the patient should take 
his/her allotted dose at the next scheduled time. If a patient needs to take the dose earlier for 
whatever reason, the patient can take the dose up to 2 hours earlier than the scheduled dose 
time. The patient should make every reasonable effort to take the capivasertib tablet(s) on 
time. 
If the paclitaxel infusion is not administered, then capivasertib can be interrupted or continued 
based on Investigator discretion. If capivasertib is continued on a weekly schedule, there 
should be 3 days off between capivasertib and subsequent paclitaxel administration.  
If treatment with paclitaxel is permanently discontinued, capivasertib may be continued on a 
weekly schedule at the Investigator’s discretion. If at the Investigator’s discretion the patient 
should continue to receive capivasertib following withdrawal from paclitaxel, any unused 
capivasertib must be returned to the pharmacy, and a new supply must be dispensed. 
Accountability must be captured in the appropriate accountability log. 
Because of the known potential for allergic reactions to paclitaxel, premedication is required 
for paclitaxel per local practice (see Section 6.1.1.3). Routine premedication is not required 
for capivasertib beyond prednisone 10 mg (or equivalent) on Days 2 through 5 in Cycle 1 for 
general prophylaxis of rash. The following therapies are recommended during study 
participation, as applicable: prophylactic anti-emetic therapy before and after paclitaxel 
treatment should be given, as needed, on a prophylactic and treatment basis in compliance 
with the standards of the center; no prophylactic anti-emetic therapy is planned for 
capivasertib, but standard anti-emetic therapy, including a 5-hydroxytryptamine receptor (5-
HT3)-antagonist, can be given, as needed, on a prophylactic and treatment basis in compliance 
with the standards of the center’s local policy. 
Administration of capivasertib during the safety run-in period 
Capivasertib administration at the standard dose (dose level 1) and in the event of 
de-escalation (dose level -1) during the safety run-in period is summarized in Table 14. 

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Table 14 
Capivasertib dispensation schedule in safety run-in period  
Dose level 
1 
-1 
Daily dose regimen of capivasertib 
400 mg bid 
4 days on (D2, D3, D4, and 
D5) and 3 days off in 4-week 
cycles: 3 weeks on 
(intermittent; see above) and 
1 week off 
320 mg bid 
4 days on (D2, D3, D4, and 
D5) and 3 days off in 4-week 
cycles: 3 weeks on 
(intermittent; see above) and 
1 week off 
Number of tablets per day 
4 tablets 200 mg 
2 tablets 200 mg bid 
4 tablets 160 mg  
2 tablets 160 mg bid  
Number of tablets per bottle 
60 ct bottles 
60 -ct/30- ct bottles 
Number of tablets per cycle 
48 tablets 
48 tablets (160 mg)  
 
Number of bottles to be dispensed 
per cycle 
One 60 ct/two 30 ct bottles 
One 60-ct/Two 30-ct bottles 
bid: Twice daily; ct: Count 
 
The dose and dose scheduling of capivasertib administered may be modified until the 
recommended dose for capivasertib in the combination therapy arm has been defined by the 
SRC. The daily dose of capivasertib, number of tablets per day, and number of capivasertib 
bottles to be dispensed at each dispensation visit may therefore differ from those described in 
Table 14. 
6.1.1.5 
Oleclumab (MEDI9447)  
Oleclumab (MEDI9447) is supplied as a
mg and
mg vial solution for infusion after 
dilution. The solution contains 50 mg/mL oleclumab (MEDI9447),
mM 
mM
 and
% (w/v)
 it has a 
pH of
and a density of
g/mL. The nominal fill volume is
mL.  
Oleclumab is a sterile, clear to opalescent, colorless to yellow solution that may contain a few 
white to off-white translucent particles. 
IP vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. Investigational 
product must be kept in original packaging until use to prevent prolonged light exposure. 
Preparation of oleclumab (MEDI9447) doses for administration with an IV bag 
Each vial selected for dose preparation should be inspected. If the solution is not clear to 
opalescent or if any discoloration or particulates are observed, the site monitor should be 
notified immediately, and the vial(s) should be stored in quarantine at refrigerated (2°C to 
8°C [36°F to 46°F]) temperature for drug accountability and potential future inspection. 
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Investigational product vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. 
Investigational product must be kept in original packaging until use to prevent prolonged light 
exposure. 
Each vial is designed for single use only and is not to be used to treat more than 1 patient. 
Preparation of DS-8201a doses for administration with an IV bag 
The dose of DS-8201a for administration must be prepared by the Investigator’s or site’s 
designated IP manager using aseptic technique. Total time from needle puncture of the DS-
8201a vial to the start of administration must not exceed: 
• 
24 hours at 2°C to 8°C (36°F to 46°F) 
• 
4 hours at room temperature 
• 
If the final product is stored at both refrigerated and ambient temperatures, the total 
time must not exceed 24 hours.  
 
Following preparation and during administration, the prepared IV bag must be covered by 
light protection cover. 
Procedures for proper handling and disposal of anticancer drugs should be followed in 
compliance with the standard operating procedures of the study site. 
Administration of DS-8201a  
DS-8201a is emetogenic, which includes delayed nausea and/or vomiting. Prior to each dose 
of DS-8201a, patients should be premedicated with a combination regimen of two or three 
medicinal products (e.g., dexamethasone with either a 5-HT3 receptor antagonist and/or a 
NK1 receptor antagonist, as well as other medicinal products as indicated) for prevention of 
chemotherapy-induced nausea and vomiting. DS-8201a will be administered using an IV bag 
containing 5% (w/v) Dextrose Injection infusion solution and delivered through an IV 
administration set with a 0.2- or 0.22-μm filter. The standard infusion time for DS-8201a is 
approximately 90 minutes ±10 minutes for the first infusion. If the first infusion is well 
tolerated and the patient does not experience an infusion-related reaction, then the minimum 
infusion time for subsequent cycles is
 However, if there are interruptions during 
the infusion, the total time must not exceed
at room temperature.  
Refer to the Pharmacy Instructions for detailed information about preparation and 
administration of DS-8201a. 
There must be no less than
between the end of the infusion of DS-8201a and the 
beginning of the infusion of durvalumab. 
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Administration of Dato-DXd 
Dato-DXd will be administered as a 6.0 mg/kg IV infusion q3w on Day 1 of each 21-day 
cycle. Based on the currently available clinical safety data, it is highly recommended that 
patients receive
agents prior to infusion of Dato-DXd and on 
subsequent days as needed.
such as
and
hould be considered and administered in accordance with the 
prescribing information or institutional guidelines.
can be 
used, if needed. Preferentially, other
agents should be used before considering the 
use of
 Premedication for IRRS is required prior to any dose of Dato-DXd and must 
include
and
 with and without
 Premedication 
with
such as
mg (or equivalent) can be given per investigator 
discretion. Patients should remain at the site for at least
post-infusion of every 
dose of Dato-DXd for close observation for possible allergic reaction. 
Dato-DXd will be administered using an IV bag containing
infusion solution and delivered through an IV administration set with a 0.2- or 0.22-μm filter. 
The standard infusion time for Dato-DXd is approximately
for the 
first infusion. If the first infusion is well tolerated and the patient does not experience an 
infusion-related reaction, then the minimum infusion time for subsequent cycles is
In the case of an IRR at any cycle, follow the TMGs. However, if there are interruptions 
during the infusion, the total cumulative time from needle puncture of the vial to the end of 
administration must not exceed
at room temperature.  
The IV line will be flushed with
according to local practices to ensure 
the full dose is administered. Infusion time does not include the final flush time.  
Refer to the Pharmacy Instructions for detailed information about preparation and 
administration of Dato-DXd. 
The participant should remain at the site for at least
post-infusion of Dato-DXd for 
close observation for possible allergic reactions and IRRs at all cycles. 
Durvalumab should not be co-administered with other drugs through the same infusion line.  
Dato-DXd will be administered first. For Cycle 1, the durvalumab infusion will start 
approximately
after the end of the infusion of Dato-DXd. If there 
are no clinically significant infusion reactions within the first cycle, and at the discretion of 
the Investigator, then for all other cycles, durvalumab can be given a minimum of
after the end of the Dato-DXd infusion. 
The participant’s weight at screening (baseline) will be used to calculate the initial dose. If, 
during the course of treatment, the participant’s weight changes
the participant’s 
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dose will be recalculated based on the participant’s updated weight. After the recalculation, 
the updated participant’s weight will be used as the new baseline weight. The site may follow 
local institutional policy for re-calculating dose based on weight changes less than
 
Dato-DXd administration at the initial dose (dose level 1) and in the event of de-escalation 
(dose level -1) during the safety run-in period is summarized in Table 18. 
Oral Care Plan 
A daily Oral care plan (OCP) will be started before study intervention initiation, and it must 
be maintained throughout the study as specified in the SoA. An oral care kit will be provided 
at study enrolment and at the beginning of each cycle thereafter until the safety follow-up 
visit, which will include a toothbrush, toothpaste, dental floss, and an alcohol-free mouthwash. 
An oral care protocol participant information guide will also be provided to each randomised 
participant before study drug initiation.  
Participants should adhere to the following guidance:  
• Gently brush their teeth after meals and at bedtime using a soft or ultra-soft toothbrush (or 
swab) and a bland-flavoured fluoride-containing toothpaste,  
• Floss their teeth every day, if able to do so without pain or causing gingival bleeding.  
• Daily use of prophylaxis with a steroid-containing mouthwash (eg, dexamethasone oral 
solution 0.1 mg/mL, 10 mL 4 times daily swish for 1 to 2 minutes then spit out; or a 
similar regimen using an alternative steroid advocated by institutional/local guidelines) is 
highly recommended.  
− 
Note: Participants are allowed to take oral nystatin suspension or other topical 
antifungal agents after the steroid-containing mouthwash according to clinician 
preference based on institutional/local guidelines. 
• In the absence of a prophylactic steroid-containing mouthwash, daily use of inert, bland 
mouth rinses (eg, with a non-alcoholic and/or bicarbonate-containing mouthwash, 4 to 
6 times a day) is recommended. 
• Prophylactic cryotherapy (ice chips or ice water held in the mouth throughout the infusion) 
should also be considered. 
 
The following algorithm, to be followed from steps 1 to 4, may be used as guidance to 
select an appropriate prophylaxis mouthwash: 
1 
Dexamethasone mouthwash 0.5 mg/5 mL swish/spit 4 times a day. If not available, then 
use: 
2 
Compounding of dexamethasone mouthwash at site/locally. If not available, then use: 
3 
Other steroid-based mouthwash at site/locally. If not available, then use: 
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4 
Non-steroid mouthwash or other local mouthwash. 
 
The OCP will also include information to educate participants on the importance of oral 
hygiene, tooth brushing, flossing, and hydration and lubrication of the oral mucosa, and on the 
benefits of adhering to their recommended OCP. 
Monitoring of Dato-DXd dose administration 
Patients will be monitored during and after infusion of Dato-DXd (and subsequent infusion of 
durvalumab). Vital signs will be measured according to the SoA (Table 5).  
Management of IP-related toxicities, including those for Dato-DXd and durvalumab, are 
described in Section 8.4.6.  
Management of study intervention-related toxicities are described in the Toxicity 
Management Guidelines (TMGs) for Dato-DXd, (see the Annex document to this CSP). As 
with any biologic product, allergic reactions to dose administration are possible. Therefore, 
appropriate drugs and medical equipment to treat acute anaphylactic reactions must be 
immediately available, and study personnel must be trained to recognise and treat anaphylaxis. 
6.1.2 
Dose and treatment regimens  
The individual treatment arms for Parts 1 and 2 of the study are summarized in Table 15. Part 
1 has 8 arms. Part 2 is anticipated to have 2 or 3 arms. 
Crossover within the study will not be permitted. For example, if a patient is enrolled into 
Arm 1 in Part 1 and experiences PD, she cannot enroll into another arm of this protocol. 
The durvalumab + paclitaxel treatment regimen (Arm 1) is summarized in Section 6.1.2.1. An 
overview of the novel treatment combination regimens (Arms 2 and 5) is provided in 
Section 6.1.2.2, and individual regimens for each treatment arm are described in 
Section 6.1.2.3 through Section 6.1.2.4. The durvalumab + DS-8201a treatment regimen (Arm 
6) is summarized in Section 6.1.2.5. The durvalumab + Dato-DXd treatment regimen (Arms 7 
and 8) is summarized in Section 6.1.2.6.  

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Table 15 
Treatment arms  
 
Study 
part 
Arm 
Study treatment 
1 
1 
Durvalumab + paclitaxel  
1 
2 
Durvalumab + paclitaxel + capivasertib (AZD5363)  
1 
3 
Removed (Protocol Version 3) 
1 
4 
Removed (Protocol Version 4)  
1 
5 
durvalumab + paclitaxel + oleclumab 
1 
6 
durvalumab + DS-8201a (trastuzumab deruxtecan) 
1 
7 
durvalumab + Dato-DXd (datopotamab deruxtecan) 
1 
8 
durvalumab + Dato-DXd (datopotamab deruxtecan) a 
2 
 
Treatment arms that meet pre-defined endpoints from Part 1 may be 
expanded in Part 2b. 
a 
Patients with PD-L1 positive status. 
b 
Refer to Section 4.1.3 (Part 2 study design overview). 
 
6.1.2.1 
Durvalumab and paclitaxel combination therapy (Arm 1)  
Patients in the durvalumab + paclitaxel combination therapy arm will receive 1500 mg 
durvalumab q4w via IV infusion and paclitaxel 90 mg/m2 in 4-week cycles (3 weeks once 
weekly and 1 week off) via IV infusion until any discontinuation criteria are met (see 
Section 7.1), including clinical progression or radiological progression (refer to Appendix F) 
and Investigator determination that the patient is no longer benefiting from treatment with IP. 
Treatment with paclitaxel will be concurrent with durvalumab (ie, starting on Cycle 1 Day 1). 
In the event that durvalumab is discontinued or temporarily held due to treatment-related 
toxicity, paclitaxel may still be administered as scheduled at the Investigator’s discretion. 
On days when both durvalumab and paclitaxel are administered, durvalumab will be 
administered first, followed by paclitaxel. 
The standard infusion time for durvalumab is 1 hour, and the standard time for paclitaxel is 
1 hour. In the event that there are interruptions during durvalumab infusion, the total allowed 
time must not exceed 8 hours at room temperature. If there are no clinically significant 
infusion reactions within the first cycle, and at the discretion of the Investigator, then for all 
other cycles, paclitaxel can be given immediately after the infusion of durvalumab has 
finished. 
Note that if a patient’s weight falls to 30 kg or below (≤30 kg), after initiation of study 
treatment, the patient should receive weight-based dosing equivalent to 20 mg/kg (Arms 1 

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through 5 only) of durvalumab q4w after consultation between the Investigator and Study 
Clinical Lead until the weight improves to >30 kg, at which point the patient should start 
receiving the fixed dosing of durvalumab 1500 mg q4w. Arms 6, 7, and 8 would not require 
weight-based dosing because the weight restriction is due to endotoxin limits per dose and is 
not applicable for doses <1500 mg. 
The dosing schedule for the combination of durvalumab + paclitaxel is shown in Figure 3. 
Figure 3 
Dosing schedule for durvalumab + paclitaxel combination therapy  
 
Q4W  Every 4 weeks. 
 
6.1.2.2 
Durvalumab + paclitaxel + novel treatment combination arms (Arms 2 and 
5): overview  
Patients in each durvalumab + paclitaxel + novel treatment combination arm will receive each 
applicable study treatment (see Table 15) according to its dose and schedule (see Table 13) 
until any discontinuation criteria are met (see Section 7.1), including clinical progression or 
radiological progression (refer to Appendix F) and Investigator determination that the patient 
is no longer benefiting from treatment with IP. 
Treatment with durvalumab, paclitaxel, and the novel oncology therapy will be concurrent 
(ie, starting on Cycle 1 Day 1). In the event that one or more of the study treatments is 
discontinued, refer to Section 7.1.1 for guidance on discontinuation of the other treatment(s). 
In the event that durvalumab is temporarily held due to treatment-related toxicity, the novel 
oncology therapy must also be held, with the exception of capivasertib, which may be 
continued in the absence of durvalumab (based on data from the PAKT study) while adhering 
to instructions indicated in Section 6.1.1.4; paclitaxel may still be administered as scheduled 
at the Investigator’s discretion. In each arm, in the event that the novel oncology therapy is 
held due to a toxicity attributed to that agent only, durvalumab and/or paclitaxel may still be 

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6.1.2.4 
Durvalumab + paclitaxel + oleclumab combination therapy arm (Arm 5)  
The dosing schedule for the combination of durvalumab + paclitaxel + oleclumab is shown in 
Figure 5. 
Figure 5 
Dosing schedule for durvalumab + paclitaxel + oleclumab combination 
therapy  
 
Q2W  Every 2 weeks; Q4W  Every 4 weeks. 
 
6.1.2.5 
Durvalumab + DS-8201a (trastuzumab deruxtecan) combination therapy 
arm (Arm 6)  
The dosing schedule for the combination of durvalumab + DS-8201a is shown in Figure 6.  
Figure 6 
Dosing schedule for durvalumab + DS-8201a (trastuzumab deruxtecan) 
combination therapy  
 
 

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Clinical Lead and the Investigator regarding whether to continue or discontinue the patient 
from treatment. The AstraZeneca Study Clinical Lead must ensure all decisions are 
appropriately documented and that the potential benefit:risk profile remains positive for the 
patient. 
6.2.3 
Methods for assigning treatment groups  
The actual treatment given to patients will be determined by the randomization scheme in the 
RTSM (IRT) (whenever appropriate). As not all cohorts will be open at a given time, patients 
can only be randomized to open cohorts. If only 1 cohort is open, treatment assignment can 
still occur. However, the intention is to randomize patients whenever appropriate. Patients 
assigned to Arms 6, 7, and 8 will need to meet the additional specific inclusion and exclusion 
criteria for Arms 6, 7, and 8, respectively. 
The randomization scheme will be produced by a computer software program that 
incorporates a standard procedure for generating randomization numbers. 
Patients will be identified to the RTSM (IRT) per country regulations. Treatment allocation 
codes will be assigned as patients become eligible for treatment assignment. Drug supply after 
allocation is completed will be managed manually by Site Pharmacists. 
6.2.4 
Methods for ensuring blinding  
This study is open-label and there is no blinding. 
6.3 
Treatment compliance  
The administration of all IPs should be recorded in the appropriate sections of the eCRF. 
Any change from the dosing schedule, does interruptions, dose reductions, and dose 
discontinuations should be recorded in the eCRF. The reason should also be documented. 
Note: Dose reductions are not permitted for durvalumab and oleclumab. 
The Investigational Product Storage Manager is responsible for managing the IP from receipt 
by the study site until the destruction or return of all unused IP. The Investigator is responsible 
for ensuring that the patient has returned all unused IP. 
Treatment compliance will be ensured by site reconciliation of study treatment dispensed as 
described in Sections 6.3.1 and 6.3.2. 
Use of study treatment in doses in excess of that specified in the protocol is considered to be 
an overdose. Refer to Section 8.4.4 for procedures in case of overdose.  

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6.3.1 
Treatment compliance for IV study drugs  
The Investigator or pharmacist must retain records of all study drugs administered at the site 
(ie, those administered IV). The Study Clinical Lead will check these records to confirm the 
compliance with the protocol administration schedule. 
6.3.2 
Treatment compliance for capivasertib  
Patients will be instructed to bring capivasertib
to the clinic for each study visit. 
Compliance will be checked by the site staff during each study visit. In case of low 
compliance, patients should be retrained by the site staff, and the retraining should be 
documented. 
Patients will be instructed to bring all
to the clinic on dispensation visits. For each cycle, patients should return all unused tablets 
during the dispensation visit of the subsequent cycle, at which point a new set of bottles will 
be dispensed to the patients. 
Accountability records should be maintained by the site staff and should be current and up to 
date. 
6.4 
Concomitant therapy  
The Investigator must be informed as soon as possible about any medication taken from the 
time of screening until the end of the clinical treatment phase of the study including the 
follow-up period following the last dose of study drug.  
Any medication or vaccine, including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements, that the patient is receiving at the time of enrollment or receives 
during the study must be recorded along with the following: 
• 
Reason for use 
• 
Dates of administration, including start and end dates 
• 
Dosage information, including dose, unit, and frequency 
 
Patients must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the Investigator. 
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.  
Restricted, prohibited, and permitted concomitant medications are described in the following 
tables and apply to all treatment arms. Refer also to the dosing modification and toxicity 
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management guidelines (see Section 8.4.6). Refer to the local prescribing information for 
paclitaxel with regard to warnings, precautions, and contraindications. 
Table 16 
Prohibited concomitant medications and foods  
Prohibited medication/class of drug: 
Usage: 
For all treatment arms 
Any investigational anticancer therapy 
other than those under investigation in this 
study 
Should not be given concomitantly while the patient is on 
study treatment 
mAbs against CTLA-4, PD-1, or PD-L1 
other than those under investigation in this 
study 
Should not be given concomitantly while the patient is on 
study treatment 
Any concurrent chemotherapy, 
radiotherapy, immunotherapy, or biologic 
or hormonal therapy for cancer treatment 
other than those under investigation in this 
study 
Should not be given concomitantly while the patient is on 
study treatment. (Concurrent use of hormones for non-
cancer-related conditions [eg, insulin for diabetes and 
hormone replacement therapy] is acceptable. Local 
treatment of isolated lesions, excluding target lesions, for 
palliative intent is acceptable [eg, by local surgery or 
radiotherapy]).  
For Arms 6, 7, and 8, radiotherapy to the thorax should be 
avoided and all radiotherapy should be reviewed with the 
study team.  
Live attenuated vaccines  
Should not be given through
after the last dose of 
IP 
Immunosuppressive medications, 
including, but not limited to, systemic 
corticosteroids at doses exceeding
mg/day of prednisone or equivalent, 
methotrexate, azathioprine, and tumor 
necrosis factor-α blockers 
Should not be given concomitantly or used for 
prior to any IP infusions. The following are 
allowed exceptions: 
• 
Use of immunosuppressive medications for the 
management of IP-related AEs 
• 
Use as premedication 
• 
Use in patients with contrast allergies 
• 
Use of inhaled, topical, intranasal co
intra-articular steroid injections, and
A temporary period of steroids will be allowed if clinically 
indicated and considered to be essential for the 
management of non-IP related events experienced by the 
patient (eg, chronic obstructive pulmonary disease, 
radiation, nausea, etc). 
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Prohibited medication/class of drug: 
Usage: 
EGFR TKIs 
Should not be given concomitantly.  
Should be used with caution in the
post last dose 
of IP 
Increased incidences of pneumonitis (with third generation 
EGFR TKIs) and increased incidence of transaminase 
increases (with 1st generation EGFR TKIs) has been 
reported when durvalumab has been given concomitantly. 
Herbal and natural remedies which may 
have immune-modulating effects 
Should not be given concomitantly unless agreed by the 
Sponsor 
Medications or foods (eg, grapefruit juice) 
that may affect IP metabolism (eg, 
CYP1A2, CYP2C19, CYP2D6, or 
CYP3A4 inhibitors/inducers) 
Should not change medications or add medications or 
foods that may affect IP metabolism (eg, CYP1A2, 
CYP2C19, CYP2D6, or CYP3A4 inhibitors/ inducers), 
unless considered clinically indicateda 
For capivasertib arm only 
Medications that may be QT prolonging 
The concomitant administration of drugs known to 
prolong the QT interval is restricted unless considered 
essential due to patient management, in which case, 
patients should be closely monitored. Information 
regarding drugs known to prolong the QT interval can be 
found in Appendix I. Standard anti-emetic therapy, 
including a 5-HT3-antagonist, can be given, as needed, on 
a prophylactic and treatment basis in compliance with the 
standards of the center’s local policy. 
Drugs or herbal supplements that are 
known to be potent inhibitors or inducers 
of CYP3A4, CYP2C9 and/or CYP2D6 
metabolism inhibition and/or MATE1 or 
OCT2 transport, and which have a narrow 
therapeutic window, as they may increase 
the exposure and toxicity of capivasertib. 
Should not be given concomitantly while the patient is on 
study treatmenta 
Drugs known to be sensitive to CYP3A4, 
CYP2C9 and/or CYP2D6 metabolism 
inhibition and/or have a narrow 
therapeutic window. If co-administration 
is necessary, then additional monitoring 
for signs of toxicity related to increased 
exposure to the substrates is required. 
Should not be given concomitantly while the patient is on 
study treatmenta 
For Arms
only 
 
Should not be given concomitantly while the patient is on 
study treatment. See Appendix O 
a 
Additional details on drug-drug interactions are provided in Appendix K. 
5-HT3  5-hydroxytryptamine receptor; AE  Adverse event; CYP  cytochrome P450; EGFR  Epidermal growth factor receptor; 
IP  Investigational product; mAb  Monoclonal antibody; PD-1  Programmed cell death 1; PD-L1  Programmed cell death 
ligand 1; TKI  tyrosine kinase inhibitors. 
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6.4.2 
Ancillary treatment for management of immuno-oncology related 
toxicities  
The study site will supply the required rescue medication and will be obtained locally. The 
following rescue medications are required to be available at the site: 
1 
Infliximab/infliximab biosimilar (eg, for colitis). 
2 
Mycophenolate (eg, for hepatitis). 
Under certain circumstances when local sourcing by the study site is not feasible or local 
regulations prevent the use of infliximab or mycophenolate for this use (as they are considered 
off-label for management of immunotherapy-related toxicities), AstraZeneca will centrally 
supply the required rescue medications, which will be labelled and accompanied by 
Prescribing Information with local language translated text in accordance with regulatory 
guidelines. Accountability and storage requirements, as specified in Section 6.1, apply for any 
study intervention supplied by AstraZeneca. If required to manage an imAE, then the 
IVRS/IWRS RTSM (IRT) will allocate the specific medication either by a kit or another 
identification number, to the pharmacist for a specific participant at the time of the event. 
As a result of imAEs that could potentially be experienced by participants on durvalumab, 
appropriate treatment (eg, steroids and specific immunosuppressant rescue medications) must 
be made readily available to this participant population.  
6.5 
Dose modification  
Dose modifications at the cohort level during the Part 1 safety run-in period are described in 
Section 6.5.1. Dose modifications in individual patients applicable to all parts of the study are 
described in Section 6.5.2 through Section 6.5.2.6. See also Section 8.4.6 on toxicity 
management. 
6.5.1 
Dose modifications at the cohort level during the safety run-in period 
of Part 1  
Part 1 of the study will have a safety run-in period for each novel treatment combination arm 
(Arms 2 through 7). In the event that the initial dose level of an oncology therapy is not 
tolerated (ie,
or more of up to 6 DLT-evaluable patients experience DLTs at the combination 
dose level), a new cohort with up to 6 new DLT-evaluable patients will be opened at a lower 
dose level (see Table 18); this process may be repeated until the lowest dose level is reached. 
Any decision to introduce additional cohorts in order to investigate an alternative dosing 
regimen will be at the discretion of AstraZeneca after discussion with the SRC. In the event 
that the lowest dose is not tolerated, no additional patients will be enrolled to evaluate that 
novel treatment combination arm. 
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6.5.2.3 
Capivasertib  
The combination of durvalumab, paclitaxel, and capivasertib may increase the risk or severity 
of overlapping toxicities. There could potentially be new, unanticipated toxicities as well. The 
Investigator should use clinical judgement when attributing a toxicity to 1 or more of the 
agents. Paclitaxel dose reductions, delays, and toxicity management guidelines are found in 
Section 6.5.2.2. Durvalumab delays and toxicity management guidelines are found in 
Section 6.5.2.1. Capivasertib dose reductions, delays, and toxicity management guidelines are 
found below.  
The following dose modifications apply to toxicities that are attributable to capivasertib. 
Investigator judgement should apply for the management of toxicities possibly related to more 
than 1 investigational medicinal product (IMP). (Durvalumab toxicity guidelines can be found 
in Section 6.5.2.1 and Section 8.4.6.) 
If a patient experiences a clinically significant and/or unacceptable toxicity (including a DLT 
related to capivasertib [ie, not attributable to the disease or disease-related processes under 
investigation] during the assessment period), capivasertib dosing will be interrupted or the 
dose reduced and supportive therapy administered as required (see Appendix I). 
Table 19 
Dose level reductions for individual patients receiving capivasertib  
 
Dose level 
Study agent 
Initial dose (level 1) 
Dose level -1 
Dose level -2 
Capivasertib 
400 mg bid oral 
4 days on (D2, D3, 
D4, and D5) and 
3 days off in 4-week 
cycles: 3 weeks on 
(intermittent; see 
above) and 1 week off 
320 mg bid oral 
4 days on (D2, D3, 
D4, and D5) and 
3 days off in 4-week 
cycles: 3 weeks on 
(intermittent; see 
above) and 1 week off 
200 mg bid oral 4 
days on (D2, D3, D4, 
and D5) and 3 days 
off in 4-week cycles: 
3 weeks on 
(intermittent; see 
above) and 1 week off 
bid  Twice daily; C  Cycle; D  day. 
 
Dose modification guidelines for general capivasertib-related toxicities are shown in Table 20. 
Refer to Section 8.4.6.3 and Appendix I for the management of capivasertib specific AEs: 
rash, hyperglycemia, and diarrhea. Appropriate and optimal treatment of the toxicity is 
assumed prior to considering dose modifications. The Study Clinical Lead may be consulted 
prior to discontinuation of study drug due to toxicities.  

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Table 20 
Dose modifications for general capivasertib-related toxicities 
NCI CTCAE v4.0 Toxicity Grade 
Action 
Grade 1 or 2 clinically significant or intolerable 
Hold dosing and follow guidance below, depending 
on outcome  
•
Resolves to baseline or clinically tolerable
within 21 days of onset
•
Grade 1 or 2 clinically significant or
intolerable does not resolved within 21 days
of onset
•
Resume dosing at same dose or one reduced
dose level as clinically appropriate
•
Discontinue study drug and observe patient
until resolution
Grade ≥3 
Hold dosing and follow guidance below, 
depending on outcome  
•
Grade ≥3 toxicity for ≤21 days and resolves
to ≤Grade 2 or baseline within 21 days of
onset
•
Grade ≥3 toxicity for >21 days
•
Resume dosing at same dose or one reduced
dose level as clinically appropriate
•
Discontinue study drug and observe patient
until resolution
NCI CTCAE v4  National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0. 
6.5.2.4 
Oleclumab  
The combination of durvalumab, paclitaxel, and oleclumab may increase the risk or severity 
of overlapping toxicities. There could potentially be new, unanticipated toxicities as well. The 
investigator should use clinical judgement when attributing a toxicity to 1 or more of the 
agents. Paclitaxel dose reductions, delays, and toxicity management guidelines are found in 
Section 6.5.2. Durvalumab delays and toxicity management guidelines are found in 
Section 6.5.2.1. Oleclumab dose reductions, delays, and toxicity management guidelines are 
found below.  
The following dose modifications apply to toxicities that are attributable to oleclumab. 
Dose delays are permitted for oleclumab therapy. However, dose reduction is not permitted. 
Specifically, dose delay is permitted for management of non-drug-related AEs up to 7 days 
after the scheduled dose with prior consultation of the Study Clinical Lead. In these instances, 
the dosing interval for the next oleclumab cycle may be shortened as clinically feasible to 
gradually align with the schedule of tumor efficacy assessment and durvalumab dosing. Two 
consecutive doses must be administered at least 10 days apart. Any dose delayed longer than 7 
days should be skipped, and the patient should receive the next scheduled dose. 

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For management of dose delays due to drug-related events, the toxicity management 
guidelines (see Section 8.4.6.4) or DLT guidelines (see Section 4.1.4) should be followed, as 
applicable. 
In summary, if a patient experiences a clinically significant and/or unacceptable toxicity 
(including a DLT related to oleclumab during the assessment period), dosing will be 
interrupted (or discontinued in the case of a DLT) or supportive therapy administered as 
required. 
On improvement of an AE for which oleclumab was temporarily interrupted, oleclumab may 
be restarted at the same dose at the discretion of the Investigator. If a further episode of the 
same AE subsequently requires dose interruption, or if a different AE subsequently requires 
dose interruption, oleclumab may be restarted at the same dose level on improvement of the 
AE. 
6.5.2.5 
DS-8201a (trastuzumab deruxtecan)  
The combination of durvalumab and DS-8201a may increase the risk or severity of potential 
overlapping toxicities. There could potentially be new, unanticipated toxicities as well. The 
Investigator should use clinical judgement when attributing a toxicity to 1 or more of the 
agents. Durvalumab delays and toxicity management guidelines are found in Section 6.5.2.1. 
DS-8201a dose reductions, delays, and toxicity management guidelines are found below and 
in Appendix L. In the event that durvalumab is temporarily held due to treatment-related 
toxicity, attributed to durvalumab only, DS-8201a can continue. In the event that DS-8201a is 
temporarily held due to treatment-related toxicity attributed to DS-8201a only, durvalumab 
can continue.  
All dose modifications (interruption, reduction, and/or discontinuation) should be based on the 
worst preceding toxicity (CTCAE version 4.03). Specific criteria for interruption, re-initiation, 
dose reduction, and/or discontinuation of DS-8201a are listed in Table 21 which is applicable 
only to TEAEs that are assessed as related to use of DS-8201a by the Investigator(s). For 
non-drug related TEAEs, follow standard clinical practice. Appropriate clinical experts should 
be consulted as deemed necessary and following the toxicity management guidelines.  
Every effort should be made to limit study drug delay, however in circumstances of adverse 
event management or medical intervention, the study drug can be held up to
from the last DS-8201a dose. During this time scheduled CT/MRI scans should continue 
as per protocol, and patients should fulfil all of the following criteria: 
• 
Study drug may be resumed with confirmation of continued benefit per RECIST 1.1. 
Scans should be performed at the frequency defined per protocol, while the drug is 
being held- At minimum 1 scan must be done within 6 weeks prior to restarting the 
study drug 
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• 
IP(s) is/are restarted within the guidance of the TMGs for DS-8201a and any 
combination agents, if appropriate 
• 
No prohibited concomitant medications have been administered since the last dose of 
DS-8201a  
 
For management of dose delays due to drug-related events, the toxicity management 
guidelines (see Section 8.4.6.4) or DLT guidelines (see Section 4.1.4) should be followed, as 
applicable. 
In summary, if a patient experiences a clinically significant and/or unacceptable toxicity 
(including a DLT related to DS-8201a during the assessment period), dosing will be 
interrupted (or discontinued in the case of a DLT) or supportive therapy administered as 
required. 
On improvement of an AE for which DS-8201a was temporarily interrupted, DS-8201a may 
be restarted at the same dose at the discretion of the Investigator. If a further episode of the 
same AE subsequently requires dose interruption, or if a different AE subsequently requires 
dose interruption, DS-8201a may be restarted at the same dose level on improvement of the 
AE (Appendix L). 
Patients for whom DS-8201a dosing is temporarily withheld for any reason may receive future 
cycles scheduled based on the date of the last DS-8201a dose. The minimal interval between 
two consecutive doses is 19 days. 
Table 21 
Dose level modification for individual patients receiving DS-8201a  
 
Dose level 
Study agent 
Initial dose (level 1) 
Dose level -1 
Dose level -2 
DS-8201a (trastuzumab 
deruxtecan) 
5.4 mg/kg IV q3w  
4.4 mg/kg IV q3w  
3.2 mg/kg IV q3w  
IV Intravenous; q3w  Every 3 weeks. 
 
Once the dose of DS-8201a has been reduced because of toxicity, all subsequent cycles should 
be administered at that lower dose level unless further dose reduction is required. More than 
2 dose reductions are not allowed, and the patient will be withdrawn from the study treatment 
if further toxicity meeting the requirement for dose reduction occurs. 
6.5.2.6 
Dato-DXd (datopotamab deruxtecan; DS-1062a)  
The combination of durvalumab and Dato-DXd may increase the risk or severity of potential 
overlapping toxicities. There could potentially be new, unanticipated toxicities as well. The 
Investigator should use clinical judgement when attributing a toxicity to one or more of the 

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agents. Durvalumab delays and toxicity management guidelines are found in Section 6.5.2.1. 
Dato-DXd delays are found below and toxicity management guidelines are included in the 
Annex document to this CSP. In the event that durvalumab is temporarily held due to 
treatment-related toxicity, attributed to durvalumab only, Dato-DXd can continue. In the event 
that Dato-DXd is temporarily held due to treatment-related toxicity attributed to Dato-Dxd 
only, durvalumab can continue. 
All dose modifications (interruption, reduction, and/or discontinuation) should be based on the 
worst preceding toxicity as per Dato-DXd TMG Annex document to this CSP.  
Specific criteria for interruption, re-initiation, dose reduction, and/or discontinuation of 
Dato-DXd are listed in Table 22 that is applicable only to TEAEs that are assessed as related 
to use of Dato-DXd a by the Investigator(s). For
 follow standard 
clinical practice. Appropriate clinical experts should be consulted as deemed necessary and 
following the toxicity management guidelines.  
Dose delay guidelines: 
A Dato-DXd dose delay due to treatment related toxicity can be delayed for up to 
cycles
from the planned date of administration (ie,
from the 
last infusion date) (see Figure 8). If a patient is assessed as requiring a dose delay of longer 
than
cycles (up t
from the last infusion date to the planned date of 
administration on a Q3W schedule), the participant must discontinue study treatment.  
Figure 8 
Dato-DXd Dose Delay Guidelines  
 
Dato-DXd = Datopotamab deruxecan. 
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Dato-DXd dose delays for conditions
should be kept as short as 
possible. If a patient cannot restart Dato-DXd treatment within
for resolution of 
intercurrent conditions
 the case should be 
discussed with the AstraZeneca study physician. All dose reductions and delay (including any 
missed doses), and the reasons for the reductions/delays are to be recorded in the eCRF.  
The dosing interval for the next Dato-DXd cycle may be shortened, as clinically feasible to 
gradually align with the schedule of tumor efficacy assessment. Dosing of Dato-DXd should 
be harmonized with durvalumab dosing upon recovery from treatment-related toxicity 
attributed to Dato-DXd only. Two consecutive doses must be administered at least
apart.  
Dose reduction guidelines: 
Up to
dose reductions will be permitted for patients receiving Dato-DXd (Table 22). Once 
the dose of Dato-DXd is reduced,
will be permitted. After the permitted 
dose reductions, if further toxicity meeting the requirement for dose reduction occurs, the 
patient will be withdrawn from the study treatment. More than
dose reductions are not 
allowed, and the study intervention will be discontinued if further toxicity that meets the 
requirement for dose reduction occurs.  
Table 22 
Dose level modification for individual patients receiving Dato-DXd  
 
Dose level 
Study agent 
Initial dose (level 1) Dose level -1 
Dose level -2 
Dato-DXd (datopotamab deruxtecan) 6.0 mg/kg IV q3w  
4.0 mg/kg IV q3w  3.0 mg/kg IV q3w  
IV  Intravenous; q3w  Every 3 weeks. 
 
Dose interruption and modification – toxicity management guidelines: 
Dose modification criteria for patients with suspected or confirmed COVID-19, also known as 
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are presented in 
Appendix O. 
Specific criteria for Dato-DXd delay, dose interruption, re-initiation, dose reduction, and/or 
discontinuation of Dato-DXd are listed in the TMG Annex document to this CSP, which is 
applicable only to TEAEs that are assessed as related to use of Dato-DXd by the 
investigator(s).
follow standard clinical practice. Appropriate 
clinical experts should be consulted as deemed necessary. 
The investigator may consider dose delays or discontinuations of Dato-DXd based on other 
events not listed in the TMGs (see the Annex document to this CSP) according to the 
participant’s condition and after discussion with the Study Clinical Lead or designee. 
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As this study is testing novel investigational products, emerging information from this study 
or another study that impacts the safety or the benefit/risk profile may lead to the permanent 
closure of any of the study arms. 
7.1.1 
Procedures for discontinuation of study treatment  
In the event that durvalumab is discontinued, the novel oncology therapy must also be 
discontinued, with the exception of capivasertib, DS-8201a, and Dato-DXd, which may be 
continued in the absence of durvalumab (based on data from the PAKT study, DS8201-A-
J101 study, and DS1062-A-J101 study, respectively). 
Paclitaxel may still be administered as scheduled at the Investigator’s discretion (for Arms 1 
through 5). For each treatment arm, in the event that the novel oncology therapy is 
discontinued due to a toxicity attributed to that agent only, durvalumab and/or paclitaxel may 
still be administered as scheduled at the Investigator’s discretion. In the event that paclitaxel is 
discontinued, durvalumab and/or the novel oncology therapy can be continued as scheduled at 
the Investigator’s discretion.  
Discontinuation of study treatment, for any reason, does not impact the patient’s participation 
in the study. A patient who decides to discontinue IP will always be asked about the reason(s) 
for discontinuation and the presence of any AE. The patient should continue attending 
subsequent study visits, and data collection should continue according to the study protocol. If 
the patient does not agree to continue in-person study visits, a modified follow-up must be 
arranged to ensure the collection of endpoints and safety information. This follow-up could be 
a telephone contact with the patient, a contact with a relative or treating physician, or 
information from medical records. The approach taken should be recorded in the medical 
records. A patient that agrees to a modified follow-up is not considered to have withdrawn 
consent or to have withdrawn from the study. 
Patients who are permanently discontinued from further receipt of IP, regardless of the reason, 
will be identified as having permanently discontinued treatment. Patients who have 
permanently discontinued will enter follow-up (see Table 7).  
Patients who permanently discontinue drug for reasons other than objective RECIST PD 
should continue to have RECIST scans performed q8w ±1 week (Arms 1 through 5) and every 
6 weeks (q6w) ±1 week (Arms 6, 7, and 8) for the first 48 weeks (relative to the date of 
treatment assignment), and then q12w ±1 week thereafter until RECIST 1.1-defined 
radiological progression or until the patient has been taken off-study (end of study, death, or 
patient withdrawal of consent) as defined the SoAs (see Section 1.1). 

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If a patient is discontinued for RECIST 1.1-defined progression, then the patient should have 
1 additional follow-up scan performed preferably at the next (and no later than the next) 
scheduled imaging visit, and no less than 4 weeks after the prior assessment of PD. 
All patients will be followed for survival until the end of the study.  
Patients who decline to return to the site for evaluations should be contacted by telephone, 
following the timing and procedures indicated in the SoAs, as an alternative.  
Patients who have permanently discontinued from further receipt of IP will need to be 
discontinued from the RTSM (IRT). 
7.2 
Lost to follow-up  
Patients will be considered lost to follow-up only if no contact has been established by the 
time the study is completed (see Section 4.4), such that there is insufficient information to 
determine the patient’s status at that time. Patients who refuse to continue participation in the 
study, including telephone contact, should be documented as “withdrawal of consent” rather 
than “lost to follow-up.” Investigators should document attempts to re-establish contact with 
missing patients throughout the study period. If contact with a missing patient is 
re-established, the patient should not be considered lost to follow-up and evaluations should 
resume according to the protocol. 
In order to support key endpoints of PFS and OS analyses, the survival status of all patients in 
the full analysis and the safety analysis sets should be re-checked, this includes those patients 
who withdrew consent or are classified as “lost to follow up.” 
• 
Lost to Follow-up – site personnel should check hospital records, the patients’ current 
physician, and a publicly available death registry (if available) to obtain a current 
survival status. (The applicable case report form [CRF] modules will be updated.) 
• 
In the event that the patient has actively withdrawn consent to the processing of their 
personal data, the survival status of the patient 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. (The applicable CRF 
modules will be updated.) 
 
7.3 
Withdrawal from the study  
Patients are free to withdraw from the study at any time (IP and assessments) without 
prejudice to further treatment. 
Patients who withdraw consent from further participation in the study will not receive any 
further IP or further study observation, with the exception of follow-up for survival, which 
will continue until the end of the study unless the patient has expressly withdrawn their 

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consent to survival follow-up. Note that the patient may be offered additional tests or tapering 
of treatment to withdraw safely. 
A patient who withdraws consent will always be asked about the reason(s) for withdrawal and 
the presence of any AE. The Investigator will follow up AEs outside of the clinical study.  
If a patient withdraws consent, they will be specifically asked if they are withdrawing consent 
to: 
• 
All further participation in the study including any further follow-up (eg, survival 
contact telephone calls) 
• 
Withdrawal from the use of any samples (see Section 8.8.6) 
 

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8 
STUDY ASSESSMENTS AND PROCEDURES  
Study procedures and their timing are summarized in the SoAs. 
The Investigator will ensure that data are recorded on the eCRFs. The Web Based Data 
Capture system will be used for data collection and query handling. 
The Investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement. The 
Investigator will sign the completed eCRFs. A copy of the completed eCRFs will be archived 
at the study site. 
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the patient should continue or discontinue study 
treatment. 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
All pre-screening and screening evaluations must be completed and reviewed to confirm that 
potential patients meet all eligibility criteria. The Investigator will maintain pre-screening and 
screening logs to record details of all patients pre-screened/screened and to confirm eligibility 
or record reasons for screening failure, as applicable.  
Procedures conducted as part of the patient’s routine clinical management (eg, blood count 
and imaging assessments) and obtained before signing of the ICF may be utilized for 
screening or baseline purposes provided the procedures met the protocol-specified criteria and 
were performed within the time frame defined in the SoA. 
Following the final DCO date by study arm, participants will be managed per SoC 
assessments at Investigator discretion.  
8.1 
Efficacy assessments  
Part 1 will evaluate safety as the primary objective. Efficacy assessments in Part 1 of ORR, 
PFS, and DoR will be derived (by AstraZeneca) using Investigator RECIST 1.1 assessments 
(Appendix F). Part 2 will evaluate efficacy as the primary objective, by conducting a 
combined analysis of Part 1 and Part 2 data, with a primary endpoint of ORR. Efficacy 
assessments in the combined analysis of Part 1 and Part 2 data will be on the endpoints of 
ORR, PFS, DoR, and PFS6, which will be derived using RECIST 1.1 assessments. OS will 
also be evaluated using cumulative data from both Parts 1 and 2. 

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Table 23 
Clinical chemistry  
Albumin 
Creatinined  
Sodium 
Alkaline 
phosphatase 
Gamma 
glutamyltransferasec 
Total bilirubina 
ALTa 
Glucosee 
Total protein 
Amylaseb 
HbA1cf 
TSHg 
ASTa 
LDH
T3 freeh (reflex) 
Bicarbonatec 
Lipaseb 
T4 freeh (reflex) 
Calcium  
Magnesiumc 
Urea or blood urea nitrogen, depending on local 
practice 
Chloridec 
Potassium 
 
a 
Tests for ALT, AST, alkaline phosphatase, and total bilirubin must be conducted and assessed concurrently. 
If total bilirubin is ≥2 × upper limit of normal (and no evidence of Gilbert’s syndrome), then fractionate into 
direct and indirect bilirubin. 
b 
It is preferable that both amylase and lipase parameters are assessed. For sites where only 1 of these 
parameters is routinely measured, either lipase or amylase is acceptable. 
c 
Bicarbonate (where available), chloride, creatinine clearance, gamma glutamyltransferase, and magnesium 
testing are to be performed at baseline, on Day 1 (first infusion day) (unless all screening laboratory clinical 
chemistry assessments are performed within 3 days prior to Day 1), and if clinically indicated. 
d 
Creatinine clearance will be calculated by the site using Cockcroft-Gault (using actual body weight).  
e 
Glucose will be evaluated in the fasted state according to the SoAs (Section 1.1). In all arms except Arm 2 
(capivasertib), fasted glucose will be evaluated only at baseline (screening) for all other assessments, fasted 
or non-fasted glucose can be used. 
f 
HbA1c will be evaluated according to the SoAs (Section 1.1). In all arms except Arm 2 (capivasertib), 
fasted HbA1c will be evaluated only at baseline (screening). HbA1c evaluation is not applicable to Arms 7 
and 8. 
g 
If TSH is measured within 14 days prior to Day 1 (first infusion day), it does not need to be repeated at Day 
1. 
h 
Free T3 or free T4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE 
related to the endocrine system. 
AE  Adverse event; ALT  Alanine aminotransferase; AST  Aspartate aminotransferase; HbA1c  Glycated 
hemoglobin; LDH  lactate dehydrogenase;T3  Triiodothyronine; T4  Thyroxine; TSH  Thyroid-stimulating 
hormone. 
 
Table 24 
Hematology  
Absolute neutrophil counta 
Absolute lymphocyte counta 
Hemoglobin 
Platelet count 
Total white cell count 
 
a 
Can be recorded as absolute counts or as percentages. 
 
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Table 25 
Coagulation  
Activated partial thromboplastin time 
International normalized ratio 
Prothrombin time 
 
Note: For coagulation parameters, activated partial thromboplastin time and international normalized ratio are 
only to be assessed at baseline on Cycle 1 Day 1 (unless all screening laboratory hematology assessments are 
performed within 3 days prior to Cycle 1 Day 1), and 24 hours prior to tumor biopsy (if applicable), unless 
clinically indicated. Assessments will also take place at screening and the end of treatment visit. 
PD  Progression of disease. 
 
Table 26 
Urinalysis  
Bilirubin 
Ketones 
Blood 
pH 
Color and appearance 
Protein 
Glucose 
Specific gravity 
Note: Urinalysis should be done at study visits according to the SoA. In all arms, urinalysis will be done at 
baseline (screening) and then as clinically indicated. 
Note: Microscopy should be used as appropriate to investigate white blood cells and use the high power field for 
red and white blood cells. 
 
If a patient shows an AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN, refer to 
Appendix E for further instructions on cases of increases in liver biochemistry and evaluation 
of potential Hy’s Law. See also Section 8.4.6 on toxicity management. These cases should be 
reported as SAEs if, after evaluation, they meet the criteria for a Hy’s law case or if any of the 
individual liver test parameters fulfill any of the SAE criteria.  
All patients should have further chemistry profiles performed at
after permanent discontinuation of IP (see the SoAs). 
Any clinically significant abnormal laboratory values should be repeated as clinically 
indicated and recorded on the eCRF. Situations in which laboratory safety results should be 
reported as AEs are described in Section 8.3.7. 
All patients with Grade 3 or 4 laboratory values at the time of completion or discontinuation 
from IP must have further tests performed until the laboratory values have returned to Grade 1 
or 2, unless these values are not likely to improve because of the underlying disease. 
8.2.2 
Physical examinations  
Physical examinations will be performed according to the assessment schedules (see the 
SoAs). Full physical examinations will include assessments of the head, eyes, ears, nose, and 
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throat and the respiratory, cardiovascular, gastrointestinal, urogenital, musculoskeletal, 
neurological, dermatological, hematologic/lymphatic, and endocrine systems. Height will be 
measured at screening only. Targeted physical examinations are to be utilized by the 
Investigator on the basis of clinical observations and symptomatology. Situations in which 
physical examination results should be reported as AEs are described in Section 8.3.7. 
8.2.3 
Vital signs 
Vital signs (BP, pulse, temperature, and respiration rate) are to be taken before blood 
collection for laboratory tests and will be evaluated according to the SoAs. Blood pressure 
assessment will include of one pulse and 3 blood pressure measurements (3 consecutive blood 
pressure readings will be recorded at intervals of at least one minute). The average of the 
3 blood pressure readings will be recorded in the eCRF. Body weight is also recorded at each 
visit along with vital signs. 
First infusion 
On the first infusion day, patients in all treatment arms will be monitored and vital signs 
collected/recorded in eCRF prior to, during, and after infusion of IP as presented in the 
bulleted list below. Patients should be carefully monitored during the initial infusion for 
possible haemodynamic changes, associated with a possible infusion reaction. 
BP and pulse will be collected from patients in all arms before and after each infusion at the 
following times (based on a
infusion or
infusion for DS-8201a [Arm 6] 
and Dato-DXd [ Arms 7 and 8]): 
•
Prior to the beginning of the infusion (measured once from approximately
before up to
[ie, the beginning of the infusion])
•
At the end of the infusion (approximately
following a
infusion
or
following a
nfusion for DS-8201a [Arm 6] and Dato-DXd
[ Arms 7 and 8])
If the infusion takes longer than
for Dato-DXd or 60 minutes for durvalumab, then 
BP and pulse measurements should follow the principles as described above or be taken more 
frequently if clinically indicated. A
observation period is recommended after the first 
infusion of durvalumab and any novel oncology therapy administered IV. If no infusion is 
done for the visit, vital signs will only be measured once for the visit. 
Subsequent infusions 
BP, pulse, and other vital signs should be measured, collected/recorded in eCRF prior to the 
start of the infusion. For Arms 7 and 8, BP and pulse are to be performed before and after 
subsequent infusions at Day 1 of each subsequent cycle and at the end of treatment (EOT). 
However, if the patient has tolerated previous infusions, BP and pulse may be collected prior 
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to the Dato-Dxd infusion (first infusion) and after completion of the durvalumab infusion (last 
infusion). 
Patients should be carefully monitored, and BP and other vital signs should be measured 
during and post infusion per institution standard and as clinically indicated. Any clinically 
significant changes in vital signs should be entered onto an unscheduled vital signs CRF page.  
Situations in which vital signs results should be reported as AEs are described in 
Section 8.3.7. For any AEs of infusion reactions, the vital signs values should be entered into 
the CRF. 
8.2.4 
Electrocardiograms  
Resting 12-lead ECGs will be recorded in triplicate according to the SoAs. ECGs should be 
obtained after the patient has been in a supine position for 5 minutes ±2 minutes and recorded 
while the patient remains in that position.  
Situations in which ECG results should be reported as AEs are described in Section 8.3.7. 
Individual sites are required to indicate in the unscheduled visit eCRF if an ECG was 
performed during study treatment. 
8.2.5 
Echocardiograms/multiple gated acquisition scans  
Echocardiogram/MUGA scans will be performed at screening, as clinically indicated 
throughout the study, and at additional timepoints in selected treatment arms (see the SoAs). 
The modality of the cardiac function assessments must be consistent within a patient (ie, if 
ECHO is used for the screening assessment, then ECHO should also be used for subsequent 
scans if required). The patients should also be examined using the same machine and operator 
whenever possible. Patients should have high-quality, standardized 2-dimensional with 
Doppler echocardiographic examinations performed by an experienced sonographer. LVEF 
determinations will be made quantitatively based on bi-plane measurements of end-diastolic 
and end-systolic left ventricular volume. 
8.2.6 
Early patient review for safety  
It is recommended that patients are contacted
after receiving the durvalumab dose in 
each of the
of study treatment (Cycle 1 Day 15,
to ensure early identification and management of toxicities. A study visit will occur 
on Day 15 of Cycle 1 and will include the assessments noted in Table 1, Table 2, Table 3, and 
Table 4. On Day 15 of Cycle 1 ( Arms 7 and 8), and Cycle 2 and Cycle 3 (Arms 1 to 8), the 
form of contact and procedures conducted will be per the SoA or at the Investigator’s 
discretion, if not specified in the SoA. 
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8.2.7 
 
Patients receiving capivasertib will be given
 This dosing diary is to be 
completed each time capivasertib is taken. 
8.2.8 
WHO/ECOG performance status  
WHO/ECOG PS will be assessed at the times specified in the assessment schedules (see the 
SoAs) based on the following: 
• 
Fully active; able to carry out all usual activities without restrictions 
• 
Restricted in strenuous activity, but ambulatory and able to carry out light work or 
work of a sedentary nature (eg, light housework or office work) 
• 
Ambulatory and capable of self-care, but unable to carry out any work activities; up 
and about more than 50% of waking hours 
• 
Capable of only limited self-care; confined to bed or chair more than 50% of waking 
hours 
• 
Completely disabled; unable to carry out any self-care and totally confined to bed or 
chair 
• 
Dead  
 
Any significant change from baseline or screening must be reported as an AE. 
8.2.9 
Other safety assessments  
8.2.9.1 
Pneumonitis/ILD investigation  
If new or worsening pulmonary symptoms (eg, dyspnea) or radiological abnormality 
suggestive of pneumonitis/ILD is observed, a full investigation is required as described in 
detail in the dosing modification and toxicity management guidelines for durvalumab (see 
Section 8.4.6.1), for DS-8201a (for patients in Arm 6; see Section 8.4.6.5), and for Dato-DXd 
(for patients in Arms 7 and 8; see Section 8.4.6.6); if this is a potential risk for the specific 
treatment arm, then specific safety management guidelines will be applied (see Section 8.4.6). 
The results of the full diagnostic workup (including high-resolution computed tomography 
[HRCT] per institutional guidelines, blood and sputum culture, hematological parameters, etc) 
will be captured in the eCRF. It is strongly recommended to perform a full diagnostic workup 
to exclude alternative causes such as lymphangitic carcinomatosis, infection, allergy, 
cardiogenic edema, or pulmonary hemorrhage. In the presence of confirmatory HRCT scans 
where other causes of respiratory symptoms have been excluded, a diagnosis of pneumonitis 
(ILD) should be considered and the dosing modification and toxicity management guidelines 
should be followed.  
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The following assessments, and additional assessments if required, will be performed to 
enhance the investigation and diagnosis of potential cases of pneumonitis. The results of the 
assessment will be collected. 
• 
Physical examination 
− 
Signs and symptoms (cough, shortness of breath, and pyrexia, etc) including 
auscultation for lung field will be assessed. 
• 
− 
• 
Other items 
− 
When pneumonitis (ILD) is suspected during study treatment, the following 
markers should be measured where possible: 
o 
ILD markers 
 and
o 
Tumor markers: particular tumor markers
 
o 
Additional clinical chemistry:
o 
Blood sample for serum PK (only for patients in Arms 6, 7, and 8) 
 
8.2.9.2 
Safety assessments for durvalumab + DS-8201a (Arm 6) and durvalumab + 
Dato-DXd ( Arms 7 and 8)  
Pulmonary assessments 
should be obtained within
prior to Cycle 1 Day 1.
hould be obtained 
before and after each infusion per the Arm 6 SoA in Table 4 and before and after each 
infusion at Day 1 for Cycle 1 to Cycle 3, prior to infusion from Cycle 4 onwards and at the 
EOT per Arms 7 and 8 SoA in Table 5 and Table 6.
should be evaluated by PI or the 
delegate physician prior to the administration of IMP at each visit. 
Pulmonary function test (PFT), as a minimum should include spirometry. Diffusion capacity 
of the lungs for carbon monoxide (DLCO) will be performed (when feasible), but for patients 
with prior severe and/or clinically significant pulmonary disorders, DLCO is a requirement. 
Pulmonary HRCT (or CT if HRCT is contraindicated) will be performed according to 
institutional guidelines as per the SoA in Table 4, Table 5, and Table 6. 
Ophthalmologic assessments  
Ophthalmologic assessments including but not limited to visual acuity testing, slit lamp 
examination, intraocular pressure measurement, fundoscopy, and fluorescein staining will be 
performed as specified in the SoA, and as clinically indicated by an ophthalmologist, or if 
unavailable, another licensed eye care provider. A suitable alternative to fluorescein staining 
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of the cornea may be used in exceptional circumstances where fluorescein is not available. An 
ophthalmologic assessment should be considered for any ocular symptoms including, but not 
limited to, dry eye, decreased or blurred vision, foreign-body sensation, photophobia, tearing, 
pain, and eye redness. All ophthalmologic assessments should be documented in the eCRF. 
Copies of all consultation reports should be filed in source notes. Please refer to the Dato-DXd 
Site Ophthalmologic Assessment Manual for further details. 
Participants who are receiving Dato-DXd should be advised to use artificial tears 
(preservative-free, if possible) 4 times daily as preventative measure and up to 8 times daily as 
clinically needed, and to avoid the use of contact lenses. The use of other eye medications (eg, 
topical corticosteroids) for prophylaxis should be at the discretion of an ophthalmologist, or if 
unavailable, another licensed eye care provider. 
Further recommendations for preventing and treating ocular surface toxicity are available in 
the SoA and the TMGs (see the TMG Annex document to this CSP). 
Any significant change from baseline must be reported as an AE (see Section 8.3.7). 
8.2.9.3 
Dental Assessments for Dato-DXd ( Arms 7 and 8)  
As per Investigator judgement, a professional dental assessment before study drug initiation 
and dental treatment, if indicated, may reduce the risk of local and systemic infections from 
odontogenic sources. A daily oral care plan (OCP) should be initiated as described in Section 
6.1.1.7. 
8.3 
Collection of adverse events  
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section. 
The definitions of an AE or SAE can be found in Appendix B. 
AE will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
patient's legally authorized representative). 
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE. For information on how to follow up AEs, 
see Section 8.3.3. 
8.3.1 
Method of detecting AEs and SAEs  
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about 
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8.3.2 
Time period and frequency for collecting AE and SAE information  
Only SAEs will be collected from the time of the patient signing the pre-screening ICF until 
the main ICF is signed. AEs and SAEs will be collected from the time of the patient signing 
the main ICF until the follow-up period is completed
after the last dose of study 
treatment). If an event that starts post the defined safety follow-up period noted above is 
considered to be due to a late-onset toxicity to study drug, then it should be reported as an AE 
or SAE as applicable.
 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as 
indicated in Appendix B. The Investigator will submit any updated SAE data to the Sponsor 
within 24 hours of it being available. Investigators are not obligated to actively seek an AE or 
SAE in former study patients. However, if the Investigator learns of any SAE, including a 
death, at any time after a patient’s last visit and he/she considers the event to be reasonably 
related to the study treatment or study participation, the Investigator should notify the 
Sponsor. 
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Appendix B. 
8.3.3 
Follow-up of AEs and SAEs  
After the initial AE/SAE report, the Investigator is required to proactively follow each patient 
at subsequent visits/contacts. All SAEs, non-serious AEs, and AESIs (as defined in Section 
8.3.14) will be followed until resolution, stabilization, the event is otherwise explained, or the 
patient is lost to follow-up.  
Any AEs that are unresolved at the patient’s last AE assessment or other assessment/visit as 
appropriate in the study are followed up by the Investigator for as long as medically indicated 
(this may be beyond the
after the last dose of study treatment), but without further 
recording in the eCRF. AstraZeneca retains the right to request additional information for any 
patient with ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
8.3.4 
Adverse event data collection  
The following variables will be collected for each AE: 
• 
AE (verbatim) 
• 
The date when the AE started and stopped 
• 
The maximum CTCAE grade reported 
• 
Changes in CTCAE grade (report only the maximum CTCAE grade for a calendar 
day) 
• 
Whether the AE is serious or not 

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• 
Investigator causality rating against the IPs (yes or no) 
• 
Action taken with regard to IPs 
• 
Administration of treatment for the AE 
• 
Outcome 
 
In addition, the following variables will be collected for SAEs where applicable: 
• 
Date the AE met criteria for SAE 
• 
Date the Investigator became aware of the SAE 
• 
Seriousness criteria  
• 
Date of hospitalization 
• 
Date of discharge 
• 
Probable cause of death 
• 
Date of death 
• 
Whether an autopsy was performed 
• 
Causality assessment in relation to study procedure(s) 
• 
Causality assessment in relation to other medication, as explained in Section 8.3.5  
• 
Description of the SAE 
 
The grading scales found in the revised NCI CTCAE version 4.03 will be utilized for all 
events with an assigned CTCAE grading. For those events without assigned CTCAE grades, 
the recommendation in the CTCAE criteria that converts mild, moderate, and severe events 
into CTCAE grades should be used. A copy of the CTCAE version 4.03 can be downloaded 
from the Cancer Therapy Evaluation Program website (http://ctep.cancer.gov). 
8.3.5 
Causality collection  
The Investigator will assess the causal relationship between IP and each AE with respect to 
each IP (durvalumab, paclitaxel, and the novel oncology therapy [if applicable]), 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 investigational product?’ 
For SAEs, causal relationship will 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 to the Clinical 
Study Protocol (CSP). 

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8.3.6 
Adverse events based on signs and symptoms  
All AEs spontaneously reported by the patient 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 CRF. 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. 
8.3.7 
Adverse events based on examinations and tests  
The results from the CSP mandated laboratory tests and vital signs will be summarized in the 
CSR. Deterioration as compared to baseline in protocol-mandated laboratory values, vital 
signs, and ophthalmologic assessments should therefore only be reported as AEs if they fulfill 
any of the SAE criteria, are a DLT, are the reason for discontinuation of treatment with the IP, 
or are considered to be clinically relevant as judged by the investigator (which may include, 
but is not limited to consideration as to whether treatment or non-planned visits were required 
or other action was taken with the study treatment, eg, dose adjustment or drug interruption). 
If deterioration in a laboratory value/vital sign/ophthalmologic assessment is associated with 
clinical signs and symptoms, the sign or symptom will be reported as an AE and the 
associated laboratory result/vital sign/ophthalmologic assessments will be considered as 
additional information. Wherever possible, the reporting Investigator uses the clinical rather 
than the laboratory term (eg, anemia versus low hemoglobin value). Any diagnosis of the 
undesirable clinical outcome of ‘left ventricular dysfunction’, a valid or qualifying reduction 
of LVEF (as measured by MUGA or ECHO) should be confirmed and included in the AE 
report. In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s). 
Deterioration of a laboratory value, which 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 (DUS), see Sections 8.3.9 and 8.3.11. 
8.3.8 
Hy’s law  
Cases wherein a patient shows elevations in liver biochemistry may require further evaluation, 
and occurrences of AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN may need 
to be reported as SAEs. Please refer to Appendix E for further instruction on cases of 
increases in liver biochemistry and evaluation of Hy’s Law. 

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8.3.9 
Pneumonitis/ILD Cases  
All potential ILD/pneumonitis cases should be reported within 24 hours, including both 
serious and non-serious potential ILD/pneumonitis cases (refer to Section 8.2.9.1). 
8.3.10 
Disease under study  
Symptoms of DUS are those that might be expected to occur as a direct result of TNBC. 
Events that are unequivocally due to DUS should not be reported as an AE during the study 
unless they meet SAE criteria or lead to discontinuation of the IP. 
8.3.11 
Disease progression  
PD can be considered as a worsening of a patient’s condition attributable to the disease for 
which the IP is being studied. It may be an increase in the severity of the DUS and/or 
increases in the symptoms of the disease. The development of new metastases, 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 an AE during the 
study. 
8.3.12 
New cancers  
The development of a new cancer should be regarded as an SAE. New primary cancers are 
those that are not the primary reason for the administration of the IP and have been identified 
after the patient’s inclusion in this study. 
8.3.13 
Deaths  
All deaths that occur during the study treatment period, or within the protocol-defined follow-
up period after the administration of the last dose of study drug, must be reported as follows: 
• 
Death clearly resulting from PD should be reported 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 progression of the DUS, the AE 
causing the death must be reported to the Study Clinical Lead 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 main and contributory causes of death. 
• 
Deaths with an unknown cause should always be reported as an SAE. It should also 
be documented in the Statement of Death page in the eCRF. A postmortem may be 
helpful in the assessment of the cause of death, and if performed, a copy of the 
postmortem results should be forwarded to AstraZeneca Patient Safety or its 
representative within the usual timeframes. 
 
Deaths occurring after the protocol-defined safety follow-up period after the administration of 
the last dose of study drug should be documented in the Statement of Death page. If the death 

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occurred as a result of an event that started post the defined safety follow-up period and the 
event is considered to be due to a late-onset toxicity to study drug, then it should also be 
reported as an SAE. 
8.3.14 
Adverse events of special interest  
An AESI is an AE of scientific and medical interest specific to understanding of the IP and 
may require close monitoring. An AESI may be serious or non-serious. The rapid reporting of 
AESIs allows ongoing surveillance of these events in order to characterize and understand 
them in association with the use of the study treatment. 
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. 
8.3.14.1 
Durvalumab  
AESIs for durvalumab include, but are not limited to, events with a potential inflammatory or 
immune-mediated mechanism and which may require more frequent monitoring and/or 
interventions such as corticosteroids, immunosuppressants, and/or endocrine hormone 
replacement therapy. These AESIs are being closely monitored in clinical studies with 
durvalumab monotherapy and combination therapy. An imAE is defined as an AESI that is 
associated with drug exposure and is consistent with an immune-mediated MOA and where 
there is no clear alternate etiology. 
Serologic, immunologic, and histologic (biopsy) data, as appropriate, should be used to 
support an imAE diagnosis. Appropriate efforts should be made to rule out neoplastic, 
infectious, metabolic, toxin, or other etiologic causes of the imAE.  
If the Investigator has any questions in regards to an event being an imAE, the Investigator 
should promptly contact the Study Clinical Lead. 
AESIs observed with anti PD-L/PD-1 agents such as durvalumab include the following: 
• 
Diarrhea/colitis and intestinal perforation 
• 
Pneumonitis/ILD 
• 
Endocrinopathies (ie, events of hypophysitis/hypopituitarism, adrenal insufficiency, 
hyper- and hypo-thyroidism, and type I diabetes mellitus) 
• 
Hepatitis/transaminase increases 
• 
Nephritis/blood creatinine increases 

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• 
Pancreatitis/serum lipase and amylase increases 
• 
Rash/dermatitis 
• 
Myocarditis 
• 
Myositis/polymyositis 
• 
Neuropathy/neuromuscular toxicity (eg, Guillain-Barré syndrome and myasthenia 
gravis) 
• 
Other inflammatory responses that are rare/less frequent with a potential 
immune-mediated etiology include, but are not limited to, pericarditis, sarcoidosis, 
uveitis, and other events involving the eye, skin, hematological, and rheumatological 
events, vasculitis, non-infectious meningitis and non-infectious encephalitis. It is 
possible that events with an inflammatory or immune-mediated mechanism could 
occur in nearly all organs. 
 
In addition, IRRs and hypersensitivity/anaphylactic reactions with a different underlying 
pharmacological etiology are also considered AESIs. 
Further information on these risks (eg, presenting symptoms) can be found in the current 
version of the durvalumab Investigator’s Brochure. More specific guidelines for their 
evaluation and treatment are described in detail in the Dose Modification and Toxicity 
Management Guidelines (see Section 8.4.6). These guidelines have been prepared by the 
Sponsor to assist the Investigator in the exercise of his/her clinical judgment in treating these 
types of toxicities. These guidelines apply to AEs considered causally related to the study 
drug/study regimen by the reporting Investigator. 
8.3.14.2 
Capivasertib  
Details on the following AESIs for capivasertib are provided in Section 2.3.2.3: 
hyperglycemia, rash, diarrhea, stomatitis, infection/lower respiratory tract infection, and QT 
prolongation. 
8.3.14.3 
Oleclumab  
Guidelines for management of patients with hypersensitivity (including anaphylactic reaction) 
and IRRs are described in Section 8.4.6. 
Infusion-related reactions 
Administration of mAbs via IV can cause an acute reaction called an IRR. Acute allergic 
reactions may also occur during the infusion of study treatment. Manifestations of IRR and 
acute allergic reactions are similar and they are managed the same way. IRRs predominantly 
occur at the first exposure to drug and are uncommon at subsequent exposures. 
Anaphylaxis 
Anaphylaxis and IRRs have some common manifestations and may be difficult to distinguish 
from each other. IRRs are commonly observed during or shortly after the first time of 

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exposure to therapeutic mAbs delivered through IV infusion. These reactions are less common 
following subsequent exposures. Unlike IRRs, anaphylaxis is a rare event, usually occurring 
after subsequent exposure to an antigen, and it is most commonly accompanied by severe 
systemic skin and/or mucosal reactions. The Investigator is advised to carefully examine 
symptoms of adverse reactions observed during or shortly after exposure to oleclumab and 
consider the above-mentioned facts prior to making a final diagnosis. Reactions occurring at 
the time of or shortly after subsequent infusions of oleclumab are to be judged by the 
Investigator at his or her own discretion. 
For the Investigator’s convenience and in order to facilitate consistency in judgments, a copy 
of the National Institute of Allergy and Infectious Disease and Food Allergy and Anaphylaxis 
Network guidance for anaphylaxis diagnosis is provided in Appendix H. 
Cardiac chest pain, transient ischemic attack, and thromboembolism 
AEs of cardiac chest pain, transient ischemic attack, and thromboembolic events are of special 
interest due to oleclumab’s potential risks of arterial calcifications, arterial ischemic disorder, 
and thrombosis. Because of this potential risk, patients with a prior history of myocardial 
infarction, stroke, or transient ischemic attack in the past 6 months are not eligible (see 
Section 5.2). These events require urgent medical management, which should be performed 
according to consensus guidelines developed by the American Heart Association or 
appropriate local standards of care. 
Edema 
Edema (eg, pulmonary or peripheral) is regarded as an AESI due to oleclumab’s potential 
risks of increased microvascular permeability. For patients who develop Grade ≥3 edema, 
doses should be omitted per Section 6.5.2.4, and therapy may be discontinued at the discretion 
of the Investigator. 
Immune complex disease 
The immune system can respond to a foreign protein, even to a humanized mAb, by producing 
human anti-human antibodies, which may result in formation of immune complexes and their 
deposition in blood vessels, joints, and glomeruli causing symptomatic disease (eg, vasculitis, 
glomerulonephritis, arthritis, and serum sickness). Patients will be monitored clinically and for 
the presence of ADAs. Patients who experience an AE suspected to be immune-complex 
related and with confirmed presence of ADAs will discontinue treatment. Immune-complex 
disease will be managed in accordance with SoC. 
8.3.14.4 
DS-8201a (trastuzumab deruxtecan)  
Based on the available non-clinical and clinical data, review of the cumulative literature, 
reported toxicities for the same class of agents and biological plausibility, the following events 
are considered to be AESIs:  

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Interstitial lung disease/Pneumonitis  
ILD/pnuemonitis is considered an important identified risk based on a comprehensive 
cumulative review of potential ILD/pneumonitis cases reviewed by the
the available safety data from the clinical development program; 
available data from recent epidemiology/literature; biological plausibility; and safety 
information from drugs of similar class. Refer to the current IB for a summary of preliminary 
clinical study data. 
LVEF decrease 
LVEF decrease in association with DS-8201a is considered to be an important potential risk 
based on the available non-clinical data, literature and available safety information for drugs 
of similar class. Refer to the current IB for a summary of preliminary clinical trial data 
associated with the use of the study treatment. 
8.3.14.5 
Dato-DXd (datopotamab deruxtecan; DS-1062a)  
Based on the available pre-clinical data, review of the cumulative literature, reported toxicities 
for drugs with similar monoclonal antibody and payload of Dato-DXd, and biological 
plausibility, the following events are considered to be AESIs: 
Interstitial lung disease/Pneumonitis 
ILD/pneumonitis is considered an important identified risk based on a comprehensive 
cumulative review of the available safety data from the clinical development program as well 
as the results of potential ILD cases reviewed by the independent ILD Adjudication 
Committee, available data from recent epidemiology/literature, biological plausibility, and 
safety information from drugs with similar monoclonal antibody and payload as Dato-DXd. 
All potential ILD/pneumonitis cases, including both serious and non-serious potential 
ILD/pneumonitis cases (potential ILD/pneumonitis is described in
. Refer to the current Investigator’s Brochure for a summary of preliminary clinical 
study data. 
Oral Mucositis/Stomatitis 
Oral mucositis/stomatitis AEs are considered as identified risks associated with Dato-DXd 
treatment. Mucosal inflammation other than oral mucositis/stomatitis is also an identified risk 
but is considered as a separate AESI (see below). All events of stomatitis/mucosal 
inflammation, regardless of seriousness, must be reported. Recommendations for preventing 
stomatitis/mucosal inflammation can be found in Section 6.1.1.7 and recommendations for 
treatment of stomatitis/mucosal inflammation can be found in the Annex document to this 
CSP. 

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If a subject develops stomatitis/mucosal inflammation, it would be important for the 
Investigator to seek consultation with either a dentist or oral surgeon as needed, and have the 
subject monitored and treated appropriately. 
Mucosal Inflammation Other than Oral Mucositis/Stomatitis 
Mucosal inflammation AEs are considered as identified risks associated with Dato-DXd 
treatment and as a separate AESI from oral mucositis/stomatitis. 
Ocular Surface Events 
Ocular surface events (eg, dry eye, keratitis) is considered as an AESI associated with 
Dato-DXd treatment. Dry eye is considered as an identified risk and keratitis as an important 
identified risk within this AESI. All Grade ≥ 3 ocular surface events and Grade ≥ 2 keratitis 
events (includes keratitis, punctate keratitis, and ulcerative keratitis) for Arms 7 and 8 should 
be reported by the investigator in eCRF EDC AE page(s) within 24 hours of becoming aware. 
The ophthalmologic assessment form manual provides assistance to the Investigator to assess 
any ocular surface toxicity. Every outlined ophthalmologic assessment should be provided in a 
source document, as per SoA in a timely manner.  
8.4 
Safety reporting and medical management  
8.4.1 
Reporting of serious adverse events  
All SAEs have to be reported, whether or not considered causally related to the IP or to the 
study procedure(s). All SAEs will be recorded in the eCRF. 
If any SAE occurs during the course of the study, then Investigators or other site personnel 
inform the appropriate AstraZeneca representatives within 1 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 the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal or 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 1 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 electronic data 
capture system, an automated email alert is sent to the designated AstraZeneca representative. 

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If the electronic data capture system is not available, then the Investigator or other study site 
staff reports an SAE to the appropriate AstraZeneca representative by telephone. 
The AstraZeneca representative will advise the Investigator/study site staff how to proceed. 
For further guidance on the definition of an SAE, see Appendix B. 
8.4.2 
Safety Data to be Collected Following the Final Data Cutoff of the 
Study  
For participants continuing to receive study medication after the final DCO for each arm and 
database closure, AEs and SAEs will be collected and reported on a paper-based report forms 
or electronically as defined by the AstraZeneca.  
In addition, it is recommended that participants continue the scheduled site visits and 
investigators monitor the participant’s safety laboratory results periodically during treatment 
with study medication in order to manage AEs, consistent with the study medication dose 
modification guidelines for management of study intervention-related toxicities (see the 
Annex document to this CSP). All data after the final DCO for each arm and database closure 
will be recorded in the participant notes but only data for AEs and SAEs will be reported via 
paper-based report forms or electronically as defined by AstraZeneca. 
All AEs and SAEs that occur in participants still receiving study medication (or within the 
follow-up period) after the final DCO must be reported within timelines detailed in Section 
8.4.1. 
8.4.3 
Pregnancy  
All pregnancies and outcomes of pregnancy with conception dates following the first date of 
study intervention, including pregnancy in the partners of male participants, should be 
reported to AstraZeneca, except if the pregnancy is discovered before the study participant has 
received any study intervention. 
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, and ectopic pregnancy) are considered SAEs. 
8.4.3.1 
Maternal exposure  
If a patient becomes pregnant during the course of the study, IP should be discontinued 
immediately. 

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Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study 
may have interfered with the effectiveness of a contraceptive medication. Congenital 
abnormalities or 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 abnormality) should be followed up and documented even if the patient 
was discontinued from the study. 
If any pregnancy occurs while the patient is on study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 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 1 or 5 
calendar days for SAEs (see Section 9.2.5) and within 30 days for all other pregnancies. 
The same timelines apply when outcome information is available. 
8.4.3.2 
Paternal exposure  
Not applicable. 
8.4.4 
Overdose  
Use of durvalumab, paclitaxel, and/or any novel oncology therapy in doses that are in excess 
of those specified in the protocol is considered to be an overdose. There is currently no 
specific treatment in the event of overdose of durvalumab or any of the novel oncology 
therapies, and possible symptoms of overdose are not established. Please refer to the local 
prescribing information for treatment in cases of an overdose related to paclitaxel. The 
Investigator will use clinical judgement to treat any overdose. Investigators should be advised 
that any patient who receives a higher dose than that intended should be monitored closely, 
managed with appropriate supportive care, and followed up expectantly. 
• 
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the CRF and on the Overdose CRF module. 
• 
An overdose without associated symptoms is only reported on the Overdose CRF 
module and not the AE module. 
 
If an overdose of a patient with durvalumab, paclitaxel, and/or any novel oncology therapy, 
with or without associated AEs/SAEs, occurs during the course of the study, then the 
Investigator or other site personnel must inform the appropriate AstraZeneca representative 
immediately, or no later than 24 hours of when he or she becomes aware of it, using the 
designated Safety e-mail address or by fax. 

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The designated Contract Research Organization/AstraZeneca representative works with the 
Investigator to ensure that all relevant information is provided to the AstraZeneca Patient 
Safety data entry site. 
For overdoses associated with an SAE, the standard reporting timelines apply, see Section 
8.3.2. For other overdoses, reporting must occur within 30 days. 
8.4.5 
Medication error, drug abuse, and drug misuse  
8.4.5.1 
Timelines  
If an event of medication error, drug abuse, or drug misuse occurs during the study, then the 
Investigator or other site personnel informs the appropriate AstraZeneca representatives 
within one calendar day, ie, immediately but no later than 24 hours of when they become 
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 
SAE associated with the event of medication error, drug abuse, or misuse (see Section 8.3.2) 
and within 30 days for all other events. 
8.4.5.2 
Medication error  
For the purposes of this clinical study a medication error is an unintended failure or mistake 
in the treatment process for an IMP/study intervention or AstraZeneca NIMP 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-8. 
8.4.5.3 
Drug abuse  
Drug abuse is the persistent or sporadic intentional, non-therapeutic excessive use of 
IMP/study intervention or AstraZeneca NIMP for a perceived reward or desired 
non-therapeutic effect. 
The full definition and examples of drug abuse can be found in Appendix B-8. 
8.4.5.4 
Drug misuse  
Drug misuse is the intentional and inappropriate use (by a study participant) of IMP/study 
intervention or AstraZeneca NIMP for medicinal purposes outside of the authorized product 
information, or for unauthorized IMPs/study intervention(s) or AstraZeneca NIMPs, outside 
the intended use as specified in the protocol and includes deliberate administration of the 
product by the wrong route. 
The full definition and examples of Drug Misuse can be found in Appendix B-8. 

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8.4.6 
Management of IP-related toxicities  
The following general guidance should be followed for management of toxicities: 
• 
Treat each of the toxicities with maximum supportive care (including withholding the 
agent suspected of causing the toxicity if required). 
• 
If the symptoms promptly resolve with supportive care, consideration should be 
given to continuing the same dose of the assigned IP along with appropriate 
continuing supportive care. If medically appropriate, dose modifications are 
permitted  
• 
All dose modifications should be documented with clear reasoning and 
documentation of the approach taken. 
 
Durvalumab and oleclumab are non-cytotoxic agents and are generally classified as non-
irritants although experience with their extravasation is limited. 
All toxicities will be graded according to NCI CTCAE version 4.03.  
8.4.6.1 
Specific toxicity management and dose modification information – 
durvalumab and durvalumab in combination with other therapies  
The Toxicity Management Guidelines have been developed to assist investigators with the 
recognition and management of toxicities associated with use of the immune-checkpoint 
inhibitors durvalumab (MEDI4736) (PD-L1 inhibitor) and tremelimumab (CTLA-4 inhibitor). 
Given the similar underlying mechanisms of toxicities observed with these 2 compounds, 
these guidelines are applicable to the management of patients receiving either drug as 
monotherapy or both in combination. Additionally, these guidelines are applicable when either 
drug is used alone or both drugs are used in combination and, also, is administered 
concurrently or sequentially with other anti-cancer drugs (ie, antineoplastic chemotherapy, 
targeted agents), as part of a protocol specific treatment regimen. The Toxicity Management 
Guidelines provide information for the management of immune-mediated reactions, IRRs, and 
non-immune mediated reactions that may be observed with checkpoint inhibitor monotherapy 
or combination checkpoint inhibitor regimens, with specific instructions for dose 
modifications (including discontinuations) and treatment interventions. Dose modifications 
with regards to hold or discontinuation of durvalumab are required actions for the 
management of potential immune-mediated events or non-immune-mediated adverse 
reactions, as described in the Dosing Modification and Toxicity Management Guideline; 
permanent discontinuation of study treatment for these adverse events is considered a 
study-specific requirement. 
Investigators are advised however to use local practice guidelines and consult local references 
for the management of toxicities observed with other cancer treatment. 

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The most current version of the toxicity management guidelines entitled “Dosing Modification 
and Toxicity Management Guidelines for Durvalumab Monotherapy, Durvalumab in 
Combination with Other Products, or Tremelimumab Monotherapy” is provided to the 
investigative site as an Annex document and is maintained within the Site Master File.  
Patients should be thoroughly evaluated and appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxic, or other etiologic causes of the imAE. Serologic, 
immunologic, and histologic (biopsy) data, as appropriate, should be used to support an imAE 
diagnosis. In the absence of a clear alternative etiology, events should be considered 
potentially immune-related. 
In addition, there are certain circumstances in which durvalumab should be permanently 
discontinued (see Section 7.1 of this protocol and the Dosing Modification and Toxicity 
Management Guidelines). 
Following the first dose of IP, subsequent administration of durvalumab can be modified 
based on toxicities observed as described in the Dosing Modification and Toxicity 
Management Guidelines. These guidelines have been prepared by the Sponsor to assist the 
Investigator in the exercise of his/her clinical judgment in treating these types of toxicities. 
These guidelines apply to AEs considered causally related to durvalumab by the reporting 
Investigator. 
Dose reductions are not permitted. In case of doubt, the Investigator should consult with the 
Study Clinical Lead. 
8.4.6.2 
Specific toxicity management and dose modification information - paclitaxel  
Guidelines for dose reduction to manage specific toxicities are provided in Section 6.5.2.2. In 
addition, Investigators should follow local standard clinical practice regarding toxicity 
management for paclitaxel. Please refer to the local prescribing information for paclitaxel. 
8.4.6.3 
Specific toxicity management and dose modification information - 
capivasertib  
General guidelines for dose reduction, interruption, and permanent discontinuation are 
summarized in Section 6.5.2.3. Guidelines for the management of general toxicity (Table 20), 
hypersensitivity, hyperglycemia, diarrhea, and maculo-papular rash that may be attributable to 
capivasertib are provided in the Guidance for Management of Specific Adverse Events of 
capivasertib (see Appendix I). 
Following the first dose of IP, subsequent administration of capivasertib can be modified 
based on toxicities observed as described in the Guidance for Management of Specific 
Adverse Events. These guidelines have been prepared by the Sponsor to assist the Investigator 
in the exercise of his/her clinical judgment in treating these types of toxicities. These 

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guidelines apply to AEs considered causally related to capivasertib by the reporting 
Investigator. 
In addition, there are certain circumstances in which capivasertib should be permanently 
discontinued (see Sections 6.5.2.3 [capivasertib] and 7.1 [all IPs] of this protocol and the 
Guidance for Management of Specific Adverse Events for capivasertib). 
8.4.6.4 
Specific toxicity management and dose modification information - oleclumab  
There are no guidelines specific to AEs attributable to oleclumab monotherapy. The 
guidelines for durvalumab in combination with other therapies may be followed. 
8.4.6.5 
Specific toxicity management and dose modification information - DS-8201a 
(trastuzumab deruxtecan)  
Following the first dose of IP, subsequent administration of DS-8201 may be modified based 
on toxicities observed as described in the Guidance for Management of Specific Adverse 
events in studies of DS-8201 (Appendix L). Guidelines for the management of general 
toxicity, ILD/pneumonitis, LVEF reduction, transaminitis, and cytopenias that may be 
attributable to DS-8201 are also provided in Appendix L.  
In addition, there are certain circumstances in which DS-8201 should be permanently 
discontinued. General guidelines for dose reduction, interruption, and permanent 
discontinuation are summarized in Section 6.5.2.5. All confirmed or suspected COVID-19 
infection events must be recorded in the eCRF as AEs. Please refer to Appendix O for 
additional information on dose modification. 
ILD/pneumonitis management guidance:  
Early diagnosis and appropriate management of events of ILD/pneumonitis are essential to 
minimise serious outcomes. Patients should be monitored closely and advised to immediately 
report signs or symptoms of ILD/pneumonitis (eg, cough, dyspnea at rest or exertion, fever, 
not otherwise explained fatigue, decrease in oxygen saturation, and/or any other new or 
worsening respiratory symptoms). ILD education is to be re-emphasized in patients with 
moderate renal impairment. Physicians should consider more frequent patient contact in 
between visits (at least once in between cycles) in order to reinforce ILD education and the 
importance of prompt reporting of symptoms, until the investigator is confident the patient is 
familiar with the requirements. 
The goal of ILD management is to supress inflammation and prevent irreversible fibrosis with 
potential fatal outcome. Corticosteroid treatment is considered to be most effective during the 
inflammatory phase of ILD. On occasions, ILD can present acutely and progress rapidly. 
Initiate management promptly at the first suspicion of ILD/pneumonitis. 

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If the AE is suspected to be ILD/pneumonitis, treatment with study drug should be interrupted 
pending further evaluations. Evaluations should include: 
• 
CT chest (HRCT preferred): the same modality should be employed as the baseline 
scan to allow for direct comparison of scans 
• 
Pulmonologist consultation (infectious disease consultation if clinically indicated) 
• 
and
if clinically indicated and feasible 
• 
Pulmonary function tests (including
and
 and
• 
Clinical laboratory tests: 
− 
COVID-19 Test 
− 
Arterial blood gases, if clinically indicated 
− 
CBC, blood culture, differential WBC, CRP 
− 
One blood sample should be collected for pharmacokinetics as soon as 
ILD/pneumonitis is suspected, if feasible. 
• 
Other tests could be considered, as needed, including
(eg,
 especially in patients with 1 or more of the following risk factors: 
lymphopenia, long-term/intermittent steroid use, brain metastases, and chronic lung 
diseases. 
 
If the AE is confirmed to be ILD/pneumonitis, promptly follow the management guidance 
outlined in the designated “Pulmonary Toxicity” Toxicity Management Guidelines. 
For DS-8201a and Dato-DXd,
will be 
established to
To ensure adequate and relevant 
evaluation, additional data may be collected to fully characterise medical history (eg, 
smoking, radiation and pulmonary history), diagnostic evaluation, treatment, and outcome of 
the event. To ensure adequate and relevant evaluation, systematic additional data collection 
will be conducted for all cases that will be brought for evaluation. This additional data 
collection will cover a more in-depth relevant medical history (eg, smoking, radiation, COPD 
and other chronic lung conditions), diagnostic evaluation, treatment, and outcome of the 
event. 
LVEF decrease management guidance:  
LVEF will be measured by either ECHO or MUGA scan. All ECHOs/MUGAs will be 
evaluated by the Investigator or delegated physician for monitoring cardiac function. 
Troponin-T will be measured at screening, EOT, and as needed based on patient-reported 
cardiac signs or symptoms suggesting congestive heart failure, myocardial infarction, or other 
causes of cardiac myocyte necrosis.  
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ECGs will be performed at screening, prior to administration of IMP at Cycle 1 Day 1, and 
every fourth cycle (once) thereafter. Triplicate ECGs will be performed at screening. 
Subsequent ECGs will be performed in triplicate only if abnormalities are noted. If 12-lead 
ECG is abnormal, follow institutional guidelines. Twelve-lead ECGs will be performed, and 
standard ECG parameters will be measured, including RR, PR, QT intervals, and QRS 
duration. All ECGs must be evaluated by Investigator or delegated physician for the presence 
of abnormalities. Whether or not measurement is performed, date performed, results, and 
findings for each parameter is to be recorded in the eCRF. The summary flow chart for 
management of LVEF decrease is also available in Appendix L. 
8.4.6.6 
Specific toxicity management and dose modification information - Dato-DXd  
Following the first dose of IP, subsequent administration of Dato-DXd may be modified based 
on toxicities observed as described in the Guidance for Management of Specific Adverse 
events in studies of Dato-DXd (Annex document to this CSP). Guidelines for the management 
of general toxicity, ILD/pneumonitis, combined elevations of aminotransferase and total 
bilirubin, IRRs including anaphylaxis, and stomatitis/mucosal inflammation that may be 
attributable to Dato-DXd are also provided in the Annex document to this CSP.  
In addition, there are certain circumstances in which Dato-DXd should be permanently 
discontinued. General guidelines for dose reduction, interruption, and permanent 
discontinuation are summarized in Section 6.5.2.6. All confirmed or suspected COVID-19 
infection events must be recorded in the eCRF as AEs. Please refer to Appendix O for 
additional information on dose modification. 
ILD/pneumonitis management guidance:  
All potential ILD/pneumonitis cases should be reported within 24 hours, including both 
serious and non-serious potential ILD/pneumonitis cases (potential ILD/pneumonitis is 
described in the Event Adjudication Site Manual). A
the 
eCRF to collect relevant
information for these potential cases regardless of 
seriousness. 
ILD/pneumonitis should be ruled out if a patient develops radiographic changes potentially 
consistent with ILD/pneumonitis or develops an acute onset of new or worsening pulmonary 
or other related signs/symptoms such as dyspnea, cough, or fever. If the AE is confirmed to 
have an etiology other than ILD/pneumonitis, but the AE is assessed as possibly causally 
related to Dato-DXd, follow the management guidance outlined in the designated “Other 
Non-Laboratory Adverse Events” dose modification section of the Dato-DXd TMGs (see the 
Annex document to this CSP).  
If the AE is suspected to be ILD/pneumonitis, treatment with study drug should be delayed 
pending further evaluations. Evaluations should include high resolution CT, pulmonologist 
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consultation (infectious disease consultation as clinically indicated), blood culture and CBC 
(other blood tests could be considered as needed), bronchoscopy and bronchoalveolar lavage 
if clinically indicated and feasible should be considered, PFTs and
 
arterial blood gases if clinically indicated, and one blood sample collection for PK analysis as 
soon as ILD/pneumonitis is suspected, if feasible. Other tests could be considered, as needed 
(eg, COVID-19 test).  
for the DS-1082a and Dato-DXd program is 
responsible for
To ensure adequate and 
relevant
 systematic additional data collection will be conducted for all 
cases that will be brought
 These additional data collections will cover a more 
in-depth relevant medical history (eg, smoking, radiation, COPD, and other chronic lung 
conditions), diagnostic evaluation, treatment, and outcome of the event. 
If the AE is confirmed to be ILD/pneumonitis, follow the management guidance outlined in 
the TMGs (see the Annex document to this CSP). All events of ILD/pneumonitis regardless of 
severity or seriousness will be followed
An autopsy in cases of Grade 5 ILD/pneumonitis is encouraged.  
Infusion-related reaction management guidance: 
All Grade ≥3 events of IRR, regardless of seriousness, must be reported in eCRF within 
24 hours. 
Premedication is required prior to any dose of Dato-DXd and must include
nd 
with or without
 Refer to the management guidance outlined 
in the Dato-DXd TMGs (see the Annex document to this CSP).  
Stomatitis/mucositis and mucosal inflammation management guidance: 
Stomatitis/mucositis and mucosal inflammation events are considered as identified risks. As 
per Investigator’s judgement, a professional dental assessment before study drug initiation and 
dental treatment, if indicated, may reduce the risk of local and systemic infections from 
odontogenic sources.  
Dato-DXd treatment toxicity management guidelines for Stomatitis/ oral mucositis and 
mucosal inflammation are provided in the Annex document to this CSP. 
Ocular surface events 
All Grade ≥ 3 ocular surface events and Grade ≥ 2 keratitis events (including keratitis, 
punctate keratitis, and ulcerative keratitis) should be reported within 24 hours of becoming 
aware. All events of ocular surface toxicity and keratitis should be
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Patients are advised to use artificial tears 4 times daily as preventative measure and up to 8 
times daily as clinically needed and avoid contact lenses. Recommendations for preventing 
and treating ocular surface toxicity are available in the SoA, Section 8.2.9.2, and the TMGs 
(see the Annex document to this CSP). See Appendix R for the non-CTCAE toxicity grading 
scale for corneal toxicity. 
The ophthalmologic assessment manual provides assistance to the licensed eye care provider 
to assess any ocular surface toxicity. Every outlined ophthalmologic assessment should be 
provided in a source document, as per SoA in a timely manner. 

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8.5 
Pharmacokinetics and Immunogenicity  
PK and immunogenicity (ADAs) will be assessed only in Part 1 of the study for Arm 1 to 
Arm 6. Pharmacokinetics and ADAs will be assessed in both Part 1 and Part 2 in Arms 7 
and 8.  
8.5.1 
Collection of samples  
8.5.1.1 
Collection of samples to measure serum or plasma concentrations  
Blood samples for determination of concentrations of durvalumab, oleclumab, and T-DXd (in 
serum), and capivasertib and Dato-DXd (in plasma), will be obtained according to the SoAs. 
PK samples will be collected in Part 1 of the study only for Arms 1 to 6 and in both Parts 1 
and 2 for Dato-DXd in Arms 7 and 8. As indicated in Table 4, Table 5, and Table 6 additional 
PK sampling and analyses will be conducted for patients in Arms 6, 7, and 8 in case treatment 
with chloroquine or hydroxychloroquine for COVID-19 is absolutely required. 
Samples for determination of durvalumab and novel oncology therapy concentrations in serum 
or plasma will be analyzed by AstraZeneca or designated third party laboratories operating on 
behalf of AstraZeneca. Samples will be collected, labeled, stored, and shipped as detailed in 
the Laboratory Manual. Full details of the analytical method used will be described in a 
separate Bioanalytical Validation Report. 
8.5.1.2 
Collection of samples to measure for the presence of ADAs  
The presence of ADA will be assessed in serum samples for durvalumab, oleclumab, and 
DS-8201a and in plasma samples for capivasertib and Dato-DXd, taken according to the 
SoAs.  
Samples will be measured for the presence of ADAs for durvalumab, oleclumab, DS-8201a, 
and Dato-DXd (see Section 1.1) using validated assays. ADA samples will be collected in 
Part 1 of the study only for Arms 1 to 6 and in both Parts 1 and 2 for Dato-DXd in Arms 7 and 
8. Tiered analysis will be performed to include screening, confirmatory, and titer assay 
components. ADA samples may also be
characterization of the
8.5.2 
Storage and destruction of pharmacokinetic and ADA samples  
PK and ADA samples will be destroyed within 15 years of CSR finalization. 
PK and ADA samples may be disposed of or destroyed and anonymized by pooling. 
Additional analyses may be conducted on the anonymized, pooled PK samples to further 
evaluate and validate the analytical method. Results from such analyses may be reported 
separately from the CSR. 
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Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation will not be reported in the CSR but 
separately in a Bioanalytical Validation Report. 
Any
samples may be used for future exploratory
research (in this case,
will be shipped to AstraZeneca-
assigned
 see details in the Laboratory Manual). 
8.6 
Pharmacodynamics  
Pharmacodynamic parameters are not evaluated in this study. 
8.7 
 
8.7.1 
Optional exploratory
 
If the patient agrees to participate in the optional
study, a blood sample will 
be collected. Participation is optional. Patients who do not wish to participate in
may still participate in the study. 
The blood sample will be obtained from the patients on Day 1 (first infusion day) prior to 
treatment administration. If for any reason the sample is not drawn on Day 1, it may be taken 
at any visit until the last study visit.
should be collected per patient for
during the study. 
In the event of
or blood sample damage, a replacement
sample may be requested from the patient. Signed informed consent will be required to obtain 
a replacement sample unless it was included in the original consent. 
See Appendix D for information regarding
 Details on processes for 
collection and shipment and destruction of these samples can be found in Appendix D or in 
the Laboratory Manual. 
8.7.2 
Storage and destruction of
 
The processes adopted for
of samples for
are 
important to maintain patient confidentiality. Samples may be stored for a maximum
r per local regulations from the date of the Last Patient’s Last Visit, after which they 
will be destroyed.
that may be used up during analyses. The results of 
any further analyses will be reported either in the CSR itself or as an addendum, or separately 
in a scientific report or publication. 
No personal details identifying the individual will be available to AstraZeneca or designated 
organizations working with the DNA. 
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containing or suspected to contain infectious substances that do not meet Category A criteria); 
see Appendix C (“IATA 6.2 Guidance Document”). 
Any samples identified as Infectious Category A materials will not be shipped, and no further 
samples will be taken from the involved patients unless agreed upon with AstraZeneca and 
appropriate labeling, shipment, and containment provisions are approved. 
8.8.5 
Chain of custody of biological samples  
A full chain of custody will be maintained for all samples throughout their life cycle. 
The Principal Investigator at each center will keep full traceability of collected biological 
samples from the patients while in storage at the center until shipment or disposal (where 
appropriate) and will keep documentation of sample shipments. 
The sample receiver will keep full traceability of the samples while in storage and during use 
until used or disposed of or until further shipment and will keep documentation of sample 
shipments. 
AstraZeneca will keep oversight of the entire life cycle through internal procedures, 
monitoring of study sites, and auditing or process checks and contractual requirements of 
external laboratory providers. 
Samples retained for further use will be stored in the AstraZeneca-assigned Biobank and will 
be registered with the AstraZeneca Biobank Team during the entire life cycle. 
8.8.6 
Withdrawal of informed consent for donated biological samples  
If a patient withdraws consent to the use of donated biological samples, the samples will be 
disposed of or destroyed and the action documented. If samples have already been analyzed, 
AstraZeneca is not obliged to destroy the results of this research. 
The Principal Investigator will: 
• 
Ensure that AstraZeneca is immediately notified of the patients’ withdrawal of 
informed consent to the use of donated samples. 
• 
Ensure that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of or destroyed and the action documented. 
• 
Ensure that the organization(s) holding the samples is/are immediately informed 
about the withdrawn consent and that samples are disposed of or destroyed, the 
action is documented, and the study site is informed. 
• 
Ensure that the patient and AstraZeneca are informed about the sample disposal. 
 

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dose. The final analysis for patients on Arm 7 and 8 will be performed when the last patient 
has had the opportunity to be followed for at least 6 months from the date of first dose. 
9.2 
Populations for analyses  
Definitions of the analysis sets for each outcome variable are provided in Table 27. 
Table 27 
Summary of outcome variables and analysis populations  
Outcome variable 
Populations 
Safety data 
 
Exposurea 
Safety Analysis Set 
AEs 
Safety Analysis Set 
Laboratory measurements 
Safety Analysis Set 
Vital signs 
Safety Analysis Set 
Physical exams 
Safety Analysis Set 
ADA-  
Safety Analysis Set 
Efficacy data 
 
ORR 
Response Evaluable Analysis Set 
DoR, PFS, change in tumorb size, PFS6c, OS 
Full Analysis Set (ITT population) 
Demography 
Full Analysis Set (ITT population) 
PK datab 
PK Analysis Set  
a 
This includes durvalumab, paclitaxel, capivasertib, oleclumab, DS-8201a, and Dato-DXd dose delays, 
reductions, and discontinuations. 
b 
Change in tumor size and PK data are applicable for Part 1 only. 
c 
PFS6 is applicable for Part 2 only (using pooled data from Part 1 and Part 2 subjects). 
d 
Subjects in the Safety Analysis Set (SAF) with a non-missing baseline anti-drug antibody (ADA) result for 
an agent and at least one non-missing post-baseline ADA result for the same agent will form a subset of the 
SAF, the ADA-evaluable set. 
ADA  Anti-drug antibody; AE  Adverse event; CI  Confidence interval; DoR  Duration of response; 
Dato-DXd  Datopotamab deruxtecan; DS-8201a  Trastuzumab deruxtecan; FAS  Full analysis set; 
ITT  Intent-to-treat; ORR  Objective response rate; OS  Overall survival; PFS  Progression-free survival; 
PFS6  Progression-free survival at 6 months following  date of first dose; PK  Pharmacokinetics. 
 
9.2.1 
Full Analysis Set  
The Full Analysis Set (FAS) will include all patients who are assigned to treatment and 
received at least 1 dose of study treatment (at least 1 IP [durvalumab, paclitaxel, or novel 
oncology therapy]). Treatment groups will be summarized according to the treatment 
received. This is the same as the Safety Analysis Set. 

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9.2.2 
Response Evaluable Analysis Set  
A subset of the FAS will include all treated patients who have measurable disease at baseline. 
This will be the primary analysis set on which ORR analyses will be performed. 
9.2.3 
Safety Analysis Set  
The Safety Analysis Set will consist of all patients who received at least 1 dose of study 
treatment (at least 1 IP [durvalumab, paclitaxel, or novel oncology therapy]). Safety data will 
not be formally analyzed but summarized using the SAF according to the treatment received. 
That is, erroneously treated patients (eg, those assigned/randomized to treatment A but 
actually given treatment B) will be summarized according to the treatment they actually 
received. 
9.2.4 
PK analysis set (Part 1 only in Arms 1 to 6 and Part 2 in Arms 7 and 
8)  
All patients who received at least 1 dose of durvalumab or novel oncology therapy per 
protocol and had at least 1 post-dose evaluable PK data point for durvalumab or the novel 
oncology therapy will be included in the PK analysis set. The population will be defined by 
AstraZeneca/MedImmune, the Pharmacokineticist, and the Statistician prior to any analyses 
being performed. 
9.3 
Outcome measures for analyses  
9.3.1 
Calculation or derivation of efficacy variables  
9.3.1.1 
RECIST 1.1-based endpoints  
The analysis of the Part 1 key secondary endpoint (ORR) and the analyses of the other 
secondary endpoints (PFS and DoR) will be based on the site Investigator assessments using 
RECIST 1.1. 
The analysis of the Part 2 primary endpoint (ORR) and the analyses of the secondary 
endpoints (PFS, DoR, and PFS6) will be based on the site Investigator assessments using 
RECIST 1.1 using pooled data from Part 1 and Part 2. 
RECIST 1.1-based endpoints are derived using confirmed responses. Sensitivity analyses 
using unconfirmed responses may also be conducted. 
9.3.1.1.1 
INVESTIGATOR RECIST 1.1-BASED ASSESSMENTS  
All RECIST 1.1 assessments, whether scheduled or unscheduled, will be included in the 
calculations. This is also regardless of whether a patient discontinues study treatment or 
receives another anticancer therapy, unless otherwise stated for that parameter/analysis. 

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At each visit, patients will be programmatically assigned a RECIST 1.1 visit response of CR, 
PR, SD, or PD depending on the status of their disease compared with baseline and previous 
assessments. Baseline will be assessed within the 28 days prior to enrollment. If a patient has 
had a tumor assessment that cannot be evaluated, then the patient will be assigned a visit 
response of not evaluable (unless there is evidence of progression in which case the response 
will be assigned as PD). 
Please refer to Appendix F for the definitions of CR, PR, SD, and PD. 
Start date for Time-to-Event endpoints: 
The start date for efficacy time-to-event endpoints such as PFS, PFS6, and OS will be the date 
of first dose of any IP, namely, durvalumab, paclitaxel, or novel oncology therapy. For 
detailed definitions, see sections below. 
9.3.1.2 
Objective response rate  
In Parts 1 and 2, ORR (per RECIST 1.1 using Investigator assessments) is defined as the 
number (%) of patients with at least 1 visit response of CR or PR that is subsequently 
confirmed on another scan. For the
 unconfirmed responses may be 
considered in decision making. 
In both study parts, data obtained up until objective PD or death, or the last evaluable 
assessment in the absence of progression, will be included in the assessment of ORR. Patients 
who go off treatment without progression, receive a subsequent therapy, and then respond will 
not be included as responders in the ORR. 
9.3.1.3 
PFS  
PFS (per RECIST 1.1, as assessed by the site Investigator) will be defined as the time from the 
date of first dose of IP (at least 1 IP [durvalumab, paclitaxel, or novel oncology therapy]) until 
the date of objective PD or death (by any cause in the absence of progression) regardless of 
whether the patient withdraws from therapy or receives another anticancer therapy prior to 
progression (ie, date of event or censoring – date of randomization/treatment assignment + 1). 
Patients 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 
patient progresses or dies after 2 or more missed visits, the patient will be censored at the time 
of the latest evaluable RECIST 1.1 assessment prior to the 2 missed visits. If the patient has no 
evaluable visits or does not have baseline data, they will be censored at Day 1 unless they die 
within 2 visits of baseline, then they will be treated as an event with date of death as the event 
date. 
The PFS time will always be derived based on assessment/scan dates and not visit dates. 
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RECIST 1.1 assessments/scans contributing toward a particular visit may be performed on 
different dates. The following rules will be applied: 
• 
The date of progression will be determined based on the earliest of the RECIST 
assessment/scan dates of the component that indicates progression. 
• 
When censoring a patient for PFS, the patient will be censored at the latest of the 
scan dates contributing to a particular overall visit assessment. 
 
RECIST scans that are reported on the eCRF beyond RECIST 1.1-defined PD will be used for 
exploratory analyses only. 
9.3.1.4 
Duration of response  
DoR (per RECIST 1.1 using Investigator assessment) will be defined as the time from the date 
of first documented response (which is subsequently confirmed) until the first date of 
documented progression or death in the absence of PD (ie, date of PFS event or censoring – 
date of first response + 1). The end of response should coincide with the date of progression or 
death from any cause used for the RECIST 1.1 PFS endpoint. 
The time of the initial response will be defined as the latest of the dates contributing toward 
the first visit response of CR or PR. If a patient does not progress following a response, then 
their DoR will be censored at the PFS censoring time. DoR will not be defined for those 
patients who do not have documented response. 
9.3.1.5 
PFS 6 months  
The PFS6 will be defined as the Kaplan-Meier estimate of PFS (per RECIST 1.1 as assessed 
by the site Investigator) at 6 months following date of first dose of IP. 
9.3.1.6 
Overall survival  
OS is defined as the time from the date of first dose of IP until death due to any cause. Any 
patient not known to have died at the time of analysis will be censored based on the last 
recorded date on which the patient was known to be alive.  
Note: Survival telephone calls will be made following the date of DCO for the analysis (these 
contacts should generally occur within 7 days of the DCO). If patients are confirmed to be 
alive or if the death date is post the DCO date, these patients will be censored at the date of 
DCO for the purposes of the CSR; further follow-up for OS may be conducted following CSR 
completion and the findings documented separately. Death dates may be found by checking 
publicly available death registries. 

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9.3.1.7 
Change in tumor size  
The best percentage change from pre-dose in tumor size is the largest decrease (or smallest 
increase) for a patient using RECIST 1.1 assessments. All measurements up until PD or the 
last evaluable assessment will be included in this evaluation. The percentage change in tumor 
size at a specific visit may also be presented and will be defined in the SAP. 
RECIST scans that are reported on the eCRF beyond RECIST 1.1-defined PD will be used for 
exploratory analyses only. 
9.3.2 
Calculation or derivation of safety variables  
9.3.2.1 
Adverse events  
Safety and tolerability will be assessed in terms of AEs (including SAEs), deaths, laboratory 
findings, vital signs, ECGs, ECHO/MUGA scan, and physical examination findings. These 
will be collected for all patients. Data from all cycles of treatment will be combined in the 
presentation of safety data. “On treatment” will be defined as assessments between date of 
start dose and 90 days following discontinuation of IP (ie, the last dose of durvalumab + 
paclitaxel combination therapy, durvalumab + paclitaxel + novel oncology therapy 
combinations, durvalumab + DS-8201a, or durvalumab + Dato-DXd). On-treatment AEs (or 
treatment-emergent AEs) will be defined as any AEs that started after dosing or that started 
prior to dosing and worsened following exposure to the treatment. 
AEs observed up until 90 days following discontinuation of the last dose of study treatment or 
until the initiation of the first subsequent therapy following discontinuation of treatment 
(whichever occurs first) will be used for the reporting of the AE summary tables. This 
approach will more accurately depict AEs attributable to study treatment only because a 
number of AEs up to 90 days following discontinuation of study treatment are likely to be 
attributable to subsequent therapy (if received). However, to assess the longer-term toxicity 
profile, AE summaries will also be produced containing AEs observed up until 90 days 
following discontinuation of the study treatment (ie, without taking subsequent therapy into 
account). Any events in this period that occur after a patient has received further therapy for 
cancer (following discontinuation of study treatment) will be flagged in the data listings. 
The Safety Analysis Set will be used for reporting of safety data. 
A separate data listing of AEs occurring more than 90 days after discontinuation of IP will be 
produced. These events will not be included in AE summaries. 
9.3.2.2 
Safety assessments  
For the change from baseline summaries for vital signs, laboratory data, and physical 
examinations, the baseline value will be the latest result obtained prior to the start of study 
treatment.  

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QTcF will be derived during creation of the reporting database using the reported ECG values 
(RR and QT) using the following formula: 
QTcF = QT/RR^ (1/3) where RR is in seconds 
Corrected calcium product 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) 
The denominator used in laboratory summaries will only include evaluable patients, that is, 
those who had sufficient data to have the possibility of an abnormality. 
For example: 
• 
If a CTCAE criterion involves a change from baseline, evaluable patients would have 
both a pre-dose and at least 1 post-dose values recorded. 
• 
If a CTCAE criterion does not consider changes from baseline to be evaluable, the 
patient need only have 1 post-dose value recorded. 
 
The denominator in vital signs data should include only those patients with recorded data. 
9.3.3 
Calculation or derivation of pharmacokinetic variables (Part 1 only)  
PK variables only apply for Part 1 of the study, except for Dato-DXd in Arms 7 and 8. 
9.3.3.1 
Population pharmacokinetics and exposure-response/safety analysis  
A population PK model may be developed using a non-linear mixed-effects modeling 
approach. The impact of physiologically relevant patient characteristics (covariates) and 
disease on PK will be evaluated. The relationship between the PK exposure and the effect on 
safety and efficacy endpoints may be evaluated. The results of such an analysis will be 
reported in a separate report. The PK, pharmacodynamic, demographic, safety, and efficacy 
data collected in this study may also be combined with similar data from other studies and 
explored using population PK and/or PK-pharmacodynamic methods. 
9.3.3.2 
Pharmacokinetic analysis  
PK concentration data and summary statistics will be tabulated. PK parameters will be 
determined from the raw data. The following PK parameters will be determined after the first 
and steady-state doses: peak and trough concentrations (as data allow). 

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9.3.4 
Immunogenicity analysis (Part 1 only)  
Immunogenicity results will be analyzed descriptively by summarizing the number and 
percentage of patients who develop detectable ADAs against each applicable novel oncology 
therapy (see Section 1.1). The immunogenicity titer will be reported for samples confirmed 
positive for the presence of ADAs. The effect of immunogenicity on PK, pharmacodynamics, 
efficacy, and safety will be evaluated, if the data allow. ADA samples may also be further 
tested for characterization of the ADA response 
9.3.5 
Calculation or derivation of biomarker variables  
Biomarker status, as defined in the exploratory objectives, may be assessed for evaluable 
patients in each cohort according to prespecified criteria that will be detailed in the SAP. 
9.3.6 
Calculation or derivation of pharmacogenetic variables  
In the case of genetic data, only the date that the patient gave consent to participation in the 
genetic research and the date the blood sample was taken from the patient will be recorded in 
the eCRF and database. The genetic data generated from the study will be stored in the 
AstraZeneca Laboratory Information Management System (LIMS) database or other 
appropriate system. This database is a secure database, which is separate from the database 
used for the main study. Some or all of the dataset from the main study may be duplicated 
within the AstraZeneca LIMS database for exploratory
 Data will be reported 
outside the CSR (please see Appendix C). 
9.4 
Statistical analyses  
Analyses will be performed by AstraZeneca or its representative. A comprehensive SAP will 
be developed and finalized before database lock and will describe the patient populations to be 
included in the analyses and procedures for accounting for missing, unused, and spurious data. 
This section is a summary of the planned statistical analyses of the primary and secondary 
endpoints. Any deviations from this plan will be reported in the CSR. 
Descriptive statistics will be used for all variables, as appropriate, and will be presented by 
treatment group. Continuous variables will be summarized by the number of observations, 
mean, standard deviation, median, minimum, and maximum. Categorical variables will be 
summarized by frequency counts and percentages for each category. Unless otherwise stated, 
percentages will be calculated out of the population total for the corresponding treatment arm. 
Baseline will be the last assessment of the variable under consideration prior to the intake of 
the first dose of IP, and the same holds for efficacy variables. 
It is anticipated that data from Arm 2 will be presented as a single cohort. In the event 
potentially material differences are observed in either safety or efficacy outcomes between the 
groups of patients recruited into Arm 2 following CSP Version 3/Version 4 and those 
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recruited to a later version, further exploratory data presentations may be generated for these 
patients. For Arm 2, patients recruited following CSP Version 4 or beyond will be evaluated 
for ORR as per the
design. 
9.4.1 
Safety analyses  
Safety is the primary objective for Part 1 and the secondary objective for Part 2. 
9.4.1.1 
Safety analyses for Part 1  
Safety and tolerability data will be presented by treatment arm using the safety population. 
Data from all cycles of treatment will be combined in the presentation of safety data. 
AEs (both in terms of MedDRA preferred terms and CTCAE grade) will be listed individually 
by patient. The number of patients experiencing each AE will be summarized by treatment 
arm and CTCAE grade. Additionally, data presentations of the rate of AEs per person-years at 
risk may be produced. 
Other safety data will be assessed in terms of clinical chemistry, hematology, and vital signs 
and summarized using appropriate summary statistics. Exposure to durvalumab + paclitaxel 
combination therapy and durvalumab + paclitaxel + novel oncology therapy with or without 
paclitaxel will be summarized. Time on study; time on the combination therapy; and (for 
applicable treatments) dose delays, dose interruptions, and dose reductions will also be 
summarized. At the end of the study, appropriate summaries of all safety data will be 
produced, as defined in the SAP.  
9.4.1.2 
Safety analyses for Part 2  
The Safety Analysis Set will be used to summarize all safety data according to the treatment 
received. Analyses of AEs and other safety data will be the same as those described for Part 1. 
Safety analyses will be based on data pooled from Part 1 and Part 2 in each treatment arm. 
9.4.2 
Efficacy analyses  
9.4.2.1 
Planned Analyses  
Efficacy will be assessed in terms of ORR, PFS, DoR, OS, and PFS6 based on patients pooled 
from Part 1 and Part 2 in each treatment arm (with the exception of Arm 1). Efficacy data will 
also be explored in terms of
status. Results of ORR statistical analysis will be 
presented using 95% exact Clopper-Pearson CIs. 
Table 28 details which endpoints are to be summarized. 
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Table 28 
Pre-planned statistical and sensitivity analyses to be conducted  
Endpoints analyzed 
Notes 
Safety 
Summary statistics for AEs, exposure, laboratory findings, and vital signs: 
Primary analysis for Part 1 for the safety population  
Objective response rate Number and percentage of patients who achieve confirmed ORR as determined by the 
Investigator according to RECIST 1.1 in each cohort are summarized with 95% 
Clopper-Pearson confidence intervals for: 
Key secondary analysis for Part 1 and primary analysis for Part 2 for the FAS 
population using Investigator RECIST 1.1 assessments 
Duration of response 
Summary statistics and KM plot by cohort for:  
Secondary analysis for the FAS population using Investigator RECIST 1.1 assessments 
Progression-free 
survival 
Summary statistics and KM plot by cohort for:  
Secondary analysis for the FAS population using Investigator RECIST 1.1 assessments 
PFS6 
The PFS6, along with its 95% CI, will be summarized (using the Kaplan-Meier curve) 
and presented by treatment arm. 
Secondary analysis for the FAS population 
Overall survival 
Summary statistics and KM plot by cohort for:  
Secondary analysis for the FAS population 
AE  Adverse event; FAS  Full Analysis Set; KM  Kaplan-Meier; ORR  Objective response rate.  
 
9.4.2.1.1 
OBJECTIVE RESPONSE RATE  
The ORR will be based on the programmatically derived RECIST 1.1 result using the 
Investigator-assessed tumor data. The ORR and 95% exact Clopper-Pearson CIs for each 
treatment arm will be utilized to enable decisions to be made regarding whether to expand the 
cohort with an additional
subjects.  
Summaries will be produced that present the number and percentage of patients with a tumor 
response (CR/PR). Overall visit response data will be listed for all patients in the FAS. For 
each treatment arm, best overall response will be summarized.  
9.4.2.1.2 
PROGRESSION-FREE SURVIVAL, DURATION OF RESPONSE, AND OVERALL 
SURVIVAL  
PFS and DoR will be derived for each treatment arm based on the Investigator tumor data. 
Descriptive data will be provided by cohort for PFS, DoR in responding patients, and OS, 
including the associated Kaplan-Meier curves (without any formal comparison of treatment 
arms or p-value attached). 
9.4.2.1.3 
PERCENTAGE CHANGE IN TUMOR SIZE  
The absolute value, change from baseline, and percentage change from baseline in tumor size 
will be summarized using descriptive statistics and presented by actual treatment group. 
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population PK and exposure/response analysis. The population PK analysis and 
exposure/response analyses will be presented separately from the main CSR. 
9.4.4 
Pharmacokinetic/pharmacodynamic relationships  
If the data are suitable, the relationship between PK exposure and efficacy/safety parameters 
may be investigated graphically or using an appropriate data modeling approach. 
9.4.5 
Biomarker data  
Summaries and analyses for exploratory biomarkers may be documented in a separate analysis 
plan and may be reported outside the CSR in a separate report. 
9.4.6 
Methods for multiplicity control  
No adjustment for multiplicity is required for between-treatment-arm comparison, as each arm 
is being evaluated independently. For testing ORR within each arm at the
 the Type I error rate is controlled at the 5% significance level.  
9.5 
analyses  
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 study protocol and letters to 
Investigators. 
An SRC will review the initial safety profile from the novel treatment combination arms in 
Part 1 after
DLT-evaluable patients have completed the first cycle or had a DLT during the 
first cycle and will review safety and tolerability data on an ongoing basis. Additional details 
on the use of the SRC during the Part 1 safety run-in period are provided in Section 4.1.4.3. 
An SRC will continue to be used throughout Part 1 and in Part 2 of the study, as appropriate. 
At the end of Part 1, there will be a planned interim analysis for futility. The
will be applied to each cohort independently
During Part 1, analyses will also be conducted by AstraZeneca in each cohort after 
approximately the
patient (durvalumab + paclitaxel arm) or 30th patient (novel treatment 
combination arms) who received at least 1 dose of study treatment (ie, evaluable patient) has 
had the opportunity for at least 2 on-treatment RECIST assessments or has discontinued due 
to PD or death prior to the second on-study scan. Study continuation onto Part 2 will depend 
on the ORR data for the first
valuable patients in Part 1 for each cohort. Details of these 
analyses will be provided in the SAP. 
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10 
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11 
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 protocol and with the following: 
• 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki as amended at 64th WMA General Assembly, Fortaleza, 
Brazil, October 2013 and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
• 
Applicable ICH Good Clinical Practice (GCP) Guidelines 
• 
Applicable laws and regulations 
 
The protocol, revised protocol, ICF, Investigator’s Brochure, 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 revised protocol 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 patients.  
AstraZeneca will be responsible for obtaining the required authorizations 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. 
The study will be performed in accordance with the AstraZeneca policy on Bioethics and 
Human Biological Samples. 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the investigator to AstraZeneca 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. 
• 
AstraZeneca 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. AstraZeneca will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, IRB/IEC, and 
investigators. 

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• 
In the European Union, the Sponsor will comply with safety reporting requirements 
and procedures as described in the European Clinical Trials Regulation (EU) No 
536/2014. All Suspected Unexpected Serious Adverse Reactions (SUSARs) to 
investigational medicinal product will be reported to the EudraVigilance database 
within the required regulatory timelines. 
• 
For all studies except those utilising medical devices, investigator safety reports must 
be prepared for suspected unexpected serious adverse reactions (SUSAR) according 
to local regulatory requirements and sponsor policy and forwarded to investigators as 
necessary. 
• 
Adherence to European Medical Device Regulation 2017/745 for clinical device 
research (if applicable), and all other applicable local regulations. 
• 
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from AstraZeneca will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. 
 
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. 
• 
AstraZeneca will comply with country-specific regulatory requirements relating to 
serious breach reporting to the regulatory authority, IRB/IEC, and investigators.  
− 
Where the EU Clinical Trials Regulation 536/2014 applies, AstraZeneca has in 
place processes to enter details of serious breaches into the European Medicines 
Agency CTIS. It is important to note that redacted versions of serious breach 
reports will be available to the public via CTIS. 
• 
If any (potential) serious breach occurs in the course of the study, investigators or 
other site personnel will inform the appropriate AstraZeneca representatives 
immediately. 
• 
In certain regions/countries, AstraZeneca has a legal responsibility to notify both the 
local regulatory authority and other regulatory agencies about such breaches. 
• 
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. 

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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 1 year after completion of the study. 
A-3 
Informed consent process  
A pre-screen ICF is to be signed by patients in Arm 8 who do not have a prior determination 
of positive PD-L1 status, to permit determination of PD-L1 expression status by local testing 
prior to the 28-day screening window. When a pre-screen ICF is signed, the main ICF should 
not be signed until PD-L1 positive expression status has been established. 
The Investigator or his/her representative will explain the nature of the study to the patient or 
his/her legally authorized representative and answer all questions regarding the study.  
Patients 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. 
Patients or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, ICH 
guidelines, privacy and data protection requirements, where applicable, and the IRB/IEC or 
study center.  
The medical record must include a statement that written informed consent was obtained 
before the patient was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
Patients 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 patient or the patient’s legally authorized 
representative.  
If a patient declines to participate in any voluntary exploratory genetic research component of 
the study, there will be no penalty or loss of benefit to the patient, and he/she will not be 
excluded from other aspects of the study. 
If a patient’s partner becomes pregnant during or within 90 days after the last dose of study 
treatment, the partner is asked to sign the "Adult Study Informed Consent Form for Pregnant 
Partners of Study Patients" and provide information about the pregnancy accordingly. 

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The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research. The Investigator or authorized designee will 
explain to each patient the objectives of the exploratory research. Patients will be told that 
they are free to refuse to participate and may withdraw their consent at any time and for any 
reason during the storage period. The patient will give a separate agreement to allow any 
remaining specimens to be used for exploratory research. Patients who decline to participate 
in this optional research will indicate this in the ICF. If a patient withdraws consent to the use 
of donated biological samples, the samples will be disposed of/destroyed, and the action 
documented. If samples already have been analyzed at the time of the request, AstraZeneca 
will not be obliged to destroy the results of this research. 
A-4 
Data protection  
The ICF will incorporate wording that complies with relevant data protection and privacy 
legislation. In some cases, such wording will be in a separate accompanying document. 
AstraZeneca will not provide individual genotype results to patients, their family members, 
their general physician, any insurance company, any employer, or any other third party, unless 
required to do so by law. 
Precautions are taken to preserve confidentiality and prevent genetic data from being linked to 
the identity of the patient. In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a patient. For example, in the case of a 
medical emergency, an AstraZeneca Physician or an Investigator might know a patient’s 
identity and might also have access to his or her genetic data. Also, regulatory authorities may 
require access to the relevant files. Even so, the patient’s medical information and the genetic 
files would remain physically separate. 
Each patient will be assigned a unique identifier by the Sponsor. Any patient records or 
datasets transferred to the Sponsor will contain only the identifier; patient names or any 
information which would make the patient identifiable will not be transferred.  
The patient 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 must also be 
explained to the patient.  
The patient must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
A-5 
Committees` structure  
The safety of all AstraZeneca clinical studies is closely monitored on an on-going basis by 
AstraZeneca representatives in consultation with Patient Safety. Issues identified will be 

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addressed; for instance, this could involve amendments to the Clinical Study Protocol and 
letters to Investigators. 
A-6 
Dissemination of clinical study data  
Any results both technical and lay summaries for this trial, will be submitted to EU CTIS 
within a year from global End of Trial Date in all participating countries, due to scientific 
reasons, as otherwise statistical analysis is not relevant. 
A description of this clinical study will be available on http://astrazenecaclinicaltrials.com 
and http://www.clinicaltrials.gov as will the summary of the main study results when they are 
available. The clinical study and/or summary of main study results may also be available on 
other websites according to the regulations of the countries in which the main study is 
conducted. 
A-7 
Data quality assurance  
All patient data relating to the study will be recorded on printed or electronic 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 agency inspections and provide direct access to source data documents.  
Monitoring details describing strategy, including definition of study-critical data items and 
processes (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 included in the Monitoring Plan(s). 
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(s). 
AstraZeneca or designee is responsible for the data management of this study including 
quality checking of the data.  
AstraZeneca assumes accountability for actions delegated to other individuals (eg, Contract 
Research Organisations). 

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Study monitors will perform ongoing source data verification as per the Monitoring Plan(s) to 
confirm that data entered into the eCRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of patients are being 
protected; and that the study is being conducted in accordance with the currently approved 
protocol 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 Global retention and Disposal (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 patient and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. 
Data reported on the CRF 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. 
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 Closure  
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 supplies have 
been collected and a study-site closure monitoring 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. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but 
are not limited to: 

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• 
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/EC 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 contract research 
organization(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. 
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 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating 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 event definitions and additional safety information  
B-1 
Definition of adverse events  
An adverse event is the development of any untoward medical occurrence (other than 
progression of the malignancy under evaluation) in a patient or clinical study patient 
administered a medicinal product and which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable 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 medicinal product.  
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 treatment has been administered. 
B-2 
Definitions of serious adverse event  
A serious adverse event (SAE) is an AE occurring during any study phase (ie, run-in, 
treatment, washout, follow-up), that fulfills one or more of the following criteria: 
• 
Results in death 
• 
Is immediately life-threatening 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital abnormality or birth defect 
• 
Is an important medical event that may jeopardize the patient or may require medical 
treatment to prevent one of the outcomes listed above 
 
Regulatory reporting requirements for serious adverse event 
• 
Prompt notification by the Investigator to the Sponsor of an SAE is essential so that 
legal obligations and ethical responsibilities toward 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 local 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, Institutional 
Review Boards (IRBs)/Independent Ethics Committees (IECs), and Investigators. 
• 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and Sponsor policy 
and forwarded to Investigators as necessary. 

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• 
An Investigator who receives safety report describing an SAE or other safety 
information (eg, summary of listing of SAEs) from the Sponsor will review and then 
file it along with the Investigator’s Brochure and will notify the IRB/IEC if 
appropriate according to local requirements. 
 
B-3 
Life threatening  
‘Life-threatening’ means that the patient 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 
patient’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). 
B-4 
Hospitalization  
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal edema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the patient was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study. 
B-5 
Important medical event or medical treatment  
Medical and scientific judgement 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, hospitalization, disability or incapacity but may jeopardize the patient 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 
judgement 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 anemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalization 
• 
Development of drug dependency or drug abuse 
 

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B-6 
CTCAE grade  
The grading scales found in the revised NCI CTCAE latest version will be utilized for all 
events with an assigned CTCAE grading. For those events without assigned CTCAE grades, 
the criteria recommended in the CTCAE manual that converts severity levels into CTCAE 
grades should be used. A copy of the CTCAE can be downloaded from the Cancer Therapy 
Evaluation Program website (http://ctep.cancer.gov). The applicable version of CTCAE 
should be described clearly. 
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B-2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Appendix B-2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Appendix B-2. 
B-7 
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 patient 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 etiology 
such as the underlying disease, other drugs, 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 
re-challenge. 
• 
Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship. 
 
In difficult cases, other factors could be considered such as: 
• 
Is this a recognized feature of overdose of the drug? 
• 
Is there a known mechanism? 

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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. 
The causality assessment is performed based on the available data including enough 
information to make an informed judgment. With limited or insufficient information in the 
case, it is likely that 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-8 
Medication error, drug abuse, and drug misuse  
Medication error 
For the purposes of this clinical study a medication error is an unintended failure or mistake 
in the treatment process for an IMP or AstraZeneca NIMP 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 recognized that could have led to an error 
 
Examples of events to be reported in clinical studies as medication errors: 
• 
Drug name confusion 
• 
Dispensing error (eg, medication prepared incorrectly, even if it was not actually 
given to the participant) 
• 
Drug not administered as indicated, eg, 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 RTSM (IRT) errors) 
• 
Wrong drug administered to participant (excluding RTSM (IRT) errors) 

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Examples of events that do not require reporting as medication errors in clinical studies: 
• 
Errors related to or resulting from RTSM (IRT), including those which 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 
  
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 IMP/study intervention or AstraZeneca NIMP 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 involves 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 drug is used with the intent of getting a perceived reward (by the study 
participant or a person not enrolled in the study) 
• 
The drug 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 (by a study participant) of IMP/study 
intervention or AstraZeneca NIMP for medicinal purposes outside of the authorized product 
information, or for unauthorized IMPs/study interventions or AstraZeneca NIMPs, outside the 
intended use as specified in the protocol, and includes deliberate administration of the product 
by the wrong route. 
Events of drug misuse, with or without associated AEs, are to be captured and forwarded to 
the data entry site (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: 

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• 
The drug is used with the intention to cause an effect in another person 
• 
The drug is sold to other people for recreational purposes  
• 
The drug is used to facilitate assault in another person 
• 
The drug is deliberately administered by the wrong route 
• 
The drug is split in half because it is easier to swallow, when it is stated in the 
protocol that it must be swallowed whole 
• 
Only half the dose is taken because the study participant feels that they were feeling 
better when not taking the whole dose 
• 
Someone who is not enrolled in the study intentionally takes the drug. 

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Appendix C 
Handling of human biological samples  
C-1 
Chain of custody of biological samples  
A full chain of custody is maintained for all samples throughout their lifecycle. 
The Investigator at each center keeps full traceability of collected biological samples from the 
patients while in storage at the center until shipment or disposal (where appropriate). 
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 documentation of receipt of arrival. 
AstraZeneca will keep oversight of the entire life cycle 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 AZ-assigned Biobanks and will be 
registered by the AstraZeneca Biobank Team during the entire life cycle. 
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  
AstraZeneca ensures that biological samples are returned to the source or destroyed at the end 
of a specified period as described in the informed consent. 
If a patient withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented. If samples are already analyzed, 
AstraZeneca is not obliged to destroy the results of this research. 
As collection of the biological sample(s) is an optional part of the study, then the patient may 
continue in the study. 
The Investigator: 
• 
Ensures patients’ withdrawal of informed consent to the use of donated samples is 
notified immediately to AstraZeneca 
• 
Ensures that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented 
• 
Ensures the organization(s) holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed of/destroyed, the action 
documented, and the signed document returned to the study site 

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• 
Ensures that the patient and AstraZeneca are informed about the sample disposal. 
 
AstraZeneca ensures the organizations holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site. 
C-3 
International Airline Transportation Association (IATA) 6.2 
guidance document  
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES 
International Airline Transportation Association (IATA) classifies biohazardous agents into 
3 categories 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.htm). For 
transport purposes the classification of infectious substances according to risk groups was 
removed from the Dangerous Goods Regulations in the 46th edition (2005). Infectious 
substances are now classified either as Category A, Category B or Exempt. There is no direct 
relationship between Risk Groups and Categories A and B. 
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 eg, Ebola, Lassa fever virus: 
• 
are to be packed and shipped in accordance with IATA Instruction 602. 
 
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are eg, Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus types 1 and 2. They are assigned the following UN number 
and proper shipping name: 
• 
UN 3373 – Biological Substance, Category B 
• 
are to be packed in accordance with UN3373 and IATA 650 
 
Exempt - all other materials with minimal risk of containing pathogens 
• 
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 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.htm) 
• 
Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content 

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• 
IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as applicable 
• 
Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and 
packaging/containment materials at all times. The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport 
is used. 
 

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only use this information for health related research purposes. Researchers may see summary 
results but they will not be able to see individual patient data or any personal identifiers.  
Some or all of the clinical datasets from the main study may be merged with the
in a suitable secure environment separate from the clinical database. 
Statistical methods and determination of sample size 
The number of patients that will agree to participate in the
is unknown. It is 
therefore not possible to establish whether sufficient data will be collected to allow a formal 
statistical evaluation or whether only descriptive statistics will be generated. A Statistical 
Analysis Plan may be prepared where appropriate. 
CCI 
CCI 

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Appendix E 
Actions required in cases of increases in liver biochemistry 
and evaluation of Hy’s law  
E-1 
Follow-up  
E-2 
Introduction  
This Appendix describes the process to be followed in order to identify and appropriately 
report Potential Hy’s Law (PHL) cases and Hy’s Law (HL) cases. It is not intended to be a 
comprehensive guide to the management of elevated liver biochemistries. Specific guidance 
on managing liver abnormalities can be found in the Dosing Modification and Toxicity 
Management Guidelines (see Section 8.4.6). 
During the course of the study, the Investigator will remain vigilant for increases in liver 
biochemistry. The Investigator is responsible for determining whether a subject meets 
potential 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 adverse event (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 the 
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 drug-induced liver injury (DILI) caused by the investigational medicinal product 
(IMP).  
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting serious adverse events (SAEs) and AEs according to the outcome of the review and 
assessment in line with standard safety reporting processes. 
E-3 
Definitions  
Potential Hy’s law 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥3 × upper limit of 
normal (ULN) together with TBL ≥2 × ULN at any point during the study following the start 
of study medication irrespective of an increase in alkaline phosphatase (ALP).  

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Hy’s law 
AST or ALT ≥3 × ULN together with TBL ≥2 × ULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, 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. 
E-4 
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 patient who meets any of the following identification criteria in 
isolation or in combination: 
• 
ALT ≥3 × ULN 
• 
AST ≥3 × ULN 
• 
TBL ≥2 × ULN 
 
The Investigator will, without delay, review each new laboratory report and, if the 
identification criteria are met, will: 
• 
Determine whether the patient meets PHL criteria (see Appendix E-3 for definition) 
by reviewing laboratory reports from all previous visits 
• 
Promptly enter the laboratory data into the laboratory electronic case report form 
(eCRF) 
 
E-4.1 
Potential Hy’s law criteria not met  
If the patient does not meet PHL criteria, the Investigator will: 
• 
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the clinical study protocol. 
 
E-4.2 
Potential Hy’s law criteria met  
If the patient does meet PHL criteria, the Investigator will: 
• 
Determine whether PHL criteria were met at any study visit prior to starting study 
treatment (see Section 8.4 Safety Reporting) 
• 
Notify the AstraZeneca representative, who will then inform the central study team  

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• 
Within 1 day of PHL criteria being met, the Investigator will report the case as an 
SAE of potential Hy’s law; serious criteria “important medical event” and causality 
assessment “yes/related” according to CSP process for SAE reporting. 
• 
For patients who met PHL criteria prior to starting IMP, the Investigator is not 
required to submit a PHL SAE unless there is a significant change* in the patients’ 
condition 
• 
The Study Clinical Lead contacts the Investigator, to provide guidance, to discuss, 
and to agree to an approach for the study patients’ follow-up and the continuous 
review of data. Subsequent to this contact, the Investigator will: 
− 
Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels or as long as medically 
indicated. Complete follow-up SAE Form as required. 
− 
Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Study Clinical Lead.  
− 
Complete the 3 Liver eCRF Modules as information becomes available  
• 
Unless an alternate etiology for the elevated liver enzymes is known, report as an 
SAE using standard reporting procedures 
 
*A “significant” change in the patient’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. 
E-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 
IMP, to ensure timely analysis and reporting to health authorities within 15 calendar days 
from the date PHL criteria were 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 CRF 
• 
If the alternative explanation is an AE/SAE, update the previously submitted 
Potential Hy’s Law SAE and AE CRFs accordingly with the new information 
(reassessing event term; causality and seriousness criteria) following the AZ standard 
processes. 
 
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP: 
• 
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 Potential Hy’s Law, 
(report term now “Hy’s Law case”) ensuring causality assessment is related to IMP 
and seriousness criteria is medically important, according to CSP process for SAE 
reporting. 
• 
Continue follow-up and review according to 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. 
 
E-6 
Actions required when potential Hy’s law criteria are met 
before and after starting study treatment  
This section is applicable to patients with liver metastases who meet PHL criteria on study 
treatment, having previously met PHL criteria at a study visit prior to starting study treatment. 
At the first on-study treatment occurrence of PHL criteria being met, the Investigator will 
determine if there has been a significant change* in the patient’s condition compared with the 
last visit where PHL criteria were met. 
• 
If there is no significant change, no action is required 

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• 
If there is a significant change, notify the AstraZeneca representative, who will 
inform the central Study Team, then follow the subsequent process described in 
Appendix E-4.2. 
 
*A “significant” change in the patient’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. 
E-7 
Actions required for repeat episodes of potential Hy’s law  
This section is applicable when a patient meets PHL criteria on study treatment and has 
already met PHL criteria at a previous on-study treatment 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 patient meet PHL criteria prior to starting study 
treatment and at first on-study treatment visit, as described in Appendix E-6? 
If No: Follow the process described in Appendix E-4.2. 
If Yes: Determine if there has been a significant* change in the patient’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 Appendix E-4.2. 
*A “significant” change in the patient’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. 

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Appendix F 
Guidelines for evaluation of objective tumor response using 
RECIST 1.1 Criteria (Response Evaluation Criteria in 
Solid Tumors)  
Introduction 
This appendix details the implementation of Response Evaluation Criteria in Solid Tumors 
v1.1 (RECIST 1.1) guidelines (Eisenhauer et al 2009). Investigator assessments will use the 
RECIST 1.1 guidelines described in this appendix. Additional special guidance is provided for 
evaluation of scans collected after a RECIST 1.1-defined radiological progression. 
Imaging modalities and acquisition specifications for RECIST 1.1  
A summary of the imaging modalities that can be used for tumor assessment of target lesions 
(TLs), non-target lesions (NTLs), and new lesions (NLs) is provided in Table 29. 
Table 29 
Summary of imaging modalities for tumor 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) 
FDG-PET/CT 
CT  Computed tomography; MRI  Magnetic resonance imaging; FDG-PET  18F-Fluoro-deoxyglucose positron 
emission tomography 
 
CT and MRI  
Computed tomography (CT) with intravenous (IV) contrast, is the preferred imaging modality, 
and magnetic resonance imaging (MRI) with IV contrast being acceptable should CT be 
contraindicated, to generate reproducible anatomical images for tumor 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, tumor assessor (eg, radiologist), and tumor 
assessment method (eg, RECIST 1.1) are used consistently for each patient throughout the 
study. The use of the same scanner for serial scans is recommended, if possible. It is important 
to follow the image collection/tumor assessment schedule as closely as possible (refer to the 
Clinical Study Protocol [CSP] Schedule of Assessments), 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 or symptoms of 

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progression), and the patient 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 artifacts (heart, major blood 
vessels, and 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 or 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 tumor evaluation are 
anatomic coverage, contrast administration, slice thickness, and reconstruction interval. 
a. Anatomic coverage: Optimal anatomic coverage for most solid tumors is the
 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 patients. Because a lesion 
later identified in a body part not scanned at baseline would be considered as a new lesion 
representing PD, careful consideration should be given to the extent of imaging coverage 
at baseline and at subsequent follow-up timepoints. This will enable better consistency 
not only of tumor measurements but also identification of a new disease. 
Required anatomical regions to be imaged for assessment of tumor burden (TLs and/or 
NTLs) at baseline and follow-up visits vary according to the study, and these are specified 
in the main CSP (eg, Schedule of Assessments). Examples include the following: 
− 
IV contrast-enhanced CT of
(including the
− 
Non-contrast CT of
and IV contrast enhanced
(including the 
− 
IV contrast-enhanced CT or MRI of
− 
IV contrast-enhanced MRI (preferred) or CT o
For
imaging, the following are scanning options in decreasing 
order of preference, with additional options (2 to 4) when patients have sensitivity to IV 
contrast or have compromised renal function: 
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− 
CT with IV CT contrast (most preferred) 
− 
CT without IV-contrast +
MRI with IV MRI contrast, if 
CT IV contrast (iodine-based) is medically contraindicated at any time during the 
study 
− 
CT without IV contrast, if both IV CT and MRI 
contrast are medically contraindicated, or the patient has compromised renal 
function 
− 
MRI with IV MRI contrast, if CT cannot be performed 
at any time during the study 
b. IV contrast administration: Optimal visualization and measurement of metastases in 
solid tumors 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 tumor lesions are demonstrated to best effect, and a consistent method is used on 
subsequent examinations for any given patient. Oral contrast is recommended to help 
visualize and differentiate structures in
 
c. Slice thickness and reconstruction interval: It is recommended that CT or MRI scans be 
acquired or reconstructed as contiguous (no gap) with
mm slice thickness throughout 
the entire anatomic region of interest for optimal lesion measurements. However, a slice 
thickness of
mm is preferred. Exceptionally, particular institutions may perform 
medically acceptable scans at slice
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. 
Chest X-ray 
Chest X-ray assessment will not be used for assessment of TL. Chest X-ray can, however, be 
used to assess NTL 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. 
Plain X-ray  
Plain X-ray may be used as a method of assessment for bone NTL and to identify the presence 
of new bone lesions.  
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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 NTL 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, 
X-ray) of the same anatomical region shall not be the only trigger for PD assessment at that.  
FDG-PET/CT  
18F-Fluoro-deoxyglucose positron emission tomography/CT (FDG-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 in the baseline or a prior FDG-
PET scan or in a location corresponding to an NL on a companion CT/MRI collected close in 
time to the FDG-PET scan. The positron emission tomography (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 FDG-PET scan available for comparison, 
and no evidence of NLs on companion CT/MRI scans, then follow-up CT/MRI assessments 
should continue per the regular imaging schedule in order to verify the unequivocal presence 
of NLs. 
At present, low dose or attenuation correction CT portions of a combined FDG-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 tumor 
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, and then the CT portion of the PET/CT can be 
used for RECIST 1.1 tumor 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. 
 
 
1 A positive FDG-PET scan lesion should be reported only when an uptake (eg, standardized uptake value) 
greater than twice that of the surrounding tissue or liver is observed. 

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Ultrasound  
Ultrasound examination will not be used for RECIST 1.1 assessment of tumors as it is not a 
reproducible acquisition method (operator-dependent), is subjective in interpretation, and may 
not provide an accurate assessment of true tumor size. Tumors identified by ultrasound will 
need to be assessed by correlative CT or MRI anatomical scan. 
Other Tumor Assessments  
Clinical examination  
Clinical examination of skin/surface lesions (by visual inspection or manual palpation) will 
not be used for RECIST 1.1 assessments. Tumors identified by clinical examination will need 
to be assessed by correlative CT or MRI anatomical scans. 
Endoscopy and laparoscopy  
Endoscopy and laparoscopy will not be used for tumor assessments, as they are not validated 
in the context of tumor assessment. 
Histology and cytology 
Histology or tumor markers on tumor biopsy samples will not be used as part of the tumor 
response assessment per RECIST 1.1.  
Results of cytological examination for the neoplastic origin of any effusion (eg, ascites, 
pericardial effusion, or pleural effusion) that appears or worsens during the study will not be 
used as part of the tumor response assessment per RECIST 1.1.  
Furthermore, an overall assessment of complete response (CR; all other disease disappears or 
reverts to normal) would be changed to PR if an effusion remains present radiologically. 
Measurability of Tumor Lesions at Baseline 
RECIST 1.1-measurable lesions at baseline: 
It is a tumor 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. 
 
 
2 The short axis is defined as the longest in-plane axis perpendicular to long axis. 

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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, or pericardial effusion 
− 
Inflammatory breast disease 
− 
Lymphangitic involvement of the 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 baseline3). 
• 
Previously irradiated lesions4 
• 
Brain metastasis 
 
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 bone 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 patient, these should be selected over 
cystic lesions as TLs. 
 
RECIST 1.1 Target Lesion 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 
 
 
3 Lymph nodes with <10 mm short axis diameter are considered non-pathological and should not be recorded or 
followed as NTLs. 
4 Localized post-radiation changes which affect lesion sizes 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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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 they should be those that lend themselves to reproducible repeated measurements. It 
may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement, in which circumstance the next largest lesion, which can be measured 
reproducibly, should be selected. 
Lymph nodes, in any location (local or regional and distant), are collectively considered as a 
single organ, with a maximum of 2 lymph node locations as TLs. A bilateral organ (eg, 
adrenal glands), a segmented organ (eg, liver), or a multi-lobed 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 millimeters. At baseline the sum of the diameters for all TL will be calculated and 
reported as the baseline sum of diameters. At follow-up visits, the sum of diameters for all TL 
will be calculated and reported as the follow-up sum of diameters. 
Special cases for target lesion assessment at baseline: 
• 
For TL 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. 
• 
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. 
• 
Tumor lesions selected for fresh screening biopsy should not be selected as TLs, 
unless imaging occurred at least approximately 2 weeks after biopsy, allowing time 
for healing.  
 
RECIST 1.1 Non-Target Lesion 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. 
Evaluation of Tumor Response and Progression  
RECIST 1.1 target lesion assessment at follow-up 
This section defines the criteria used to determine objective tumor visit response for 
RECIST 1.1-defined TLs. The imaging modality, location, and scan date of each TL identified 

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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 millimeters. The sum of the diameters for all TL at each follow-up visit will be 
compared to the baseline sum of diameters (for response or SD) or to the smallest prior (nadir) 
sum of diameters (for progression).  
Special cases for target lesion 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, then record the sum of the diameters of those parts.  
• 
If 2 or more TLs merge, then the sum of the diameters of the combined lesion should 
be recorded for 1 of the lesions and 0 mm recorded for the other lesion(s). If the 
merged 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 case report form 
will trigger an overall visit response of PD. 
• 
When a TL has had any intervention eg, definitive radiotherapy, embolization, 
surgery, transarterial chemoembolization, etc, during the study, the size of the TL 
should still be provided where possible and the intervention recorded in the 
RECIST 1.1 case report form 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. 
 

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Table 30 
RECIST 1.1 evaluation of target lesions  
Complete response (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. 
Partial response (PR) 
At least a 30% decrease in the sum of the diameters of TL, taking as 
reference the baseline sum of diameters 
Stable disease (SD) 
Neither sufficient decrease in sum of diameters to qualify for PR nor 
sufficient increase to qualify for PD 
Progression of disease (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 also demonstrate an 
absolute increase of at least 5 mm from nadir. 
Not evaluable (NE) 
Only relevant if any of the TLs at follow-up were not assessed or not 
evaluable (e.g. missing anatomy) or had a lesion intervention at this 
visit. Note: if the sum of diameters meets the PD criteria, PD 
overrides not evaluable as a TL response 
Not applicable (NA) 
Only relevant if no TLs present at baseline 
TL  Target lesion. 
 
RECIST 1.1 Non-Target Lesion Assessment at Follow-Up 
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at 
baseline. 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 tumor burden has increased sufficiently to merit unequivocal progression by 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. 

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Table 31 
RECIST 1.1 evaluation of non-target lesions  
Complete response (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 NTL. 
Progression (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. 
Not evaluable (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 during the visit. 
Note: for patients 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 (NA) 
Only relevant if no NTLs present at baseline 
PD  Progression of disease; NTL  Non-target lesion; TL  Target lesion. 
 
RECIST 1.1 New Lesion Identification at Follow-Up 
Details including the imaging modality, the date of scan, and the location of any NLs will be 
recorded in the case report form. The presence of 1 or more NLs is assessed as progression. 
The finding of an NL should be unequivocal: ie, not attributable to differences in scanning 
technique, change in imaging modality, or findings thought to represent something other than 
tumor. If an NL is equivocal, for example because of its small size, the treatment and tumor 
assessments should be continued until the previously (pre-existing) new lesion 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 a NL and will indicate PD. 
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 32. 

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Table 32 
RECIST 1.1 overall visit response  
Target lesions 
Non-target lesions 
New lesions 
Overall visit response 
CR 
CR 
No 
CR 
CR 
NA 
No 
CR 
NA 
CR 
No 
CR 
CR 
Non-CR/non-PD  
No 
PR 
CR 
NE 
No  
PR 
PR 
Non-PD, non-NE, or non-NA 
No 
PR 
SD  
Non-PD, non-NE, or non-NA 
No 
SD 
NA 
Non-CR/non-PD 
No 
SD (Non-CR/non-PDa) 
NE 
Non-PD, non-NE, or non-NA 
No 
NE 
NA 
NE 
No 
NE 
NA 
NA 
No 
NED 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
a 
Non-CR/non-PD for overall response if only NTLs (no TLs) are present at baseline. 
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; PR  Partial response; SD  Stable disease; PD  Progression of disease; NA  Not 
applicable (only relevant if there were no target lesions at baseline or no non-target lesions at baseline); NE  Not 
evaluable; NED  No evidence of diseases (only relevant if there were neither target lesions nor non-target lesions 
at baseline); NTL  Non-target lesion; TL  Target lesion.  
 
The following overall visit responses are possible depending on the extent of tumor disease at 
baseline: 
• 
For patients with TLs (at baseline): CR, PR, SD, PD, or NE 
• 
For patients with NTLs only (at baseline): CR, Non-CR/Non-PD, PD, or NE 
• 
For patients with no disease at baseline: no evidence of disease (available as an 
option in the electronic case report form), PD, or NE 
 
Evaluation of Scans Subsequent to RECIST 1.1-Defined Progression 
A follow-up scan is requested at least
after
and no longer than the next regularly scheduled imaging visit. The follow-up 
scans provide additional information to the Investigator for patient management and further 
treatment decisions, and since the published RECIST 1.1 guidelines (Eisenhauer et al 2009) 
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Appendix G 
International Airline Transportation Association (IATA) 6.2 
guidance document  
Labelling and shipment of biohazard samples 
International Airline Transportation Association (IATA) classifies biohazardous agents into 
3 categories. For transport purposes the classification of infectious substances according to 
risk groups was removed from the Dangerous Goods Regulations (DGR) in the 46th edition 
(2005). Infectious substances are now classified either as Category A, Category B or Exempt. 
There is no direct relationship between Risk Groups and categories A and B. 
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 eg, Ebola, Lassa fever virus: 
• 
are to be packed and shipped in accordance with IATA Instruction 602. 
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are eg, Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus (HIV) types 1 and 2. They are assigned the following UN 
number and proper shipping name: 
• 
UN 3373 – Biological Substance, Category B 
• 
are to be packed in accordance with UN3373 and IATA 650 
Exempt - all other materials with minimal risk of containing pathogens 
• 
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  
• 
Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content 
• 
IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as applicable 
• 
Samples routinely transported by road or rail are patient to local regulations which 
require that they are also packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and 
packaging / containment materials at all times. The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport 
is used. 
 

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Appendix H 
National Institute of Allergy and Infectious Disease and Food 
Allergy and Anaphylaxis Network guidance for anaphylaxis 
diagnosis  
The National Institute of Allergy and Infectious Disease and Food Allergy and Anaphylaxis 
Network define anaphylaxis as a serious allergic reaction that is rapid in onset and may cause 
death. They recognize 3 categories of anaphylaxis, with criteria designated to capture from 
80% of cases (category 1) to >95% of all cases of anaphylaxis (for all 3 categories). 
Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal 
tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula) AND 
AT LEAST ONE OF THE FOLLOWING: 
a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced 
peak expiratory flow [PEF], hypoxemia) 
b. Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction 
(eg, hypotonia [collapse], syncope, incontinence) 
 
Two or more of the following that occur rapidly after exposure to a likely allergen for that 
patient (minutes to several hours): 
a. Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen 
lips-tongue-uvula) 
b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia) 
c. Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence) 
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting) 
 
Reduced BP after exposure to known allergen for that patient (minutes to several hours): 
a. Infants and children: low systolic BP (age-specific) or greater than 30% decrease 
in systolic BP 
b. Adults: systolic BP of less than 90 mmHg or greater than 30% decrease from that 
person’s baseline 
 
Reference: 
Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson FN Jr, Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: summary report - 
second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol 2006;117:391-7. 

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Appendix I 
Guidance for management of specific adverse events in 
studies of capivasertib was removed to an Annex 

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Appendix J 
Guidance for management of specific adverse events in 
studies of selumetinib was removed  
 
 
 

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Appendix K 
Guidance regarding potential interactions of capivasertib 
with concomitant medications  
Drugs that may influence capivasertib pharmacokinetics 
Based on results from in vitro studies, capivasertib is a substrate of cytochrome P450 
(CYP)3A4, although data suggests that glucuronidation may be the major metabolic route. 
Co-administration of some CYP3A4 inhibitors may increase exposure to capivasertib and 
hence potentially affect toxicity, while CYP3A4 inducers may decrease the exposure to 
capivasertib and may potentially affect efficacy. 
The following list (Table 33) is not intended to be exhaustive, and a similar restriction will 
apply to other agents that are known to modulate CYP3A4 activity. Appropriate medical 
judgment is required. Please contact AstraZeneca with any queries you have on this issue. 
Table 33 
CYP3A4-interacting medication that should be avoided or used with 
caution  
Medication 
Recommendation 
Rationale 
Clarithromycin 
Cobicistat 
Itraconazole 
Ketoconazole 
Nefazodone 
Posaconazole  
Protease inhibitors (ritonavir, 
saquinavir, indinavir, tipranavir, 
telaprevir, elvitegravir, lopinavir, 
nelfinavir, and boceprevir) 
Telithromycin  
Troleandomycin 
Voriconazole  
Should be avoided 2 weeks 
prior to capivasertib 
administration and for 2 days 
following discontinuation of 
capivasertib. 
Potent CYP3A4 inhibitors, 
which may increase the 
capivasertib exposure. 
Carbamazepine  
Enzalutamide  
Phenobarbital  
Phenytoin  
Rifabutin  
Rifampicin 
Mitotane 
St John’s wort 
Should be avoided 2 weeks 
(3 weeks for St John’s wort 
and 4 weeks for 
enzalutamide) prior to 
capivasertib administration.  
Potent CYP3A4 inducers, 
which may reduce the 
capivasertib exposure.  

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Medication 
Recommendation 
Rationale 
Aprepitant 
Diltiazem 
Erythromycin  
Fluconazole  
Verapamil  
May be used with caution.a 
Moderate CYP3A4 inhibitors 
which might increase the 
capivasertib exposure. 
a 
Drugs are permitted, but caution should be exercised, and patients monitored closely for possible drug 
interactions. Please refer to full prescribing information for all drugs prior to co-administration with 
capivasertib.  
 
Drugs that may be influenced by capivasertib 
There are currently no data confirming that there are any pharmacokinetic (PK) interactions 
between capivasertib and CYP3A4, CYP2D6, or CYP2C9 substrates. Likewise, there are no 
confirmed interactions with MATE1 or OCT2 substrates. The potential interactions detailed 
below (Table 34) are considered on the basis of pre-clinical data and physiologically-based 
PK modelling. The following list is not intended to be exhaustive, and a similar restriction will 
apply to other agents that are known to be sensitive to CYP3A4, CYP2D6, and/or CYP2C9 
metabolism and/or MATE1 or OCT2 transport and have a narrow therapeutic window. 
Appropriate medical judgment is required. Please contact AstraZeneca with any queries you 
have on this issue. 
Table 34 
CYP3A4, CYP2D6, or CYP2C9 substrates that should be avoided or 
used with caution  
Medication 
Recommendation 
Rationale 
Alfentanil  
Atorvastatin 
Carbamazepine 
Cerivastatin 
Cyclosporin 
Diergotamine 
Ergotamine 
Fentanyl 
Lovastatin 
Simvastatin 
Sirolimus  
Tacrolimus 
Should be avoided 1 week prior 
to capivasertib administration 
and for 1 week following 
discontinuation of capivasertib. 
CYP3A4 substrates, whose 
exposure may be increased 
by capivasertib. 

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Medication 
Recommendation 
Rationale 
Amitriptyline 
Atomoxetine  
Desipramine 
Doxepin 
Metoprolol 
Nefazodone 
Nebivolol 
Perphenazine 
Tolterodine 
Trimipramine 
Tropisetron 
Should be avoided 1 week prior 
to capivasertib administration 
and for 1 week following 
discontinuation of capivasertib. 
CYP2D6 substrates, whose 
exposure may be increased 
by capivasertib. 
Haloperidol 
Tramadol 
Should be avoided 1 week prior 
to capivasertib administration 
and for 1 week following 
discontinuation of capivasertib. 
Combined CYP3A4 and 
CYP2D6 substrates, whose 
exposure may be increased 
by capivasertib. 
Alprazolam  
Domperidone 
Erythromycin  
Felodipine  
Isradipine 
Midazolam  
Methylprednisolone 
Nifedipine  
Pimozide  
Quinidine 
Sertraline 
Tamoxifen 
Trazodone  
Triazolam 
May be used with caution.a 
CYP3A4 substrates, whose 
exposure may be increased 
by capivasertib. 
Fluoxetine 
Paroxetine 
Venlafaxine 
May be used with caution.a 
CYP2D6 substrates, whose 
exposure may be increased 
by capivasertib. 
Warfarin 
May be used with caution.a 
CYP2C9 substrate, whose 
exposure may be increased 
by capivasertib. 
a 
Drugs are permitted, but caution should be exercised, and patients monitored closely for possible drug 
interactions. Please refer to full prescribing information for all drugs prior to co-administration with 
capivasertib. 
 

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Table 35 
MATE1 and/or OCT2 transporter substrates that should be used with 
caution  
Medication 
Recommendation 
Rationale 
Dofetilide 
May be used with cautiona 
MATE1 and OCT2 substrate with a narrow 
therapeutic window whose exposure may be 
increased by capivasertib 
Metformin 
See Section 8.4.6.3 
MATE1 and OCT2 substrate whose exposure 
may be increased by capivasertib 
Procainamide 
May be used with cautiona 
OCT2 substrate with a narrow therapeutic 
window whose exposure may be increased by 
capivasertib 
a 
Drugs are permitted but caution should be exercised, and patients monitored closely for possible drug 
interactions. Please refer to full prescribing information for all drugs prior to co-administration with capivasertib.  
 
Guidance for statins 
Atorvastatin, cerivastatin, lovastatin, and simvastatin should be avoided due to the potential 
for increased exposure through inhibition of CYP3A4 by capivasertib (Table 34).  
Fluvastatin, pravastatin, and rosuvastatin are minimally influenced by CYP3A4 inhibitors, 
conveying a relatively low potential for clinically significant drug-drug interactions via this 
mechanism. 
Capivasertib also has a potential to inhibit the organic-anion-transporting polypeptide 1B1 
transporter, which is implicated in the distribution and clearance of many of the statins. The 
predicted increase in the area under the plasma concentration-time curve is 1.3-fold for 
pravastatin and 1.5-fold for rosuvastatin. It is, therefore, recommended that doses of 
pravastatin be capped to 40 mg once daily (QD) and rosuvastatin be capped to 10 mg QD 
when combined with capivasertib, including 1 week prior to capivasertib administration and 
for 1 week following discontinuation of capivasertib. 
In summary, rosuvastatin (up to 10 mg QD), pravastatin (up to 40 mg QD), and fluvastatin are 
appropriate agents to be used in patients included in capivasertib studies who require statin 
therapy. 
Additional resources 
For additional inhibitors, inducers, and substrates, please refer to: 
https://drug-interactions.medicine.iu.edu/Clinical-Table.aspx 
• 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/D
rugInteractionsLabeling/ucm093664.htm 
 

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Appendix L 
Guidance for management of specific adverse events in 
studies of DS-8201a (trastuzumab deruxtecan)  
If AE causality is possibly, probably, or definitely related to both durvalumab and DS-8201a, 
the most conservative toxicity guidance (either durvalumab or DS-8201a) should be adopted. 
Discussion with the Sponsor’s Study Clinical Lead is recommended in such cases. 
Further guidance on ILD/pneumonitis management and LVEF management is provided in 
Section 6.5.2.5 and below. 
Treat each of the toxicities with maximum supportive care (including withholding the agent 
suspected of causing the toxicity if required). 
If medically appropriate, dose modifications are permitted for DS-8201a. In addition, 
guidelines on DS-8201a dose modifications are provided in Section 6.5.2.5. In the event of 
toxicity that cannot be managed by following the toxicity management guidelines for DS-
8201a and durvalumab, consider stopping treatment with DS-8201a. 
All dose modifications should be documented with clear reasoning and documentation of the 
approach taken. Dose reductions are not permitted without prior agreement with the Study 
Clinical Lead. 
All dose modifications (interruption, reduction, and/or discontinuation) (Section 6.5.2.5) 
should be based on the worst preceding toxicity. Specific criteria for interruption, re-initiation, 
dose reduction, and/or discontinuation of DS-8201a are listed in Table 27 below, which is 
applicable only to TEAEs that are assessed as related to use of DS-8201a by the investigator. 
For non-drug related TEAEs, follow standard clinical practice. Appropriate clinical experts 
should be consulted as deemed necessary. 
If AE causality is possibly, probably, or definitely related to both durvalumab and DS-8201a, 
the most conservative toxicity guidance (either durvalumab or DS-8201a) should be adopted. 
Discussion with the Sponsor’s Study Clinical Lead is recommended in such cases. All 
confirmed or suspected COVID-19 infection events must be recorded in the eCRF as AE. 
Please refer to Appendix O for additional information on dose modification. 
 

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Table 36 
Toxicity management guidelines for DS-8201a  
Worst toxicity CTCAE v4.03 
Grade (unless otherwise specified) 
Management guidelines for DS-8201a 
No toxicity 
Maintain dose and schedule 
Infusion-related reaction 
Grade 1  
(Mild transient reaction; infusion 
interruption not indicated; intervention 
not indicated) 
If infusion related reaction (such as fever and chills, with and without 
nausea/vomiting, pain, headache, dizziness, dyspnoea, and/or 
hypotension) is observed during administration, the infusion rate should 
be reduced by 50%, and subjects should be closely monitored.  
If no other reactions appear, the subsequent infusion rate could be 
resumed at the initial planned rate.  
Grade 2  
(Therapy or infusion interruption 
indicated but responds promptly to 
symptomatic treatment (eg, 
antihistamines, nonsteroidal 
anti-inflammatory drugs (NSAIDs), 
narcotics, and/or IV fluids); 
prophylactic medications indicated for 
≤24 hrs) 
Administration of DS-8201a should be interrupted and symptomatic 
treatment started (eg, antihistamines, NSAIDs, narcotics, and/or IV 
fluids). 
If the event resolves or improves to Grade 1, infusion can be restarted at 
a 50% reduced infusion rate. 
Subsequent administrations should be conducted at the reduced rate. 
Grade 3 or 4  
Prolonged (eg, not rapidly responsive 
to symptomatic medication and/or brief 
interruption of infusion), recurrence of 
symptoms following initial 
improvement, hospitalization indicated 
for clinical sequelae or life-threatening 
consequences, and urgent intervention 
indicated 
Administration of DS-8201a should be discontinued immediately and 
permanently. 
Urgent intervention indicated. Antihistamines, steroids, epinephrine, 
bronchodilators, vasopressors, intravenous fluid therapy, oxygen 
inhalation, etc, should be administered.  
Haematologic toxicity (if supportive therapy fails [as clinically indicated and according to local practice], 
consider additional Toxicity Management Guidelines as below)  
For any Grade 4 hematological toxicity with significant clinical symptoms that does not resolve with treatment 
within 4 weeks, resuming the IMP may be possible if the toxicity resolves, in consultation with the study 
physician. 
Neutrophil count decreased and/or white blood cell count decreased 
Grade 3  
Delay dose until resolved to ≤Grade 2, then maintain dose 
Grade 4 
Delay dose until resolved to ≤Grade 2, then Reduce dose 1 level 
Febrile neutropenia (absolute 
neutrophil count <1 × 109/L, fever 
>38.3°C, or a sustained temperature of 
≥38 °C for more than 1 hour) 
Delay dose until resolved, then Reduce dose by 1 level 

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Table 36 
Toxicity management guidelines for DS-8201a  
Worst toxicity CTCAE v4.03 
Grade (unless otherwise specified) 
Management guidelines for DS-8201a 
Lymphocyte count decreased 
Grade 1 to Grade 3 lymphopenia 
No dose modification 
Grade 4  
(<0.2 × 109/L) 
Delay dose until resolved to ≤Grade 2: 
− 
If resolved in ≤14 days from day of onset, then maintain dose 
− 
If resolved in >14 days from day of onset, then reduce dose 1 level 
Anaemia 
Grade 3  
(Haemoglobin <8.0 g/dL); transfusion 
indicated 
Delay dose until resolved to ≤Grade 2, then maintain dose 
Grade 4  
Life threatening consequences urgent 
intervention indicated 
Delay dose until resolved to ≤Grade 2, then reduce dose 1 level 
Platelet count decreased 
Grade 3  
(platelets <50 to 25 × 109/L) 
Delay dose until resolved to ≤Grade 1: 
− 
If resolved in ≤7 days from day of onset, then maintain dose 
− 
If resolved in >7 days from day of onset, then reduce dose 1 level 
Grade 4  
(platelets <25 × 109/L) 
Delay dose until resolved to ≤Grade 1, then reduce dose 1 level 
Cardiac toxicity  
Symptomatic CHF 
Discontinue subject from study treatment 
Decrease in LVEF 10% to 20% 
(absolute value), but LVEF >45% 
Continue treatment with DS-8201a 
LVEF 40% to ≤45% and decrease is 
<10% (absolute value) from baseline 
Continue treatment with DS-8201a 
Repeat LVEF assessment within 3 weeks 
LVEF 40% to ≤45% and decrease is 
10% to 20% (absolute value) from 
baseline 
Interrupt DS-8201a dosing 
Repeat LVEF assessment within 3 weeks. 
If LVEF has not recovered to within 10% (absolute value) from 
baseline, discontinue subject from study treatment 
If LVEF recovers to within 10% from baseline, resume study drug 
treatment 
LVEF <40% or >20% (absolute value) 
drop from baseline 
Interrupt DS-8201a dosing. 
Repeat LVEF assessment within 3 weeks. 
If LVEF <40% or >20% drop from baseline is confirmed, discontinue 
subject from study treatment 
If LVEF has recovered to > 40% and decrease is < 20% from baseline, 
follow appropriate guidance above.  

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Table 36 
Toxicity management guidelines for DS-8201a  
Worst toxicity CTCAE v4.03 
Grade (unless otherwise specified) 
Management guidelines for DS-8201a 
Electrocardiogram QTc Prolonged 
Grade 3  
(Average QTc ≥ 501 ms or > 60 ms 
change from baseline) 
 
Delay dose until resolved to ≤Grade 1 (corrected QT ≤480 ms), then 
determine if another medication the subject was taking may be 
responsible and can be adjusted or if there are any changes in serum 
electrolytes that can be corrected, then if attributed to DS-8201a, reduce 
dose 1 level 
Grade 4  
(Torsade de pointes or polymorphic 
ventricular tachycardia or 
signs/symptoms of serious arrhythmia) 
Discontinue subject from study treatment 
Pulmonary Toxicity 
Any evidence of ILD/pneumonitis should be promptly investigated. 
Work-up of suspected ILD/pneumonitis: 
If a subject develops radiographic changes potentially consistent with 
ILD/pneumonitis or develops new or worsening pulmonary or other 
related signs/symptoms such as dyspnoea (resting or exertional), cough 
fever, unexplained fatigue or decrease in oxygen saturation, rule out 
ILD/pneumonitis. 
Evaluations should include: 
• 
High resolution CT (HRCT) (preferred)/CT; the same 
modality should be employed as the baseline scan to allow for 
direct comparison of scans 
• 
Pulmonologist consultation (infectious disease consultation as 
clinically indicated) 
• 
Bronchoscopy and bronchoalveolar lavage if clinically 
indicated and feasible 
• 
Pulmonary function tests (including forced vital capacity 
(FVC) and carbon monoxide (CO) diffusing capacity) and 
pulse oximetry (SpO2)  
• 
Clinical laboratory tests: 
− 
COVID-19 test 
− 
Arterial blood gases if clinically indicated  
− 
Blood culture, blood cell count (CBC), differential 
white blood cell count (WBC), C-reactive protein 
(CRP), 
− 
One blood sample collection for PK analysis as soon as 
ILD/pneumonitis is suspected, if feasible 
Other tests could be considered, as needed including PCP screening (eg, 
beta-D-glucan test, BAL) especially in patients with 1 or more of the 
following risk factors: lymphopenia, long-term/intermittent steroid use, 
brain metastases, and chronic lung diseases. 
Appropriate management for ILD/pneumonitis should be instituted 
promptly as per management guideline below when ILD is suspected.  

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Table 36 
Toxicity management guidelines for DS-8201a  
Worst toxicity CTCAE v4.03 
Grade (unless otherwise specified) 
Management guidelines for DS-8201a 
If the AE is confirmed to have an aetiology other than treatment-related 
ILD/pneumonitis, follow the management guidance outlined in the 
“Other Non-Laboratory Adverse Events” dose modifications. 
If another aetiology for the AE cannot be identified and it could be 
related to DS-8201a, then follow the ILD/pneumonitis management 
guidance as outlined below. 
Consideration should be given to the possibility of an alternate etiology 
occurring concurrently with Drug-induced-ILD. 
Whenever corticosteroids have been administered the dose should be 
tapered gradually over at least 4 weeks even if an alternate etiology is 
confirmed. 
All events of ILD/pneumonitis regardless of severity or seriousness will 
be followed until resolution. 
Grade 1 
Management: 
• 
Monitor and closely follow up in 2 to 7 days for onset of 
clinical symptoms and pulse oximetry then weekly as 
indicated 
• 
Consider follow-up imaging in 1 to 2 weeks (or as clinically 
indicated) 
• 
Consider starting systemic steroids (eg, at least 0.5 mg/kg/day 
prednisone or equivalent) until improvement, followed by 
gradual taper over at least 4 weeks 
• 
If worsening of diagnostic observations despite initiation of 
corticosteroids, then follow Grade 2 guidelines* 
 
Dose modification: 
The administration of DS-8201a must be interrupted. DS-8201a can be 
restarted only if the event is fully resolved to Grade 0: 
− 
If resolved in ≤28 days from day of onset, then maintain dose 
− 
If resolved in >28 days from day of onset, then reduce dose 1 level  
If the event Grade 1 ILD/pneumonitis occurs beyond cycle day 22 and 
has not resolved within 18 weeks from the last infusion, the drug should 
be discontinued. 
*If a subject is asymptomatic, then the subject should still be 
considered as Grade 1 even if steroid treatment is given. 

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Table 36 
Toxicity management guidelines for DS-8201a  
Worst toxicity CTCAE v4.03 
Grade (unless otherwise specified) 
Management guidelines for DS-8201a 
Grade 2 
Dose Modification: 
Permanently discontinue subject from study treatment. 
 
Management: 
Promptly start and treat with systemic steroids (eg, at least 1 mg/kg/day 
prednisone or equivalent) for at least 14 days, followed by gradual 
taper over at least 4 weeks 
• 
Monitor symptoms closely 
• 
Re-image as clinically indicated 
• 
If worsening or no improvement in clinical or diagnostic 
observations in 3 to 5 days,  
− 
Consider increasing dose of steroids (eg, 2 mg/kg/day 
prednisone or equivalent) and switching treatment 
administration to intravenous (eg, methylprednisolone) 
− 
Re-consider additional work-up for alternative etiologies 
as described above 
− 
Escalate care as clinically indicated 
Grade 3 or 4 
Dose modification: 
Permanently discontinue subject from study treatment. 
 
Management: 
• 
Hospitalisation required 
• 
Promptly initiate empiric high-dose methylprednisolone IV 
treatment (eg, 500-1000 mg/day for 3 days), followed by at 
least 1.0 mg/kg/day of prednisone (or equivalent) for at least 
14 days, followed by gradual taper over at least 4 weeks 
• 
Re-image as clinically indicated 
• 
If still no improvement within 3 to 5 days,  
− 
Re-consider additional work-up for alternative etiologies 
as described above 
− 
Consider other immunosuppressants and/or treat per local 
practice  
Ocular 
Grade 3 
Delay dose until resolved to ≤Grade 1: 
− 
If resolved in ≤7 days from day of onset, then maintain dose 
− 
If resolved in >7 days from day of onset, then reduce dose 1 level 
Grade 4 
Discontinue subject from study treatment 

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Table 36 
Toxicity management guidelines for DS-8201a  
Worst toxicity CTCAE v4.03 
Grade (unless otherwise specified) 
Management guidelines for DS-8201a 
Blood creatinine increased 
Grade 3  
(>3.0 to 6.0 × ULN) 
Delay dose until resolved to ≤Grade 2 or baseline, then reduce dose 1 
level 
Grade 4  
(>6.0 × ULN) 
Discontinue subject from study treatment 
Hepatic toxicity 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) with simultaneous blood bilirubin 
increased 
AST/ALT ≥3.0 x ULN with 
simultaneous total bilirubin 
≥2.0 × ULN 
Delay study medication until drug-induced liver injury can be ruled out. 
If drug-induced liver injury is ruled out, the subject should be treated 
accordingly, and resumption of study drug may occur after discussion 
between the Investigator and Sponsor.  
If drug-induced liver injury cannot be ruled out from diagnostic 
workup, permanently discontinue study treatment. 
Monitor AST/ALT and total bilirubin twice weekly until resolution or 
return to baseline. 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT 
Grade 2  
(>3.0 to 5.0 × ULN if baseline was 
normal; >3.0 to 5.0 × baseline if 
baseline was abnormal) 
No action for Grade 2 AST/ALT  
(>5.0 to 20.0 × ULN if baseline was 
normal; >5.0 to 20.0 × baseline if 
baseline was abnormal) 
In subjects without liver metastases and 
subjects with liver metastases and 
baseline level ≤3 × ULN 
Repeat testing within 3 days. Delay dose until resolved to ≤Grade 1 if 
baseline ≤3 x ULN, otherwise delay dose until resolved to ≤ baseline, 
then: 
− 
If resolved in ≤7 days from day of onset, then maintain dose 
− 
If resolved in >7 days from day of onset, then reduce dose 1 level 
(>8.0 to 20.0 × ULN if baseline was 
normal; >8.0 to 20.0 × baseline if 
baseline was abnormal) 
In subjects with liver metastases, if the 
baseline level was >3 × ULN 
Repeat testing within 3 days. Delay dose until resolved to ≤ baseline 
level: 
− 
If resolved in ≤7 days from day of onset, then maintain dose 
− 
If resolved in >7 days from day of onset, then reduce dose 1 level 
Grade 4  
(>20 × ULN if baseline was normal; 
>20.0 × baseline if baseline was 
abnormal) 
Discontinue subject from study treatment 

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Table 36 
Toxicity management guidelines for DS-8201a  
Worst toxicity CTCAE v4.03 
Grade (unless otherwise specified) 
Management guidelines for DS-8201a 
Blood bilirubin increased 
Grade 2  
(>1.5 to 3.0 × ULN if baseline was 
normal; >1.5 to 3.0 × baseline if 
baseline was abnormal) 
If no documented Gilbert’s syndrome or liver metastases at baseline, 
delay dose until resolved to ≤Grade 1: 
− 
If resolved in ≤7 days from day of onset, then maintain dose 
− 
If resolved in >7 days from day of onset, then reduce dose 1 level  
If documented Gilbert’s syndrome or liver metastases at baseline, 
continue study treatment 
Grade 3  
(>3.0 to 10.0 × ULN if baseline was 
normal; >3.0 to 10.0 × baseline if 
baseline was abnormal) 
If no documented Gilbert’s syndrome or liver metastases at baseline, 
repeat testing within 3 days. Delay dose until resolved to ≤Grade 1: 
− 
If resolved in ≤7 days from day of onset, then reduce dose 1 level 
− 
If resolved in >7 days from day of onset, then discontinue DS-
8201a 
 
If documented Gilbert’s syndrome or liver metastases at baseline, 
repeat testing within 3 days. Delay dose until resolved to <Grade 2: 
− 
If resolved in ≤7 days from day of onset, then reduce dose 1 level 
− 
If resolved in >7 days from day of onset, then discontinue DS-
8201a 
Grade 4  
(>10.0 × ULN if baseline was normal; 
>10.0 × baseline if baseline was 
abnormal) 
Discontinue subject from study treatment 
Blood alkaline phosphatase increased 
Grade 3  
(>5.0 to 20.0 × ULN if baseline was 
normal; >5.0 to 20.0 × baseline if 
baseline was abnormal) 
Or Grade 4  
(>20.0 × ULN if baseline was normal; 
>20.0 × baseline if baseline was 
abnormal) 
No modification unless determined by the Investigator to be clinically 
significant or life-threatening. 
Gastrointestinal 
Nausea 
Grade 3 
Inadequate oral caloric or fluid intake, 
tube feeding, TPN, or hospitalization 
indicated  
Delay dose until resolved to ≤Grade 1:  
− 
If resolved in ≤7 days from day of onset, then maintain dose 
− 
If resolved in >7 days from day of onset, then reduce dose 1 level 

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Table 36 
Toxicity management guidelines for DS-8201a  
Worst toxicity CTCAE v4.03 
Grade (unless otherwise specified) 
Management guidelines for DS-8201a 
Diarrhoea/Colitis 
Grade 3 
Increase of ≥ 7 stools per day over 
baseline, hospitalization indicated, 
severe increase in ostomy output 
compared to baseline; limiting self-care 
ADL 
Severe abdominal pain, peritoneal signs 
Delay dose until resolved to ≤Grade 1: 
− 
If resolved in ≤3 days from day of onset, then maintain dose 
− 
If resolved in >3 days from day of onset, then reduce dose 1 level 
Grade 4 
Life-threatening consequences, urgent 
intervention indicated  
Discontinue subject from study treatment 
Other laboratory adverse events 
Severe or medically significant but not 
immediately life-threatening, 
hospitalization or prolongation of 
existing hospitalization indicated, and 
limiting self-care ADL 
Delay dose until resolved to ≤Grade 1 or baseline level:  
− 
If resolved in ≤7 days from day of onset, then maintain dose 
− 
If resolved in >7 days from day of onset, then reduce dose 1 level 
Life-threatening consequences and 
urgent intervention indicated 
Discontinue subject from study treatment 
Other non-laboratory adverse events 
Grade 3 
Delay dose until resolved to ≤Grade 1 or baseline:  
− 
If resolved in ≤7 days from day of onset, then maintain dose 
− 
If resolved in >7 days from day of onset, then reduce dose 1 level  
Grade 4 
Discontinue subject from study treatment 
All dose modifications should be based on the worst preceding toxicity. 
CTCAE: Common Terminology Criteria for Adverse Events; IMP Investigational medicinal product. 

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Appendix M Guidance for management of specific adverse events of 
Dato-DXd (datopotamab deruxtecan) was removed to an 
Annex  
 

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Appendix N 
Durvalumab weight-based dose calculation  
For durvalumab dosing done depending on patient weight. Weight-based dosing should be 
utilized for patients ≤30 kg (for Arms 1 through 5 only): 
1 
Dose: X mg/kg 
2 
Patient weight: Y kg 
3 
Dose for patient: XY mg = X (mg/kg) × Y (kg) 
4 
Dose to be added into infusion bag: Dose (mL) = XY mg/50 (mg/mL)  
where 50 mg/mL is durvalumab nominal concentration. 
The corresponding volume of durvalumab should be rounded to the nearest tenth mL (0.1 
mL).  
5 
The number of vials required for dose preparation is the next greatest whole number of 
vials from the following formula: 
Number of vials = Dose (mL)/10.0 (mL/vial) 
 
Example:  
1 
Dose: 20 mg/kg for Arms 1 through 5 
2 
Patient weight: 30 kg 
3 
Dose for patient (eg, patients in Arms 1 through 5: 600 mg = 20 (mg/kg) × 30 (kg) 
4 
Dose to be added into infusion bag:  
Dose (mL) = 600 mg / 50 (mg/mL) = 12.0 mL 
5 
The number of vials required for dose preparation:  
Number of vials = 12.0 (mL) / 10.0 (mL/vial) = 2 vials 
 

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Appendix O 
Instructions Related to COVID-19 (For Arms 6, 7, and 8 
Only)  
Benefit Risk Consideration for COVID-19 
The emergence of the coronavirus disease 2019-nCoV (COVID-19) presents a potential safety 
risk for patients. Several risk mitigation factors have been implemented in this study. Notably, 
the eligibility criteria will exclude participants with COVID-19 infections (Section 5.2). 
Moreover, with the outbreak of COVID-19, there is the potential for increased use of 
chloroquine and hydroxychloroquine to treat severely symptomatic patients or even for 
prophylactic use. Chloroquine and hydroxychloroquine have shown in vitro to substantially 
affect the pH of the lysosome, a key intracellular compartment involved in the trafficking and 
payload release of DS-8201a and Dato-DXd. As it is unknown whether 
chloroquine/hydroxychloroquine may affect the safety and efficacy of DS-8201a or Dato-
DXd, to be eligible for this clinical trial, use of chloroquine and hydroxychloroquine treatment 
must be completed 14 days prior to the first dose of DS-8201a or Dato-DXd (Section 5.1). 
During study treatment, chloroquine and hydroxychloroquine are considered prohibited 
concomitant medications. However, in case treatment with chloroquine or 
hydroxychloroquine treatment is absolutely required for COVID-19, study treatment must be 
interrupted. After chloroquine or hydroxychloroquine is administered for COVID-19, then a 
washout period of at least 14 days is required before restarting study treatment. 
Lastly, due to the potential overlapping impact of DS-8201a or Dato-DXd and COVID-19 on 
the lung, the Sponsor has also provided in this Appendix a dose modification and management 
plan for patients with confirmed or suspected COVID-19 who are being treated with DS-
8201a or Dato-DXd. 
With these measures in place, it is considered the anticipated potential benefits for the patients 
enrolled in this study outweigh the potential risks. 
Inclusion criteria 
• 
Has adequate treatment washout period before randomization/enrollment, defined as: 
• 
Chloroquine/Hydroxychloroquine: ≥ 14 days 
 
Prior and concomitant medications 
Concomitant treatment with chloroquine or hydroxychloroquine is not allowed during the 
study treatment. If treatment with chloroquine or hydroxychloroquine treatment is absolutely 
required for COVID-19, study treatment must be interrupted. If chloroquine or 
hydroxychloroquine is administered, then a washout period of at least 14 days is required 
before restarting study treatment. 

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Dose modification criteria 
All confirmed or suspected COVID-19 infection events must be recorded in the eCRF as AE. 
Dose modifications will be based on the worst CTCAE grade. All interruptions or 
modifications must be recorded on the AE and drug exposure eCRFs. Please use CTCAE 
v4.03 general grading criteria to evaluate COVID-19. 
Dose modification criteria for suspected or confirmed COVID-19 
If COVID-19 infection is suspected, delay DS-8201a or Dato-DXd and rule out COVID-19 
per local guidance. 
• 
If COVID-19 is ruled out, follow study protocol. 
• 
If COVID-19 is confirmed or diagnosis is suspected after evaluation, manage 
COVID-19 per local guidance until recovery of COVID-19 defined as no 
signs/symptoms, at least 1 negative reverse transcription-polymerase chain reaction 
(RT-PCR) test result, and nearly or completely resolved chest CT findings. Then 
follow below dose modifications: 
 
COVID-19 Severity  
Toxicity Management Guidance 
Grade 1 
(asymptomatic incidental COVID-
19 test positive on screening) 
Resume DS-8201a or Dato-DXd and durvalumab at the same dose after 
at least 1 negative RT-PCR test result, and nearly or completely 
resolved chest CT findings 
Grade 2 
(moderate symptoms; oral 
intervention indicated) 
One negative RT-PCR test result, no signs/symptoms 
Imaging outcome: 
− 
Maintain same dose if chest CT findings are completely resolved 
− 
Reduce dose 1 level if chest CT findings are nearly resolved 
− 
Durvalumab can be resumed 
Grade 3 
(dyspnea and pneumonia 
symptoms; hospitalization 
indicated) 
One negative RT-PCR test result, no signs/symptoms  
Imaging outcome: 
− 
Reduce dose 1 level if chest CT findings are completely resolved 
− 
Durvalumab can be resumed 
− 
Otherwise, discontinue all study treatments 
Grade 4 
 (life-threatening consequences; 
urgent intervention indicated) 
Discontinue all study treatments 
Note: If PCR testing is not available, the subject must not have any sign/symptoms for at least 2 weeks, in 
addition to meeting the requirement for chest CT imaging. 
 
Any adverse event that is not related or possibly not related to study treatment, the study 
treatment can be delayed for the length of time required until it is safe to resume treatment. 
The maximum delay of 18 weeks for DS-8201a and 84 days for the Dato-DXd is only 

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applicable for adverse events causally related to study treatment and not applicable to isolated 
COVID-19 infections. 
Durvalumab can be restarted with DS-8201a or Dato-DXd when appropriate and by following 
the guidance above. 
• 
Closely monitor signs/symptoms after restarting DS-8201a or Dato-DXd, initially 
with a phone call every 3 days for the first week, and then with a weekly phone call 
thereafter, for a total of 6 weeks. 
• 
If an event is suspected to be drug-related ILD/pneumonitis, treatment with the study 
drug should be delayed pending further evaluations, and this event should be 
managed as per the protocol. ILD/pneumonitis management guideline for DS-8201a 
(Appendix L) or Dato-DXd (Annex document to this CSP) should be followed.  
 
If patients have a delay in dosing that results in one or more cycles of both durvalumab and 
DS-8201a/Dato-DXd being skipped, then when treatment is restarted, the next dose should be 
marked in the eCRF as the subsequent cycle with action taken of dose delayed due to an 
adverse event. 
Blood sample for DS-8201a or Dato-DXd PK analysis in patients who received 
chloroquine/hydroxychloroquine  
PK blood draws will be taken at the following timepoints for patients in the DS-8201a or 
Dato-DXd arms during the chloroquine or hydroxychloroquine treatment period: 
• 
Before the first dose of chloroquine/hydroxychloroquine dosing  
• 
Before chloroquine/hydroxychloroquine dosing on Day 3 or 4  
• 
End of chloroquine/hydroxychloroquine treatment  
• 
Pre-dose on the day of restarting DS-8201a or Dato-DXd treatment. If DS-8201a or 
Dato-DXd is restarted, then the normal DS-8201a or Dato-DXd PK blood sample 
collection can resume 
 

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Appendix P 
Changes related to mitigation of study disruptions due to 
Cases of civil crisis, natural disaster, or public health crisis  
Note: The 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 patients become infected with SARS-CoV-2 or similar pandemic infection), during 
which patients 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 
agreement from the Sponsor. 
P-1 
Reconsent of study patients during study interruptions  
During study interruptions, it may not be possible for the patients 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. 
Local and regional regulations and/or guidelines regarding reconsent of study patients should 
be checked and followed. Reconsent may be verbal if allowed by local and regional 
guidelines. Visiting the study sites for the sole purpose of obtaining reconsent should be 
avoided. 
P-2 
Telemedicine visit to replace on-site visit (where applicable)  
In this appendix, the term “telemedicine visit” refers to remote contact with the patients 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. A telemedicine contact with the 
patients will allow adverse events and concomitant medications to be reported and 
documented. 
P-3 
Data capture during telemedicine or remote visits  
Data collected during telemedicine or remote visits will be captured by the qualified health 
care professional (HCP) from the study site or third-party vendor service (TPV) in the source 
documents, or by the patients themselves. 

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Appendix Q 
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Appendix S 
Abbreviations  
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation or special term 
Explanation 
5-HT3 
5-Hydroxytryptamine receptor 
ADA 
Anti-drug antibody 
ADC 
Antibody-drug conjugate 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AKT 
Protein kinase B 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AMP 
Adenosine monophosphate 
aPTT 
activated partial thromboplastin time 
ASCO 
American Society of Clinical Oncology 
ASO 
Antisense oligonucleotide 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration-time curve 
BC 
Breast cancer 
BD 
Twice daily 
BICR 
Blinded independent central review 
bid 
Twice daily 
BoR 
Best overall response 
BP 
Blood pressure 
BRCA 
Breast cancer susceptibility gene 
CAP 
College of American Pathologists 
CAR 
Chimeric antigen receptor 
CD 
Cluster of differentiation 
cEt 
Constrained ethyl 
CI 
Confidence interval 
Cmax 
Maximum concentration 
CNS 
Central nervous system 
COPD 
Chronic obstructive pulmonary disease 
COVID-19 
Coronavirus disease 2019-nCoV 

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Abbreviation or special term 
Explanation 
CR 
Complete response 
CRC 
Colorectal cancer 
CRF 
Case report form 
CSP 
Clinical Study Protocol 
CSR 
Clinical study report 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTIS 
Clinical Trials Information System 
CTLA-4 
Cytotoxic T-lymphocyte–associated antigen 4 
CYP 
Cytochrome P450 
Dato-DXd 
Datopotamab deruxtecan; DS-1062a 
DCO 
Data cutoff 
DCR 
Disease control rate 
DES 
Data entry site 
DISH 
Dual in situ hybridization 
DKA 
Diabetic ketoacidosis 
DLBCL 
Diffuse large B cell lymphoma 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
DoR 
Duration of response 
DUS 
Disease under study 
DS8201a 
Trastuzumab deruxtecan; T-DXd 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EOT 
End of treatment 
ER 
Estrogen receptor 
ERK 
Extracellular signal regulated kinase 
EU 
European Union 
FAS 
Full Analysis Set 
CCI 
CCI 

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Abbreviation or special term 
Explanation 
FDA 
Food and Drug Administration 
FDG-PET 
18F-Fluoro-deoxyglucose positron emission tomography 
FFPE 
Formalin-fixed and paraffin-embedded 
FISH 
Fluorescent in-situ hybridization 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte colony-stimulation factor 
GI 
Gastrointestinal 
GMP 
Good Manufacturing Practice 
HbA1c 
Glycosylated hemoglobin 
HBcAb 
Hepatitis B core antibody 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCC 
Hepatocellular carcinoma 
HCV 
Hepatitis C virus 
HDV 
Hepatitis D virus 
HER2 
Human epidermal growth factor receptor 2 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HLA 
Human-leukocyte antigen 
HR 
Hazard ratio 
HRCT 
High-resolution computed tomography 
IBW 
Ideal body weight 
IC50 
Half maximal inhibitory concentration 
ICF 
Informed consent form 
ICH 
International Council on Harmonisation 
iCRO 
imaging Contract Research Organization 
IEC 
Independent Ethics Committee 
IFN-γ 
Interferon-gamma 
IgG 
Immunoglobulin G 
IHC 
Immunohistochemistry 
IL 
Interleukin 
ILD 
Interstitial lung disease 
imAE 
Immune-mediated adverse event 

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Abbreviation or special term 
Explanation 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
IP 
Investigational product  
irAE 
Immune-related adverse event 
IRB 
Institutional Review Board 
IRR 
Infusion-related reaction 
IRT 
Interactive Response Technology 
ITT 
Intention-to-treat 
IV 
Intravenous(ly) 
LFT 
Liver function test 
LIMS 
Laboratory Information Management System 
LVEF 
Left ventricular ejection fraction 
mAb 
Monoclonal antibody 
MAPK 
Mitogen-activated protein kinase 
MDSC 
Myeloid-derived suppressor cell 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEK 
Mitogen-activated protein kinase/extracellular signal-regulated 
kinase (MAPK/ERK kinase) 
MHC 
Major histocompatibility complex 
MOA 
Mechanism of action 
MRI 
Magnetic resonance imaging 
MSS-CRC 
Microsatellite stable colorectal cancer  
MTD 
Maximum tolerated dose 
mTOR 
Mammalian target of rapamycin 
MUGA 
Multiple gated acquisition 
muSTAT3 
Murine STAT3 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NE 
Not evaluable 
NGS 
Next generation sequencing 
NK 
Natural killer 
NL 
New lesion 
CCI 
CCI 

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Abbreviation or special term 
Explanation 
NSCLC 
Non-small cell lung cancer 
NTL 
Non-target lesion 
OCP 
oral care protocol 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progression of disease 
PD-1 
Programmed cell death 1  
PD-L1 
Programmed cell death ligand 1 
PD-L2 
Programmed cell death ligand 2 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PFT 
Pulmonary function test 
PFS6 
Progression-free survival at 6 months following date of first dose 
of IP 
PgR 
Progesterone receptor 
PI3K 
Phosphoinositide-3-kinase 
PIK3CA 
Phosphoinositide-3-kinase, catalytic, alpha polypeptide 
PK 
Pharmacokinetic(s) 
PKB 
protein kinase B 
PR 
Partial response 
PS 
Performance status 
PSSR 
Project Specific Safety Requirement 
PT 
Prothrombin time 
PTAP 
Post Trial Access Program 
PTT 
Partial thromboplastin time 
PTEN 
Phosphatase and tensin homolog 
q12w 
Every 12 weeks 
q1w 
Every 1 week 
q2w 
Every 2 weeks 
q3w 
Every 3 weeks 
q4w 
Every 4 weeks 
q8w 
Every 8 weeks 
QD 
Once daily 

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Abbreviation or special term 
Explanation 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RECIST 1.1 
Response Evaluation Criteria In Solid Tumors, version 1.1 
RNA 
Ribonucleic acid 
RP2D 
Recommended Phase II dose 
RT-PCR 
Reverse transcription-polymerase chain reaction 
RTSM 
Randomisation and Trial Supply Management System 
SAE 
Serious adverse event 
SAF 
Safety Analysis Set 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SC 
Subcutaneous(ly) 
SCCHN 
Squamous cell carcinoma of the head and neck 
SoA 
Schedule of Activities 
SoC 
Standard of care 
SMQ 
Standardized MedDRA Queries 
SRC 
Safety Review Committee 
STAT3 
Signal transducer and activator of transcription 3 
T3 
Triiodothyronine 
T4 
Thyroxine 
TAM 
Tumor-associated macrophage 
TBL 
Total bilirubin 
TdP 
Torsade de Pointes 
TEAE 
Treatment-emergent adverse event 
TESAE 
Treatment-emergent serious adverse event 
TIL 
Tumor-infiltrating lymphocyte 
TL 
Target lesion 
TMB 
Tumor mutational burden 
TMG 
Toxicity Management Guidelines 
TNBC 
Triple negative breast cancer 
TQ 
Targeted questionnaire 
TROP2 
Trophoblast cell surface protein 2 
TSH 
Thyroid-stimulating hormone 
CCI 
CCI 

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Abbreviation or special term 
Explanation 
ULN 
Upper limit of normal 
US 
United States 
WHO 
World Health Organization 
w/v 
Weight to volume